JP2003321442A - Novel difluoroprostaglandin amide derivatives - Google Patents

Abstract

[PROBLEMS] To provide a prostaglandin (PG) derivative useful as a pharmaceutical product in which the carboxy group at the 1-position is amidated and has two fluorine atoms at the 15-position, and a medicament containing the derivative as an active ingredient In particular, provision of a medicament for the prevention or treatment of eye diseases. A 15-deoxy-15,15-difluoroPG derivative (formula 1) and a pharmaceutical comprising the derivative as an active ingredient. However, A is a vinylene group, R ¹ is an aryloxyalkyl group, X is methylene, R ² and R ³ are hydrogen atoms, R ⁴ and R ⁵ are hydrogen atoms, substituted alkyl groups, and the like. [Chemical 1]

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 15-deoxy-15,15 in which the carboxy group at the 1-position is a carboxamide group or a group derived from a carboxamide group, and two fluorine atoms are bonded at the 15-position. -Difluoroprostaglandin derivative, and a medicament containing the prostaglandin derivative as an active ingredient, particularly a medicament for preventing or treating eye diseases.

[0002]

2. Description of the Related Art Natural prostaglandins (hereinafter, prostaglandins are referred to as PG) are a group of physiologically active substances synthesized in vivo, and are cells of various tissues as local hormones having various physiological activities. Adjusting function. Among them, in particular, PGFs, which are a type of natural PG, are used as a parturition-inducing agent, a glaucoma therapeutic agent, a domestic animal sexual cycle regulator, and the like. In addition, these PGs may be applicable to indications such as therapeutic agents for osteoporosis, and the development of PG derivatives with higher efficacy and less side effects is being studied.

For 15-deoxy-15-fluoro PGF _{2 α} having one fluorine atom at the 15-position of PG having a natural skeleton, see Dokl.Akad.Nauk SSSR, 250.
(2), 468-469, 1980.

Further, there is a report on 15-deoxy-15,15-difluoro PGF _{2 α} 's (Japanese Patent Laid-Open No. HEI-1)
1-071344). Also 15-deoxy-15,15
-Difluoro PGF _{2 α} is described as a therapeutic agent for glaucoma or ocular hypertension, which has a high intraocular pressure-lowering effect and low side effects.

[0005]

However, PGs having a carboxy group at the 1-position being a carboxamide group or a group derived from a carboxamide group and having two fluorine atoms at the 15-position have synthetic examples and physical properties. , No biological activity was reported at all.

[0006]

[Means for Solving the Problems] In order to impart the unique properties of a fluorine atom to PGs, the present inventors have synthesized new PGs and investigated to clarify their physical properties and physiological activities. I went. As a result, the 1-position carboxy group of the prostanoic acid skeleton was converted to a carboxamide group or a group derived from a carboxamide group, and a novel 15-deoxy-15,15-difluoroPG derivative having two fluorine atoms bonded was obtained. It has been found that the compound has excellent physical properties and physiological activity, and further that it is an excellent compound as a medicine.

That is, the present invention provides a 15-deoxy-15,15-difluoroPG derivative represented by the following formula (1),
And a pharmaceutical containing the PG derivative as an active ingredient.

[0008]

[Chemical 2]

However, the symbols in the formula (1) have the following meanings. A: ethylene group, vinylene group, ethynylene group, -OCH
₂ - or -SCH ₂ -. _{X: -CH 2 -, - O-} , or -S-. R ¹ : a linear alkyl group having 3 to 8 carbon atoms, a linear alkenyl group having 3 to 8 carbon atoms, a linear alkynyl group having 3 to 8 carbon atoms,
A group selected from a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group, and an aryloxyalkyl group, or a group in which one or more hydrogen atoms in the selected group are substituted. R ² and R ³ : each independently a hydrogen atom or 1 carbon atom
~ 20 acyl groups. R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, an aralkyl group, or a hydroxyl group, an alkoxy group, a carboxy group and an alkoxy. An alkyl group having 1 to 6 carbon atoms which may be substituted with a group selected from a carbonyl group. Overlap of solid and dashed lines: single bond, cis double bond, or trans double bond.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the nomenclature of compounds in the present specification, the numbers used to indicate the position of the PG skeleton are the numbers corresponding to the numbers of the prostanoic acid skeleton. In the present specification, a group in which a hydrogen atom of an alkyl group is substituted,
Also referred to as a substituted alkyl group. The same applies to other groups. Further, the "lower organic group" refers to an organic group having 6 or less carbon atoms. The lower organic group preferably has 4 or less carbon atoms.

The "alkyl group" may be linear or branched. Unless otherwise specified, the alkyl group is preferably a lower alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group,
A tert-butyl group, a pentyl group, a hexyl group and the like can be mentioned.

The "alkenyl group" may be linear or branched. Unless otherwise specified, the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms. Examples of the alkenyl group include vinyl group, allyl group, 1-propenyl group, isopropenyl group, 3-butenyl group, 3-pentenyl group, 4-hexenyl group and the like.

Unless otherwise specified, the "alkynyl group" is preferably a lower alkynyl group having 2 to 6 carbon atoms. The alkynyl group may be linear or branched. Examples of the alkynyl group include 1-propynyl group, 2-propynyl group, 3-butynyl group, 3-pentynyl group, 4-hexynyl group and the like.

The "alkoxy group" is preferably a lower alkoxy group having 1 to 6 carbon atoms, and particularly preferably an alkoxy group having 1 to 4 carbon atoms. The alkoxy group may be linear or branched. Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "aryl group" means a monovalent aromatic hydrocarbon group, preferably a phenyl group.

As the substituted aryl group, at least one hydrogen atom in the aryl group is substituted with a lower alkyl group, a halogen atom, a halogenated (lower alkyl) group, a lower alkoxy group, a (lower alkyl) amino group or the like. Preferred groups are The substituted aryl group is preferably a substituted phenyl group, particularly a monohalophenyl group (eg chlorophenyl group, fluorophenyl group, bromophenyl group etc.), dihalophenyl group (eg dichlorophenyl group, difluorophenyl group, dibromophenyl group etc.),
Trihalophenyl groups (eg trichlorophenyl groups,
Trifluorophenyl group, tribromophenyl group, etc.),
(Halogenated lower alkyl) substituted phenyl group (eg trifluoromethylphenyl group etc.), (lower alkoxy) phenyl group (eg methoxyphenyl group, ethoxyphenyl group etc.), di (lower alkoxy) phenyl group (eg dimethoxyphenyl group, A diethoxyphenyl group and the like), a tri (lower alkoxy) phenyl group (for example, a trimethoxyphenyl group, a triethoxyphenyl group and the like), a tolyl group and the like are preferable.

The term "aralkyl group" refers to an alkyl group substituted with an aryl group. As the aryl group portion,
A phenyl group is preferred. The alkyl group part in the aralkyl group is preferably an alkyl group having 1 to 4 carbon atoms.
Examples of the aralkyl group include a benzyl group, a benzhydryl group, a trityl group, a phenylethyl group and the like.

The "cycloalkyl group" refers to a cyclic alkyl group having 3 or more membered rings, and a cycloalkyl group having 3 to 8 membered rings is preferable. Examples of the substituent in the substituted cycloalkyl group include a lower alkyl group, a halogen atom and a lower alkoxy group. Examples of the cycloalkyl group and the substituted cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, methylcyclohexyl group, dimethylcyclopentyl group, dimethylcyclohexyl group, chlorocyclohexyl group, or dichloro group. Examples thereof include a cyclohexyl group.

The "halogenated alkyl group" means a group in which one or more hydrogen atoms in the alkyl group are substituted with a halogen atom, and a lower halogenated alkyl group having 1 to 6 carbon atoms is preferable. Examples of the halogenated alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a pentafluoroethyl group,
A chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group and the like can be mentioned.

The term "acyl group" means a monovalent group formed by removing a hydroxyl group from the carboxy group of a carboxylic acid. Examples of the carboxylic acid include saturated aliphatic carboxylic acid, unsaturated aliphatic carboxylic acid, carbocyclic carboxylic acid, and heterocyclic carboxylic acid. Examples of carbocyclic carboxylic acids include saturated aliphatic rings, unsaturated aliphatic rings, or aromatic rings, and compounds in which a carboxy group is bonded to a carbon atom forming a ring therein.

15-deoxy-1 represented by the formula (1)
5,15-DifluoroPG derivative (hereinafter, referred to as PG of the present invention
As the derivative (1), the following compounds are preferable from the viewpoint of physiological activity and physical properties.

That is, A is preferably a vinylene group or an ethylene group. The vinylene group may be in the cis form or in the trans form, and a trans vinylene group is particularly preferable. Incidentally, A is -OCH ₂ -, - SCH ₂ - bond orientation when it is is not particularly limited, it is preferable that each oxygen atom or a sulfur atom bonded to the ring.
The X -CH ₂ - it is preferred. The overlapping portion of the solid line and the broken line is preferably a cis double bond.

R ¹ is a linear alkyl group having 3 to 8 carbon atoms,
A group in which a hydrogen atom in a linear alkyl group having 3 to 8 carbon atoms is substituted (hereinafter, referred to as "substituted (linear alkyl group having 3 to 8 carbon atoms) group".
It is written as. The same applies to other groups. ), A linear alkenyl group having 3 to 8 carbon atoms, a substituted (linear alkenyl group having 3 to 8 carbon atoms) group, a linear alkynyl group having 3 to 8 carbon atoms, or a substituted (linear chain alkynyl having 3 to 8 carbon atoms) group (Hereinafter, these groups are collectively referred to as a group (r ¹ ).) When the linear alkyl group portion, the linear alkenyl group portion, and the linear alkynyl group portion have 5 to 6 carbon atoms, respectively. preferable.

When a substituent is present in the group (r ¹ ), a methyl group is preferable, and the number of substituted methyl groups is preferably 1 or 2. The group (r ¹ ) is n-
Pentyl group, 2-methylhexyl group, 1-methyl-3-
A pentynyl group, a 1-methyl-3-hexynyl group, or a 1,1-dimethyl-3-hexynyl group is preferable.

When the group (r ¹ ) has a substituent other than a methyl group, the substituent is preferably a cycloalkyl group. For example, the group (r ¹ ) substituted with a cycloalkyl group is a cycloalkyl-substituted group (having 3 to 8 carbon atoms).
Linear alkyl) group, cycloalkyl group substitution (C3-C3)
8 straight-chain alkenyl) groups and the like. The cycloalkyl group as a substituent is preferably a cyclopentyl group or a cyclohexyl group.

R ¹ is a C 3-8 cycloalkyl group, a substituted (C 3-8) cycloalkyl group, an aralkyl group, a substituted aralkyl group, an aryloxyalkyl group, a substituted (aryloxy) alkyl group If it is (hereinafter, also referred to as collectively these groups groups (r ^2).), the ring structure moiety in the group (r ^2), the alkyl group having 1 to 6 carbon atoms, a halogen atom, an oxygen It may be substituted with an atom-containing substituent, a sulfur atom-containing substituent, a nitrogen atom-containing substituent, or the like, and preferably an alkyl group having 1 to 3 carbon atoms or a halogen atom is substituted. The group (r ² ) is preferably an aryloxyalkyl group or a substituted (aryloxy) alkyl group.

When the group (r ² ) is a cycloalkyl group having 3 to 8 carbon atoms, it is preferably a cyclopentyl group or a cyclohexyl group, and when it is a substituted (3 to 8 carbon atom) cycloalkyl group. A cycloalkyl group having 3 to 8 carbon atoms substituted with one or more lower alkyl groups is preferred, and a cyclopentyl group substituted with an alkyl group having 1 to 4 carbon atoms, substituted with an alkyl group having 1 to 4 carbon atoms A cyclohexyl group is preferred.

When the group (r ² ) is an aralkyl group, an aralkyl group having a benzene ring or a naphthalene ring is preferable. When the group (r ² ) is a substituted aralkyl group, examples of the substituent include a lower alkyl group, a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group and the like. The alkylene group portion in the aralkyl group and the substituted aralkyl group preferably has 1 to 4 carbon atoms. As the aralkyl group, a benzyl group and a phenylethyl group are preferable. The substituted aralkyl group is preferably a benzyl group or a phenyl group in a phenylethyl group, which is substituted with a methyl group, an ethyl group, or a halogen atom.

When the group (r ² ) is an aralkyl group or a substituted aralkyl group, specific examples thereof include benzyl group, 2-phenylethyl group, 3-methylphenylmethyl group and 2- (3-methylphenyl). Ethyl group, 3-trifluoromethylphenylmethyl group, 2- (3-trifluoromethylphenyl) ethyl group, 3-chlorophenylmethyl group, 2- (3-chlorophenyl) ethyl group, 2-
(3,5-dichlorophenyl) ethyl group, or 2-
(3,4-dichlorophenyl) ethyl group and the like can be mentioned.

When the group (r ² ) is an aryloxyalkyl group, an aryloxyalkyl group having a benzene ring is preferable, and a phenyloxyalkyl group is particularly preferable. When the group (r ² ) is a substituted aryloxyalkyl group, the hydrogen atom of the aryl group is a halogen atom,
It is preferably substituted with a halogenated alkyl group, an alkoxy group, or a hydroxyl group. The number of carbon atoms in the alkyl group portion of the aryloxyalkyl group and the substituted aryloxyalkyl group is preferably 1 to 3.

Further, the substituted aryloxyalkyl group is preferably a phenyl group substituted with 1 to 3 halogen atoms or a phenyl group substituted with 1 to 3 halogenated alkyl groups.

Examples of the aryloxyalkyl group or the substituted aryloxyalkyl group include phenoxymethyl group, 3-chlorophenoxymethyl group, 3-fluorophenoxymethyl group, 3-trifluoromethylphenoxymethyl group and 3,5-dichloro group. Phenoxymethyl group, 3,4
-Dichlorophenoxymethyl group, 3,5-difluorophenoxymethyl group, 3,4-difluorophenoxymethyl group, 3,5-bis (trifluoromethyl) phenoxymethyl group, or 3,4-bis (trifluoromethyl)
Examples thereof include a phenoxymethyl group, and a phenoxymethyl group, a 3-chlorophenoxymethyl group, a 3,5-dichlorophenoxymethyl group, or a 3,4-dichlorophenoxymethyl group is particularly preferable.

Particularly preferred R ¹ is a linear alkyl group having 3 to 8 carbon atoms, an aryloxyalkyl group, or a substituted aryloxyalkyl group.

R ² and R ³ are each independently a hydrogen atom or an acyl group having 1 to 20 carbon atoms, preferably a hydrogen atom. The PG derivative (1) of the present invention in which R ² and R ³ are an acyl group having 1 to 20 carbon atoms can be converted into a physiologically active compound by hydrolysis in vivo, and thus is useful as a prodrug. Is.

R ⁴ and R ⁵ are each independently a hydrogen atom,
It may be substituted with an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, an aralkyl group, or a group selected from a hydroxyl group, an alkoxy group, a carboxy group and an alkoxycarbonyl group. It is an alkyl group having 1 to 6 carbon atoms.

When an alkyl group moiety is present in R ⁴ and R ⁵ , the moiety may be linear or branched.

The PG derivative (1) of the present invention is a compound of 15-deoxy-15,15-difluoro PGF having the same basic skeleton (for example, PGF ₂ represented by the following formula (2)).
_α derivative. Hereinafter referred to as PGF _{2 α} derivative (2). The same applies to compounds represented by other formulas. Is preferably used as a raw material.

The 15-deoxy-15,15-difluoro PGFs can be synthesized according to the method described in JP-A-11-071344. For example, a ketone (3) having a desired ω chain is subjected to a fluorination reaction to produce a lactone (4) having an ω chain having two fluorine atoms at the 15-position, and then the lactone (4) is reduced. Then, the lactol (5) is converted into the lactol (5), and the phospholane (6) is reacted with the lactol (5) to introduce an α chain unit, whereby a PGF _{2 α} derivative (2) is obtained. Phospholanes (6) are obtained from phosphonium salts (7).

However, in the following formula, R ¹ , R ² , A, and X
Represents the same meaning as in formula (1), and R ²⁰ represents
A hydrogen atom or a hydroxyl-protecting group is shown. Z is a hydroxyl group,
Alternatively, it represents an alkoxy group having 1 to 20 carbon atoms. Y represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom. R ⁶ represents a group selected from an alkyl group, an aryl group and an aralkyl group, a group in which one or more hydrogen atoms in the selected group are substituted, or a dialkylamino group. When Z is a hydroxyl group, the corresponding compound (phosphorane (6), phosphonium salt (7), PGF _{2 α} derivative (2)) may form a salt with a base. Examples of the salt with a base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as potassium salt and magnesium salt, and ammonium salts such as ammonium salt and N-alkyl substituted ammonium salt.

[0041]

[Chemical 3]

The configuration of formulas (2) to (7) is P
It may be different from the G derivative (formula (1)). Further, the steric configuration of the substituent bonded to the cyclopentane ring in formulas (2) to (5) is not specified.

Except when R ¹ has a specific substituent,
Ketones (3) are known compounds. The novel ketones (3) in which R ¹ has a specific substituent can be produced by the same method as the known ketones (3). For example, 3-
A novel ketone (3) can be produced by reacting a substituted dialkyl-2-oxopropylphosphonate with a corey lactone having a formyl group.

Various known fluorination methods can be applied to the lactone (4) by fluorinating the ketone (3). For example, a method of reacting in an inert solvent using various nucleophilic fluorinating agents is adopted.

When the ketone (3) has a functional group capable of being fluorinated during the fluorination reaction, it is preferable to protect the functional group with a protecting group in advance. For example, when R ² is a hydrogen atom, it is protected with a protecting group to give 1
It is preferable to fluorinate the carbonyl group at the 5-position and then perform deprotection. In the case of protecting the 11-position hydroxyl group in ketones (3) with an acyl group may be R ² of the final compounds without deprotection, new after deprotection R ²
May be introduced.

As a method for deprotecting the protected hydroxyl group, a conventional method can be adopted. For example, "New Experimental Chemistry Course 14 Synthesis and Reactions of Organic Compounds (I), (II), (V)" (Maruzen),
"Protective Groups in Organic
The method described in "Synthesis" (TW Greene, J.Wiley & Sons) and the like can be used.

In the fluorination reaction of the ketones (3), it is preferable to use a fluorinating agent. As the fluorinating agent,
Known or known nucleophilic fluorinating agents can be used. For example, Tomoya Kitazume, Takashi Ishihara, Takeo Taguchi "Chemistry of Fluorine"
(Koudansha Scientific) and the like. Further, in order to increase the reactivity of the fluorinating agent and suppress side reactions, 1 of the ketones (3) is used.
The carbonyl group at the 5-position may be reacted with an oxime, a hydrazone, a thioacetal, a diazo compound or the like, and then a fluorinating agent may be allowed to act thereon. For example, Olah et al. (Synlett., 1990, 594, Synlett., 1994, 425), Katz.
Enellenbogen et al.'s method (J.Org.Chem., 51, 3508 (198
6)), Hiyama et al.'S method (Synlett., 1991, 909), and Fujisawa et al.'S method (J. Fluorine Chem., 71, 9 (1995)).

The nucleophilic fluorinating agent is preferably used in the presence of an inert solvent. Examples of the inert solvent include halogen solvents, ether solvents, hydrocarbon solvents, ester solvents, polar solvents, and mixed solvents thereof.

Lactones obtained by fluorination reaction (4)
Is then reduced to lactol (5). The reduction of the lactone (4) is preferably carried out by a method of acting a reducing agent in an inert solvent. For example, the method described in "New Experimental Chemistry Course 15 Oxidation and Reduction (II)" (Maruzen), "4th Edition Experimental Chemistry Course 26 Organic Synthesis VIII, Asymmetric Synthesis / Reduction / Sugar / Labeled Compounds" (Maruzen), etc. Can be used.

As the reducing agent used for the reduction of the lactone (4), various hydrides are preferable. For example, a hydride of a metal containing silicon, a metal-hydrogen complex compound, a borohydride compound and the like can be mentioned, and diisobutylaluminum hydride [DIBAH], sodium bis (2-methoxyethoxy) aluminum hydride and the like are preferable. Examples of the inert solvent used for reducing the lactone (4) include ether solvents, hydrocarbon solvents, polar solvents, and mixed solvents thereof. The configuration of the hydroxyl group of the lactol (5) produced by the reduction reaction is not particularly limited.

Lactols (5) produced by reduction of lactones (4) are then reacted with phospholanes (6) to give PGF _{2 α} derivatives (2). The phospholanes (6) are produced from the corresponding phosphonium salts (7) in an inert solvent in the presence of a base, and the produced phospholanes (6) are the lactols (5) as they are without isolation.
It is preferably used for the Wittig reaction with Phosphoranes (6) are manufactured by "New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I)" (Maruzen), "4th Edition Experimental Chemistry Course 19 Organic Synthesis I, Hydrocarbons and Halogen Compounds" (Maruzen ) Etc., the method of Schaaf et al. (J.
Med. Chem., 22, 1340 (1979)) can be adopted. As Z in the phospholanes (6) and the phosphonium salts (7), a hydroxyl group is preferable. Examples of the inert solvent include ether solvents, hydrocarbon solvents, polar solvents, aqueous solvents, alcohol solvents, and mixed solvents thereof.

PGF _{2 α} derivative (2) obtained by the above method
The PG derivative (1) of the present invention is obtained by reacting the 1-position carboxy group of the above with amines.

[0053]

[Chemical 4]

Specifically, the amidation reaction of the 1-position carboxy group of the PGF _{2 α} derivative (2) can be carried out by a method of condensing a carboxylic acid or a derivative thereof with an amine. When Z in the formula (2) is an alkoxy group, the condensation reaction is
It may be carried out as it is or after it is converted into a carboxylic acid.

The amount of amine used in this condensation reaction is
Usually, it is 0.1 to PGF _{2 α} derivative (2).
The molar amount is preferably 50 times, and particularly preferably 1 to 20 times. The reaction temperature is preferably -50 ° C to + 200 ° C, particularly preferably 0 ° C to 150 ° C.

As a reaction for condensing a carboxylic acid moiety and an amine to form an amide reaction, a known method can be used. In general, methods used for amide synthesis and peptide synthesis are used, and for example, new experimental chemistry course “Synthesis and Reaction of Organic Compounds (II)” (Maruzen), Toshio Goto, Tetsuo Shiba, Teruo Matsuura “ Organic Chemistry Experiment Tebiki 4-
It is possible to use the methods described in the textbooks such as the synthetic reaction [II] ”(chemical coterie).

For example, a method of mixing a carboxylic acid or a carboxylic acid ester with an amine for condensation, a method of converting a carboxylic acid into an acid halide such as an acid chloride or an active ester and reacting with an amine, a condensing agent for a carboxylic acid and an amine And the like.

As a method of mixing and condensing a carboxylic acid or a carboxylic acid ester and an amine, a method of mixing and heating in a solvent having a boiling point of room temperature or higher is usually mentioned. Furthermore, condensation may be performed by further azeotroping with a solvent to cause dehydration or dealcoholization reaction.

As a method of converting a carboxylic acid into an acid halide or an active ester and reacting with an amine, for example, a method of converting into an acid chloride using thionyl chloride or oxalic acid chloride, N-hydroxysuccinimide, N-
After conversion into various active esters using hydroxybenzotriazole, pentafluorophenol, etc.,
Examples include a method of reacting with an amine. The condensation reaction is carried out by triethylamine, diisopropylamine, N-methylmorpholine, pyridine, sodium hydroxide, potassium hydroxide,
It may be carried out in the presence of a base such as sodium carbonate or sodium hydrogen carbonate.

As a method for reacting a carboxylic acid and an amine in the presence of a condensing agent, various known condensing agents can be used. Examples of the condensing agent include N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate [BOP],
Benzotriazol-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate [PyB
OP], O-benzotriazol-1-yl-N, N,
N ', N'-tetramethyluronium tetrafluorophosphate [HBTU] etc. are mentioned. Condensing agent is N
-Hydroxybenzotriazole, or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine may be used together with the additive. Also,
The condensation reaction is triethylamine, diisopropylamine,
N-methylmorpholine, pyridine, sodium hydroxide,
It may be carried out in the presence of a base such as potassium hydroxide, sodium carbonate or sodium hydrogen carbonate.

The amidation reaction of the 1-position carboxy group of the PGF _{2 α} derivative (2) is preferably carried out in the presence of an inert solvent. As the inert solvent, an ether solvent,
A hydrocarbon solvent, a halogen solvent, a polar solvent, or a mixed solvent thereof is preferable, and tetrahydrofuran (TH
F) dimethoxyethane, diethyl ether, toluene,
Xylene, hexane, heptane, methylene chloride, chloroform, dimethylformamide, dimethylsulfoxide, acetone and the like are usually used.

Positions 9 and 1 of the PG derivative (1) of the present invention
Although the above reaction can be carried out without protecting the hydroxyl group at the 1-position, the hydroxyl group is protected by the method described in, for example, "New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (V)" (Maruzen). It is also possible to protect with a group before carrying out the above reaction. Examples of the protective group include a triorganosilyl group, an alkyl group, an aralkyl group, and a monovalent group having a cyclic ether structure. The triorganosilyl group is preferably a group in which three alkyl groups, aryl groups, aralkyl groups or alkoxy groups are bonded to a silicon atom, and particularly preferably a group in which three lower alkyl groups or aryl groups are bonded to a silicon atom. . Specific examples of the protecting group include a tetrahydropyranyl group, a tert-butyldimethylsilyl group,
A tert-butyldiphenylsilyl group, a triethylsilyl group, a triphenylsilyl group, a triisopropylsilyl group or the like is preferable. The protective group for the hydroxyl group can be easily deprotected.

When the PG derivative (1) of the present invention has an acyloxy group at the 9- or 11-position, the PG derivative (1) is highly lipophilic and has physiological activity by hydrolysis in vivo. It can be a useful prodrug that can be converted into a compound.

The compound is preferably produced by acylating the PG derivative (1) having a hydroxyl group at the 9- or 11-position. For the acylation, a method of binding an acyl group to a hydroxyl group can be mentioned. The method is described in "New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (II)" (Maruzen), "4th Edition Experimental Chemistry Course 22 Organic Synthesis IV, Acids, Amino Acids and Peptides" (Maruzen), etc. Can be adopted. Examples of the compound forming the acyl group include carboxylic acid,
Examples thereof include acid anhydrides and carboxylic acid halides.

Since the PG derivative (1) of the present invention has an asymmetric carbon in its structure, it has various stereoisomers and optical isomers. In the present invention, all of these stereoisomers are present. , Optical isomers, and mixtures thereof.

Specific examples of the PG derivative (1) of the present invention include the following compounds.

[Examples of PG Derivative (1) of the Present Invention] Compounds in which A, R ¹ , R ⁴ and R ⁵ in the following formula (1) have the structures shown in Tables 1 to 3 below are mentioned.

[0068]

[Chemical 5]

[0069]

[Table 1]

[0070]

[Table 2]

[0071]

[Table 3]

The PG derivative (1) of the present invention is useful as a medicine, and is used for eye diseases, inflammatory diseases, allergic / immune diseases, digestive system diseases, central nervous system diseases, circulatory system diseases,
It can show excellent effects as a drug such as an analgesic, a therapeutic agent for osteoporosis, and an anticancer agent. Particularly, the PG derivative (1) of the present invention is useful as a drug for eye diseases. Eye diseases include glaucoma, ocular hypertension, retinopathy, conjunctivitis, uveitis, retinitis and the like. As inflammatory diseases, acute hepatitis, chronic hepatitis, cirrhosis, cholecystitis, cholangitis, acute pancreatitis, chronic pancreatitis,
Chronic peritonitis, acute peritonitis, cystitis, acute nephritis, chronic nephritis, encephalitis, polyneuritis, meningitis, myelitis, arthritis, rheumatoid arthritis, bronchitis, pneumonia, peritonitis, phlebitis,
Pericarditis, rhinitis, pharyngitis, otitis media, otitis externa, etc. are included.

The allergic / immune diseases include bronchial asthma, allergic dermatitis, allergic rhinitis, atopy, rheumatism, collagen disease and the like. Digestive system diseases include gastric ulcer, gastritis, duodenal ulcer, ulcerative colitis,
Includes Crohn's disease and the like. Central nervous system diseases include insomnia, anxiety, depression, schizophrenia, dementia and the like. The cardiovascular diseases include peripheral circulatory disorders, Burger's disease, Raynaud's disease, angina, myocardial infarction, heart failure, pulmonary hypertension, pulmonary embolism, diabetes, cerebral infarction, cerebral thrombosis, deafness, Meniel's disease and the like.

[0074]

The present invention will be described in detail below with reference to specific examples, but the present invention is not limited to these examples.

[Example 1] (1S, 5R, 6R, 7R) -2
-Oxa-7-benzoyloxy-6-[(1E) -4
-Phenoxy-3-oxo-1-butenyl] -bicyclo [3.3.0] octane-3-one

Dimethyl 2-oxo-3-phenoxy-propylphosphonate (26.5 g) in THF (260 m)
Lithium chloride (3.39 g) and triethylamine (10.9 mL) were added to the L) solution under ice cooling. After stirring for 15 minutes, (1S, 5R, 6R, 7R) -6-formyl-7-benzoyloxy-2-oxa-bicyclo [3.
3.0] Octane-3-one (18.1 g) in methylene chloride (65 mL) was added. Stir at 0 ° C for 1 hour,
Saturated aqueous solution of ammonium chloride / ethyl acetate = 1
The mixture was poured into a / 1 mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried and concentrated. Silica gel column chromatography (hexane / ethyl acetate = 1 / 3-
Purification by 2/1) gave the title compound (19.8 g).

¹ H-NMR (CDCl ₃ ): δ 2.29
(Ddd, J = 15.6, 4.9, 0.2 Hz, 1
H), 2.45-2.51 (m, 1H), 2.60 (d
t, J = 15.6, 6.6 Hz, 1H), 2.83-
2.95 (m, 3H), 4.67 (s, 2H), 5.0
8 (td, J = 4.6, 1.7 Hz, 1H), 5.31
(M, 1H), 6.60 (dd, J = 15.6, 1.0
Hz, 1H), 6.84-6.87 (m, 2H), 6.
91 (dd, J = 15.6, 7.8 Hz, 1H), 6.
98 (t, J = 7.3 Hz, 1H), 7.25-7.2
9 (m, 2H), 7.44 (t, J = 7.3 Hz, 2
H), 7.58 (dt, J = 7.3, 1.2 Hz, 1
H), 7.97 (dd, J = 8.3, 1.2 Hz, 2
H).

[Example 2] (1S, 5R, 6R, 7R) -2
-Oxa-7-benzoyloxy-6-[(1E)-
3,3-Difluoro-4-phenoxy-1-butenyl]
-Synthesis of bicyclo [3.3.0] octane-3-one

Morpholinosulfatrifluoride (78.4 g) was added to a solution of the enone (19.8 g) synthesized in Example 1 in methylene chloride (150 mL) at 0 ° C. The mixture was stirred at room temperature for 180 hours, poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. Purify by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (1
3.7 g) was obtained.

¹ H-NMR (CDCl ₃ ): δ2.2-
2.9 (m, 6H), 4.17 (t, J = 11.5H
z, 2H), 5.09 (m, 1H), 5.29 (m, 1)
H), 5.89 (dt, J = 15.6, 11.0 Hz,
1H), 6.15 (m, 1H), 6.85 (d, J =
7.8Hz, 2H), 6.99 (t, J = 7.3Hz,
1H), 7.27 (m, 2H), 7.41 (m, 2)
H), 7.55 (t, J = 7.3 Hz, 1H), 7.9
7 (d, J = 7.3 Hz, 2H).

¹⁹ F-NMR (CDCl ₃ ): −104.
0 (m).

[Example 3] (1S, 5R, 6R, 7R) -2
-Oxa-7-hydroxy-6-[(1E) -3,3-
Synthesis of difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octane-3-one

Fluoride synthesized in Example 2 (13.7 g)
Was dissolved in methanol (160 mL), potassium carbonate (2.55 g) was added, and the mixture was stirred at room temperature for 3 hours. The pH was adjusted to 7 with acetic acid, water was added, and the mixture was extracted with ethyl acetate.
Purify by silica gel column chromatography (hexane / ethyl acetate = 1/2 to 2/3) to give the title compound 10.6.
g) was obtained.

¹ H-NMR (CDCl ₃ ): δ2.0-
2.8 (m, 6H), 4.09 (m, 1H), 4.20
(T, J = 11.5 Hz, 2H), 4.94 (m, 1
H), 5.84 (dt, J = 15.6, 11.2 Hz,
1H), 6.07 (m, 1H), 6.91 (d, J =
7.8 Hz, 2 H), 7.02 (t, J = 7.3 Hz,
1H), 7.31 (m, 2H).

¹⁹ F-NMR (CDCl ₃ ): −103.
6 (m).

[Example 4] (1S, 5R, 6R, 7R) -2
-Oxa-3,7-dihydroxy-6-[(1E)-
3,3-Difluoro-4-phenoxy-1-butenyl]
-Synthesis of bicyclo [3.3.0] octane

Synthesized in Example 3 (1S, 5R, 6R, 7
R) -2-Oxa-7-hydroxy-6-[(1E)-
3,3-Difluoro-4-phenoxy-1-butenyl]
-Bicyclo [3.3.0] octan-3-one (10.
6 g) in THF (53 mL) at -78 ° C. in toluene solution of diisobutylaluminum hydride (1 mol / mol).
L, 81 mL) was added and stirred for 30 minutes. Methanol (8 mL) and hydrochloric acid (2 mol / L, 122 mL) were added,
Extraction with ethyl acetate gave a crude product (11.0 g).

¹ H-NMR (CDCl ₃ ): δ1.8-
2.9 (m, 6H), 3.96 (m, 1H), 4.19
(T, J = 11.5 Hz, 2H), 4.60-4.71
(M, 1H), 5.56-5.65 (m, 1H), 5.
82 (m, 1H), 6.11 (m, 1H), 6.91
(D, J = 8.3 Hz, 2H), 7.00 (m, 1
H), 7.30 (t, J = 7.8Hz, 2H).

¹⁹ F-NMR (CDCl ₃ ): −103
(M).

Example 5 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20
-Synthesis of tetranor PGF _{2 α} isopropyl ester

4-Carboxybutyltriphenylphosphonium bromide (60.0 g) in THF (220 mL)
A THF solution of sodium bis (trimethylsilyl) amide (1 mol / L, 270 mL) was added to the suspension, and the mixture was stirred at room temperature for 1 hour. The lactol synthesized in Example 4 (11.
A solution of 0 g) in THF (44 mL) was added at 0 ° C., and the mixture was stirred for 3 hours. The reaction was stopped by adding cold water, the mixture was washed with ethyl acetate, the aqueous layer was acidified, and the mixture was extracted with ethyl acetate.
Purified by silica gel column chromatography (hexane / ethyl acetate = 2/3 to 1/3), and carboxylic acid (7.5
9 g) was obtained.

A solution of the synthesized carboxylic acid (7.59 g) in acetone (38 mL) was added at 0 ° C. to 1,8-diazabicyclo [5.4.0] undec-7-ene (10.2 m).
L) and 2-iodopropane (9.3 mL) were added, and the mixture was heated to 30 ° C. and stirred for 18 hours. The reaction solution was diluted with ethyl acetate, washed with a 5% aqueous citric acid solution and an aqueous sodium hydrogen carbonate solution, and subjected to silica gel column chromatography (hexane /
Purify with ethyl acetate = 2/3) to give the title compound (4.77).
g) was obtained.

¹ H-NMR (CDCl ₃ ): δ1.22
(D, J = 6.4 Hz, 6 H), 1.59 (m, 1
H), 1.66 (m, 2H), 1.83 (m, 1H),
2.0-2.4 (m, 7H), 2.47 (m, 1H),
4.02 (m, 1H), 4.19 (t, J = 11.5H
z, 2H), 4.19 (m, 1H), 4.99 (m, 1)
H), 5.38 (m, 2H), 5.80 (dt, J = 1)
5.6, 11.2Hz, 1H), 6.10 (m, 1
H), 6.91 (d, J = 8.2 Hz, 2H), 6.9.
6 (m, 1H), 7.25 (m, 2H).

¹⁹ F-NMR (CDCl ₃ ): −103.
2 (m).

Example 6 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20
-Synthesis of tetranor PGF _{2 α} methyl ester

In the same manner as in Example 5, the above carboxylic acid was methyl-esterified to synthesize the title compound (1.0 g).

¹ H-NMR (CDCl ₃ ): δ1.60
(M, 1H), 1.67 (m, 2H), 1.84 (m,
1H), 2.0-2.4 (m, 8H), 2.47 (m,
1H), 3.66 (s, 3H), 4.02 (m, 1
H), 4.20 (t, J = 12.0 Hz, 2H), 4.
20 (m, 1H), 5.38 (m, 2H), 5.80
(Dt, J = 16.4, 10.8 Hz, 1H), 6.1
0 (m, 1H), 6.91 (m, 2H), 7.00
(M, 1H), 7.30 (m, 2H).

¹⁹ F-NMR (CDCl ₃ ): −103.
7 (m).

Example 7 9,11-O-bis (tetrahydropyran-2-yl) -16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,2
Synthesis of 0-tetranor PGF _{2 α} methyl ester

16-phenoxy-15-synthesized in Example 6
Deoxy-15,15-difluoro-17,18,1
9,20-Tetranor PGF _{2 α} methyl ester (1.
0 g) was dissolved in methylene chloride (10 mL), and 3,4-
Dihydro-2H-pyran (1.11 mL) and pyridinium p-toluenesulfonate (61.3 mg) were added, and the mixture was stirred at room temperature for 1 hr. The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.237 g).

¹ H-NMR (CDCl ₃ ): δ1.3-
2.7 (m, 24H), 3.38 (m, 1H), 3.4
6 (m, 1H), 3.64 (s, 3H), 3.70-
4.05 (m, 4H), 4.10 (m, 1H), 4.1
6 (m, 1H), 4.55-4.70 (m, 2H),
5.32-5.40 (m, 2H), 5.82 (m, 1
H), 6.10 (m, 1H), 6.91 (m, 2H),
7.00 (m, 1H), 7.30 (m, 2H).

¹⁹ F-NMR (CDCl ₃ ): −103.
2 (m).

Example 8 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20
-Synthesis of tetranor PGF _{2 α} (2-hydroxyethyl) carboxamide (Compound A)

The methyl ester prepared in Example 7 (237 m
Toluene (3 mL), ethanolamine (0.5 g)
(mL) and heated under reflux for 36 hours. Saturated saline was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (chloroform / methanol 20: 1) to obtain the corresponding ethanolamide (206 mg). This was dissolved in methanol (3 mL), p-toluenesulfonic acid (10 mg) was added, and the mixture was stirred at room temperature for 1.5 hr. Methanol was concentrated under reduced pressure, and silica gel column chromatography (chloroform / methanol 20: 1 to 10:
Purified in 1), the title compound (88 mg) was synthesized.

¹ H-NMR (CDCl ₃ ): δ1.50-
1.80 (m, 4H), 2.00 (m, 2H), 2.1
5 (m, 4H), 2.32 (m, 1H), 2.43
(M, 1H), 3.33 (m, 2H), 3.63 (s,
3H), 3.88 (s, 2H), 3.98 (s, 1
H), 4.12 (s, 1H), 4.16 (t, J = 1)
2.0 Hz, 2H), 5.33 (m, 2H), 5.76
(Dt, J = 15.8, 11.2 Hz, 1H), 6.0
8 (m, 1H), 6.72 (s, 1H), 6.89
(M, 2H), 6.97 (m, 1H), 7.27 (m,
2H).

¹⁹ F-NMR (CDCl ₃ ): −103.
0 (m).

Example 9 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20
-Synthesis of tetranor PGF _{2 α} (2-methoxyethyl) carboxamide (Compound B)

Methanol (4 mL) and 2N NaOH (2 mL) were added to the methyl ester (1 g) synthesized in Example 7, and the mixture was stirred at room temperature for 10 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with chloroform and ethyl acetate. After drying over magnesium sulfate, concentration under reduced pressure and carboxylic acid (9,11-O-bis (tetrahydropyran-2-yl) -16-phenoxy-15-deoxy-15,15-difluoro-17,
18,19,20-Tetranor PGF _{2 α} ) (912 m
g) was obtained.

To this carboxylic acid (231 mg) was added toluene (5 mL) and N, N-dimethylformamide (31 μm).
L) and oxalic acid chloride (698 μL) were added under ice cooling. Next, 2-methoxyethylamine (348 μL) was added, and the mixture was stirred at 0 ° C. for 2 hr and then poured into saturated aqueous sodium hydrogen carbonate.
The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography (chloroform / methanol = 20
/ 1) to give the corresponding amide (329 mg). This was dissolved in methanol (3 mL), p-toluenesulfonic acid (10 mg) was added, and the mixture was stirred at room temperature for 2 hours. It was poured into saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (chloroform / methanol = 50 / 1-20 / 1) to synthesize the title compound (113 mg).

¹ H-NMR (CDCl ₃ ): δ1.51
(M, 1H), 1.63 (m, 2H), 1.78 (d,
J = 14.6 Hz, 1H), 1.90-2.15 (m,
6H), 2.32 (m, 1H), 2.44 (m, 1
H), 3.30 (s, 3H), 3.37 (m, 4H),
3.59 (d, J = 5.3 Hz, 1H), 3.63
(D, J = 7.0 Hz, 1H), 3.98 (m, 1
H), 4.12 (m, 1H), 4.15 (t, J = 1)
1.7 Hz, 2H), 5.33 (m, 2H), 5.76
(Dt, J = 15.8, 11.3 Hz, 1H), 6.0
8 (m, 1H), 6.24 (s, 1H), 6.87
(D, J = 7.9 Hz, 2H), 6.95 (t, J =
7.3 Hz, 1 H), 7.25 (t, J = 8.0 Hz,
2H).

¹⁹ F-NMR (CDCl ₃ ): −103.
1 (m).

[Example 10] 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,2
Synthesis of 0-tetranor PGF _{2 α} (ethoxycarbonylmethyl) carboxamide (Compound C)

9,11-O-bis (tetrahydropyran-2-yl) -16-phenoxy-15 synthesized in Example 9
-Deoxy-15,15-difluoro-17,18,1
Toluene (5 mL) and N, N-dimethylformamide (31) were added to 9,20-tetranor PGF _{2 α} (231 mg).
μL) and oxalic acid chloride (698 μL) were added under ice cooling. Next, triethylamine (558 μL) and glycine ethyl ester hydrochloride (558 mg) were added, and the mixture was stirred at 0 ° C. for 2 hours.
After stirring for an hour, the mixture was poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (chloroform / methanol = 20/1) gave the corresponding amide (268 mg). This was dissolved in methanol (3 mL), p-toluenesulfonic acid (10 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. It was poured into saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (chloroform / methanol = 50 / 1-40 / 1) to synthesize the title compound (73 mg).

¹ H-NMR (CDCl ₃ ): δ1.25
(T, J = 7.0 Hz, 3H), 1.55 (m, 1
H), 1.66 (m, 2H), 1.80 (d, J = 1)
5.0 Hz, 1H), 1.95-2.25 (m, 6
H), 2.34 (m, 1H), 2.45 (m, 1H),
3.21 (br s, 2H), 3.97 (d, J = 5.
3Hz, 1H), 4.00 (m, 1H), 4.13
(D, J = 3.2 Hz, 1H), 4.17 (t, J = 1
1.7 Hz, 2 H), 4.18 (q, J = 7.0 Hz,
2H), 5.35 (m, 2H), 5.77 (dt, J =
15.8, 11.3Hz, 1H), 6.08 (m, 1
H), 6.31 (s, 1H), 6.89 (d, J = 7.
9Hz, 2H), 6.95 (t, J = 7.3Hz, 1
H), 7.25 (t, J = 7.9 Hz, 2H).

¹⁹ F-NMR (CDCl ₃ ): −103.
1 (m).

[Example 11 (Formulation example)] A typical formulation example of eye drops and eye ointment using the PG derivative (1) of the present invention is shown.

[0117]   1) Eye drops in 100 mL     10 mg of the PG derivative (1) of the present invention     Concentrated glycerin 2500mg     Polysorbate 80 2000mg     Sodium dihydrogen phosphate dihydrate 200 mg     Sterile purified water     1N hydrochloric acid or 1N sodium hydroxide suitable amount     pH 6.0

In the above formulation, by changing the amount of the PG derivative (1) of the present invention and appropriately increasing or decreasing the amount of the additive, 0.00005% (w / v) ophthalmic solution, 0.0001
% (W / v) eye drop, 0.001% (w / v) eye drop,
0.005% (w / v) eye drop, 0.05% (w / v)
An eye drop and a 0.1% (w / v) eye drop can be prepared.

[0119]   2) 100 g of eye ointment     0.1 g of the PG derivative (1) of the present invention     Liquid paraffin 20.0g     White petrolatum 77.9g     Purified lanolin 2.0g

[Example 12 (Pharmacological test)] In order to find the usefulness of the PG derivative (1) of the present invention as a medicine for eye diseases, the influence on the intraocular pressure was examined.

1) Effect on intraocular pressure As an example of examining the effect of tromethamine salt or isopropyl ester of PGF _{2 α} on intraocular pressure, a method using a cynomolgus monkey is known (Exp. Eye Res., 61, 677-
683 (1995)). Therefore, the effect of the PG derivative (1) of the present invention (hereinafter, referred to as a test compound) on the intraocular pressure was examined in a single eye drop test according to the method described in the above literature.

(A) Single Eye Drop Test (Experimental Method) Male cynomolgus monkeys having a body weight of 5.6 to 7.7 kg (5 to 7 years old) were used in the experiment, and the test compound was administered immediately before and 8 hours after the administration. Each intraocular pressure was measured. In addition, the intraocular pressure was measured using an applanation tonometer without anesthesia.

(Preparation of eye drops) A physiological saline solution of the test compound (using polysorbate 80 as a solubilizing agent)
0.03% (w / v) was used as an eye drop. Further, a solution containing only the base material containing no test compound was used as a control.

(Results) Table 4 shows, as an example of the experimental results, 0.03% (w / w) of compound A, compound B or compound C.
v) Maximum intraocular pressure drop width when 20 μl of eye drops was applied to one eye (the minimum value of the intraocular pressure after instillation was extracted for each individual regardless of the measurement time, and this minimum intraocular pressure value was calculated from the initial intraocular pressure value. The value obtained by subtracting The test result is an average value of 2 cases. However, in the numerical unit in Table 4, 1 mmH
g = 133.322 Pa.

[0125]

[Table 4]

[0126]

INDUSTRIAL APPLICABILITY The present invention provides a PG derivative which is useful as a medicine and which has a carboxy group at the 1-position amidated and has two fluorine atoms at the 15-position. The PG derivative (1) of the present invention is a compound that can be easily produced by applying a known production method.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 25/00 A61P 25/00 27/00 27/00 27/06 27/06 29/00 29/00 35 / 00 35/00 37/00 37/00 37/08 37/08 (72) Inventor Nobuaki Miyawaki 3-9-19 Shimoshinjo, Higashiyodogawa-ku, Osaka City, Osaka Prefecture Santen Pharmaceutical Co., Ltd. (72) Inventor, Matsuo Yu Osaka 3-9-19 Shimoshinjo, Higashiyodogawa-ku, Osaka, Japan Santen Pharmaceutical Co., Ltd. (72) Inventor Atsushi Shimazaki F-term (3) 19-3, Shitenshinjo, Shimoshinjo-ku, Osaka-shi, Osaka, Osaka (Reference) 4C086 AA01 AA02 AA03 DA02 MA01 MA02 MA07 MA28 MA58 NA14 ZA02 ZA33 ZA36 ZA66 ZA97 ZB11 ZB13 ZB26 4H006 AA01 AA03 AB27 UE14 UE51

Claims (10)

[Claims] 1. 15-deoxy-1 represented by the following formula (1):
5,15-Difluoroprostaglandin derivative. [Chemical 1] However, the symbols in the formula (1) have the following meanings. A: ethylene group, vinylene group, ethynylene group, -OCH
₂ - or -SCH ₂ -. _{X: -CH 2 -, - O-} , or -S-. R ¹ : a linear alkyl group having 3 to 8 carbon atoms, a linear alkenyl group having 3 to 8 carbon atoms, a linear alkynyl group having 3 to 8 carbon atoms,
A group selected from a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group, and an aryloxyalkyl group, or a group in which one or more hydrogen atoms in the selected group are substituted. R ² and R ³ : each independently a hydrogen atom or 1 carbon atom
~ 20 acyl groups. R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, an aralkyl group, or a hydroxyl group, an alkoxy group, a carboxy group and an alkoxy. An alkyl group having 1 to 6 carbon atoms which may be substituted with a group selected from a carbonyl group. Overlap of solid and dashed lines: single bond, cis double bond, or trans double bond. 2. The prostaglandin derivative according to claim 1, wherein A is an ethylene group or a vinylene group. 3. The prostaglandin derivative according to claim 1, wherein X is —CH ₂ —. 4. The prostaglandin derivative according to claim 1, wherein R ² is a hydrogen atom. 5. The prostaglandin derivative according to claim 1, wherein R ⁴ is a hydrogen atom. 6. The prostaglandin derivative according to claim 1, wherein R ¹ is an aryloxyalkyl group or a group in which one or more hydrogen atoms in the aryloxyalkyl group are substituted. 7. The prostaglandin derivative according to claim 1, wherein R ¹ is a phenoxymethyl group, a 3,5-dichlorophenoxymethyl group or a 3-chlorophenoxymethyl group. 8. A medicament containing the prostaglandin derivative according to any one of claims 1 to 7 as an active ingredient. 9. A medicament for preventing or treating an eye disease, which comprises the prostaglandin derivative according to any one of claims 1 to 8 as an active ingredient. 10. The medicine according to claim 9, wherein the eye disease is glaucoma or ocular hypertension.