JPH07304668A - Intraocular tension depressant - Google Patents

Abstract

PURPOSE:To obtain an intraocular tension depressant or glaucoma therapeutic agent in the form of an eye drop containing a specific compound, having excellent intraocular tension reducing effect, and having no toxicity and side effects, thus useful as e.g. a medicine for glaucoma. CONSTITUTION:The objective intraocular tension depressant or glaucoma therapeutic agent in the form of an eye drop contains a compound (a salt, ester, other derivative) of formula I [R<1> is a lower alkyl, a lower alkenyl or a group of formula R<5>-A-B (R<5> is H, a lower alkyl, etc.; A is O or S; B is a lower alkylene or single bond); R<2> is a lower alkyl, a lower alkenyl or a group of formula C(R<6>)(R<7>)(R<8>) (R<6> is OH or a lower alkoxyl; R<7> and R<8> each H, a lower alkyl, etc.); R<3> is carboxyl or a group of formula CON(R<9>)(R<10>)(R<9> and R<10> each is H, a lower alkyl, an aryl, etc.); R<4> is carboxy (carbonyl) or tetrazol-5-yl], e.g. a compound of formula II. The dose of this agent is, in terms of the compound of formula I, pref. 0.001-50 (esp. 0.01-20)mg/kg b.w. a day.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

The present invention is of the general formula (I)

[0003]

[Chemical 4]

[Wherein R ¹ is a lower alkyl group, a lower alkenyl group or a group having the formula R ⁵ -AB- (wherein R 1
⁵ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aliphatic acyl group, A represents an oxygen atom or a sulfur atom, and B represents a single bond or a lower alkylene group. R ² is a lower alkyl group, a lower alkenyl group or a group having the formula —C (R ⁶ ) (R ⁷ ) (R ⁸ ), wherein R ⁶ represents a hydroxyl group or a lower alkoxy group, R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, an aryl group or an aralkyl group, and R ³ is a carboxy group or Expression −
A group having CON (R ⁹ ) (R ¹⁰ ) (in the formula, R ⁹ and R ^9
10 is the same or different and represents a lower alkyl group in which 1 to 3 hydrogen atoms, a lower alkyl group or a group selected from the substituent group (I) is substituted. And R ⁴ represents a carboxy group, a carboxycarbonyl group or a tetrazol-5-yl group. ], A pharmacologically acceptable salt thereof, or an ester or other derivative thereof, and an excellent ocular pressure lowering agent for eye drops and / or a therapeutic agent for glaucoma for eye drops.

Substituent group (I) Aryl group, 5- to 6-membered heteroaromatic ring group, halogen atom,
Hydroxyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, amino group, aliphatic acylamide group and aromatic acylamide group.

[0006]

2. Description of the Related Art Conventionally, it has been described that an angiotensin II inhibitor is used for the purpose of lowering intraocular pressure.
Moreover, all the descriptions themselves are intended for use by oral administration.

On the other hand, if it is used only for the purpose of lowering intraocular pressure, local administration with few side effects is preferable, and it has been desired from the past. In 91/15206, it was only disclosed that an angiotensin II inhibitor (particularly, DUP-753 represented by the following formula) can be used for treatment of ocular hypertension by instillation.

However, the invention disclosed in the above-mentioned International Publication was not sufficiently effective for use as a pharmaceutical by topical administration of eye drops.

[0009]

[Chemical 5]

[0010]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention The inventors of the present invention have conducted extensive studies over a long period of time on a new intraocular pressure lowering agent for eye drops and / or a therapeutic agent for glaucoma for eye drops. The present invention has been completed based on the finding that it has an excellent effect of lowering intraocular pressure and / or an effect of treating glaucoma even by local administration, and that it has no side effect due to local administration of eye drops.

[0011]

[Constitution of the invention]

[0012]

The novel intraocular pressure lowering agent for eye drops and / or therapeutic agent for glaucoma for eye drops of the present invention is represented by the general formula (I):

[0013]

[Chemical 6]

[Wherein R ¹ is a lower alkyl group, a lower alkenyl group or a group having the formula R ⁵ -AB- (wherein R 1
⁵ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aliphatic acyl group, A represents an oxygen atom or a sulfur atom, and B represents a single bond or a lower alkylene group. R ² is a lower alkyl group, a lower alkenyl group or a group having the formula —C (R ⁶ ) (R ⁷ ) (R ⁸ ), wherein R ⁶ represents a hydroxyl group or a lower alkoxy group, R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, an aryl group or an aralkyl group, and R ³ is a carboxy group or Expression −
A group having CON (R ⁹ ) (R ¹⁰ ) (in the formula, R ⁹ and R ^9
10 is the same or different and represents a lower alkyl group in which 1 to 3 hydrogen atoms, a lower alkyl group or a group selected from the substituent group (I) is substituted. And R ⁴ represents a carboxy group, a carboxycarbonyl group or a tetrazol-5-yl group. ], A pharmacologically acceptable salt thereof, or an ester or other derivative thereof, and more preferably, in the above, (1)
R ¹ is a group having the formula R ⁵ —AB—, where R ⁵ is
A hydrogen atom, a lower alkyl group or an aliphatic acyl group is shown, A is an oxygen atom or a sulfur atom, and B is a single bond or a lower alkylene group. ) Is a composition, (2) R ¹ is a lower alkyl group or a lower alkenyl group, (3) R ¹ is a lower alkyl group, (4) R ¹ is A composition, which is an alkyl group having 1 to 4 carbon atoms, (5) R ¹ is a composition, which is an alkyl group having 2 to 4 carbon atoms, and (6) R ² is a compound represented by the formula-C.
A group having (R ⁶ ) (R ⁷ ) (R ⁸ ) (in the formula, R ⁶ is
R ⁷ and R ⁸ represent a hydroxyl group or a lower alkoxy group.
Are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkenyl group. ) Is a composition,
(7) A composition wherein R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a lower alkyl group, (8) R ⁶ is
In the hydroxyl group, R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, (9) R ⁷ and R ⁸ are the same or different, and a hydrogen atom Or a composition having 1 to 2 carbon atoms, a composition (10) R ² is a 1-hydroxy-1-methylethyl group, (11) R ³ is a carboxy group or a formula- A group having CON (R ⁹ ) (R ¹⁰ ) (in the formula, R ⁹
And R ¹⁰ are the same or different and each represents a hydrogen atom or a lower alkyl group. ) Is the composition, (12) R ³
Is a carboxy group, a composition (13) R ⁴ is a carboxy group or a tetrazol-5-yl group, and a composition (14) R ⁴ is a tetrazol-5-yl group. , (15)

[0015]

[Chemical 7]

A compound having the above formula, a pharmaceutically acceptable salt thereof, or an ester or other derivative thereof,
Or a composition containing (16)

[0017]

[Chemical 8]

A compound having the above formula, a pharmaceutically acceptable salt thereof, or an ester or other derivative thereof,
A composition containing a.

Substituent Group (I) Aryl group, 5- to 6-membered heteroaromatic ring group, halogen atom,
Hydroxyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, amino group, aliphatic acylamide group and aromatic acylamide group.

"Lower alkyl group" in the definition of R ¹ , R ² , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , and R ⁹
And the "lower alkyl group" of the "lower alkyl group substituted with 1 to 3 groups selected from the substituent group (I)" in the definition of R ¹⁰ includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-
Methylbutyl, neopentyl, 1-ethylpropyl, n
-Hexyl, isohexyl, 4-methylpentyl, 3-
Methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2, A linear or branched alkyl group having 1 to 6 carbon atoms such as 3-dimethylbutyl and 2-ethylbutyl is shown, and preferably a linear or branched alkyl group having 1 to 4 carbon atoms. More preferably, R ¹ and R ² are linear or branched alkyl groups having 2 to 4 carbon atoms, and R ⁵ , R ⁷ , R ⁸ and R
“Lower alkyl group” in the definition of ⁹ and R ¹⁰ , and “a lower alkyl group substituted with 1 to 3 groups selected from the substituent group (I)” in the definition of R ⁹ and R ^10.
The "lower alkyl group" is a straight chain alkyl group having 1 to 2 carbon atoms.

The "lower alkenyl group" in the definition of R ¹ , R ² , R ⁷ and R ⁸ is ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1
-Methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-
2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1- Ethyl-3-butenyl, 1-pentenyl,
2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-
3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-
4-pentenyl, 1-hexenyl, 2-hexenyl, 3
There may be mentioned a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms such as -hexenyl, 4-hexenyl and 5-hexenyl, and preferably a straight chain or branched chain having 3 to 5 carbon atoms. It is a chain alkenyl group.

The "cycloalkyl group" in the definition of R ⁵ , R ⁷ and R ⁸ is cyclopropyl, cyclobutyl,
It represents a 3- to 10-membered saturated cyclic hydrocarbon group which may be condensed, such as cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl, and is preferably a 5- to 10-membered saturated cyclic hydrocarbon group.

The “aliphatic acyl group” in the definition of R ⁵ and the “aliphatic acyl group” in the “aliphatic acylamide group” in the definition of the substituent group (I) are, for example, formyl, acetyl, propionyl, butyryl, Isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl,
Dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,1
3-dimethyltetradecanoyl, heptadecanoyl, 1
5-methylhexadecanoyl, octadecanoyl, 1-
"Alkylcarbonyl group" such as methylheptadecanoyl, nonadecanoyl, eicosanoyl and henicosanoyl; "carboxylated alkylcarbonyl group" such as succinoyl, glutaroyl, adipoyl; chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl "Halogeno lower alkylcarbonyl group";"lower alkoxy lower alkylcarbonyl group" such as methoxyacetyl; (E) -2-methyl-
An "unsaturated alkylcarbonyl group" such as 2-butenoyl can be mentioned, and an "alkylcarbonyl group" is preferable.

The "lower alkylene group" in the definition of B is, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, penta. Mention may be made of a linear or branched alkylene group having 1 to 6 carbon atoms such as methylene and hexamethylene, preferably a linear or branched alkylene group having 1 to 4 carbon atoms, More preferably, methylene,
Ethylene, trimethylene and tetramethylene, most preferably methylene and ethylene.

R ⁶ and “lower alkoxy group” in the definition of Substituent group (I) and “lower alkoxy” in the “lower alkoxycarbonyl group” in the definition of Substituent group (I) mean the above “lower alkyl group”. Represents a group bonded to an oxygen atom, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n
-Hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, A linear or branched alkoxy group having 1 to 6 carbon atoms such as 1,3-dimethylbutoxy and 2,3-dimethylbutoxy is shown, preferably a linear or branched chain having 1 to 4 carbon atoms. It is an alkoxy group.

The "lower alkynyl group" in the definition of R ⁷ and R ⁸ is ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-
Ethyl-2-propynyl, 2-butynyl, 1-methyl-
2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2- Pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1
-Methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2
There may be mentioned a linear or branched alkynyl group having 2 to 6 carbon atoms such as -methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and preferably, It is a linear or branched alkynyl group having 3 to 5 carbon atoms.

The "aryl group" in the definition of R ⁷ and R ⁸ and the substituent group (I) is, for example, an aromatic hydrocarbon having 5 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl. A group may be mentioned, preferably phenyl and naphthyl, more preferably phenyl. The above "aryl group"
May be fused with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include a group such as 2-indanyl.

The "aralkyl group" in the definition of R ⁷ and R ⁸ is benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α. "A lower alkyl group" substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4. 5-trimethylbenzyl,
4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl,
Lower alkyl such as 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl, 4-methoxycarbonylbenzyl, lower alkoxy, nitro, halogen , 1 to 3 aryls in which the aryl ring is substituted with a cyano, alkoxycarbonyl group
Shows a lower alkyl group substituted with a benzyl group, preferably,
The "lower alkyl group" is an "aralkyl group" having 1 to 4 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms substituted with 1 to 2 aryl groups. .

“5 to 6” in the definition of the substituent group (I)
The "membered heteroaromatic ring group" refers to a 5- to 6-membered heteroaromatic ring group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and includes, for example, furyl, thienyl, pyrrolyl, azepinyl,
Aromatic heterocyclic groups such as pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl can be mentioned, and preferred. Represents a 5- to 6-membered heteroaromatic ring group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,
Examples thereof include aromatic heterocyclic groups such as thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and more preferably imidazolyl, oxazolyl, isoxazolyl, Thiazolyl, triazolyl, tetrazolyl and pyridyl.

The "halogen atom" in the definition of the substituent group (I) is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom and a chlorine atom.

The "aromatic acyl group" of the "aromatic acylamide group" in the definition of the substituent group (I) is, for example, "arylcarbonyl group" such as benzoyl, α-naphthoyl and β-naphthoyl; 2-bromobenzoyl, 4
"Halogenoarylcarbonyl group" such as chlorobenzoyl; "lower alkylated arylcarbonyl group" such as 2,4,6-trimethylbenzoyl, 4-toluoyl; "lower alkoxylated such as 4-anisoyl" Arylcarbonyl group "; 2-carboxybenzoyl, 3-
"Carboxylated arylcarbonyl group" such as carboxybenzoyl and 4-carboxybenzoyl; "Nitrated arylcarbonyl group" such as 4-nitrobenzoyl and 2-nitrobenzoyl; 2- (methoxycarbonyl) benzoyl Examples include "lower alkoxycarbonylated arylcarbonyl group";"arylated arylcarbonyl group" such as 4-phenylbenzoyl, and more preferably "arylcarbonyl group". Is.

"Pharmaceutically acceptable salt" refers to the salt of Compound (I) of the present invention, and therefore it is preferably a sodium salt. Alkali metal salts, such as potassium salts, lithium salts,
Alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenyl Glycine alkyl ester salt, ethylenediamine salt, N-
Methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt,
N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-
Amine salts such as benzyl-phenethylamine salts, piperazine salts, tetramethylammonium salts, organic salts such as tris (hydroxymethyl) aminomethane salts; halogenated salts such as hydrochloride, hydrobromide, hydroiodide Inorganic acid salts such as hydrogenates, nitrates, sulfates and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonate, p-toluenesulfone Organic acid salts such as aryl sulfonates such as acid salts, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate; and glycine salts, Amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate can be mentioned.

When the compound (I) of the present invention is left in the air or recrystallized, it may absorb water, become adsorbed with water, or become a hydrate. Such salts are also included in the present invention.

“Ester or other derivative thereof”
When the compound (I) of the present invention has a hydroxyl group, the group is a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as an enzymatic reaction”. It may be a modified derivative and / or, when the compound (I) of the present invention has a carboxy group or a carboxycarbonyl group, the group may be a “general protecting group” or an “in vivo enzyme”. A derivative modified with a “protecting group capable of being cleaved by a biological method such as a reaction” or an amide of the carboxy group or the carboxycarbonyl group is referred to as such a derivative.

The "general protecting group" means a protecting group which can be cleaved by a chemical method such as reduction reaction or hydrolysis.
Examples of the “general protective group” related to the “hydroxyl group” include, for example,
The "aliphatic acyl group"; the "aromatic acyl group"; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as 4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl A "tetrahydrofuranyl or tetrahydrothiofuranyl group" such as; trimethylsilyl,
Triethylsilyl, isopropyldimethylsilyl, tert
A tri-lower alkylsilyl group such as -butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropylsilyl, one or two of such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl. "Silyl group" such as tri-lower alkylsilyl group substituted with aryl group; methoxymethyl, 1,
1-dimethyl-1-methoxymethyl, ethoxymethyl,
Lower alkoxymethyl group such as propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis ( "Alkoxymethyl group" such as halogeno lower alkoxymethyl such as 2-chloroethoxy) methyl; lower alkoxylated ethyl group such as 1-ethoxyethyl, 1- (isopropoxy) ethyl,
"Substituted ethyl group" such as halogenated ethyl group such as 2,2,2-trichloroethyl; the above "aralkyl group"; lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl , An alkoxycarbonyl group such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl; vinyloxycarbonyl, allyloxycarbonyl Such as "alkenyloxycarbonyl group"; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
Mention may be made of an "aralkyloxycarbonyl group" in which the aryl ring may be substituted with 1 to 2 lower alkoxy or nitro groups such as 4-nitrobenzyloxycarbonyl, while "carboxyl group or The "general protecting group" for the "carboxycarbonyl group" is preferably the above "lower alkyl group"; the above "lower alkenyl group"; the above "lower alkynyl group";
-Trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4
-A "halogeno lower alkyl group" such as fluorobutyl, 6-iodohexyl and 2,2-dibromoethyl; 2-
Hydroxyethyl, 2,3-dihydroxypropyl, 3
-Hydroxypropyl, 3,4-dihydroxybutyl,
Hydroxy "lower alkyl group" such as 4-hydroxybutyl; "aliphatic acyl" such as acetylmethyl-
Examples thereof include "lower alkyl group"; the above "aralkyl group"; and the above "silyl group". The "protecting group capable of being cleaved by a biological method such as an enzymatic reaction in the living body" means a protective group which is cleaved by a biological method such as an enzymatic reaction in the human body to generate a free acid or a salt thereof. Whether or not it is such a derivative is determined by intravenously or orally administering it to experimental animals such as rats and mice, and then examining the body fluids of the animals, and examining the original compound or its pharmacologically acceptable salt. Can be determined by being able to detect, and the "hydroxyl group" relating to the "protecting group that can be cleaved by a biological method such as an enzymatic reaction in vivo" is, for example, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyl. Oxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1- Le mill oxyethyl, 1-acetoxyethyl, 1-propionyloxy-ethyl, 1-butyryloxy-ethyl, 1
-Pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1
-Butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1
-Acetoxybutyl, 1-propionyloxybutyl,
Like 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl. 1-(“aliphatic acyl” oxy) “lower alkyl group”, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1- Cyclohexylcarbonyloxypropyl, 1-Cyclopentylcarbonyloxybutyl, 1-
1-such as cyclohexylcarbonyloxybutyl
(“Cycloalkyl” carbonyloxy) “lower alkyl group”, 1-(“aromatic acyl” oxy) “lower alkyl group” such as benzoyloxymethyl, “1- (acyloxy)“ lower alkyl group ””; Methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, Cyclohexyloxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1-
(Ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy)
Ethyl, 1- (tert-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl,
1- (hexyloxycarbonyloxy) ethyl, 1-
(Cyclopentyloxycarbonyloxy) ethyl, 1
-(Cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1 -(Ethoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) propyl,
1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- ( Pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy)
Butyl, 1- (ethoxycarbonyloxy) butyl, 1
-(Propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxy Carbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1
"(Ethoxycarbonyloxy) hexyl" such as "1
-(Alkoxycarbonyloxy) alkyl group "; (5
-Phenyl-2-oxo-1,3-dioxolen-4-
Yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5
-(4-Methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-
Yl] methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2
-Oxo-1,3-dioxolen-4-yl) methyl,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methyl, (5-ethyl-2-oxo-1,3-
Dioxolen-4-yl) methyl, (5-propyl-2
-Oxo-1,3-dioxolen-4-yl) methyl,
(5-Isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-2-oxo-
Such as 1,3-dioxolen-4-yl) methyl
-Oxo-1,3-dioxolenylmethyl group ";" phthalidyl group "such as phthalidyl, dimethylphthalidyl, and dimethoxyphthalidyl; the" aliphatic acyl group ";the" aromatic acyl group ";"Half-ester salt residue of acid";"phosphoric acid ester salt residue";"ester-forming residue of amino acid and the like"; carbamoyl group; carbamoyl group substituted with 1 to 2 lower alkyl groups; and pivaloyl Examples thereof include "1- (acyloxy) alkyloxycarbonyl group" such as oxymethyloxycarbonyl, and preferably "2-oxo-1,3-dioxorenylmethyl group", "phthalidyl group", "Aliphatic acyl group"
And “aromatic acyl group”, on the other hand, “protecting group capable of being cleaved by a biological method such as enzymatic reaction in vivo” relating to “carboxy group or carboxycarbonyl group”
Specifically, methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1 Lower alkoxy lower alkyl groups such as -methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl, lower alkoxylated lower alkoxy lower alkyl groups such as 2-methoxyethoxymethyl , "Alkoxy lower alkyl" such as "aryl" oxy "lower alkyl group" such as phenoxymethyl, halogenated lower alkoxy lower alkyl group such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, etc. "Group"; such as "methoxycarbonylmethyl""lower Alkoxy "carbonyl" lower alkyl group ""; cyanomethyl, "cyano" lower alkyl group "such as 2-cyanoethyl"; methylthiomethyl,
“Lower alkyl” thiomethyl group such as ethylthiomethyl; “aryl” thiomethyl group such as phenylthiomethyl, naphthylthiomethyl; “halogen” such as 2-methanesulfonylethyl, 2-trifluoromethanesulfonylethyl "Lower alkyl" sulfonyl "lower alkyl group" which may be substituted with ";""aryl" sulfonyl "lower alkyl group" such as 2-benzenesulfonylethyl, 2-toluenesulfonylethyl; "1- (acyloxy ) "Lower alkyl group"";the" phthalidyl group ";the" aryl group ";the" lower alkyl group ";the" carboxyalkyl group "such as carboxymethyl; and the" amino acid amide formation residue "such as phenylalanine. Group ", and preferably,
"Alkoxy lower alkyl group", "1- (acyloxy) lower alkyl group", "phthalidyl group", "lower alkyl group" and "amide-forming residue of amino acid".

The compound contained in the composition of the present invention may have an asymmetric carbon in the molecule, and in this case, there exist stereoisomers each having R-coordinate and S-coordinate. ,
Each of them, or any mixture thereof, is encompassed by the present invention.

The compounds contained in the composition of the present invention are all known compounds, for example, (1) JP-A-5-7.
8328, (2) JP-A-6-49036, (3) EP245637A, (4) EP253.
310A, (5) EP291969A, (6) EP
323841A, (7) EP324377A, (8)
EP380959A, (9) EP392317A,
(10) EP399731A, (11) EP399
732A, (12) EP400835A, (13)
EP400974A, (14) EP401030A,
(15) EP403158A, (16) EP403
159A, (17) EP407102A, (18)
EP407342A, (19) EP409332A,
(20) EP411507A, (21) EP411
766A, (22) EP41594A, (23)
EP412848A, (24) EP415886A,
(25) EP419048A, (26) EP420
237A, (27) EP424317A, (28)
EP42521A, (29) EP425921A,
(30) EP426021A, (31) EP427
463A, (32) EP 492257A, (33)
EP430300A, (34) EP430709A,
(35) EP432737A, (36) EP434
038A, (37) EP434249A, (38)
EP435827A, (39) EP437103A,
(40) EP438869A, (41) EP442
473A, (42) EP443568A, (43)
EP443983A, (44) EP445811A,
(45) EP446062A, (46) EP447
342A, (47) EP449699A, (48)
EP450566A, (49) EP453210A,
(50) EP454511A, (51) EP455
423A, (52) EP456442A, (53)
EP456510A, (54) EP459136A,
(55) EP461039A, (56) EP461
040A, (57) EP465323A, (58)
EP465368A, (59) EP467207A,
(60) EP467715A, (61) EP468
372A, (62) EP468470A, (63)
EP470543A, (64) EP470794A,
(65) EP470795A, (66) EP475
206A, (67) EP475898A, (68)
EP479479A, (69) EP480204A,
(70) EP480659A, (71) EP481
448A, (72) EP481414A, (73)
EP483683A, (74) EP485929A,
(75) EP487252A, (76) EP487
745A, (77) EP488532A, (78)
EP490587A, (79) EP490820A,
(80) EP495626A, (81) EP495
627A, (82) EP497121A, (83)
EP497150A, (84) EP497516A,
(85) EP503162A, (86) EP510
812A, (87) US4340598, (88)
US4355042, (89) US4820843,
(90) US4870186, (91) US487
4867, (92) US4880804, (93)
US4916129, (94) US5015151,
(95) US5039814, (96) US504
1552, (97) US 5043349, (98)
US5045540, (99) US5049565,
(100) US5053329, (101) US5
057522, (102) US5064825, (1
03) US5066586, (104) US508
1127, (105) US5087634, (10
6) US5087702, (107) US5093
346, (108) US5098920, (109)
US5100897, (110) US510288
0, (111) US5104891, (112) U
S5126342, (113) US5128327,
(114) US5128356, (115) US5
130318, (116) US5130439, (1
17) US5137906, (118) US513
8069, (119) WO8906233, (12
0) WO9100277, (121) WO9100
281, (122) WO9107404, (123)
WO9111909, (124) WO911199
9, (125) WO9112001, (126) W
O9112002, (127) WO9113063,
(128) WO91114367, (129) WO9
114679, (130) WO9115206, (1
31) WO9115209, (132) WO911
5479, (133) WO 9115479, (13
4) WO91131613, (135) WO9117
148, (136) WO9118888, (137)
WO9119697, (138) WO911971
5, (139) WO9200067, (140) W
O9200068, (141) WO920285,
(142) WO9200977, (143) WO9
202257, (144) WO9202508, (1
45) WO9202510, (146) WO920
4335, (147) WO9204343, (14
8) WO9205161, (149) WO9206
081, (150) WO9207852, (151)
WO9210179, (152) WO921018
0, (153) WO9210181, (154) W
O9210182, (155) WO9210183,
(156) WO9210184, (157) WO9
210185, (158) WO9210186, (1
59) WO9210187, (160) WO921
0188, and (161) the method disclosed in the document of WO9211255, preferably JP-A-5-78.
It can be manufactured by the method disclosed in Japanese Patent No. 328 and Japanese Patent Application Laid-Open No. 6-49036.

The "ester or other derivative" of the carboxy group and / or the carboxycarbonyl group is produced from the corresponding carboxylic acid salt or free carboxylic acid as follows. When such a protection reaction belongs to alkylation, <Method 1> a compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group and a compound represented by the general formula R ¹¹ -X And, in a solvent in the presence of a base, usually at −20 ° C. to 120 ° C. (preferably 0 to 80 ° C.) for 0.5 to 10 hours.

In the above formula, R ¹¹ represents a corresponding residue of an ester or other derivative, X represents a halogen atom such as chlorine, bromine, iodine; methanesulfonyloxy, ethanesulfonyloxy, etc. Lower alkanesulfonyloxy group; halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy; benzenesulfonyloxy, p-toluenesulfonyloxy, p
A group that leaves as a nucleophilic residue, such as an arylsulfonyloxy group such as -nitrobenzenesulfonyloxy, is shown.

Examples of the compound having the general formula R ¹¹ -X include aliphatic acyloxymethyl halides such as acetoxymethyl chloride, pivaloyloxymethyl bromide and pivaloyloxymethyl chloride, ethoxycarbonyloxymethyl chloride, Lower alkoxycarbonyloxyalkyl halides such as isopropoxycarbonyloxymethyl chloride, 1- (ethoxycarbonyloxy) ethyl chloride, 1- (ethoxycarbonyloxy) ethyl iodide, phthalidyl halides, or (5-methyl- 2-oxo-1,3-dioxolen-4-yl) methyl halides can be mentioned.

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, aliphatic hydrocarbons such as hexane and heptane; benzene, Aromatic hydrocarbons such as toluene and xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone,
Ketones such as methyl ethyl ketone and methyl isobutyl ketone; Nitriles such as acetonitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-
Examples thereof include amides such as methylpyrrolidinone and hexamethylphosphorotriamide.

The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, hydroxide Alkali metal hydroxides such as barium and lithium hydroxide; Inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxy , Potassium tert-butoxide, and lithium methoxide. Metal alkoxides; N- methylmorpholine, triethylamine, tributylamine,
Diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino)
Pyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N
-Diethylaniline, 1,5-diazabicyclo [4.
3.0] Nona-5-ene, organic bases such as 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene or butyllithium , Lithium diisopropylamide,
Mention may be made of organometallic bases such as lithium bis (trimethylsilyl) amide.

<Method 2> A compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group and a compound represented by the general formula R ¹¹ —OH [in the above formula, R ¹¹ is as described above] Show the same meaning. ] With the presence or absence of a base in a solvent, a method of reacting with a "condensing agent".

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably, aliphatic hydrocarbons such as hexane and heptane; benzene, Aromatic hydrocarbons such as toluene and xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide,
Examples thereof include amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide.

The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,
Pyridine, 4-pyrrolidinopyridine, picoline, 4-
(N, N-dimethylamino) pyridine, 2,6-di (te
rt-Butyl) -4-methylpyridine, quinoline, N, N
There may be mentioned organic bases such as dimethylaniline and N, N-diethylaniline.

The "condensing agent" used is (1) a combination of a phosphoric acid ester such as diphenylphosphoryl azide or diethyl cyanophosphate and the above base; (2) 1,3-dicyclohexylcarbodiimide, 1,
3-diisopropylcarbodiimide, 1-ethyl-3-
Carbodiimides such as (3-dimethylaminopropyl) carbodiimide; (3) Combination of the carbodiimides with the bases; (4) The carbodiimides with N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene. A combination of N-hydroxys such as -2,3-dicarboximide; (5) 2,2'-dipyridyl disulfide, 2,
A combination of disulfides such as 2'-dibenzothiazolyl disulfide and phosphines such as triphenylphosphine and tributylphosphine; (6) N, N'-disuccinimidyl carbonate, di-2-pyridyl carbonate , S, S'-bis (1-
(7) carbonates such as phenyl-1H-tetrazol-5-yl) dithiocarbonate; (7) phosphinic chlorides such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; 8) N, N'-disuccinimidyl oxalate,
N, N'-diphthalimido oxalate, N, N'-bis (5-norbornene-2,3-dicarboxyimidyl) oxalate, 1,1'-bis (benzotriazolyl) oxalate, 1,1 Oxalates such as'-bis (6-chlorobenzotriazolyl) oxalate and 1,1'-bis (6-trifluoromethylbenzotriazolyl) oxalate; (9) the phosphines and diethyl azodicarboxylate;
A combination of azodicarboxylic acid esters such as 1,1 ′-(azodicarbonyl) dipiperidine or azodicarboxamides; (10) a combination of the phosphines and the above bases; (11) N-ethyl-5-phenyliso N-lower alkyl-5-, such as oxazolium-3'-sulfonate
Arylisoxazolium-3′-sulfonates; (12) Diheteroaryl diselenides such as di-2-pyridyldiselenide; (13) Arylsulfonyltria such as p-nitrobenzenesulfonyltriazolide Zolides; (14) 2-Chloro-1-methylpyridinium 2-halo-1-lower alkylpyridinium halides such as iodide; (15) 1,1′-oxalyldiimidazole, N,
Imidazoles such as N'-carbonyldiimidazole; (16) 3-lower alkyl-2-halogen-benzothiazolium fluoroborates such as 3-ethyl-2-chloro-benzothiazolium fluoroborate (17) 3-lower alkyl-benzothiazole-2-cerones such as 3-methyl-benzothiazole-2-theron; (18) Phosphates such as phenyldichlorophosphate and polyphosphate ester; (19) Chloro (20) Trimethylsilyl chloride, halogenosilanes such as triethylsilyl chloride; (21) Combination of a lower alkanesulfonyl halide such as methanesulfonyl chloride with the following bases: (22) N, N, N, N, N ', N'-tetra lower alkylhalogenoformamidium chlorides such as N', N'-tetramethylchloroformamidium chloride; can be mentioned, but preferably, carbodiimides,
And a combination of a phosphine and an azodicarboxylic acid ester or an azodicarboxamide.

Incidentally, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be used in catalytic amounts in combination with other bases, and in order to carry out the reaction effectively. , Dehydrating agents such as molecular sieves, quaternary ammonium salts such as benzyltriethylammonium chloride, tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6, 3,4-dihydro-2H-. Pyrido [1,
An acid scavenger such as 2-a] pyrimidin-2-one can also be added.

The reaction temperature is -20 ° C to 80 ° C, preferably 0 ° C to room temperature. The reaction time is
The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 1 day, varying mainly depending on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used.

<Method 3> Correspondence between a compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group and a solvent such as methanol, ethanol, propanol and butanol in the presence of an acid catalyst. A method of reacting with alcohol. As the solvent used,
There is no particular limitation as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably the same alcohol as the reagent; aliphatic hydrocarbons such as hexane and heptane;
Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane ,
Examples thereof include ethers such as dimethoxyethane and diethylene glycol dimethyl ether, and more preferably the same alcohol as the reagent. The acid catalyst to be used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, but preferably, such as hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid. Inorganic acid or Bronsted acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or organic acid such as boron trichloride, boron trifluoride, boron tribromide Lewis acids or acidic ion exchange resins can be mentioned. Reaction temperature is 0 ° C to 100 ° C
The temperature is preferably 20 ° C. to 60 ° C.
The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but it is usually 1 hour to 24 hours.

<Method 4> A carboxylic acid of a compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group is treated with a halogenating agent (for example, phosphorus pentachloride, thionyl chloride,
Oxalyl chloride etc.) at room temperature for 30 minutes to 5 hours, and in the presence of the corresponding acid halide or organic base such as triethylamine, treatment with chloroformates such as methyl chloroformate and ethyl chloroformate. Then, after conversion into a mixed acid anhydride, in an inert solvent, in the presence of a base (eg, triethylamine, etc.), the corresponding alcohol compound is added to -10
A method of reacting at 10 ° C to 150 ° C (preferably around room temperature) for 10 minutes to 15 hours (preferably 30 minutes to 10 hours). The inert 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; methylene. Halogenated hydrocarbons such as chloride and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane, or nitriles such as acetonitrile.

<Method 5> A carboxylic acid of a compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group is treated with a diazoalkane such as diazomethane or diazoethane (usually an ether solution of diazoalkane). And a method of bringing them into contact with each other at around room temperature (depending on the type of reaction system, heating may be performed if necessary).

It is achieved by any one of the above methods.

<Method 6> In the case of lower alkylation, the compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group is replaced by <Method 1>.
It is also carried out by reacting with a dialkylsulfate such as dimethylsulfate or diethylsulfate in the presence of the same base as described in 1 above according to a conventional method.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. It is obtained by separating, drying over anhydrous magnesium sulfate and the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, such as silica gel, alumina, or magnesium-silica gel florisil. Column chromatography using various carriers; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and
It can be separated and purified by appropriately combining the distribution column chromatography methods using a carrier such as Haas Co., Ltd.) and Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.) and eluting with a suitable eluent.

Further, in the reaction for producing a salt of carboxylic acid, (1) in the case of a metal salt of carboxylic acid, a compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group It can be obtained by contacting with the hydroxide, carbonate or the like of the above in an aqueous solvent. As the aqueous solvent used, for example, water: alcohols such as methanol and ethanol, a mixed solvent of water and an organic solvent such as acetone is suitable. A mixed solvent of a hydrophilic organic solvent and water is particularly preferable. The reaction is usually carried out preferably near room temperature, but may be carried out under heating if necessary.

(2) In the case of amine salt of carboxylic acid A compound represented by the general formula (I) having a carboxy group and / or a carboxycarbonyl group is brought into contact with a corresponding amine in a solvent according to a conventional method. Obtained by Examples of the solvent to be used include water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; nitrites such as acetonitrile; and mixed solvents of these with water, but alcohols are preferable. It is a kind.

(3) In the case of amino acid salt of carboxylic acid It is obtained by contacting the corresponding amino acid with the corresponding free carboxylic acid in an aqueous solvent. Examples of the aqueous solvent used include water; alcohols such as methanol and ethanol; mixed solvents of ethers such as tetrahydrofuran and water; and the like. The reaction is usually performed under heating, preferably at about 50 to 60 ° C.

Further, the ester or other derivative of the hydroxyl group is produced from the corresponding compound as follows. Having <Method A> hydroxyl, a compound represented by formula (I), a compound having the general formula R ¹² -X ', or a compound having the general formula ^{R 12 -O-R 12 (R} 12 is acyl In the above formula, R ¹² is a corresponding residue of an ester or other derivative, and X ′ represents a leaving group. Such a leaving group is usually a nucleophilic residue. It is not particularly limited as long as it is a group capable of leaving as a group, but preferably a halogen atom such as chlorine, bromine and iodine; a lower alkoxycarbonyloxy group such as methoxycarbonyloxy and ethoxycarbonyloxy; chloroacetyloxy, Halogenated alkylcarbonyloxy groups such as dichloroacetyloxy, trichloroacetyloxy, trifluoroacetyloxy; lower such as methanesulfonyloxy, ethanesulfonyloxy Alkanesulfonyloxy group; halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy; arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy And a halogen atom, a halogeno lower alkanesulfonyloxy group, and an arylsulfonyloxy group are more preferred. ] 1 to 4 equivalents (preferably 2 to 3 equivalents) of the above are reacted in a solvent in the presence or absence of a base.

Specific examples of the compound having the general formula R ¹² -X 'include, for example, aliphatic acyl halides such as acetyl chloride, propionyl chloride, butyryl bromide, valeryl chloride, hexanoyl chloride; methoxycarbonyl chloride, methoxycarbonyl. Lower alkoxycarbonyl halides such as bromide, ethoxycarbonyl chloride, propoxycarbonyl chloride, butoxycarbonyl chloride, hexyloxycarbonyl chloride or acylhalides such as arylcarbonyl halides such as benzoyl chloride, benzoyl bromide, naphthoyl chloride or trimethylsilyl chloride. , Silyl halides such as triethylsilyl bromide, aralkyl halides such as benzyl chloride and benzyl bromide. Id acids or pivaloyloxymethyl chloride, mention may be made of a carbonyl-lower alkyl halides such as ethoxycarbonyloxymethyl chloride. Specific examples of the compound having the general formula R ¹² —O—R ¹² include aliphatic carboxylic acid anhydrides such as acetic anhydride, propionic anhydride, valeric anhydride, and hexanoic anhydride. ,
It is also possible to use mixed acid anhydrides such as formic acid and acetic acid. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent,
Preferred are aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated compounds such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene. Hydrocarbons; Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Acetonitrile, isobutyro Nitriles such as nitriles; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotria It can be mentioned amides such as de. The base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
Organic bases such as N-dimethylamino) pyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline can be mentioned. Incidentally, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be used in catalytic amounts in combination with other bases,
In order to make the reaction effective, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, dibenzo-1.
Crown ethers such as 8-crown-6 can also be added. The reaction temperature is usually from -20 ° C to the reflux temperature of the solvent used, but preferably 0 ° C.
To the reflux temperature of the solvent used. The reaction time varies depending mainly on the reaction temperature, the raw material compound, the base used or the type of solvent used, but is usually 10 minutes to 3 days, and preferably 1 hour to 6 hours. <Method B> A compound represented by the general formula (I) having a hydroxyl group and a compound represented by the general formula R ¹² —OH (when R ¹² is an acyl group) [wherein R ¹² is the same as defined above] Show significance. ] With the above-mentioned "condensation agent" in the presence or absence of a base in a solvent. As the solvent used, the above <Method 2 is used.
The same as the solvent used in>.

As the base to be used, the above <Method A>
The same bases as described in can be used. The reaction temperature is −20 ° C. to 80 ° C.,
The temperature is preferably 0 ° C. to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 3 days, and preferably 30 minutes to 1 day.

<Method C> General Formula (I) Having a Hydroxyl Group
And a compound having the general formula R ¹² —OH (when R ¹² is an acyl group) [In the above formula, R ¹² has the same meaning as described above. ] In the presence of a halogenated phosphoric acid dialkyl ester such as diethyl chlorophosphate and a base in a solvent.

It is carried out according to any one of the above methods.

As the solvent used, the above <Method 3> is used.
The same as the solvent used in.

As the base used, the above <Method A>
The same bases as described in can be used. The reaction temperature is 0 ° C. to the reflux temperature of the solvent used, and preferably room temperature to 50 ° C. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 3 days, and preferably 30 minutes to 1 day.

<Method D> General formula (I) having a hydroxyl group
When the compound represented by is lower-alkylated, it is carried out by reacting with a dialkylsulfate such as dimethylsulfate or diethylsulfate in the presence of a base. The base used is preferably sodium hydride,
Alkali metal hydrides such as potassium hydride and lithium hydride. The reaction temperature is 0 to 120 ° C. (preferably 20 to 80 ° C.), and the reaction time is 1 to 24 hours (preferably 1 to 16 hours).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture by a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. It is obtained by separating, drying over anhydrous magnesium sulfate and the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, such as silica gel, alumina, or magnesium-silica gel florisil. Column chromatography using various carriers; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and
It can be separated and purified by appropriately combining a distribution column chromatography method using a carrier such as Haas Co., Ltd.) or Diaion HP-20 (Mitsubishi Kasei Co., Ltd.).

[0067]

INDUSTRIAL APPLICABILITY The novel composition for eye drops 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.

The composition of the present invention may be administered in the form of an ophthalmic pharmaceutical composition suitable for topical administration to the eye, such as solution, suspension, gel, ointment or solid insert.

The formulation of these ophthalmic compositions has a lower limit of 0.01%, preferably 0.1%, and an upper limit of 10%, preferably 5%, containing the active drug. Can be included.

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 can 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 are, for example, water, mixtures of water with water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum-based jellies. , Ethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl myristate and other conveniently acceptable carriers.
Pharmaceutical formulations also include non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, excipients, eg polyethylene glycols 200, 300, 400 and 600, carbowaxes 1000, 1500, 4000, 6000 and 1000.
0, methyl p-hydroxybenzoate, p-hydroxybenzoic acid esters such as propyl p-hydroxybenzoate, quaternary ammonium compounds known to have pasteurizing properties and nontoxic to use (eg, , Benzethonium chloride, benzalkonium chloride), antibacterial agents such as phenylmercuric salts, buffer components such as thimerosal, methyl and propylparaben, benzyl alcohol, phenylethanol, sodium chloride, sodium borate, sodium acetate, gluconate buffer Agents and sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediaminetetraacetic acid and the like can also be included.

In addition, suitable ophthalmic excipients can be used as carrier media for the purposes of the present invention, which include conventional phosphate buffer excipient systems (eg sodium phosphate buffer, potassium phosphate). Buffering agents), isotonic boric acid excipients, isotonic sodium chloride excipients, isotonic sodium borate excipients and the like.

The pharmaceutical preparation should also be in the form of a solid intercalating agent which remains almost completely after administration of the drug or in the form of a biodegradable intercalating agent which dissolves in tear fluid or otherwise disintegrates. You can also

In general, the active drug of the present invention has a lower limit of about 0.001 mg / kg of body weight, preferably about 0.
01 mg can be used as the upper limit of about 50 mg, preferably about 20 mg. 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 and Formulation Examples.

[0077]

[Experimental Example 1] [Experimental method] New Zealand White rabbits having a body weight of 2 to 3 kg were used. Kurihara et al. (Ophthalmology, No. 6)
2 to 64, Vol. 4, 1990), an intraocular pressure elevation model was prepared and the intraocular pressure lowering effect of the test compound was examined.
That is, the rabbit was anesthetized with urethane and then the tonometer (A
The intraocular pressure was measured using lcon Applanation Pneumatonography). A local anesthetic was applied to the eyes of the rabbit, and then 0.1 ml of 5% aqueous sodium chloride was injected into the vitreous body through a 30-gauge injection needle. It was confirmed that the intraocular pressure increased 30 minutes after the injection, and then 50 μl of the test drug solution was instilled. Then, the intraocular pressure was measured at 30 minute intervals for 2 hours. [Results] Area of a portion surrounded by the intraocular pressure curve of the control group (no drug instillation) and the intraocular pressure curve of the group instilled with the test compound (AU
C) and the maximum intraocular pressure lowering width were calculated and used as an index of the intraocular pressure lowering action. The results are summarized in Table 1, and the composition of the present invention showed an excellent effect of improving ocular hypertension.

[0078]

[Chemical 9]

Table 1 Intraocular pressure lowering action ───────────────────────────────────── Compound eye drop concentration AUC Maximum intraocular pressure drop width (%) (mmHg / hr) (mmHg) ─────────────────────────────────── --Compound A 1.0 11.18 9.8 Compound B 1.0 3.21 2.6 Compound C 1.0 3.98 2.7 Compound D 0.2 6.21 6.4 Compound E 1. 0 4.90 7.6 Compound F 1.0 4.93 4.7 Compound G 1.0 5.45 8.6 Compound H 1.0 5.58 8.6 Compound I 1.0 5.33 7. 3 DUP753 1.0 0.28 1.3 DUP753 3.0 2.38 3.5 ───────────────────────────── ──── ──

[0080]

[Formulation Example 1] (Eye drops) Active drug 0.002 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 014 g Sterile purified water Appropriate amount Sodium hydroxide Appropriate amount ------------------ Total amount 100 ml An ophthalmic solution was prepared by a conventional method at pH 7.0.

[0081]

[Formulation Example 2] (Eye drops) Active drug 0.002 g Disodium phosphate 0.500 g Monosodium phosphate 1.100 g Sodium chloride 0.300 g Benzethonium 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.

[0082]

[Formulation Example 3] (Eye drops) Active drug 0.002 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 of pH 7.0.

[0083]

[Reference Example 1] 4- (1-hydroxy-1-methylethyl) -2-pro
Pyr-1- [4- (2-tetrazol-5-yl) ben
Zyl] imidazole-5-carboxylic acid 5- (1-hydroxy-1-methylethyl) -2-propylimidazole-4-carboxylate ethyl 1.00 g
Of N, N-dimethylacetamide in 10 ml of
% Oily sodium hydride 0.20 g was added. 3 at room temperature
After stirring for 0 minutes, 4- (2-trityltetrazole-
A solution of 1.95 g of 5-yl) benzyl bromide in 20 ml of N, N-dimethylacetamide was added dropwise. The reaction solution was stirred at room temperature for 2 hours, ethyl acetate and water were added to the reaction solution, and the ethyl acetate layer was separated. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1: 1) as a solvent system to give crystalline 4-
(1-Hydroxy-1-methylethyl) -2-propyl-1- [4- (2-trityltetrazol-5-yl)
Benzyl] imidazole-5-carboxylate ethyl 1.5
1 g was obtained.

Melting point: 187-189 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 0.98 (3H, t,
J = 7.5Hz), 1.20 (3H, t, J = 7.5Hz), 1.68 (6H, s), 1.65
-1.78 (2H, m), 2.66 (2H, t, J = 8Hz), 4.24 (2H, q, J =
7.5Hz), 5.53 (2H, s), 5.78 (1H, s), 7.04 (2H, d, J = 8H
z), 7.17 -7.41 (15H, m), 8.13 (2H, d, J = 8Hz) A solution of 1.40 g of the above compound in 15 ml of acetic acid and 5 ml of water was stirred at 60 ° C for 3.5 hours, then cooled and precipitated. The product was filtered off. The filtrate was concentrated, the remaining small amount of acetic acid and water were removed by azeotropic distillation with toluene, and the residue was subjected to silica gel column chromatography with methanol-methylene chloride (1: 4) to give a gum-like substance. 4- (1-hydroxy-
1-methylethyl) -2-propyl-1- [4- (2-
Tetrazol-5-yl) benzyl] imidazole-5
-0.78 g of ethyl carboxylate was obtained.

0.78 g of this compound in 12 ml of dioxane
Lithium hydroxide monohydrate 0.486 g water 11
The ml solution was added, and the mixture was stirred at room temperature for 4.5 hours. Dioxane was distilled off under reduced pressure, 11.6 ml of 1N hydrochloric acid was added to the residual aqueous solution, sodium chloride was further added for the purpose of salting out, and the target compound was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crystalline residue. This was collected by filtration with isopropyl ether to obtain 0.41 g of the desired compound.

Melting point: 194-196 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ ppm: 0.89
(3H, t, J = 7.5Hz), 1.58 (6
H, s), 1.62 (2H, sextet, J
= 7.5 Hz), 2.63 (2H, t, J = 8H
z), 5.71 (2H, s), 7.18 (2H,
d, J = 8.5 Hz), 8.00 (2H, d,
J = 8.5Hz)

Claims (17)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R ¹ represents a lower alkyl group, a lower alkenyl group or a compound represented by the formula R ⁵
A group having —AB— (in the formula, R ⁵ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aliphatic acyl group, A represents an oxygen atom or a sulfur atom, and B represents a single bond. Or a lower alkylene group), and R ² is a lower alkyl group, a lower alkenyl group or the formula —C
A group having (R ⁶ ) (R ⁷ ) (R ⁸ ), wherein R ⁶ represents a hydroxyl group or a lower alkoxy group, and R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group, A lower alkenyl group, a lower alkynyl group, a cycloalkyl group, an aryl group or an aralkyl group), and R ³ is a carboxy group or a formula —CON (R ⁹ ) (R ¹⁰ ).
(Wherein R ⁹ and R ¹⁰ are the same or different and each is a hydrogen atom, a lower alkyl group or a group selected from the substituent group (I)).
A lower alkyl group having 3 to 3 substituents is shown. And R ⁴ represents a carboxy group, a carboxycarbonyl group or a tetrazol-5-yl group. ], A pharmacologically acceptable salt thereof, or an ester or other derivative thereof, and an ocular hypotensive agent for eye drops and / or a therapeutic agent for glaucoma for eye drops. Substituent group (I) aryl group, 5- to 6-membered heteroaromatic ring group, halogen atom,
Hydroxyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, amino group, aliphatic acylamide group and aromatic acylamide group. 2. The group according to claim 1, wherein R ¹ is a group having the formula R ⁵ —A—B— (wherein R ⁵ is a hydrogen atom, a lower alkyl group or an aliphatic acyl group, and A is Which represents an oxygen atom or a sulfur atom, and B represents a single bond or a lower alkylene group). 3. The method according to claim 1, wherein R ¹ is a lower alkyl group or a lower alkenyl group.
Composition. 4. The composition according to claim 1, wherein R ¹ is a lower alkyl group. 5. The composition according to claim 1, wherein R ¹ is an alkyl group having 1 to 4 carbon atoms. 6. The composition according to claim 1, wherein R ¹ is an alkyl group having 2 to 4 carbon atoms. 7. In one item selected from claims 1 to 6, R ² is a group having the formula —C (R ⁶ ) (R ⁷ ) (R ⁸ ), wherein R ⁶ is A hydroxyl group or a lower alkoxy group, and R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkenyl group).
Composition. 8. The composition according to claim 7, wherein R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a lower alkyl group. 9. The composition according to claim 7, wherein R ⁶ is a hydroxyl group, and R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. 10. The composition according to claim 9, wherein R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms. 11. One selected from claim 1 to claim 6.
Wherein R ² is a 1-hydroxy-1-methylethyl group,
Composition. 12. The method according to claim 1, wherein R ³ is a carboxy group or a formula —CON (R ⁹ ) (R ¹⁰ ).
And R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom or a lower alkyl group. 13. The composition according to claim 1, wherein R ³ is a carboxy group. 14. The composition according to claim 1, wherein R ⁴ is a carboxy group or a tetrazol-5-yl group. 15. The composition according to claim 1, wherein R ⁴ is a tetrazol-5-yl group. 16. The method according to claim 1, wherein A composition containing a compound having the above formula, a pharmaceutically acceptable salt thereof, or an ester or other derivative thereof. 17. The method according to claim 1, wherein A composition containing a compound having the above formula, a pharmaceutically acceptable salt thereof, or an ester or other derivative thereof.