WO2001055102A1 - Novel difluoroprostaglandin derivative - Google Patents

Abstract

A compound represented by the following formula (1); and a medicine containing the compound as the active ingredient. In the formula, A is an ethylene or vinylene group, etc.; X is -CH2-, etc.; P and Q each is -CO- or -CH(OR2)- (R2 is hydrogen, etc.); R1 is C¿3-8? linear alkyl, etc.; R?3¿ is hydrogen, acyl, etc.; R?4 and R5¿ each is hydrogen, etc.; and the double line composed of a solid line and a broken line indicates a single bond or a cis or trans double bond. (1)

Description

 Description New difluoroprostaglandin derivative

 <Technical field>

 The present invention relates to a 15-dexoxy-15,15-difluoroprostaglandin derivative in which the carboxy group at the 1-position is a hydroxyl group or a group derived from a hydroxyl group. And a medicament containing the prostaglandin derivative as an active ingredient, particularly a medicament for preventing or treating ocular diseases.

<Background technology>

 Natural prostaglandins (hereinafter, prostaglandins are referred to as PG) are a group of physiologically active substances synthesized in the body, and regulate local cell functions of various tissues in living organisms as local hormones having various physiological activities. ing. Among them, PGEs, which are a kind of natural PG, have various effects related to pain and inflammation in addition to vasodilatory effect, bronchodilator effect, gastric acid secretion inhibitory effect, gastric mucosal protective effect, uterine contractile effect, etc. Since it has it, it is used as a blood flow improving agent, a gastric ulcer treatment agent, a labor-inducing agent and the like.

 In addition, PGFs are used as a birth inducer, an agent for treating glaucoma, an agent for regulating estrous cycle of livestock, and the like. In addition, PGDs are said to be involved in various actions related to allergy, immune response, and inflammation, in addition to central nervous action, sleep-inducing action, platelet aggregation inhibitory action, and the like. In addition, these PGs have the potential to be applied to anticancer drugs, osteoporosis drugs, analgesics, drugs for central nervous system inflammation, etc.Therefore, the development potential of PG derivatives with higher effects and fewer side effects is being studied. .

The following reports have been reported on 15-dexoxy-15-fluoro PGs having one fluorine atom at the 15-position of PG having a natural skeleton. That is, 1 5-de Okishi -.. 15 by B EZG 1 o V et al for Furuoro PGA _2, 1 5-de Okishi one 1 5 Furuoro for P GB ₂ is B ioor g K hi m, 5 (1 0), 1531-1 536, 1979, etc., 15-Deoxy 15-Fluoro P GF _2a, 15 Dokishi - 15 Furuoro PGE _2, and 1 5 Dokishi -.. 1 5 For Furuoro _{PG 1 2, Do kl Ak a} d N auk SSSR, 250 (2), 468 -469, 1980 Etc. are reported.

As an example of a PG having two fluorine atoms at the 15-position of the PG skeleton, an example of the synthesis of 13,14-dihydro_15-deoxy-1,15,15-difluoro-20-methyl-PGE, methyl ester is described. (JP-A-7-70054). Further, there is a report on 15-doxy 15,15-difluoro PGF _2a (Japanese Patent Laid-Open No. 11-071 344). 15-Doxy-15,15-difluoro PGF _2a is described as a therapeutic agent for glaucoma or ocular hypertension, which has a high intraocular pressure-lowering effect and low side effects.

On the other hand, it was reduced at the 1-position carboxy group of PG, 2-hydroxymethyl - there is a report of a method for manufacturing the P GF _2a compound (JP-A 7-165703, JP-A-10 1 82 465). In addition, it has been described that 2-hydroxymethyl-PGF _2a and its ether form have a higher intraocular pressure lowering effect than the parent compound (Japanese Patent Application Laid-Open Nos. 5-507928 and 6-503346).

 There is also a report on PGs in which the carboxy group at the 1-position is reduced and has one fluorine atom at the 15-position (W098Z21 181), but the production method and physiological activity are not described.

 However, for PGs in which the carboxy group at the 1-position is reduced and two fluorine atoms at the 15-position, no synthesis examples, physical properties, physiological activities, etc. have been reported, and eye diseases, especially glaucoma Nor is it known about the effects of preventing or treating ocular hypertension.

<Disclosure of Invention>

The present inventors have synthesized novel PGs in order to impart the unique properties possessed by the fluorine atom to PGs, and studied to clarify their physical properties and physiological activities. As a result, the carboxy group at position 1 of the prostanoic acid skeleton is reduced, and A new 15-dexoxy 15,5-difluoro PG derivative, in which two fluorine atoms are bonded to an elemental atom, has excellent physical properties and physiological activities. In addition, it is used in medicine, especially glaucoma and ocular hypertension. It has been found that the compound is an excellent compound as a prophylactic or therapeutic agent for eye diseases such as.

In particular, the 15-doxy-1,5,15-difluoro PG derivative of the present invention in which the carboxy group at the 1-position has become —C (OR ³ ) R ⁴ R ⁵ has the same carbon skeleton as that of the 15-doxy mono PG derivative. It has been found that it has higher lipophilicity and better absorbability to the living body than the 15,5-difluoro PG derivative.

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

However, the symbols in the formula have the following meanings.

A: Ethylene group, vinylene group, ethinylene group, 100 CH ₂ —, or 1 SCH ₂ X: — CH ₂ —, — O—, or — S—.

P, Q: each independently —CO—, -CH (OR ² )-(R ² is each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 1 to 20 carbon atoms. ), Or one CH ₂ —. However, P and Q do not become one CO at the same time <

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 cycloalkyl group having 3 to 8 carbon atoms, an alkyl group, And a group selected from aryloxyalkyl groups, or a group in which one or more hydrogen atoms in the selected groups are substituted.

R ³ : hydrogen atom, alkyl group, alkenyl group, alkynyl group, having 3 to 8 carbon atoms A group selected from a cycloalkyl group, an aryl group, an aralkyl group, and an acyl group, or a group in which one or more hydrogen atoms in the selected group are substituted.

R ⁴ and R ⁵ each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, Aryl group or aralkyl group.

 Overlap between solid and dashed lines: single bond, cis double bond, or trans double bond.

<Best mode for carrying out the invention>

 In the nomenclature of the compound in the present specification, a number corresponding to a number in the prostanoic acid skeleton is used as a number indicating a position in the PG skeleton. In this specification, a group in which a hydrogen atom of an alkyl group has been substituted is also referred to as a substituted alkyl group. The same applies to other groups. The “lower group” means a group having 6 or less carbon atoms. The carbon number of the lower group is preferably 4 or less.

 An “alkyl group” may be straight-chain 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, and a hexyl group.

 An “alkenyl group” may be straight-chain or branched. The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms unless otherwise specified. Examples of the alkenyl group include a vinyl group, an aryl group, a 1-propenyl group, an isopropyl group, a 3-butenyl group, a 3-pentenyl group, and a 4-hexenyl group.

 An “alkynyl group” may be straight-chain or branched. The alkynyl group is preferably a lower alkynyl group having 2 to 6 carbon atoms unless otherwise specified. Examples of the alkynyl group include a 1-propynyl group, a 2-propynyl group, a 3-butynyl group, a 3-pentynyl group, and a 4-hexynyl group.

An “alkoxy group” may be straight-chain or branched. An alkoxy group is A lower alkoxy group having 1 to 6 carbon atoms is preferred, and an alkoxy group having 1 to 4 carbon atoms is particularly preferred. Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.

 “Halogen atom” refers to a fluorine, chlorine, bromine, or iodine atom.

“Aryl group” refers to a monovalent aromatic hydrocarbon group, and a phenyl group is preferred. As the _t- substituted araryl group, one or more hydrogen atoms in the aryl group are a lower alkyl group, a halogen atom, or a halogen atom. A group substituted with a substituted (lower alkyl) group, a lower alkoxy group, or a (lower alkyl) amino group is preferred. The substituted aryl group is preferably a substituted phenyl group, particularly a monohalophenyl group (for example, chlorophenyl group, fluorophenyl group, bromophenyl group, etc.), a dihalophenyl group (for example, dichlorophenyl group, difluorophenyl group, dibromophenyl group, etc.). , Trihalophenyl group (for example, trichlorophenyl group, trifluorophenyl group, tribromophenyl group, etc.), (lower alkyl halide) phenyl group (for example, trifluoromethylphenyl group, etc.), (lower alkoxy) phenyl group (Eg, methoxyphenyl, ethoxyphenyl, etc.), di (lower alkoxy) phenyl (eg, dimethoxyphenyl, diethoxyphenyl, etc.), tri (lower alkoxy) phenyl (eg, trimethoxyphenyl) Group, triethoxy phenylene Le group), mono (lower alkyl) phenyl group (e.g., tolyl group, etc.) and the like arbitrarily.

 “Aralkyl group” refers to an alkyl group substituted with an aryl group. As the aryl group, a phenyl group is preferred. The alkyl group 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, and a phenylethyl group.

The “cycloalkyl group” refers to a cyclic alkyl group having three or more members, and is preferably a 3- to 8-membered cycloalkyl group. As the substituent in the substituted cycloalkyl group, low Lower alkyl groups, halogen atoms, lower alkoxy groups and the like. 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, and dimethylcyclohexyl. Group, chlorocyclyl hexyl group, or dichlorocyclohexyl group.

 “Halogenated alkyl group” refers to a group in which at least one hydrogen atom in the alkyl group has been replaced by 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, and a bromomethyl group. No.

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

 As the 15-dexoxy15,15-difluoro PG derivative represented by the formula (1) (hereinafter, also referred to as the PG derivative (1) of the present invention), the following compounds are considered from the viewpoint of physiological activity and physical properties. preferable.

That is, A is preferably a vinylene group or an ethylene group. The vinylene group may be in a cis form or a trans form, and a trans vinylene group is particularly preferable. When A is —OCH ₂ — or SCH ₂ —, the direction of the bond is not particularly limited, and the bond is preferably bonded to the ring by an oxygen atom or a sulfur atom. X is preferably —CH ₂ —. The overlap between the solid line and the broken line is preferably a cis double bond.

R ¹ is a straight-chain alkyl group having 3 to 8 carbon atoms, a group in which a hydrogen atom in the straight-chain alkyl group having 3 to 8 carbon atoms is substituted (hereinafter referred to as “substituted (straight-chain alkyl group having 3 to 8 carbon atoms)” No Write down. The same applies to other groups. ), A linear alkenyl group having 3 to 8 carbon atoms, a substituted (linear alkynyl group having 3 to 8 carbon atoms), a linear alkynyl group having 3 to 8 carbon atoms, or substituted (linear alkynyl group having 3 to 8 carbon atoms) ) Group (hereinafter collectively referred to as these groups

(R ¹⁾ and also referred to as. ), The linear alkyl group, the linear alkenyl group, and the linear alkynyl group each preferably have 5 to 6 carbon atoms.

When a substituent is present in the group (r ′), a methyl group is preferred, and the number of substituted methyl groups is preferably one or two. The group (Γ ') is preferably an η-pentyl group, a 2-methylhexyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, or a 1,1-dimethyl-3-hexynyl group. . When the group (r ¹ ) has a substituent other than a methyl group, the substituent is preferably a cycloalkyl group. For example, examples of the group (Γ ′) substituted by a cycloalkyl group include a cycloalkyl-substituted (C 3-8 straight-chain alkyl) group, a cycloalkyl group-substituted (C 3-8 straight-chain alkenyl) group, and the like. . As the cycloalkyl group as the substituent, a cyclopentyl group or a cyclohexyl group is preferable.

R ¹ is a cycloalkyl group having 3 to 8 carbon atoms, substituted (3 to 8 carbon atoms) cycloalkyl group, aralkyl group, substituted aralkyl group, aryloxyalkyl group, substitution (aryloxyalkyl) ) is a group also referred to as (collectively these groups groups (r ^2).

), The ring structure in the group (r ² ) is substituted with an alkyl group having 1 to 6 carbon atoms, a halogen atom, an oxygen atom-containing substituent, a sulfur atom-containing substituent, or a nitrogen atom-containing substituent. It is preferable that the alkyl group or the halogen atom having 1 to 3 carbon atoms is substituted. As the group (r ² ), an aryloxyalkyl group and a substituted (aryloxyalkyl) group are preferred.

Here, when the group (r ² ) is a cycloalkyl group having 3 to 8 carbon atoms, a cyclopentyl group or a cyclohexyl group is preferable, and when the group is a substituted (3 to 8 carbon atoms) cycloalkyl group, A C 3 -C 8 substituted with one or more lower alkyl groups. A cycloalkyl group is preferred, and a cyclopentyl group substituted with an alkyl group having 1 to 4 carbon atoms, and a cyclohexyl group substituted with an alkyl group having 1 to 4 carbon atoms are preferred. Here, 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, and a hydroxyl group. The number of carbon atoms in the alkylene group in the aralkyl group and the substituted alkyl group is preferably 1 to 4. As the aralkyl group, a benzyl group and a phenylethyl group are preferable. As the substituted aralkyl group, a phenyl group in a benzyl group or a phenylethyl group is preferably a methyl group, a ethyl group, or a group substituted with a halogen atom.

When the group (r ² ) is an aralkyl group or a substituted aralkyl group, specific examples include a benzyl group, a 2-phenylethyl group, a 3-methylphenylmethyl group, and a 2- (3-methylphenyl) ethyl group , 3-trifluoromethylphenylmethyl, 2- (3-trifluoromethylphenyl) ethyl, 3-chlorophenylmethyl, 2- (3-chlorophenyl) ethyl, 2- (3 , 5-dichloromouth phenyl) group or 2- (3,4-dichlorophenyl) ethyl group. When the group (r ² ) is an aryloxyalkyl group, an aryloxyalkyl group having a benzene ring is preferred, and a phenyloxyalkyl group is particularly preferred. When the group (r ² ) is a substituted aryloxyalkyl group, the hydrogen atom of the aryl group is preferably substituted with a halogen atom, a halogenated alkyl group, an alkoxy group, or a hydroxyl group. The alkyl group moiety in the aryloxyalkyl group and the substituted aryloxyalkyl group preferably has 1 to 3 carbon atoms.

 Further, as the substituted aryloxyalkyl group, a phenoxyalkyl group substituted with 1 to 3 halogen atoms or a phenyloxy group alkyl group substituted with 1 to 3 halogenated alkoxy groups is preferable.

Examples of the aryloxyalkyl group or the substituted aryloxyalkyl group include phenoxymethyl, 3-chlorophenoxymethyl, and 3-fluorophenoxy. Methyl group, 3-trifluoromethylphenoxymethyl group, 3,5-dichlorophenoxymethyl group, 3,4-dichlorophenoxymethyl group, 3,5-difluorophenoxymethyl group, 3,4-difluorophenyl Enoxymethyl group, 3,5-bis (trifluoromethyl) phenoxymethyl group, or 3,4-bis (trifluoromethyl) phenoxymethyl group, etc .; phenoxymethyl group, 3-chlorophenoxymethyl group, 3,5-dichloro A phenoxymethyl group or a 3,4-dichlorophenoxymethyl group is particularly preferred.

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

P and Q are each independently —CO—, —CH (OR ² ) —, or —CH ₂ —. Here, R ² is each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 1 to 20 carbon atoms, and is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. When R ² is an alkyl group having 1 to 6 carbon atoms, the group is preferably a linear group, and particularly preferably a methyl group or an ethyl group. The PG derivative (1) of the present invention in which R ² is an acyl group having 1 to 20 carbon atoms is useful as a prodrug because it can be converted into a physiologically active compound by hydrolysis in a living body. In particular, when R ² is an acyl group having an alkyl group having 4 to 18 carbon atoms, the PG derivative (1) of the present invention is useful as a prodrug having improved lipophilicity, and is preferable.

 As the PG derivative (1) of the present invention, as the PG skeleton (the PG skeleton is a skeleton based on prostanoic acid) in the compound, a compound having a basic skeleton of PGF is preferable. That is, the PG derivative (1) of the present invention is preferably a 15-doxy-15,15-difluoro PGF derivative.

R ³ is a group selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group, an aralkyl group, and an acyl group, or a hydrogen atom in the selected group. At least one is a substituted group.

When an alkyl group moiety is present in R ³ , the moiety may be straight-chain or branched. There may be. The alkyl group preferably has 1 to 6 carbon atoms. When R ³ is a substituted group, the substituent exemplified for R ¹ is preferable.

As R ³ , a hydrogen atom, an alkyl group, or an alkylcarbonyl group is preferable, and particularly, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms is preferable. In particular, the PG derivative (1) in which R ³ is an alkylruponyl group is useful as a prodrug because it can be converted to PG having bioactivity by hydrolysis in vivo. When R ³ is an alkylcarbonyl group, the type of the alkyl group can be selected to control the lipophilicity of the compound.

R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms , An aryl group, or an aralkyl group, and R ⁴ and R ⁵ are preferably a hydrogen atom. -The PG derivative (1) of the present invention is a compound obtained by reducing a 1-carboxy group or a 1-ester group of a 15-doxy-1,15-difluoro PG having the same basic skeleton to form a first alcohol (for example, It is preferable to use the following PGF _2a ) as a raw material.

Among these 15-deoxy-15,15-difluoro PGs, those having a carbon skeleton similar to that of the natural type can be produced by referring to a general PG production method. In other words, starting from a Co lactone lactone as a starting material, an ω chain is introduced into the lactone, and the obtained ketones (3) are subjected to a fluorination reaction to form carbon atoms corresponding to the 15-position. It is converted to lactones (4) with an introduced ω chain to which two fluorine atoms are bonded. Next, after reducing the lactones (4) to the lactols (5), an α chain is introduced by a Wittig reaction with a phosphorane (6) synthesized from a phosphonium salt (7), and if necessary, a hydroxyl group is Deprotect or acylate, PGF _2a derivative

 Obtain (2).

However, scale ¹ in the formula, R ^2, A, and X are the same meaning as the meaning in formula (1) Z represents a hydroxyl group or an alkoxy group having 1 to 20 carbon atoms. Y represents a hydrogen atom or a logen 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. Compounds in which Z is a hydroxyl group (phosphoranes (6), phosphonium salts (7), PGF ₂ „derivatives (2)) may form a salt with a base. Alkali metal salts such as salts and potassium salts; alkaline earth metal salts such as potassium salts and magnesium salts; and ammonium salts such as ammonium salts and N-alkyl-substituted ammonium salts.

(Me 3 coz (6)

 H

Y—

COZ (7) The PGF _2a derivative (2) having an unnatural skeleton can be synthesized with reference to the method described in JP-A-11-07344. For example, keto with the desired ω chain The lactones (3) are subjected to a fluorination reaction to produce lactones (4) with an ω chain having two fluorine atoms at the 15-position, and then the lactones (4) are reduced to lactols ( The PGF _2a derivative (2) can be obtained by converting the lactol (5) with a phosphorane (6) to introduce a heavy chain unit. Phosphoranes (6) are obtained from phosphonium salts (7).

 The configurations of formulas (2) to (7) may be different from the PG derivatives (formula (la) and formula (1b)). Also, the configuration of the substituent bonded to the cyclopentane ring in the 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 ′ has a specific substituent are known ketones

It can be manufactured by the same method as (3). For example, a novel ketone (3) can be produced by reacting a dialkyl 3-substituted 1-2-oxopropyl phosphonate with a colilactone having a formyl group.

 Various known fluorination methods can be applied to carry out the fluorination reaction of the ketones (3) to the lactones (4). For example, a method of reacting in an inert solvent using various nucleophilic fluorinating agents is employed.

When the ketone (3) has a functional group that can be fluorinated during the fluorination reaction, it is preferable that the functional group be protected in advance by a protecting group. For example, when R ² is a hydrogen atom, it is preferable to protect with a protecting group, fluorinate the carbonyl group at the 15-position, and then perform deprotection. When the hydroxyl group at position 11 in ketones (3) is protected with an acyl group, R ² of the final compound may be used without deprotection, and after deprotection, new R ² may be introduced. Is also good.

The method for deprotection of the protected hydroxyl group can be a conventional method. For example, "New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I), (11), (V)" (Maruzen), "Protective Z Groups / Innoorganic Synthesis" (TW Greene, J.W. ile y & S on s). In the fluorination reaction of ketones (3), it is preferable to use a fluorinating agent. H As the fluorinating agent, a known or well-known nucleophilic fluorinating agent can be used. For example, there are nucleophilic fluorinating agents described in "Chemistry of Fluorine" by Tomoya Kitazume, Takashi Ishihara, and Takeo Taguchi (Kodansha Scientifits). Also, in order to increase the reactivity of the fluorinating agent and suppress side reactions, the carbonyl group at the 15-position of ketones (3) is reacted with an oxime, hydrazone, thioacetal, or diazo compound. A fluorinating agent may act. For example, the method of Olah et al. (Syn 1 et 1990, 594, Syn let t., 1994, 425), the method of Kat Ka enelle nb og en et al. (J. Org. Chem., 51, 3508 (1986)), the method of Hiyama et al. (Syn lett., 1991, 909), and the method of Fujisawa et al. U. 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 a halogen-based solvent, an ether-based solvent, a hydrocarbon-based solvent, an ester-based solvent, a polar solvent, and a mixed solvent thereof.

 The lactones (4) obtained by the fluorination reaction are then reduced to ease! Le

(5). The lactones (4) are preferably reduced by a method in which a reducing agent is allowed to act in an inert solvent. For example, "New Experimental Chemistry Lecture 15 Oxidation and Reduction (II)" (Maruzen), "4th Edition Experimental Chemistry Lecture 26 Organic Synthesis VIII, Asymmetric Synthesis, Reduction, Sugar, Labeled Compounds" (Maruzen) Method can be used.

 Various hydrides are preferable as the reducing agent used for the reduction of lactones and (4). Examples include hydrides of metal containing silicon, metal hydride complex compounds, borohydride compounds, diisobutylaluminum hydride [DI BAH], sodium bis (2-methoxyethoxy) aluminum hydride, etc. Is preferred. Lactones

Examples of the inert solvent used for the reduction in (4) include an ether solvent, a hydrocarbon solvent, a polar solvent, and a mixed solvent thereof. The configuration of the hydroxyl group of the lactols (5) formed by the reduction reaction is not particularly limited.

Lactols (5) formed by reduction of lactones (4) Reacts with orchids (6) to form PGF _2a derivative (2). Phosphoranes (6) are produced from the corresponding phosphonium salts (7) in an inert solvent in the presence of a base, and the resulting phosphoranes (6) are directly isolated from lactols (5) without isolation.用 い る It is preferably used for the Ittsch reaction. The methods for producing phosphoranes (6) are described in “New Experimental Chemistry Lecture, 14 Synthesis and Reaction of Organic Compounds (I)” (Maruzen), “Fourth Edition Experimental Chemistry Lecture, 19 Organic Synthesis I, Hydrocarbons and Halogen Compounds” (Maruzen) ), And the method of Shachai et al. (J. Med. Chem., 22, 1340 (1979)). As Z in the phosphoranes (6) and the phosphonium salts (7), a hydroxyl group is preferable. Examples of the inert solvent include an ether solvent, a hydrocarbon solvent, a polar solvent, an aqueous solvent, an alcohol solvent, and a mixed solvent thereof.

One example of a specific synthetic route for the PGF _2a derivative (2) is shown by the following formula. In the following formula, B z represents a benzyl group, Me represents a methyl group, and i Pr represents an isopropyl group.

The carboxy group at position 1 of the PGF _2a derivative (2) obtained by the above method is directly reduced, Alternatively, it is converted to an ester derivative and then reduced to a hydroxymethyl group to obtain a PGF _2a derivative ( _1a ).

Specifically, the reduction of the carboxy group at the 1-position of the PGF _2a derivative (2) can be performed by a method of converting a carboxylic acid or a derivative thereof to an alcohol, and it is preferable to carry out a chemical reduction reaction in an inert solvent. Examples of the method include the methods described in “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (I)” (Maruzen), “4th Edition Experimental Chemistry Course 20 Organic Synthesis II. Alcohol and Amin” (Maruzen) and the like. Can be adopted.

When Z is an alkoxy group, the reduction reaction may be performed as it is, reduced after conversion to carboxylic acid, or performed after conversion of carboxylic acid to ester. In general, the amount of the reducing agent used in this reduction reaction is preferably 0.01 to 50 equivalents, and particularly preferably 1 to 20 equivalents to the PGF _2a derivative (2). The reaction temperature is preferably from -150 to +100, particularly preferably 180 °. ~ 0 ^ is preferred.

When Z is an alkoxy group, the reducing agent used in the reduction reaction of the PGF _2a derivative (2) is preferably a hydride, particularly diisobutylaluminum hydride [DIB AH], dialkylaluminum alkoxide, lithium aluminum hydride [LAH] , Triethylsilane, trichlorosilane, sodium borohydride, sodium trimethoxyborohydride, trialkoxyaluminum lithium hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diborane, and the like are preferable, and aluminum hydride is particularly preferable. Lithium, DI BAH, sodium bis (2-methoxyethoxy) aluminum hydride, disiamilporan, or lithium tri (sec-butyl) borohydride is preferred.

When Z is an alkoxy group, the reduction reaction of the PGF _2a derivative (2) is preferably performed in the presence of an inert solvent. As the inert solvent, an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof is preferable, and getyl ether, tetrahydrofuran (THF), tert-butyl methyl ether, or toluene is particularly preferable.

Various PG derivatives (Formula (1b), Formula (1c), Formula (1d)) It can be synthesized from the GF _2a derivative (la). However, ~ scale ⁵ in the formula, A, and X represents the same meaning as in the formula (1). P ′ and Q ′ are each independently —CO—, —CH (OR ²⁰ ) — (R ² ° is each independently a hydrogen atom or a hydroxyl-protecting group.) Or one CH ₂ Indicates-.

For example, the PGF _2a derivative (lb) converts a hydroxyl group bonded to the carbon atom at position 1 of the PGF _2a derivative (la) to a secondary or tertiary alcohol, if desired, and then converts the hydroxyl group to the desired one. It can be synthesized by converting the OR ^3.

The PGE derivative (lc) in which Q ′ is —CH (OH) — is protected after protecting the hydroxyl group at the 11-position of the PGF _2a derivative (lb) and, if a hydroxyl group is present at the 1-position, after protecting the hydroxyl group. The hydroxyl group at position 9 is oxidized to a carbonyl group, and then the protected water It can be synthesized by deprotecting the acid group. Another method for producing the PGE derivative (lc) is to protect the hydroxyl group at position 11 of the lactones (4), convert them to lactols (5), introduce the α-chain by the Itttig reaction, The 9-position is oxidized to a carbonyl group, and the 11-position is further deprotected to a hydroxyl group. The PGD derivative (Id) in which P 'is -CH (ΟΗ) is a PGF _{2a In the} derivative (la), if the 9-position and 1-position hydroxyl groups are present, protect the hydroxyl group, oxidize the 11-position hydroxyl group, and then deprotect the protected 9-position hydroxyl group Can be synthesized by

The PG derivative (1) having a secondary or tertiary hydroxyl group at the 1-position oxidizes the PGF _2a derivative ( _2a ) at the 1-position to form an aldehyde or ketone. It is obtained by reacting with an appropriate Grignard reagent or an organic lithium compound. Examples of the method include “New Laboratory Chemistry 14, Synthesis and Reaction of Organic Compounds (11)” (Maruzen) and “New Laboratory Chemistry 15, Oxidation and Reduction (I1-1, I1-2)” (Maruzen) , “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (I)” (Maruzen), etc. can be used. Oxidizing agents used for the oxidation reaction include oxygen, dimethyl sulfoxide, chromium oxide and the like. The oxidizing agent is preferably used in a solvent in the presence of a catalyst.

 A PG derivative (1) in which a carbonyl group is present at the 9-position or 11-position and a secondary or tertiary hydroxyl group is present at the 1-position is described in “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (V According to the method described in (Maruzen), after protecting the carbonyl group of the PG derivative (1) having a corresponding skeleton and a primary hydroxyl group at the first position with a protecting group, reduction or oxidation is performed. And then reacting it with a Grignard reagent or an organolithium compound. Examples of the carbonyl group-protecting group include acetals such as ethylene acetal, propylene acetate and distil acetal, and ketones; dithioacetals such as 1,2-dithiane and 1,3-dithiane; Evening varieties.

R ³ of the PG derivative (1) of the present invention is an alkyl group, an alkenyl group, an alkynyl A group selected from the group consisting of a cycloalkyl group having 3 to 8 carbon atoms, an aryl group and an aralkyl group, or a group in which at least one hydrogen atom in the selected group is substituted, R ³ is hydrogen It can be produced by a method of reacting a halogen compound with the PG derivative (1) as an atom. For example, the method described in “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (I)” (Maruzen) can be adopted.

 When the PG derivative (1) of the present invention has a hydroxyl group at the 9-position and the Z-position or the 11-position, for example, it is described in “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (V)” (Maruzen) It is preferable to carry out the above-mentioned reaction after protecting the hydroxyl group with a protecting group by the above method. Examples of the protecting 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 in particular, a lower alkyl group or aryl group is bonded to a silicon atom by three groups. Individually bonded groups are preferred. Specific examples of the protecting group include a tetrahydrovinylyl group, t tert -butyldimethylsilyl group, t tert -butyldiphenylsilyl group, triethylsilyl group, triphenylsilyl group, and triisopropylsilyl group. The hydroxyl protecting group can be easily deprotected.

When the PG derivative (1) of the present invention has an alkoxy group at the 9-position or the 11-position, it can be produced by a method of reacting a halogen compound with the PG derivative (1) wherein R ² is a hydrogen atom. In this case, when the PG derivative (1) of the present invention has a hydroxyl group at the 1-position, the hydroxyl group at the 1-position in the PG derivative having a hydroxyl group at the 1-position and R ² being a hydrogen atom is as described above. It is preferable to produce by a method of reacting with a halogen compound after protection by the method described above.

 When the PG derivative (1) of the present invention has an acyloxy group at the 1-, 9-, or 11-position, the PG derivative (1) has high lipophilicity and is hydrolyzed in vivo. It can be a useful prodrug that can be converted to a biologically active compound.

The compound is preferably produced by esterifying a PG derivative (1) having a hydroxyl group at the 1-, 9- or 11-position. Esterification is based on hydroxyl group And a method of bonding a thiol group. Examples of such methods include “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (11)” (Maruzen), “4th Edition Experimental Chemistry Course 22 Organic Synthesis IV, Acids, Amino Acids and Peptides” (Maruzen), etc. Can be adopted. Examples of the compound that becomes the group of the acyl group include carboxylic acid, acid anhydride, and carboxylic acid halide.

 The acyl group that can be bonded to the 1-position hydroxyl group of the PG derivative (1) is a saturated or unsaturated aliphatic acyl group, a saturated or unsaturated cycloaliphatic acyl group, an aromatic acyl group, or a heterocyclic acyl group. And an alkyl group-containing acyl group. As the acyl group bonded to the 9-position or the 11-position, an acyl group having 1 to 20 carbon atoms is preferable.

 In the case of synthesizing a PG derivative (1) having a carboxy group at the 9-position or 11-position, it is preferable to oxidize the PG derivative (1) having a hydroxyl group at the 9-position or 11-position. Examples of the oxidation method include those described in “New Experimental Chemistry Course 15 Oxidation and Reduction (I-I 1), (I-I 2)” (Maruzen), “4th Edition Experimental Chemistry Course 23 Organic Synthesis V” (Maruzen), etc. Oxidation with chromic acid or dimethyl sulfoxide is preferred. Jones oxidation, Collins oxidation, acid oxidation with pyridinum chromatochromate, or Swern oxidation is particularly preferred.

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

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

(1D-1)

 (ID—2)

 (IE-1)

 (IE-2)

R ²¹ Q

 (IF-2)

[Example of PGD derivative]

In the formula (1D_1), compounds ((ID-101) to (1D-148)) in which A, R ¹ , R ² , and R ³ have the structures shown in the following table, may be mentioned.

(table 1)

AR ¹ R ² R ³ lD-101 Ethylene group Pentyl group HH

 1D-102 trans -vinylene group pentyl group H H

 ID- 103 Ethylene group Phenoxymethyl group H H

 1D-104 trans-vinylene group Phenoxymethyl group H H

 1D-105 Ethylene 3-chlorophenoxymethyl H H

 ID- 106 trans—Hinylene group 3-Chlorophenoxymethyl group H H

 1D-107 Ethylene 3,5-dichlorophenoxymethyl H H

 1D-108 trans-Hinylene ¾ 3, 5-dichlorophenoxymethyl group H H

 ID-109 Ethylene group Pentyl group H-acetyl group lD-110 trans-vinylene group Pentyl group H-acetyl group

1D-I1] Ethylene, phenoxymethyl, H-acetyl

1D-112 trans-vinylene group phenoxymethyl group H acetyl group

1D-113 Ethylene group 3-Chlorophenoxymethyl group H-Acetyl group

1D-114 trans-Hinile & 3-chlorophenoxymethyl group H acetyl group

1D-115 Ethylene 3,5-dichlorophenoxymethyl H-acetyl

ID- 116 trans-Hinylene 3,5-dichlorophenoxymethyl H-acetyl

ID- 117 Ethylene group Pentyl group H Bivaloyl group

1D-118 trans -Hinylene group Pentyl group H Bivaloyl group

ID- 119 Ethylene group Phenoxymethyl group H Bivaloyl group

ID- 120 trans -vinylene group Phenoxymethyl group H Vivaloyl group

ID-121 Ethylene group 3-chlorophenoxymethyl group H Bivaloyl group

ID- 122 trans -vinylene group 3-chlorophenoxymethyl group H bivaloyl group

ID- 123 Ethylene 3,5-dichlorophenoxymethyl H Bivaloyl

ID- 124 trans-vinylene¾ 3, 5-dichlorophenoxymethyl group H Bivaloyl group (Table 2)

AR ¹ R ² R 3

ID- 125 Ethylene group Pentyl group Methyl group H

 1D-126 trans-vinylene group Pentyl group Methyl group H

 ID-127 Ethylene group Phenoxymethyl group Methyl group H

 ID- 128 trans -vinylene group phenoxymethyl group methyl group H

 ID-129 Ethylene group 3-Chlorophenoxymethyl group Methyl group H

 ID- 130 trans -Daniren 3 -Chlorophenoxymethyl group Methyl group H

 ID-131 Ethylene 3,5-dichlorophenoxymethyl Methyl H

 ID- 132 trans-Hinylene 3,5-dichlorophenoxymethyl Methyl H

 ID-133 Ethylene group Pentyl group Methyl group Acetyl group

ID- 134 trans-daniren ¾ Pentyl group Methyl group Acetyl group

ID-135 Ethylene group Phenoxymethyl group Methyl group Acetyl group

ID- 136 trans-daniren ¾ phenoxymethyl group methyl group acetyl group

ID-137 Ethylene group 3-Chlorophenoxymethyl group Methyl group Acetyl group

ID-138 trans-Hinylene ¾ 3-chlorophenoxymethyl group Methyl group Acetyl group

1D-139 Ethylene 3,5-dichlorophenoxymethyl methyl Methyl acetyl

1D-140 trans-vinylene group 3,5-dichlorophenoxymethyl group methyl group acetyl group

ID-1 "Ethylene group Pentyl group Methyl group Bivaloyl group

ID- 142 trans Vinylene winding Pentyl methyl group Vivaloyl group

ID-143 Ethylene group Phenoxymethyl group Methyl group Bivaloyl group

ID-144 trans-Hinylene s phenoxymethyl group Methyl group Vivaloyl group

1D-145 Ethylene 3-chlorophenoxymethyl Methyl Bivaloyl

ID-146 trans-Hinile s 3-chlorophenoxymethyl group Methyl group Bivaloyl group

ID-147 Ethylene 3,5-dichlorophenoxymethyl methyl Methyl Bivaloyl

ID-148 trans-Hinylene ¾ 3,5-dichlorophenoxymethyl group Methyl group Bivaloyl group In the formula (ID-2), compounds ((1D-201) to (1D-248)) in which A, RR ² , and R ³ have the structures shown in the following table are mentioned.

 (Table 3)

(Table 4)

 A R 2 3 丄 T〗 /, 甚, 、, 其

 ぺ 、 Nono_Noshire Sweet

 n_ 7

1 Π U Z Z δ ι rans ―Reno Streets

 , Sweet. W sweet

 ナ ク 7 7 7 7 7

ϊ υ-Ιόυ t rans -Hireno ό- 7

 Sweet

 I l) -Zo l Enareno winding ί) —Nurono eno

 t rans-hinireno 6, i)

 -L66 Enareno group

11)-4 1 rans-vinylene ¾ eno: nore it sweet

 Nanore Nanore

ID-Zoo, sweet

 Enareno noeno ten nanore winding ma

 Nanore J with nanore l u-Z o t rans-Hiniren no eno no ten nasore winding nano rema J J ϋnanore ¾ amenareno kami 6- u u nono ten nanorema

 Nano res tl Nano res trans- 1 Reno fe Clos mouth eno no ten nanore; ^ Nanore maso ナ ノ -Nanore ¾ Ϊ マ マ マ ェ ナ レ ン グ ン グΛ t rans-heileno sweet

 ロ, ¾ ________________________________________________________

1 U Z41 Kamishi-sushi Reno, 'Henkou No-no-re ^ Nore-L. ./ ヾ \ 门 U Zino) | レ, ¾,

1 U l ^ i \ rans c-~ ■ Reno Alley ヽ ノ ^ ノ レ ^ 甘 ‐ ア ノ レ レ しHapa 'n LJ Tsu no ϊΙ, street sweet i ϋ r thousand, no jin fu j cho ~ no no, n thousand j les ~ ^ · ^ ¹ ) ^ ^ ^ E ba pi j

1D-244 ans -Hinylene phenoxymethyl group Methyl group Vivaloyl group

1D-245 Ethylene 3-chlorophenoxymethyl Methyl Bivaloyl

1D-246 trans-vinylene group 3-chlorophenoxymethyl group methyl group bivaloyl group

1D-247 Ethylene 3,5-dichlorophenoxymethyl methyl Methyl pivaloilyl

ID-248 ans-Hinylene 3,5-dichlorophenoxymethyl methyl Methyl Bivaloyl [Example of PGE derivative]

In the formula (l E- l) A, RR 2, and R ³ of compound a structure shown in the following table ((IE- 10 1) ~ ( 1 E- 148)) can be mentioned.

 (Table 5)

(Table 6)

In the formula (] .E-2), compounds ((1E—201) to (1E—248)) in which A, R ¹ , R ² , and R ³ have the structures shown in the following table are mentioned.

 (Table 7)

AR ¹ R ² R ³

1E-201 Ethylene group Pentyl group H H

 1E-202 trans -Hinylene group Pentyl group H H

 1E-203 Ethylene group Phenoxymethyl group H H

 1E-204 ans -Hinylene group Phenoxymethyl group H H

 1E-205 Ethylene group 3-chlorophenoxymethyl group H H

 1E-206 trans-Hinylene ¾ 3 _chlorophenoxymethyl group H H

 1E-207 Ethylene 3,5-dichlorophenoxymethyl H H

 1E-208 trans-Hinylene 3,5-dichlorophenoxymethyl H H

 1E-209 Ethylene group Pentyl group H-Acetyl group

1E-210 trans-Hinylene Pentyl group H acetyl group

1E-211 Ethylene group Phenoxymethyl group H-Acetyl group

1E-212 trans-Hinylene phenoxymethyl group H acetyl group

1E-213 Ethylene 3-chlorophenoxymethyl H-acetyl

1E-214 trans-Hinylene 3-chlorophenoxymethyl group H-acetyl group

1E-215 Ethylene 3,5-dichlorophenoxymethyl H-acetyl

IE-216 trans-Hinile 3, 5-dichlorophenoxymethyl group H-acetyl group

IE-217 Ethylene group Pentyl group H Bivaloyl group

IE-218 trans-hinile ペ ン pentyl group H bivaloyl group

IE-219 Ethylene group Phenoxymethyl group H Bivaloyl group

1E-220 irans-vinylene group phenoxymethyl group H bivaloyl group

IE-221 Ethylene 3 chlorophenoxymethyl H Bivaloyl

IE-222 trans -Hinylene 3 -Chlorophenoxymethyl group H Bivaloyl group

IE-223 Ethylene 3,5-dichlorophenoxymethyl H Bivaloyl

IE-224 trans-Hinylene ¾ 3,5-dichlorophenoxymethyl group H Bivaloyl group (Table 8)

 D 2

 I Γν

 "Sushi Reno

lt-ίίΌ Top winding sweet

 J, ソ 11 —-. ^ Sweet tl

lh-Z b trans-hinylene ⁰ ,, ~ T-) 1 sweet

 ぺ Nonazole Nasolé

 Oh sweet

 \ E-in Enareno

 1E-228 trans-Hinileno group Phenoquinmethylyl group Terile Η

 1E-229 ナ ¾ ¾ 口 ¾

 1E- 30 trans-Hinylene Alley 3-ku O mouth

 1E-231 Ethylene 3,5-cyclophene

 Factory ,,,,! -.

 1E-232 trans-Hinylene avenue 3,5-chlorochlorophenomena

 1E-233 Ethylene group Pliers J-Street Menarile group Arsenal group

1E-234 irans-Healen group Pliers J-le group Menarile group Senarile group

1E-235 Ethylene group Menare group Acenare group

 ^ Methyl group

 1E-236 trans-Hinylene ¾ phenoxymethylene group Menare group Arsenal group

1E-237 Ethylene group 3—Black mouth

 —

 1E-238 irans-Hiren-k 巷 3 3

1E-239 丄 Nalene group 5-N-chloroenoenoquine Menena Nanole

 Shi-ichi 1 sweet

 1E-240 irans- レ ¾ ¾ 5- ン ク ロ ロ エ メ メ ナ ナ ナ ナ

 1 sweet —) 1 sweet

1E- 41 Enareno Heteninore Metenore Dani /, b ^ f Nore trans-rT Sweet Re ⁰ , ヾ No Hinireno Heno Nanore Nanore J / ヽ J Nore Roll Sweet

1 Ε ώ4ο

 丄 Freno ~ no J no no10 no kifu nore sweet fu nore ° / ヾ 门 LJ itsuno Ϊshire no ^^

IE-244 trans-Hinile> & phenoxymethyl group Methyl group Vivaloyl group

IE-245 Ethylene 3-chlorophenoxymethyl Methyl Bivaloyl

IE-246 trans-Hinylene ¾3-chlorophenoxymethyl group Methyl group Bivaloyl group

IE-247 Ethylene 3,5-dichlorophenoxymethyl methyl Methyl Bivaloyl

IE-248 trans-Hinylene 3,5-dichlorophenoxymethyl group Methyl group Bivaloyl group [Example of PGF derivative]

Compounds in which A, RR ² R ²² , and R ³ in the formula (IF-1) have the structures shown in the following table ((IF-101) to (1F-; L72)).

 (Table 9)

AR ¹ R ²¹ R ²² R ³

 1F-101 Ethylene-based pliers H H H

 1F-102 1 rans -vinylene group pentyl group H H H

 1F-103 Ethylene group Phenoxymethyl H H H

 1F-104 trans—vinylene group phenoxymethyl H H H

 1F-105 Ethylene group 3-chloro mouth phenoxymethyl Λ¾ H H H

 1F-106 trans-t n s 3-chlorophenoxymethyl group H H H

 1F-107 Ethylene 3,5-dichlorophenoxymethyl H H H

 1F-108 trans -vinylene group 3,5-dichlorophenoxymethyl group H H H

 1F-109 Ethylene group Pliers H H Acetyl group

 1F-110 ans-Hinylene¾ Pentyl group H H acetyl

 1F-111 Ethylene group Phenoxymethyl H H Acet

 1F-112 trans-Hinylene phenoxymethino L¾ H H acetyl group

 1F-113 Ethylene group 3-cyclophenoxymethyl H H ace ^

 1F-114 ans-Hinile s 3-chlorophenoxymethyl group H H acetyl group

 1F-115 Ethylene 3,5-dichlorophenoxymethyl H H acetyl

 1F-116 trans-Hinylene 3,5-dichlorophenoxymethyl group H H acetyl group

 IF-117 Ethylene pliers H H Vivaloy

 IF-118 ans—vinylene group Pliers H H Vivaloyl group

IF-119 Ethylene phenoxymethyl H H Vivaloy

 IF-120 trans-vinylene group Phenoxymethy H H Vivaloyl group

IF-121 Ethylene group 3-Chlorophenoxymethyl ^ ¾ H H Bivaloyl group

IF-122 trans-Hinylene Alley 3-Cloth phenoxymethyl group H H Vivaloyl group

IF-123 Ethylene 3,5-dichlorophenoxymethyl H H piperoyl

IF-124 trans-Hinylene 3,5-dichlorophenoxymethyl HH Vivaloy (Table 10)

A ^{1 1} RR ^Λ

 IF-125 丄 Nalene group Pentyl group H Methyl group Η

1F-126 trans-vinylene group pentyl group H methyl group Η

IF-127 Ethylene group Phenoxymethyl group H Methyl group Η

IF-128 trans—Hinylene phenoxymethino H Methyl Η

IF-129 Ethylene group 3-Chlorophenoxymethyl group H Methyl group Η

IF-130 trans—vinylene group 3-chlorophenoxymethylyl group H methyl group Η

IF-131 Ethylene 3,5-dichlorophenoxymethyl H-methyl Η

IF- 132 trans -vinylene group 3,5-dichlorophenoxymethyl group H

1F-133 Ethylene group Pentyl group H Methyl group Acetyl group

IF-134 trans -Hinylene ¾ pentyl group H methyl acetyl group

IF-135 Ethylene group Phenoxymethyl group H Methyl group Acetyl group

1F-136 trans -Hinylene¾ phenoxymethyl group H methylacetyl group

1F-137 Ethylene group 3-Chlorophenoxymethyl group H Methyl group Acetyl group

IF-138 trans-Hinile & 3-chlorophenoxymethylyl group H Methyl group Acetyl group

IF-139 Ethylene 3,5-dichlorophenoxymethyl H-Methylacetyl

1F-140 trans -vinyle> 3,5-dichlorophenoxymethylyl group H methyl group acetyl group

IF-141 Ethylene group Pentyl group H Methylation Pivaloyl group

IF-142 trans-hinile & pentyl group H methyl group Pivaloy

】 F-143 丄 Nalene ¾Noeno Dried Jl¾H Mena

IF-144 Trans-Hinile & Huenoximechi! ¾ H Mechiri Vivaloy aside

IF-145 Ethylene 3-chlorophenoxymethyle H

1F-146 trans-vinylene 3-chlorophenoxymethyl group H methyl group Bivaloyl group

IF-147 Ethylene 3,5-dichlorophenoxymethylile H-methyl Bivaloyl

IF -148 trans-Hinylene 3,5-dichlorophenoxymethyl H-methyl Bivaloyl (Table 11)

 A R ti-^ °

IF-149 Ethylene group Pentyl group Methyl H Η

 1F-150 trans—vinylene group pentyl group methyl group H Η

 IF-151 Ethylene phenoxymethyl J メ チ ル Methyl H Η

 IF-152 trans-vinylene group Phenyloxymethyl group H Η

 1F-153 Ethylene group 3-chlorophenoxymethyl group

 IF-154 trans-vinylene¾ 3-chlorophenoxymethyl methyl group HΗ

 IF-155 Ethylene 3,5-dichlorophenoxymethyl «Methyl H Η

 IF-156 trans-Pinylene ¾ 3, 5-Dichlorophenoxymethi J

 IF-157 ethylene group pentyl group methyl group H acetyl group

IF-158 trans-vinylene ¾ pentyl group methyl group H acetyl group

IF-159 Ethylene group Phenoxymethyl meth-H acetyl group

IF-160 trans-vinylene phenoxymethyl J ¾ methyl H acetyl group

IF-161 Ethylene group 3-chloro phenoxymethyl group Methyl H acetyl group

IF-162 trans-vinylene s 3-chlorophenoxymethyl group

1F-163 Ethylene 3,5-dichlorophenoxymethyl methyl M H-acetyl

1F-164 trans -vinylene ¾ 3, 5-dichlorophenoxymethylyl group Methizo 1 S H acetyl group

IF-165 Ethylene group Pentyl group Methyl group H

IF-166 trans -vinylene pentyl group Methyl group H pivaloyl group

IF-167 Ethylene group Phenoxymethyl group Methyl ¾H

IF-168 trans -Hinylene phenoxymethyl group Methyl H Bivaloyl group

IF-169 Ethylene 3-chlorophenoxymethyl methylyl H

IF-170 trans -Hinylene 3-chlorophenoxymethylyl group Methino! ^ H Vivaloy annihilation

1F-171 Ethylene 3,5-dichlorophenoxymethyl Methyl H Bivaloyl

IF-mt rans—Pinylene 3,5-dichlorophenoxymethi JbS Methi H Vivaloy In the formula ^{(IF- 2) A, RR 21} , R 22, and R ³ is a structure shown in the following table 6 ((1 F- 20 1) ~ (1 F- 272)) can be mentioned.

 (Table 12)

AR ¹ R ² 'R ²² R ³

 1F-201 Ethylene group Pentyl group Η Η Η

 1F-202 trans-Hinile s Pentyl group Η Η Η

 1F-203 Ethylene group phenoxymethyl ¾ Η Η Η

 1F-204 trans-Hinylene phenoxymethyl チ Η Η

 1F-205 Ethylene group 3-chlorophenoxymethyl group Η Η Η

 1F-206 trans-Hinylene group 3-H π-open phenoxymethyl group Η Η Η

 1F-207 Ethylene 3,5-dichlorophenoxymethyl J J 基 Η Η

 1F-208 trans-Hinile & 3, 5-dichlorophenoxymethylyl group Η Η Η

 1F-209 Ethylene group Pentyl group Η セ acetyl group

1F-210 trans-vinylene group Plier elimination Η セ acetyl group

1F-211 Ethylene group Phenoxymethyl J ¾ Η セ Acetyl group

1F-212 trans-Hinylene s phenoxymethylyl L¾ Η Ηacetyl group

1F-213 Ethylene 3-chlorophenoxymethyl! ^ Η セ acetyl group

1F-214 trans -vinylene group 3-chlorophenoxymethyl Η Η acetyl group

1F-215 Ethylene 3,5-dichlorophenoxymethylile Η セ acetyl

1F-216 trans-Hinile & 3,5-dichlorophenoxymethylyl L «Η Η acetyl group

1F-217 Ethylene group Pentyl group Η Η Vivaloy

1F-218 trans-Hinile s pentyl group

1F-2I9 Ethylene group Phenoxymethyl JUS Η Η Vivaloyl group

1F-220 trans-Hinylene Port phenoxymethylyl lS Η Η Vivaloyl group

1F-221 Ethylene 3-phenoxymethyl Λ¾ メ Η Vivaloyl ^

1F-222 trans—Hinylene group 3-Chlorophenoxymethyl group

1F-223 Ethylene 3,5-dichlorophenoxymethyl Η Η Vivaloy

1F-224 trans-Hinylene fe 3,5-dichlorophenoxymethyl group Η Η Pivaloino (Table 13)

AR ¹ R ²¹ _R 22 R ³

IF-225 Ethylene group Pentyl group H Methyl H

 IF-226 trans-vinylene pentyl group H methyl l ^ H

 IF-227 Ethylene group phenoxymethyl Λ «H methyl H

 IF-228 trans-vinylene group phenoxymethyl S H methyl J H

 1F-229 Ethylene group 3-chloro phenoxymethyl group H Methyl H

 IF- 230 trans -Hinylene 3-chlorophenoxymethyl J

 1F-231 Ethylene 3,5-dichlorophenoxymethyl Jl ^ H methyl H

 IF-232 ans-hinylene 3,5-dichlorophenoxymethyli! ^ H

 IF-233 Ethylene group Pentyl group H Methyl group Acet

I F-234 trans-Hinylene group Pentyl group H Methyl group Acetyl group

I F-235 ethylene group phenoxymethyl H methyl group acetyl group

1F-236 Irans-Hinile & phenoxymethyl Λ «H methylacetyl group

IF-237 Ethylene 3-chloro phenoxymethyl H methyl «acetyl group

IF-238 trans -Hinylene 3-chloro phenoxymethy J

IF-239 Ethylene 3,5-dichlorophenoxymethyl! ^ H Methyl group Acetyl group

IF-240 trans -Hinylene 3,5-dichlorophenoxymethyl H Hethyl acetyl

IF-241 Ethylene group Pentyl group H ^ Bivaloyl group

I F-242 trans-Hinylene ¾ Pentyl group H Methi Vivaloyl ¾

I F-243 Ethylene group Phenoxymethylyl 1 ^ H Methybivaloyl group

IF-244 trans-Hinylene phenoxymethyli! ^ H

I F-245 Ethylene group 3-chlorophenoxymethyl H methyl! ^ Bivaloyl group

I F-246 trans-vinylene group 3-chlorophenoxymethyl group H methyl group Pivaloy

IF-247 Ethylene 3,5-dichlorophenoxymethyl Jl¾H Methyl Bivaloyl

IF-248 trans-Hinylene ¾ 3,5-dichlorophenoxymethyl J-H H-methyl Bivaloyl (Table 14)

The novel PG derivative (1) of the present invention has higher lipophilicity and better absorbability in a living body than the 15-dexoxy15,15-difluoro PG derivative having the same carbon skeleton. In addition, the PG derivative (1) of the present invention has high chemical stability. In particular, those in which an alcoholic hydroxyl group or an etheric oxygen atom is bonded to the carbon atom at position 1 are not hydrolyzed. It is a compound that is not easily decomposed.

 The PG derivative (1) of the present invention is useful as a medicament, and is used as an ophthalmic disease, inflammatory disease, allergic / immune disease, digestive system disease, central nervous system disease, circulatory system disease, analgesic, osteoporosis therapeutic agent, It can exhibit excellent effects as a drug such as an anticancer drug. Eye diseases include glaucoma, ocular hypertension, retinopathy, conjunctivitis, uveitis, retinitis and the like. Inflammatory diseases include acute hepatitis, chronic hepatitis, cirrhosis, cholecystitis, cholangitis, acute knee inflammation, chronic tengitis, chronic peritonitis, acute peritonitis, cystitis, acute nephritis, chronic nephritis, encephalitis, polyneuritis Includes inflammation, meningitis, myelitis, arthritis, rheumatoid arthritis, bronchitis, pneumonia, pleurisy, phlebitis, pericarditis, rhinitis, pharyngitis, otitis media, otitis externa. Allergy · Immunological diseases include bronchial asthma, allergic dermatitis, allergic rhinitis, atopy, rheumatism, collagen disease, etc. Gastrointestinal disorders include gastric ulcer, gastritis, duodenal ulcer, ulcerative colitis, Crohn's disease and the like. Central nervous system disorders include insomnia, anxiety, depression, schizophrenia, and dementia. Cardiovascular diseases include peripheral circulatory disorders, Bajja's disease, Reino's disease, angina, myocardial infarction, heart failure, pulmonary hypertension, pulmonary embolism, diabetes, cerebral infarction, cerebral thrombosis, hearing loss, Meniere's disease, etc. It is.

In particular, the PG derivative (1) of the present invention has an excellent intraocular pressure lowering effect, and has little effect on eye irritation and eye tissues such as cornea, iris and conjunctiva. Furthermore, its usefulness as a medicine is extremely high because of its high corneal permeability and high intraocular absorption. Therefore, the medicament of the present invention is particularly effective as an agent for preventing or treating glaucoma or ocular hypertension. The medicament of the present invention is used by topically administering a preparation containing the above-mentioned compound of the present invention as an active ingredient to the eye by a method such as eye drops. Examples of the dosage form include eye drops such as eye drops and ointments, injections, and the like, and the compound of the present invention can be formulated using commonly used techniques. For example, in the case of eye drops, isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbine monomonolate (hereinafter referred to as polysorbate 80), polyoxyl stearate 40, surfactants such as polyoxyethylene hydrogenated castor oil, It can be formulated as necessary using stabilizers such as sodium phosphate and sodium edetate, and preservatives such as benzalkonium chloride and paraben, and the pH should be within the acceptable range for ophthalmic preparations. The range of ~ 8 is preferred.

 The dose can be appropriately selected in consideration of symptoms, age, dosage form, etc., but if it is an ophthalmic solution, 0.0005 to 1% (wZv), preferably 0.0005 to 0.5 (w / v) It should be instilled once to several times a day.

(Example)

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

 [Example 1] (1 S, 5 R, 6 R, 7 R) — 2-oxa-1 7-benzoyloxy 6 — [(1 E) 14-phenoxy-1 3-oxo-1 1-butenyl] -bicyclo [3.3 . 0] Synthesis of octane-3-one

To a solution of 26.5 g of dimethyl 2-oxo-3-phenoxymonopropylphosphonate in 26.5 g of THF (26 OmL) was added 3.39 g of lithium chloride and 10.9 mL of triethylamine under ice-cooling. After stirring for 15 minutes, (1S, 5R, 6R, 7R) -16-formyl-17-benzoyloxy-12-oxabicyclo [3.3.0] octan-3-one 18.1 g A solution of methylene chloride (65 mL) was added. The mixture was stirred at 0 for 1 hour, and the reaction solution was poured into a saturated aqueous ammonium chloride solution of ethyl acetate = 1Z1 mixture and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried and concentrated ₍ purified by silica gel column chromatography (ethyl hexanoacetate = 1 to 3 to 2 1)) to obtain 19.8 g of the title compound.

_{Ή-NMR (CDC 1 3)} :. 02. 29 (dd d, J = 15. 6, 4. 9, 0. 2Hz, 1H), 2. 45-2 5 1 (m, 1H), 2. 60 (dt, J = 15.6, 6.6Hz, 1H), 2.83-2.95 (m, 3H), 4.67 (s, 2H), 5.08 (td, J = 4.6, 1.7 Hz, 1 H), 5.31 (m, 1 H), 6.60 (dd, J = 15.6, 1.0 Hz, 1 H), 6.84-6.8 7 (m, 2H), 6.91 (dd, J = 15.6.7.8Hz, 1H), 6.9

8 (t, J = 7.3 Hz, 1 H), 7.25-729 (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 2H).

 [Example 2] (IS, 5R, 6R, 7R) 12-oxa-7-benzoyloxy-6-[(1E) -13,3-difluoro-4-phenoxy-1-1-butenyl] -bicyclo [3 . 3.0] Synthesis of octane-3-one

 To a solution of 19.8 g of the enone synthesized in Example 1 in methylene chloride (15 OmL), 78.4 g of morpholinosulfatrifluoride was added at 0. After stirring at room temperature for 180 hours, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Purification by silica gel column chromatography (hexane Z-ethyl acetate = 2/1) gave 13.7 g of the title compound.

One _{NMR (CDC 1 3):.} . 62. 2-2 9 (m, 6H), 4. 17 (t, J = 1 1. 5Hz, 2 H), 5. 09 (m, 1H), 5. 29 (m, 1 H), 5.89 (dt, J = 15.6 1 1.OH z, 1H), 6.15 (m, 1 H), 6.85 (d, J = 7.8 Hz, 2H), 6.99 (t, J = 7.3Hz, 1H), 7.27 (m, 2H), 7, 41 (m, 2H), 755 (t, J = 7.3H z 1 H), 7.97 (d, J: 7.3 Hz, 2 H).

I9 'Fp - NMR (CDC 1 3): - 104. 0 (m).

 [Example 3] (IS, 5 R, 6R, 7 R) — 2-oxa 7-hydroxy-6-[(IE) — 3,3-difluoro-4-phenoxy — 1-butenyl] —bicyclo [3.3. 0] Synthesis of octane-3-one

 13.7 g of the fluoride synthesized in Example 2 was dissolved in 16 OmL of methanol, and 2.55 g of potassium carbonate was added, followed by stirring at room temperature for 3 hours. After adjusting the pH to 7 with acetic acid, water was added, and the mixture was extracted with ethyl acetate. Purification by silica gel column chromatography (ethyl hexanoacetate == 1/2 to 2/3) gave 10.6 g of the title compound.

Ή-NMR (CDC 1 J: 62.0-2.8 (m, 6 H), 4.09 (m, 1 H), 4.20 (t, J = 11.5 Hz, 2 H), 4.94 (m, 1 H), 584 (dt, J = 15.6, 1 1.2 Hz, 1 H), 6.07 (m, 1H), 691 (d, J = 7.8Hz, 2H), 7.02 (t, J = 7.3Hz, 1H), 7.31 (m, 2H).

_{^{1 9 F -NMR (CDC 1 3}} ): - 1 0 3. 6 (m).

 [Example 4] (IS, 5 R, 6 R, 7 R) 12-oxa-1,3,7-dihydroxy-6-[(1E) —3,3-difluoro-4--1-phenoxy-1-butenyl] -bicyclo [3.3.0] Synthesis of octane

 (1S, 5R, 6R, 7R) -12-oxax-7-hydroxy-6-[(1E) —3,3-difluoro-4-phenoxy-11-butenyl] -bicyclo [3] synthesized in Example 3 [3.0] Octane-13-one To a solution of 10.6 g of THF (53 mL) was added a toluene solution of diisobutylaluminum hydride (1 mol ZL, 8 mL) at 178, and the mixture was stirred for 30 minutes. Methanol (8 mL) and hydrochloric acid (2 mol ZL 122 mL) were added, and the mixture was extracted with ethyl acetate to obtain 11.0 g of a crude product.

_{Ή-NMR (CDC 1 3)} δ 1. 8- 2. 9 (m, 6H), 3. 9 6 (m, 1 H), 4. 1 9 (t, J = l l. 5H z, 2H) , 4.60 -4.71 (m, 1H), 5.56-5.65 (m, 1H), 5.82 (m, 1H), 6.11 (m, 1H) 1H), 6.91 (d, J = 8.3Hz, 2H), 7000 (m, 1H) 7.30 (t, J = 7.8Hz, 2H).

_{^{I 9 F -NMR (CDC 1 3}} ): - 1 0 3 (m).

[Example 5] Synthesis of 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGF _2a isopropyl ester

4 To a suspension of 60.0 g of lipoxybutyltriphenylphosphonium bromide in 60.0 g of THF (22 OmL) was added a solution of sodium bis (trimethylsilyl) amide in THF (1 mol ZL, 27 OmL). For 1 hour. A solution of 11.1 g of lactol synthesized in Example 4 in THF (44 mL) was added at 0 ° C., and the mixture was stirred for 3 hours. Stop the reaction by adding cold water, wash with ethyl acetate, acidify the aqueous layer, Extracted with ethyl acetate. Purification by silica gel column chromatography (ethyl hexanenoacetate = 2-3-1-3) gave 7.59 g of carboxylic acid.

 In a solution of 7.59 g of the synthesized carboxylic acid in acetone (38 mL), 0 to 1,8-diazabicyclo [5.4.0] pendant power—7-ene (10.2 mL), 2-propane ( 9.3 mL), 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 solution of citric acid and aqueous sodium bicarbonate, and purified by silica gel column chromatography (ethyl hexanenoacetate = 23) to obtain 4.77 g of the title compound.

_{Ή-NMR (CDC 1 3)} : δ 1. 22 (d, J = 6. 4Hz, 6 H), 1. 59 (m, 1H), 1. 66 (m, 2 H), 1. 83 (m , 1 H), 2.0—2.4 (m, 7H), 2.47 (m, 1 H), 4.02 (m, 1 H), 4.19 (t, J = 1 1. 5Hz, 2H), 4.19 (m, 1H), 4.99 (m, 1H), 5.38 (m, 2H), 5.80 (dt, J = 15.6, 1 1.2Hz, 1H), 6.10 (m, 1H), 6.91 (m, 2H), 7.00 (m, 1H), 30.m (2H) .

_{^{19 F - NMR (CDC 1 3}} ): - 1 03. 7 (m).

[Example 6] 2- Dekarubokishi 2-hydroxymethyl - 1 6-phenoxy one 1 5 - Dokishi - 1 5, 1 5-difluoromethoxy-1 7, 1 8, 1 9, 20-tetranor synthesis of P GF _2a

To a suspension of lithium aluminum hydride (0.5 1 g) in THF (102 mL) was added dropwise a solution of isopropyl ester (3.04 g) synthesized in Example 5 in THF (12 mL) at 178 ° C. . After stirring for 1 hour, ethanol (4 mL) and hydrochloric acid (1 mol ZL, 25 mL) were added, extracted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate to obtain 1.87 g of the title compound.

Ή-NMR (CDC 1): d 3 8 4 5 (m, 1 H), 4 1

(dd, J = 7.03, 14.35, 2H), 1.50-: L. 60 (m, 3H), 1.79 (dd, J = 2.34, 1 4.64, 1H), 2.12 to 2.18 (m, 3H), 2.28 to 2.37 (m, 1H), 2.40 to 2.50 (m, 3H) 1H), 3.60 (dt, J = 1.47, 6.44, 2H), 3.98 to 4.02 (m, 1H), 4.15 to 4.18 ( m, 1H), 4.19 (t, J = 11.72, 2H), 5.36 to 5.42 (m, 2H), 5.81 (dt, J = 1 1 .1 3, 15.82, 1H), 6.10 (ddt, J = 2.34, 9-08, 15.82, 1H), 6.92 (d, J = 8.79, 2H), 7.00 (t, J = 7.32, 1H), 7.29 (t, J = 7.32, 2H).

_{^{I9 F -NMR (CDC 1 3)}} : - 1 0 3. 5 8 (m).

[Example 7] 2-Decarboxy-2-bivaloyloxymethyl-16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGF _2a (compound 15 ) Synthesis

 0.56 g of the compound obtained in Example 6 was dissolved in pyridine (10 mg), and at 0, bivaloyl chloride (0.17 mL) was added. Three hours later, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The concentrate was purified by silica gel column chromatography (ethyl hexanoacetate = 1Z2) to obtain Compound 15 (0.31).

Ή-NMR (CDC 1): 6 1.18 (s, 9 H) 34 ~: L.43 (m, 2H), 1.55 ~: L.64 (m, 2H), 1.82 (dd, J = 2.05, 14.64, 1H), 2.04 ~ 2.18 (m, 4H), 2.26 to 2.33 (m, 1H), 2.43 to 2.48 (m, 2H), 4.01 to 4.05 (m, 1H), 4.03 (t, J = 6.44, 2H), 4.16 to 4.22 (m, 1H), 4.19 (t, J-1 1 42, 2H), 5-34 to 5.44 (m, 2H), 5.80 (dt, J = 11.13, 15.52, 1H), 6.10 (ddt , J = 2.34, 9.08, 15.5 2, 1H), 6.91 (d, J = 7.91, 2H), 6.99 (t, J = 7. 62, 1H), 7.29 (t, J = 7.62, 2H).

_{^{19 F- NMR (CDC 1 3)}} : - 1 0 3. 6 2 (m).

[Example 8] 2-Decarboxy-2-bivaloyloxymethyl-15-deoxy-15,15-difluoro-11-methoxy-16-phenoxy-17,18,19,20-tetranor Synthesis of PGF _2a

 To a solution of compound 2 (304 mg) obtained in Example 7 in dimethylformamide (2 mL) were added 0.066 mL of methyl iodide and 150 mg of silver oxide, and the mixture was stirred at room temperature for 16 hours. The insoluble material was filtered and purified by column chromatography (ethyl acetate Z hexane = 14) to obtain 128 mg of the title compound (Compound 3).

(Compound 3)

_{^{J H-NMR (CDC 1 3}} ): 6 1. 1 7 (s, 9H), 1. 3 3- 1. 4 1 (m, 2 H), 1. 52 - 1. 6 2 (m, 2 H ), 1.86-2.16 (m, 6H), 2.25-2.33 (m, 1H), 2.48-2.54 (m, 1H), 328 (s, 3H), 3.63 (m, 1H), 4.01 (m, 2H), 4.07-4.20 (m, 3H), 5.32-2-5 .4 3 (m, 2H), 5.78 (dt, J = 15.8, 11.1 Hz, 1H), 6.13 (m, 1H), 6.8889 (m, 2H), 6.98 (m, 1H), 7.27 (m, 2H). _{^{19 F- NMR (CDC 1 3)}} : - 1 03. 2 (m).

[Example 9] 2-Decarboxy-2-hydroxymethyl-15-doxy-15,15-difluoro-16-phenoxy-1,5,6-dihydro-17,18,19,20-tetranor PGF _2a , And 2-Decarpoxy-1-hydroxymethyl-15-deoxy-15,15-difluoro-16_phenoxy-15,6,13,14-tetrahydro-17,17,18,19,20 —Synthesis of tetranor PGF _{2 u To} a solution of the compound (0.500 g) obtained in Example 6 in benzene Z ethanol = 3Z 1 (24 mL) was added 12 mg of tris (triphenylphosphine) rhodium (I) Ogum. The mixture was stirred at room temperature under a hydrogen atmosphere for 133 hours. To the residue obtained by concentration was added ethyl hexane acetate = 1/1, the insolubles were filtered, and the mixture was concentrated and purified by column chromatography (formaldehyde methanol = 20Z1). '2-Decarboxy-2-hydroxymethyl-15-deoxy15,15-difluoro-16-phenoxy-1-5,6-dihydro-17,18,19,20-tetranor? 0? _2a (compound 4) 1 74 mg, and 2-decarboxy-2-hydroxymethyl-15-dexoxy15,15-difluoro-16-phenoxy-5,6,13,14-tetrahydro-17,18 , 19,20-tetranor PGF _{2 ((} (Compound 5) 309 mg was obtained.

(Compound 4)

_{^ -NMR (CDC 1 3):} 6 1. 2- 1. 6 (m, 1 3 H), 1. 7 8- 1. 8 3 (m, 1 H), 2. 1 2 (ddd, J = 1 4. 9, 7. 6, 4. 7 Hz, 1 H), 2.39 (m, 1 H), 3.59 (t, J = 6.6 Hz, 2 H), 4.0 0 (m, 1H), 4.16-4. 21 (m, 3H), 5.77 (dt, J = 15.5, 11.3Hz, 1H), 6.08 (ddt, J = 15.8, 9.1, 2.6Hz, 1H), 6.91 (m, 2H), 6.99 (m, 1H), 7.29 (m, 2 H). ^{1 9} F - negation _{R (CDC 1 3): -} 1 0 3. (m).

(Compound 5)

_{^{! H-NMR (CDC 1 3}} ): 6 1. 2 - 2. 3 (m, 2 OH), 3. 6 0 (t, J = 6. 6H z, 2H), 3. 9 2 (m, 1 H), 4.12 (t, J = 11.7 Hz, 2H), 4.16 (m, 1H), 6.92 (m, 2H), 7.00 (t , J2 7.5Hz, 1H), 7.30 (m, 2H).

^{1 9 F-NMR (CDC 1} 3): - 1 0 5. 6 (m).

[Example 10] 15-Doxy-15,15-difluoro-9,11-bis (t-butyldimethylsilyloxy) _16-phenoxy-17,18,19,20- Tetranor PGF _2a isopropyl ester (hereinafter referred to as disilyl ether), and 15-deoxy-15,15-difluoro-11-t-butyldimethylsilyloxy-16-phenoxy-17,18,1 Synthesis of 9,20-tetranor PGF _2a isopropyl ester (hereinafter referred to as monosilyl ether) A solution of the isopropyl ester (12.00 g) synthesized in Example 5 in dimethylformamide (117 mL) was diluted to zero. After cooling, 2.65 g of imidazole and 5.32 g of t-butyldimethylsilyl chloride were added, and the mixture was heated to room temperature and stirred for 16 hours. Hexane / ethyl acetate = 1: 1 was added to the residue obtained by concentration, and insolubles were removed by filtration. The filtrate was concentrated, and the residue was purified by column chromatography (cloform formnomethanol = 20Zl) to obtain 2.38 g of disilyl ether and 8.95 g of monosilyl ether.

 (Disilyl ether)

_{^ -NMR (CDC 1 3):} δ - 0. 0 2 (s, 3 H), - 0. 0 1 (s 3H), 0. 0 3 (s, 3H), 0. 0 5 (s, 3 H), 0.84 (s, 9Η) 0.89 (s, 9H), 1.11 (d, J = 6.2, 6H), 1.43-2.5

3 (m, 12 H), 3.87 (m, 1 H), 4.12 (m, 1 H), 4. 17 (m, 1H), 4.98 (m, 1H), 5, 26-5.44 (m, 2H), 5.80 (dt, J = 15.5, 11.1Hz 1H) , 6.03 (m, 1H), 691 (m, 2H), 6.99 (m, 1H) _; 7.29 (m, 2H).

_{^{19 F- NMR (CDC 1 3)}} 03 2 (m).

 (Monosilyl ether)

_{^ -NMR (CDC 1 3) δ} 0. 03 (s, 3H), 0. 04 (s, 3 H), 0. 86 (s, 9H); 1. 22 (d, J = 6. 2, 6H ), 1.55—2.45 (m, 12H), 4.02 (m, 1H), 4.11—4.21 (m, 3H), 4.99 (m, 1H) _; 5.33—5.46 (m, 2H), 5.76 (dt, J = 14.9,]. 4Hz, 1H), 6.04 (ddt, J = 15.7, 9.2, 2.3Hz, H), 6.91 (m, 2H), 7000 (t, J = 7.

3H z H), 7.30 (m, 2H)-

_{^{9 F-NMR (CDC 1 3}} ): - 1 03. 3 (m)

[Example 1 1] 2-Decarboxy-2-hydroxymethyl-15-deoxy-15,15-difluoro-9,11-bis (t-butyldimethylsilyloxy) 1-16-phenoxy-17 Of 1,8,1,9,20-tetranor PGF _2a

 To a solution of the disilyl ether (2.38 g) synthesized in Example 10 in ether (25 mL) was added lithium aluminum hydride (792 mg) at -78. After 3 hours, the temperature was raised to 0 ° C, and the mixture was further stirred for 1 hour, and then ethyl acetate (20 mL) was added dropwise. Hydrochloric acid (1 mol ZL, 28 mL) was added, extracted with ethyl acetate, washed with water, dried and concentrated to obtain 2.27 g of the title compound.

 H-NMR (CDC 1 J: δ 0.03 (s, 3H), — 0.02 (s

3H), 0.02 (s, 3H), 0.05 (s, 3H), 0.83 (s, 9H) 0.89 (s, 9H), 1.32-2.53 (m , 1 2 H), 3.58 (t, J = 6-6 Hz, 2 H), 3.87 (dt, J = 8.1, 5.0 Hz, 1 H), 4 08-4.19 (m , 3H), 5.28—5.42 (m, 2H), 5.80 (dt, J = 15.5, 11.3Hz, 1H), 6.03 (m, 1H), 6.91 (d, J = 7. 5Hz, 2 H), 6. 99 (t, 1 H), 7. 29 (m, 2 H) 1 9 F- NMR (CDC 1 3): - 103. 2 (m) .

[Example 12] 2-Decarboxy-2-methoxymethyl-15-dexoxy15,15-difluoro-9,11-bis (t-butyldimethylsilyloxy) -1 16-phenoxy-1,17,18,19, Synthesis of 20-tetranor PGF _2a

 In a similar manner to Example 8, using the compound (0.93 g) obtained in Example 11, 337 mg of the title compound was obtained.

_{- NMR (CD C 1 3)} : δ - 0. 03 (s, 3H), - 0. 0 2 (s 3H), 0. 02 (s, 3 H), 0. 04 (s, 3 H), 0.83 (s, 9H) 0.89 (s, 9H), 1.31—2.52 (m, 12H), 3.30 (s, 3H), 3.33 (t, J = 6.6 Hz, 2 H), 3.86 (mt, 1 H), 4.08-4.1 9 (m, 3H), 5.27—5.40 (m, 2 H), 5.79 ( dt, J = 15.2, 11.3Hz, 1H), 6.02 (m, 1H), 6.91 (m, 2H), 6.98 (m, 1H), 7.28 (m , 2H).

_{^{19 F-NMR (CDC 1 3}} ): - 103. 2 (m).

[Example 13] 2-Decarpoxy 2-ethoxymethyl-15-Doxy-15,15-difluoro-9,11-bis (t-butyldimethylsilyloxy) -16 16-phenoxy-17,18,19,20 —Synthesis of tetranor PGF _2a

 Using the compound (0.202 g) obtained in Example 11 and tyl iodide (0.156 mL), 69 mg of the title compound was obtained in the same manner as in Example 8.

_{^{X H-NMR (CDC 1 3}} ): δ - 0. 02 (s, 3H), - 0. 0 1 (s 3H), 0. 02 (s, 3H), 0. 05 (s, 3H), 0 84 (s, 9H) 0.89 (s, 9H), 1.18 (t, J = 6.5 Hz, 3H), 1.25-162 (m, 6H), 1.96—2 27 (m, 5 H), 2.50 (m, 1 H), 3.37 (t, J = 6.7 Hz, 2 H), 3.44 (q, J = 7.0 Hz, 2 H) , 3.87 (m, 1 H), 4.10—4.19 (m, 3 H), 5.28—540 (m, 2 H), 5.79 (dt, J = 15.5 , 11.1 H z, 1 H), 6 03 (m, 1 H), 6.91 (d, J = 7.9 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1 H), 7.29 (m, 2 H)- _{^{1 9 F- NMR (CDC 1 3}} ): - 1 03. 2 (m).

[Example 14] Synthesis of 2-decarboxy-2-methoxymethyl-15-deoxy-15,15-difluoro-16-phenoxy-1 17,18,19,20-tetranor PGF _2u

 A solution of the compound obtained in Example 12 (327 mg) in acetonitrile (5 mL) was cooled to 0 ° C, a 46% aqueous hydrofluoric acid solution (1.0 mL) was added, and the mixture was stirred for 3 hours. Aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. Purification by silica gel column chromatography (hexane Z ethyl acetate = 1Z1) gave 167 mg of the title compound (compound 6).

(Compound 6)

^L H - field _{R (CDC 1 3): δ} 1. 35 - 1. 42 (m, 2 H), 1. 5 2- 1. 62 (m, 3H), 1. 81 (m, 1 H), 2.00-2.16 (m, 4H), 2.26-2.34 (m, 1H), 2.45 (m, 1H), 3.31

(s, 3H), 3.36 (t, J = 6.4Hz, 2H), 4.01 (m, 1H) 4.16-4.22 (m, 3H), 5.39 ( m, 2 H), 5.80 (dt, J = 15.8, 11.1 Hz, 1H), 6.10 (ddt, J = 15.8, 9.1 2.3 Hz, 1H ), 6.91 (m, 2H), 6.99 (m, 1H), 7.29

(m, 2H).

_{^{19 F-NMR (CDC 1 3}} ): - 103. 2 (m).

[Example 15] 2- Dekarubokishi 2 _ ethoxymethyl - 1 5 Dokishi 1 5, 15-difluoro chromatography: I 6- phenoxy one 17, 18, 19, 20-tetranor synthesis of P GF _2a

The title compound was obtained in the same manner as in Example 14 using the compound (69 mg) obtained in Example 13. (Compound 7) was obtained 35 mg _t

 (Compound Ί)

_{^ -NR (CDC 1 3):} (5 1. 1 9 (t J = 7. OH z, 3H), 1. 36 - 1. 45 (m, 2 H), 1. 53- 1. 66 (m , 3H), 1.82 (m, 1H), 2.01 -2.16 (m, 4H), 2.26 -2.36 (m, 1H), 2.45 (m, 1H) , 3.40 (m, 2H), 3.46 (Q, J = 7.0 Hz, 2H), 3.99-4.03 (m, 1H), 4.15-4.22 (m, 3H), 5.33-5.45 (m, 2H), 5.80 (dt, J = 15.5, 11.1 Hz, 1H), 6.10 (ddt, J = 15 .8, 9.1, 2.3 Hz, 1H), 6.91 (m, 2H), 7.00 (m, 1H), 7.30 (m, 2H) ¹⁹ F-NMR (CDC 1 ₃ ):-103.2 (m).

[Example 16] 2-Decarboxy-2-methoxymethyl-15-dexoxy-15,15-difluoro-16-phenoxy-1.5,6-dihydro-17,18,19,20-tetranor PGF ₂ . , And 2-Decarboxy-2-methoxymethyl-15-doxy-15,15-difluoro-16-phenoxy-1-5,6,13,14-tetrahydro-17,18,19,20-tetranor Synthesis of PGF _{2 2 Using} the compound obtained in Example 14 (115 mg), in the same manner as in Example 9, 2-decarboxy 2-methoxymethyl-15-dexoxy-15,15-difluoro-16 - phenoxy one 5, 6-dihydro-1 7, 18, 1 9, 20-tetranor PGF _{2 a} (compound 8) 28 mg, and 2-decarboxy - 2-methoxymethyl-1 5-Dokishi - 1 5, 1 5 There were obtained 64 mg of difluoro-16-phenoxy-5,6,13,14-tetrahydro-17,18,19,20-tetranor PGF _2a (compound 9). (Compound 8)

_{^ -NMR (CDC 1 3):} δ 1. 2- 1. 6 (m, 1 3H), 1. 83 (m, 1H), 2 · 1 0 (m, 1 H), 2. 40 (m, 1H), 3.32 (s, 3H), 3.34 (t, J = 6.6Hz, 2H), 4.02 (m, 1H), 4.16-4.22 (m, 3H), 5.78 (dt, J = 1 5.5, 11.1 lHz,

1H), 6.08 (ddt, J = 15.8, 9.1, 2.3Hz, 1H), 6.91 (d, J = 7.9Hz, 2H), 7-00 (t , J = 7.3Hz, 1H), 7.30 (m, 2H).

_{^{1 9 F- NMR (CDC 1 3}} ): - 1 03. 2 (m)

(Compound 9)

_{. W - NMR (CDC 1 3} ): δ 1. 2-2 3 (m, 1 8 H), 3 33 (s, 3 H), 3. 36 (t, J = 6. 6Hz, 2 H), 3.94 (m, 1H) 4.12 (t, J = 11.1Hz, 2H), 4.19 (m, 1H), 6.92 (m, 2H), 7.00 ( m, 1 H), 7.30 (m, 2 H).

^{1 9 F - NMR (CDC 1} 3): - 1 05. 6 (m).

[Example 17] 2-Decarboxy-2-acetoxymethyl-15-deoxy-15 _: 15-difluoro-9,11-bis (t-butyldimethylsilyloxy) 1-16 1-phenoxy-17, Synthesis of 18, 19, 20-tetranor PGF _2a

 Example 11 A solution of the compound obtained in 1 (200 mg) in methylene chloride (2 mL) was cooled to 0, and pyridine (0.039 mL), acetic anhydride (0.045 mL), and 4-dimethylaminopyridine (3.9 mg) were added. The mixture was heated to room temperature and stirred for 16 hours. Water was added, and the mixture was extracted with black-mouthed form. Silica gel column chromatography (acetic acid

= 1/1 0) to give 193 mg of the title compound. _{^ -NMR (CDC 1 3):} δ - 0. 02 (s, 3H), - 0. 0 1 (s 3H), 0. 03 (s, 3H), 0 05 (s, 3H), 0. 84 (s, 9H) 0.90 (s, 9H), 1.3-2 5 (m, 12H), 2.03 (s, 3H) 3.87 (m, 1H) 4.02 ( t J = 6.7 Hz, 2 H), 4.1 1-4.

20 (m, 3H), 527-5.43 (m, 2H), 5.80 (dt, J = 15.5, 11.1 Hz 1H), 6-03 (m, 1H), 6.91 (m, 2H) 6.99 (m, 1H) 7.29 (m, 2H).

_{^{1 9 F- NMR (CDC 1 3}} ): - 103. 2 (m).

[Example 18] Synthesis of 2-decarboxy-2-acetoxymethyl-15-deoxy15 15-difluoro-16-phenoxy-1,17,19,20-tetranor PGF _2a

 In a similar manner to Example 14 using the compound (193 mg) obtained in Example 17, 79 mg of the title compound (Compound 10) was obtained.

(Compound 10)

! H-NMR (CDC 1 Jδ… 39 (m, 2H), 1.57—1.64 (m, 3H), 1.82 (m, 1H), 2.03 (s, 3H) , 2.05—234 (m, 5H), 2.46 (m, 1H), 4.00—4.06 (m, 3H), 4.16-.22 (m, 3H) , 5.39 (m, 2H), 5.80 (dt, J = 15.5, 11.1 Hz, 1H), 6.10 (ddt, J = 15.5, 9.12.3) H z, 1H), 6 - 91 (m, 2 H), 7. 00 (t, J = 7. 3 Hz, 1 H), 7. 29 (m, 2H) - 1 9 F-NMR (CDC 1 ₃ ):-103.2 (m).

[Example 19] Synthesis of 15-dexoxy 15,15-difluoro-9-methoxy-11-tert-butyldimethylsilyloxy-16-phenoxy-1,17,18,19,20-tetranor PGF _2a isopropyl ester Using the monosilyl ether (6.00 g) obtained in Example 10 as in Example 8, 34 lmg of the title compound was obtained.

_{- NMR (CDC 1 3):} 6 - 0. 01 (s, 3H), 0. 00 (s, 3H), 0. 84 (s, 9H), 1. 2 1 (d, J = 6. 4Hz, 6H), 1.53—1.72 (m, 4H), 1.94-2.47 (m, 8 H), 3.23 (s 3H), 3.55 (m, 1 H), 3 90 (m, 1H), 4.13-4. 21 (m, 3H), 4.98 (m, 1H), 5.34 (m, 2H), 5.78 (dt J = 15.8, 11.1 Hz, 1H), 6.00 (m, 1H), 6.90 (m, 2H), 6.98 (m, 1H), 7.28 ( m, 2H).

_{^{19 F- NMR (CDC 1 3)}} : - 1 03. 2 (m).

[Example 20] Synthesis of 15-dexoxy 15, 15 difluoro-1- 9-methoxy-16 -phenoxy 17, 18,19,20-tetranor PGF _2a isopropyl ester

Using the compound (22 Omg) obtained in Example 19, and in the same manner as in Example 14, 187 mg of the title compound was obtained.

_{^{X H-NMR (CDC 1 3}} ):. Δ 1. 20 (d, J = 6. 2Hz, 6H), 1. 55 - 1. 67 (m, 3 H) 1. 89 -2 12 (m, 5 H), 2.20-2.43 (m, 4H) 3.27 (s, 3H), 3.62 (m, 1H), 3.94 (m, 1H), 4.7 (t , J = 1 1.6 Hz, 2H), 4.97 (m,

1H), 5.34 (m, 2H), 5.77 (dt, J = 15.8 11.1 Hz 1H), 6.08 (ddt, J = 15.5, 9. 1, 2.3 Hz, 1H), 6.90 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 7.27 (m, 2H).

_{^{19 F-NMR (CDC 1 3}} ): - 1 03. 2 (m).

[Example 2 1] 2-Decarboxy-2-hydroxymethyl-15-Doxy15 Synthesis of L 5-difluoro-9-methoxy-16-phenoxy-17,18,19,20-tetranor PGF _2a

 The title compound was obtained in the same manner as in Example 11 using the compound (94 mg) obtained in Example 20.

(Compound 11) 7 lmg was obtained.

(Compound 11)

 ^ -NMR (CDC 1 J: δ 3642 (m, 2 H), 1.5

1-1.64 (m, 3H), 1.89-2.11 (m, 5H), 2.31 (m, 1H), 2.42 (m, 1H), 3. 29 (s, 3H), 3.60 (t, J = 66Hz, 2H), 3.64 (m, 1H), 3.96 (m, 1H), 4.19 (t J = 11.6 Hz, 2H), 5.35 (m, 2H), 5.79 (dt, J = 15.8, 11.1 Hz, 1H), 6.09 (m, 1H), 6.91 (m, 2H), 699 (m, 1H), 7.29 (m, 2H).

^{1 9 F - NMR (CDC 1} 3): - 1 03. 2 (m).

[Example 22] 2-Decarboxy-2-hydroxymethyl-15-dexoxy 15: 15-difluoro-9-methoxy-11 1-t-butyldimethylsilyloxy-16-phenoxy-17,18,19 Of 2, 20-tetranor PGF _2a

 Using the compound (118 mg) obtained in Example 19, and in the same manner as in Example 11, 1 19 mg of the title compound was obtained.

_{^{: H-NMR (CDC 1 3}} ): 6 - 0. 0 1 (s, 3 H), 0. 0 1 (s, 3H), 0. 84 (s, 9H), 1. 36- 1. 41 ( m, 2 H), 1.5 0—

1.60 (m, 3H) 1.69 (ddd, J = 1.4, 5.6, 2.3Hz, 1H), 1.97-207 (m, 3H), 2. 1 5-2. 3 1 (m, 2 H), 2.44 (m, 1 H) 3.24 (s, 3 H), 3.55 -3.6.1 (m, 3 H), 3.9 1 (dt J = 8.2, 5.6 Hz, 1 H), 4.16 (m, 2

H), 5.35 (m, 2H), 5.78 (dt, J = 15.5, 11 Hz, 1H), 6.00 (m, 1H), 6.90 (m, 2H), 6.98 (t, J = 73Hz, 1H), 7.28 (m, 2H).

_{^{1 9 F- NMR (CDC 1 3}} ): - 1 03. 2 (m).

[Example 23] Synthesis of 2-decarboxy-2-acetoxymethyl-15-deoxy-1515-difluoro-9-methoxy-16-phenoxy-17,18,19,20-tetranor PGF _2a

Using the compound obtained in Example 22 (118 mg), 2-decalpoxy-2-acetoxymethyl-15-deoxy-15,15-difluoro-9-methoxy-11 in the same manner as in Example 11 one t-butyldimethylsilyl O carboxymethyl - 1 6-phenoxy one 1 7, 1 8, 19, to obtain a 20-tetranor P GF _2a 1 16 mg. This was treated in the same manner as in Example 14 to obtain 84 mg of the title compound (Compound 12).

(Compound 12)

_{^{] H-NMR (CDC 1 3}} ):. Δ 1. 34- 1. 42 (m, 2 H), 1 - 5 7- 1. 64 (m, 3H), 1. 90-2 1 0 (m, 8 H), 2.28-- 2.

36 (m, 1H), 2 39 -2.45 (m, 1H), 3.29 (s, 3H), 3.64 (m, 1H) 3.97 (m, 1H), 4. 03 (t, J = 6.7Hz 2H), 4.19 (t J = 11.6Hz 2H), 5.35 (m, 2H), 579 (dt, J = 1 55, 11.1 Hz 1 H), 6.09 (m, 1 H), 691 (m, 2H), 699 (t, J = 73 Hz, 1 H), 7.29 (m, 2 H).

_{^{19 F - NMR (CDC 1 3}} ): - 103 2 (m)

[Example 24] Synthesis of 15-deoxy15,15-difluoro-11-methoxy-16-phenoxy-17,18,19,20-tetranor PGF _2a isopropyl ester

Using the isopropyl ester synthesized in Example 5 (2.50 g), This gave 1.90 g of the title compound.

_{^ -NMR (CDC 1 3) 6} 1. 20 (d, J = 6. 2H z, 6 H), 1. 5 2 - 2. 5 5 (m, 1 2 H), 3. 2 9 (s, 3 H), 3.64 (m, 1 H), 4.13 (m, 1 H), 4.19 (t, J = 1 1.6 Hz, 2 H), 4.98 (m, 1 H 1 H), 5.38 (m, 2 H), 5.78 (dt, J = 1 5.5, 1 1-1 Hz, 1 H), 6.13 (m, 1 H), 6.90 (m, 2H), 6.99 (m, 1H), 7.28 (m, 2H).

_{^{19 F - NMR (CDC 1 3}} ): - 1 0 3. 3 (m).

[Example 25] 2-Decarboxy-2-hydroxymethyl-15-deoxy-15,15-difluoro-11-methoxy-1-16-phenoxy-17,18,19,20-tetranor PGF ₂ synthesis of _a

 Using the compound (192 mg) obtained in Example 24, 165 mg of the title compound (Compound 13) was obtained in the same manner as in Example 11.

(Compound 13)

_{W - NMR (CDC 1 3)} : (5 1. 3 5- 2. 2 0 (m, 5H), 2. 2 2 one 2. 5 5 (m, 4H) , 3. 2 7 (s, 3H) , 3.57 (t, J = 6.6Hz, 2H), 3.63 (m, 1H), 4.09 (m, 1H), 4.19 (t, J = 1 1.4 Hz, 2H), 5.37 (m, 2 H), 5.78 (dt, J = 15.7, 11.4 Hz, 1 H), 6.13 (dd, J = 15.7, 9.4Hz, 1H), 6.89 (d, J = 8.8Hz, 2H), 6.97 (t, J = 7.3Hz 1H), 7. 2 7 (m, 2 H)-

¹⁹ F - negation _{R (CDC 1 3): -} 1 0 3. 2 (m).

[Example 26] 2-Decarboxy-2-hydroxymethyl-15-doxy-1 15 15-difluoro-11-methoxy-1 16-phenoxy-1 5,6-dihydro-1 Synthesis of 7, 18, 19, 20-tetranor PGF _2u

Using 165 mg of the compound (compound 13) synthesized in Example 25, 102 mg of the title compound (compound 14) was obtained in the same manner as in Example 9.

(Compound 14)

_{! H-NMR (CDC 1 3} ):. 0 1. 2-2 5 (m, 16 H), 3. 3 0 (s, 3H), 3. 62 (t, J = 6. 6Hz, 2H), 3.66 (m, 1H) 4.16 (m, 1H), 4.20 (t, J = l l. 6Hz, 2H), 5.77 (dt, J = 15.5, 1 1.lHz , 1H), 6.13 (m, 1H), 6.91 (d, J = 8.8Hz, 2H), 7.01 (m, 1H), 7.30 (t, J = (7.8 Hz, 2H).

¹⁹ F—NMR (CDC 1 J: —103.3 (m).

[Example 27 (Formulation example)]

 A typical formulation example of eye drops and eye ointment using compound 6 synthesized in Example 14 is shown.

 1) Ophthalmic solution in 10 OmL

 Compound 61 Omg

 Concentrated glycerin 250 Omg

 Polysorbate 80 200 Omg

 Sodium dihydrogen phosphate dihydrate 20 Omg

 Sterile purified water

 1 N hydrochloric acid or 1 N sodium hydroxide

 PH 6.0

In the above formulation, the amount of compound 6 was changed, and the amount of the additive was appropriately increased or decreased, so that 0.0005% (wZv) ophthalmic solution, 0.0001% (w / v) ophthalmic solution, 0.0 01% (w / v) ophthalmic solution, 0.005% (w / v) ophthalmic solution, 0.05% (wZv) ophthalmic solution and 0.1% (wZV) ophthalmic solution can be prepared.

 In the above formula, instead of compound 6, compound 15 synthesized in Example 7, compound 3 synthesized in Example 8, compound 8 synthesized in Example 16, compound 10 synthesized in Example 18, and compound 21 synthesized in Example 21 Using Compound 11 or Compound 12 synthesized in Example 23, the amount of the additive was appropriately increased or decreased to give 0.0005% (w / v) ophthalmic solution, 0.0001% (w / V), respectively. Ophthalmic solution, 0.001% (wZV) Ophthalmic solution, 0.005% (w / v) Ophthalmic solution, 0.05% (w / v) Ophthalmic solution and 0.1% (wZv) ophthalmic solution Can be prepared.

2) 100 g of eye ointment

 Compound 6 0.1 g

 Liquid paraffin 20.0 g

 77.9 g of white Pserin

 Purified lanolin 2.0 g

 A similar eye ointment can be prepared using Compound 3, Compound 8, Compound 10, Compound 11, Compound 12, or Compound 15 instead of Compound 6 in the above formulation.

 [Example 28 (Pharmacological test)]

 In order to find usefulness of the compound of the present invention as a medicament for ocular diseases, the effect on intraocular pressure was examined.

 1) Influence on intraocular pressure

As an example of studying the effect of PGF _2a tromethamine salt, diisopropyl ester, on intraocular pressure, there is a report using a cynomolgus monkey (Exp. Eye Res., 61, 677-683 (1995)). Therefore, the effect of the compound of the present invention on intraocular pressure was examined by a single ophthalmic test according to the method described in the above literature.

 (a) Single point, eye test

 (experimental method)

Male cynomolgus monkeys weighing 5.6 to 7.7 kg (5 to 7 years old) were used for the experiment. The intraocular pressure was measured immediately before administration of the test compound and up to 8 hours after administration. The intraocular pressure was measured using an applanation tonometer without anesthesia.

 (Preparation of eye drops)

 A physiological saline solution of the test compound (Polysorbate 80 was used as a solubilizer) 0.005% (w / v) was used as an ophthalmic solution. In addition, a solution containing only the base without the test compound was used as a control.

 (Result)

 Table 15 shows an example of the experimental results.Compound 3, compound 6, compound 8, compound 10, compound 11, compound 12, or compound 15 each containing 0.005% (w / v) ophthalmic solution in one eye This shows the change over time of the intraocular pressure with respect to the initial intraocular pressure (the intraocular pressure immediately before instillation) when 20/1 was applied. The test results are the average of two cases. However, in the numerical unit in Table 15, lmmHg = 1 33.322 Pa.

 (Table 15)

As shown in Table 15, the compound of the present invention exhibited an excellent intraocular pressure lowering effect, and continuity of the intraocular pressure reduction was observed even 6 to 8 hours after instillation. The intraocular pressure lowering effect was superior to the control. This confirms that the compound of the present invention exhibits an excellent intraocular pressure lowering effect and is useful as an intraocular pressure lowering agent. Industrial potential>

 The present invention relates to a 15-dexoxy-15,15-difluoroprostaglandin in which the carboxy group at the 1-position is a hydroxyl group or a group derived from the hydroxyl group, and two fluorine atoms are bonded to the 15-position. A gin derivative and a medicament containing the prostaglandin derivative as an active ingredient, particularly a medicament for preventing or treating glaucoma, ocular hypertension and the like.

Claims

The scope of the claims

1. A 15-dexoxy-15,15-difluoroprostaglandin derivative represented by the following formula (1).

However, the symbols in the formula have the following meanings.

A: Ethylene, vinylene, ethinylene, one OCH ₂ —, or — S CH ₂ X: — CH ₂ —, —O—, or one S—.

P, Q: each independently, one CO—, one CH (OR ² ) one (R ² is independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 1 to 20 carbon atoms. ), Or one CH ₂ —. However, P and Q do not become one CO at the same time

R ′: 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 cycloalkyl group having 3 to 8 carbon atoms, an alkyl group, And a group selected from aryloxyalkyl groups, or a group in which one or more hydrogen atoms in the selected groups are substituted.

R ³ : a group selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group, an aralkyl group, and an acyl group, or a hydrogen atom in the selected group A group in which at least one is substituted.

R ^4, R ^5: each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, 2 carbon atoms

An alkenyl group having 6 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, or an aralkyl group.

 Overlap between solid and dashed lines: single bond, cis double bond, or trans double bond.

2. The prostaglandin according to claim 1, wherein A is an ethylene group or a vinylene group. Derivatives.

3. The prostaglandin derivative according to claim 1, wherein X is —CH ₂ —.

4. The method according to any one of claims 1 to 3, wherein one of P and Q is —CH (OR ² ) —, and the other is one CH (OR ² ) or —CH ₂ —. The prostaglandin derivative according to the above.

5. prostaglandin derivative according to claim 1 or Re noise R ² is a hydrogen atom or an alkyl group of carbon number 1-6.

6. The prostaglandin derivative according to any one of claims 1 to 5, wherein R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom.

7. R ³ is a hydrogen atom, an alkyl group prostaglandin derivative according to any les ^ deviation of claims 1 to 6 or an alkylcarbonyl group,.

8. The prostaglandin derivative according to any one of claims 1 to 7, wherein R ¹ is an aryloxyalkyl group or a group in which one or more hydrogen atoms in the aryloxyalkyl group are substituted.

9. The prostaglandin derivative according to any one of claims 1 to 8, wherein R ¹ is a phenoxymethyl group, a 3,5-dichlorophenoxymethyl group, or a 3-chlorophenoxymethyl group.

 10. A medicament comprising the prostaglandin derivative according to any one of claims 1 to 9 as an active ingredient.

 1 1. A medicament for preventing or treating an eye disease, comprising the prostaglandin derivative according to any one of claims 1 to 9 as an active ingredient.

 12. The medicament according to claim 11, wherein the eye disease is glaucoma or ocular hypertension.