JP2000080075A - 15-deoxy-15,15-difluoroprostaglandin derivative, and its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent physical properties and excellent physiological activities and useful as a medicine. SOLUTION: A prostaglandin derivative selected from the derivatives of 15-deoxy-15,15-difluoroprostaglandins E, D, I, A, B and J, or a salt thereof, preferably a prostaglandin derivative of formula I [A is ethylene or the like; X is CH2 or the like; R1 is a 3-8C alkyl or the like; P, Q are each CO or the like; Z is OR3 (R3 is H or the like) or the like] or its salt (excluding 13,14- dihydro-15-deoxy-15,15-difluoro-20-methylprostaglandin E1 methyl ester), for example, 15-deoxy-15,15-difluoroprostaglandin E2 ethyl ester. For example, 15- deoxy-15,15-difluoroprostaglandin E can be synthesized by protecting the 11- hydroxy group of a compound of formula II (R2 is H or an acyl), oxidizing the 9-hydroxy group and subsequently removing the protecting group from the 11-position.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 15-deoxy-1
It relates to a 5,15-difluoroprostaglandin derivative or a salt thereof.

[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 a living body, and are used as local hormones having various physiological activities in living tissues. Regulates cell function. Among them, in particular, PG which is a kind of natural PG
Class E has various actions related to pain and inflammation in addition to vasodilatory action, bronchodilatory action, gastric acid secretion inhibitory action, gastric mucosal protective action, uterine contractile action, etc. It is used as an agent and a labor-inducing agent. 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. Therefore, in order to develop these as new drugs, development of PG derivatives having higher effects and no side effects is being studied internally and externally. Further, as new indications of the PG derivative, drugs for treating osteoporosis, anticancer drugs, drugs for treating neurogenic inflammation, analgesics, antiallergic agents, and the like are being studied.

[0003] 15-deoxy-1 which is a derivative in which one fluorine atom is introduced at the 15-position of PG having a natural skeleton.
5-FluoroPGs have been reported by Bezglov et al. For example, 15-deoxy-15-fluoro PGA ₂ , 15-deoxy-15-fluoro PGB ₂
(Bioorg. Khim., 5 (10), 1531-
1536,1979), 15-deoxy-15-fluoro-PGF ₂ alpha, 15-deoxy-15-fluoro-PGE
₂ , 15-deoxy-15-fluoro PGI ₂ (Dok
l. Akad. Nauk SSSR, 250 (2), 4
68-469, 1980).

As far as the present inventor knows, 15-deoxy-15,15-difluoro PGs, which are derivatives in which two fluorine atoms have been introduced into the 15-position of PG, have been known as 1
Regarding 5-deoxy-15,15-difluoro PGEs, JP-A-7-70054 discloses 13,14-dihydro-1.
Only one synthesis example of 5-deoxy-15,15-difluoro-20-methyl PGE1 methyl ester is described, and its biological activity is not known at all.

[0005]

There are few reports on derivatives in which two fluorine atoms are introduced at the 15-position of PG.
Little is known about its synthesis method, physical properties, and biological activity. That is, for PGs having two fluorine atoms at the 15-position, 13,14-dihydro-
Only one example of 15-deoxy-15,15-difluoro-20-methyl PGE ₁ methyl ester was reported, and no PGDs, PGAs, PGBs, and PGJs were known.

[0006]

Means for Solving the Problems The present inventor synthesizes novel PGs in order to impart the unique properties of a fluorine atom to PGs, and examines them to clarify their physical properties and physiological activities. went. As a result, a novel 15-deoxy-15,15-difluoroPG derivative or a salt thereof in which two fluorine atoms are bonded to a carbon atom corresponding to the 15-position of the prostanoic acid skeleton is converted to a specific difluoroPGE or monofluoroPG It has been found that the compound has superior physical properties and physiological activity, and is a superior compound as a pharmaceutical.

That is, the present invention relates to 15-deoxy-1
Derivatives of 5,15-difluoroprostaglandin E,
Derivatives of 15-deoxy-15,15-difluoroprostaglandin D, derivatives of 15-deoxy-15,15-difluoroprostaglandin I, derivatives of 15-deoxy-15,15-difluoroprostaglandin A, 15- Deoxy-15, 15-difluoroprostaglandin B derivatives, and 15-deoxy-15,
A 15-deoxy-15,15-difluoroprostaglandin derivative selected from derivatives of 15-difluoroprostaglandin J, or a salt thereof (provided that 13,1
Excluding 4-dihydro-15-deoxy-15,15-difluoro-20-methylprostaglandin E ₁ methyl ester. )I will provide a.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following description of the present specification,
When the organic group is “lower”, it means having 1 to 6 carbon atoms. More preferred lower organic groups are organic groups having 1 to 4 carbon atoms.
The “alkyl group” may be linear or branched, and a lower alkyl group is preferable unless otherwise specified.
Suitable examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, 1-
Methylpentyl group, 1,1-dimethylpentyl group, 1-
Methylhexyl, 2-methylpentyl, and 2-
And a methylhexyl group.

The term "substituted alkyl group" refers to a group in which at least one hydrogen atom of the alkyl group has been substituted with a monovalent substituent, and examples of the substituent include a halogen atom, a cycloalkyl group, and a cycloalkyl group. Alkoxy, thienyl, substituted thienyl, furyl, aralkyloxy, thienyloxy, substituted thienyloxy, furyloxy, alkoxy, substituted alkoxy, thioalkoxy, or alkyl Amino groups and the like are preferred.

Unless otherwise specified, the "alkenyl group" is preferably a lower alkenyl group (2-6 carbon atoms), and particularly preferably a straight-chain or branched alkenyl group having one unsaturated bond in the group. . Suitable examples include vinyl, allyl, 1-propenyl, isopropenyl, 3-butenyl, 3-pentenyl, 4-hexenyl, 1-methyl-3-pentenyl, 1-methyl- Examples include a 3-hexenyl group, a 1,1-dimethyl-3-pentenyl group, a 1,1-dimethyl-3-hexenyl group, a 2-methyl-3-pentenyl group, and a 2-methyl-3-hexenyl group. "Substituted alkenyl group"
Refers to a group in which at least one hydrogen atom of an alkenyl group is substituted with a monovalent substituent, and the substituent is preferably a halogen atom, an alkoxy group, a thioalkoxy group, an alkylamino group, or the like.

The “alkynyl group” is preferably a lower alkynyl group (lower in the case of an alkynyl group means 2 to 6 carbon atoms) unless otherwise specified. Certain linear or branched alkynyl groups are particularly preferred. Suitable examples thereof include a 1-propynyl group, a 2-propynyl group, a 3-butynyl group, a 3-pentynyl group, a 4-hexynyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, 2-methyl-3-pentynyl group, 2-methyl-3-hexynyl group,
1,1-dimethyl-3-pentynyl group and 1,1-
And a dimethyl-3-hexynyl group. “Substituted alkynyl group” means one of the hydrogen atoms of an alkynyl group.
At least one group refers to a group substituted with a monovalent substituent, and the substituent is preferably a halogen atom, an alkoxy group, a thioalkoxy group, an alkylamino group, or the like.

The "cycloalkyl group" is preferably a 3- to 8-membered cycloalkyl group. The term "substituted cycloalkyl group" refers to a group in which one or more hydrogen atoms of a cycloalkyl group are substituted with a substituent. Examples of the substituent include a lower alkyl group, a halogen atom, and an alkoxy group. preferable. Preferred examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Preferable examples of the substituted cycloalkyl group include a methylcyclohexyl group, a dimethylcyclopentyl group, a dimethylcyclohexyl group, a chlorocyclohexyl group, and a dichlorocyclohexyl group.

"Aryl group" refers to a monovalent aromatic hydrocarbon group. “Substituted aryl group” refers to a group in which one or more hydrogen atoms in the aryl group have been substituted with a substituent. Examples of the substituent include lower alkyl groups, halogen atoms, halogenated alkyl groups, alkoxy groups, hydroxyl groups, acyl groups Group, an alkylamino group, an acylamino group, or a nitro group. As the aryl group, a phenyl group, a tolyl group, or a naphthyl group is preferable, and a phenyl group is particularly preferable.

Examples of the substituted aryl group include a halophenyl group (eg, chlorophenyl group, fluorophenyl group, bromophenyl group, etc.), a dihalophenyl group (eg, dichlorophenyl group, difluorophenyl group, dibromophenyl group, etc.), and a trihalophenyl group (eg, Trichlorophenyl group, trifluorophenyl group, tribromophenyl group, etc.), halogenated alkyl-substituted phenyl group (eg, trifluoromethylphenyl group), alkoxyphenyl group (eg, methoxyphenyl group, ethoxyphenyl group, etc.), dialkoxyphenyl Groups (eg, dimethoxyphenyl group, diethoxyphenyl group, etc.) and trialkoxyphenyl groups (eg, trimethoxyphenyl group, triethoxyphenyl group, etc.) are preferred.

The "aralkyl group" refers to an alkyl group substituted with an aryl group, and the aryl group as a substituent is preferably a phenyl group, a tolyl group, or a naphthyl group. The alkyl group in the aryl-substituted alkyl group preferably has 1 to 4 carbon atoms. Preferred examples of the aralkyl group include a benzyl group, a benzhydryl group,
Examples include a trityl group and a phenethyl group. "Substituted aralkyl group" refers to a group in which one or more hydrogen atoms of an aralkyl group are substituted with a substituent, and examples of the substituent include a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group, Examples include an acyl group, an acylamino group, and a nitro group.

The "aryloxyalkyl group" refers to an alkyl group substituted with an aryloxy group. As the aryloxy group as a substituent, a phenoxy group, a tolyloxy group, or a naphthyloxy group is preferable. “Substituted aryloxyalkyl group” refers to a group in which one or more hydrogen atoms of an aryloxyalkyl group have been substituted with a substituent. Examples of the substituent include a halogen atom, a halogenated alkyl group, an alkoxy group, Examples include a hydroxyl group, an acyl group, an acylamino group, and a nitro group.

As the "alkoxy group", generally used alkoxy groups are widely used, but lower alkoxy groups are preferable, and linear or branched alkoxy groups having 1 to 4 carbon atoms are more preferable. Suitable examples include methoxy, ethoxy, propoxy, and butoxy groups.

"Halogen" refers to fluorine, chlorine, bromine and iodine. “Halogenated alkyl group” refers to an alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms, and lower halogenated alkyl groups are preferred. Preferable examples thereof 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.

The term "acyl group" refers to a monovalent or polyvalent group formed by removing a hydroxyl group from all carboxyl groups of a carboxylic acid. Examples of the carboxylic acid include a saturated aliphatic carboxylic acid, an unsaturated aliphatic carboxylic acid, a carboxylic acid having a cyclic aliphatic hydrocarbon group, a carboxylic acid having a cyclic aromatic hydrocarbon group, and a carboxylic acid having a heterocyclic group. No. Examples of the carboxylic acid having a cycloaliphatic hydrocarbon group include carboxylic acids having a saturated or unsaturated cycloaliphatic hydrocarbon group.

The 15-deoxy-15,15-difluoroPG derivative of the present invention is 15-deoxy-15,15-
Derivative of difluoroprostaglandin E, derivative of 15-deoxy-15,15-difluoroprostaglandin D, derivative of 15-deoxy-15,15-difluoroprostaglandin I, 15-deoxy-15,1
5-Difluoroprostaglandin A derivative, 15-
A derivative selected from deoxy-15,15-difluoroprostaglandin B derivative and 15-deoxy-15,15-difluoroprostaglandin J derivative
-Deoxy-15,15-difluoroprostaglandin derivative or a salt thereof (provided that 13,14-dihydro-15-deoxy-15,15-difluoro-20-
Excludes methyl prostaglandin E ₁ methyl ester. ).

Preferred 15-deoxy-15,15 of the present invention
The 15-difluoro PG derivative is 15-deoxy-1
Derivatives of 5,15-difluoroprostaglandin E,
And 15-deoxy-15,1 selected from 15-deoxy-15,15-difluoroprostaglandin D
5-difluoroprostaglandin derivative or a salt thereof (provided that 13,14-dihydro-15-deoxy-
Excluding 15,15-difluoro-20-methyl-prostaglandin E ₁ methyl ester. ).

Further, the 15-deoxy-15,1 of the present invention
The 5-difluoro PG derivative is represented by the formula (1):
-Deoxy-15,15-difluoroprostaglandin derivative or a salt thereof (where A is an ethylene group, P
There -CO-, Q is -CH (OH) -, X is -CH ₂ -,
Compounds in which Z is OCH ₃ , R ¹ is an n-hexyl group, and the overlap between the solid line and the broken line is a single bond are excluded. Is preferred.

[0023]

Embedded image

However, the symbols in the formula (1) have the following meanings:
Is shown. A: ethylene group, vinylene group, ethynylene group, -OCH
_Two -Or -SCH _Two -. X: -CH_Two -, -O-, or -S-. Solid and dashed
Overlap: single bond, cis double bond, or trans double
Join. R¹ : An alkyl group having 3 to 8 carbon atoms, substituted 3 carbon atoms
Alkyl group of 8 to 8, alkenyl group of 3 to 8 carbon atoms, substitution
C3 to C8 alkenyl group, C3 to C8
A alkynyl group, a substituted alkynyl group having 3 to 8 carbon atoms,
C3-8 cycloalkyl group, substituted C3
~ 8 cycloalkyl groups, aralkyl groups, substituted
Aralkyl group, aryloxyalkyl group, or
Substituted aryloxyalkyl groups. P and Q: each independently represents -CO-, -CH (OR^Two )
-Or -CH_Two And P and Q are simultaneously -CO
-, Not -CH (OR^Two )-Not (just
Then R^Two Is independently a hydrogen atom or an acyl group
Is shown. ). Also, R^Two One of Z and Z is a single bond
May be formed. Z: -OR^Three , -NHCOR^Four , -NHSO_Two R^Five , −
SR⁶ Or -NR⁷ R⁸ . Also, R^Two Of one and Z and
May together form a single bond (provided that R
^Three , R^Four , R^Five , R⁶ , R⁷ , And R⁸ Respectively
Independently hydrogen atom, alkyl group, substituted alkyl
Group, alkenyl group, substituted alkenyl group, alkynyl
Group, substituted alkynyl group, cycloalkyl group,
Substituted cycloalkyl, aryl, substituted
Reel, aralkyl, or substituted aralkyl
Represents a kill group. ).

Hereinafter, a compound represented by the formula (1)
Also described as compound (1). ] Will be described. A in the formula (1) is preferably a vinylene group or an ethylene group. The vinylene group may be either a cis or trans form, preferably a trans vinylene group. When A is —OCH ₂ — or —SCH ₂ —, it is preferable that A is bonded to the ring by an oxygen atom or a sulfur atom. As X in the formula (1), -CH ₂ - are preferred.
The overlap between the solid line and the broken line in the formula (1) is a single bond, a cis double bond, or a trans double bond. The overlap between the solid line and the broken line is preferably a cis double bond.

R ¹ in the formula (1) has 3 to 8 carbon atoms.
An alkyl group, a substituted alkyl group having 3 to 8 carbon atoms,
An alkenyl group having 3 to 8 carbon atoms, a substituted 3 to 8 carbon atoms
Alkenyl group having 3 to 8 carbon atoms, substituted alkynyl group having 3 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, substituted cycloalkyl group having 3 to 8 carbon atoms, aralkyl Preferred are a group, a substituted aralkyl group, an aryloxyalkyl group, or a substituted aryloxyalkyl group.

When R ¹ is an unsubstituted group, it can be classified into a group having a chain structure and a group having a ring structure according to the structure of those groups. As the group having a chain structure, an alkyl group,
Alkenyl groups and alkynyl groups are preferred, and groups having a ring structure are preferably cycloalkyl groups, aralkyl groups, and aryloxyalkyl groups. When R ¹ is a group having a chain structure, an alkyl group having 5 to 8 carbon atoms,
Or an alkynyl group having 5 to 8 carbon atoms is preferable.

Specific examples of the case where R ¹ is a group having a chain structure include the following groups. n-propyl group, n-
Butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, 1-methylpentyl, 1,1-dimethylpentyl, 1-methylhexyl, 2- Methylpentyl, 2-methylhexyl, 3-pentenyl, 1-methyl-3-pentenyl, 1-methyl-3-hexenyl, 1,1-dimethyl-3-pentenyl, 1,1-dimethyl- 3-hexenyl group, 2-methyl-3-pentenyl group, 2-methyl-3
-Hexenyl group, 3-pentynyl group, 1-methyl-3-
Pentynyl group, 1-methyl-3-hexynyl group, 2-methyl-3-pentynyl group, 2-methyl-3-hexynyl group, 1,1-dimethyl-3-pentynyl group, 1,1-dimethyl-3-hexynyl Base.

Particularly preferred examples of R ¹ having a chain structure include n-pentyl, 1,1-dimethylpentyl, 2-methylhexyl, 1-methyl-3-pentynyl, 1-methyl -3-hexynyl group and 1,1-dimethyl-3-hexynyl group. As R ¹ which is a group containing a ring structure, a cycloalkyl group, an aralkyl group, or an aryloxyalkyl group is preferable.

When R ¹ is a cycloalkyl group, the cycloalkyl group preferably has 3 to 8 carbon atoms. As the cycloalkyl group, a cyclopentyl group or a cyclohexyl group is particularly preferred. When R ¹ is an aralkyl group, R ¹ is preferably an alkyl group having a phenyl group and having 1 to 2 carbon atoms, and is preferably a phenylmethyl group, a 2-phenylethyl group, a 2-methylphenylmethyl group, A methylphenylmethyl group, a 4-methylphenylmethyl group, a 2- (3-methylphenyl) ethyl group and the like are particularly preferred. When R ¹ is an aryloxyalkyl group, the aryl group is preferably a phenyl group, a tolyl group or a naphthyl group. Preferable examples of the group include a phenoxymethyl group and a 4-tolyloxymethyl group.

When R ¹ is a substituted group, it can be classified into a group having a chain structure and a group having a ring structure. When R ¹ is a group having a chain structure, examples thereof include a group having a chain structure substituted with a substituent having a chain structure. Examples of the group include a substituted alkyl group and a substituted alkenyl group. And substituted alkynyl groups are preferred. Suitable substituents in this case are a halogen atom, an alkoxy group and a substituted alkoxy group, and specifically, a 5,5,5-trifluoropentyl group, a 6,6,6-trifluorohexyl group, ,
2,2-trifluoromethylpentyl group, 2,2,2-
Examples include a trifluoromethylhexyl group, a butoxymethyl group, a pentoxymethyl group, a propoxymethyl group, a 3- (trifluoromethoxy) propyl group, and a 4- (trifluoromethyl) butoxy group.

On the other hand, when R ¹ is a substituted group and a group having a ring structure, examples thereof include a substituted (group containing a ring structure) and a group having a ring structure. Substituted groups are included. Further, as the substituted (group containing a ring structure), a group having one or more groups not containing a ring structure (for example, an alkyl group or the like) as a substituent is preferable.

Examples of the case where R ¹ is substituted (group containing a ring structure) include, for example, a substituted cycloalkyl group. The cycloalkyl group has 3 to 8 carbon atoms. As the substituted cycloalkyl group, a group in which at least one hydrogen atom of the cycloalkyl group is substituted with a lower alkyl group is preferable. R ¹ is a cyclopentyl group substituted with an alkyl group having 1 to 4 carbon atoms;
A cyclohexyl group substituted by an alkyl group having 1 to 4 carbon atoms is preferable.

Examples of the case where R ¹ is substituted (group containing a ring structure) include, for example, an aralkyl group substituted with R ¹ . As the substituent, a halogen atom, a halogenated alkyl group, an alkoxy group, or a hydroxyl group is preferable. Further, the alkyl portion of the aralkyl group (that is, the alkylene group) preferably has 1 to 4 carbon atoms. R ¹ is a lower alkyl group (1 or 2
), A halogenated alkyl group, and / or an alkyl group having 1 to 2 carbon atoms having a phenyl group substituted with a halogen atom (1 or 2), and a 3-trifluoromethylphenylmethyl group, 2- ( 3-trifluoromethylphenyl) ethyl group, 3-chlorophenylmethyl group, 2- (3-chlorophenyl) ethyl group, 2- (3
5-dichlorophenyl) ethyl group and 2- (3,4
-Dichlorophenyl) ethyl and the like are particularly preferred.

Examples of the case where R ¹ is substituted (group containing a ring structure) include, for example, an aryloxyalkyl group substituted with R ¹ . As the substituent, a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group, or the like is preferable, and an aryl group portion is preferably substituted. The aryl group portion is preferably a phenyl group or a naphthyl group. As the substituent, a halogen atom or a halogenated alkyl group is preferable, and the number of substituents is preferably 1 to 3. Further, the number of carbon atoms in the alkyl group portion is preferably 1 to 3. Preferred examples of the group include 3-chlorophenoxymethyl group, 3-fluorophenoxymethyl group, 3-trifluoromethylphenoxymethyl group, 3,5-dichlorophenoxymethyl group, 3,4
-Dichlorophenoxymethyl group, 3,5-difluorophenoxymethyl group, 3,4-difluorophenoxymethyl group, 3,5-bis (trifluoromethyl) phenoxymethyl group, and 3,4-bis (trifluoromethyl)
Phenoxymethyl group and the like.

In another embodiment in which R ¹ is a substituted group and a group having a ring structure, the group substituted with a group having a ring structure includes a ring structure. Preferred are an alkyl group substituted with a substituent, an alkenyl group substituted with a substituent having a ring structure, and an alkynyl group substituted with a substituent having a ring structure. Examples of the substituent having a ring structure include a cycloalkyl group, a thienyl group, a furyl group,
Aralkyloxy, cycloalkoxy, thienyloxy, substituted thienyloxy, furyloxy and the like are preferred. Preferred examples of the group include a cyclohexylmethyl group, a cyclopentylmethyl group, a benzyloxymethyl group, a cyclopentyloxymethyl group, a 2-thienyloxymethyl group, a 3-thienyloxymethyl group,
And a 2-furyloxymethyl group.

R ¹ is a natural or various non-natural PG
Groups corresponding to the ω chain portion of the class are preferred. Of these,
Particularly preferred R ¹ is an aryloxyalkyl group or a substituted aryloxyalkyl group, and is a phenoxymethyl group, 3-chlorophenoxymethyl group, 3,5-
A dichlorophenoxymethyl group or a 3- (trifluoromethyl) phenoxymethyl group is preferred.

P and Q in the formula (1) are as follows: P is -CO- and Q is -CH (OR ² )-or -CH _2- , or P is -CH (OR ² ) -Or -C
H ₂ - a is and when Q is -CO- are preferable.
R ^{2 in} P and Q each independently represents a hydrogen atom or an acyl group. R ² is preferably a hydrogen atom. Further, a compound in which R ² is an acyl group can be converted into a physiologically active compound by being hydrolyzed in a living body, and thus is useful as a prodrug. When R ² is an acyl group, the acyl group is preferably an acyl group having 2 to 20 carbon atoms, and particularly preferably an acyl group having 2 to 20 aliphatic hydrocarbons. In particular, a fluorine-containing PG derivative in which R ² is an acyl group of an aliphatic linear hydrocarbon group having 4 or more carbon atoms is useful as a prodrug having improved lipophilicity. In addition, one of R ² and Z may form a single bond together, and an embodiment in that case will be described later.

Z in the formula (1) is -OR ³ , -NHCO
R ⁴ , —NHSO ₂ R ⁵ , —SR ⁶ , or —NR ⁷ R ⁸
It is. Also, one of R ² and Z may form a single bond together (provided that R ³ , R ⁴ , R ⁵ , R
⁶ , R ⁷ and R ⁸ are each independently a hydrogen atom,
Alkyl group, substituted alkyl group, alkenyl group, substituted alkenyl group, alkynyl group, substituted alkynyl group, cycloalkyl group, substituted cycloalkyl group, aryl group, substituted aryl group, aralkyl group Or a substituted aralkyl group. ).

When R ^{3 to} R ⁸ are an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group or a substituted group thereof, they may be linear or branched. . When R ^{3 to} R ^{8 in} Z are each an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, or the like, the number of carbon atoms is preferably 20 or less, particularly preferably 8 or less. Also, R ^{3 to} R ⁸ are:
When these groups are substituted, these groups having 20 or less carbon atoms (preferably 8 or less carbon atoms) are preferably substituted groups. When R ^{3 to} R ⁸ in Z are each a substituted cycloalkyl group, a substituted aryl group, or a substituted aralkyl group, the substituent is preferably bonded to a ring. preferable.

Preferable examples of R ^{3 to} R ^{8 in} Z include the following groups. When each of R ^{3 to} R ⁸ is an alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an n-pentyl group, an n-hexyl group, Examples include an n-heptyl group, an n-octyl group, an n-decyl group, a 1-methylpentyl group, and a 2-methylhexyl group.

When each of R ^{3 to} R ⁸ is a substituted alkyl group, an alkyl group substituted with a halogen atom, an alkyl group substituted with an alkoxy group, an alkyl group substituted with a substituted alkoxy group, or a substituted alkyl group substituted with a cycloalkyl group. Preferred are alkyl groups. The alkyl group substituted with a halogen atom preferably has 1 to 6 carbon atoms. The alkyl group substituted with an alkoxy group and the alkyl group substituted with a substituted alkoxy group preferably have 1 to 6 carbon atoms. The carbon number of the alkyl group portion of the group is 1
To 2 are preferred. Examples of the halogen-substituted alkyl group include a trifluoromethyl group and a pentafluoroethyl group. Examples of the alkoxy-substituted alkyl group include a methoxymethyl group, a methoxyethyl group, a (methoxyethoxy) ethyl group, an ethoxyethyl group, a butoxymethyl group, and a butoxyethyl group. Substituted alkoxy group Examples of the substituted alkyl group include a (methoxyethoxy) ethyl group and a (ethoxyethoxy) ethyl group. Examples of the cycloalkyl-substituted alkyl group include a cyclobutylmethyl group,
Examples include a cyclopentylmethyl group and a cyclohexylmethyl group.

When R ^{3 to} R ⁸ are each an alkenyl group, allyl, 2-butenyl, 3-pentenyl,
Is mentioned. When each of R ^{3 to} R ⁸ is an alkynyl group, examples thereof include a propargyl group and a 3-pentynyl group.

When R ^{3 to} R ⁸ are each a cycloalkyl group, those having 3 to 10 carbon atoms are preferred. Specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 2,2-dimethylcyclopropyl group, a 3-cyclopenten-1-yl group,
A 3-cyclohexen-1-yl group, a cyclooctyl group and the like.

When R ^{3 to} R ⁸ are each an aryl group or a substituted aryl group, a phenyl group or a substituted phenyl group is preferred. The substituent in the substituted phenyl group is preferably an alkyl group (preferably having 1 to 4 carbon atoms), a methyl halide group, a halogen atom, an alkoxy group, an acyl group, an acylamino group, or a nitro group. Specific examples of the aryl group or the substituted aryl group include a phenyl group, a 4-methylphenyl group,
-(T-butyl) phenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 4-
Chlorophenyl group, 4-acetylphenyl group, 4-benzoylphenyl group, 4-acetylaminophenyl group, 4
-Benzoylaminophenyl group, 3-nitrophenyl group, 4-nitrophenyl group and the like.

When each of R ^{3 to} R ⁸ is an aralkyl group or a substituted aralkyl group, an aralkyl group having a phenyl group and having 4 or less carbon atoms (preferably 1 or 2 carbon atoms) is preferred. preferable. As the substituted aralkyl group, a group in which a substituted group is bonded to a phenyl group portion of an alkyl group having a phenyl group is preferable. As the substituent, an alkyl group (preferably having 4 or less carbon atoms), methyl halide A group, a halogen atom, an alkoxy group, an acyl group, an acylamino group, or a nitro group is preferred. The alkyl group portion of the aralkyl group or the substituted aralkyl group may have a branch. Preferred examples of the aralkyl group or the substituted aralkyl group include a benzyl group, a phenethyl group, a benzhydryl group, a trityl group, a 3-methylphenylmethyl group, and a 3-chlorophenylmethyl group.

As an example of a case where one of R ² and Z together form a single bond, a compound in which Z is OH and R ² is a hydrogen atom (that is, the terminal of the α chain is a carboxyl group and , A compound in which a hydroxyl group is bonded to at least one of the carbon atom at the 9-position and the carbon atom at the 11-position), and a compound formed by an esterification reaction between the carboxyl group and the hydroxyl group. Or an example of a compound in which the 11-position is cyclized with an ester bond. The compound cyclized by the ester bond is useful as a prodrug because it can be hydrolyzed in a living body and converted into a biologically active compound.

As R ^{3 in} Z, a hydrogen atom, an alkyl group, a cycloalkyl group and an aralkyl group are preferred. R
^{4 to} R ⁸ each represent a hydrogen atom, an alkyl group,
Cycloalkyl, aryl, and aralkyl groups, or substituted groups are preferred. The substituent in the substituted group is preferably a halogen atom or an alkyl group having 1 to 4 carbon atoms bonded to a ring.
Particularly, R ⁴ and R ^{6 to} R ⁸ are each preferably an alkyl group or a phenyl group, and R ⁵ is a lower alkyl group,
It is preferably a phenyl group or a trifluoromethyl group.

Further, Z is particularly preferably -OR ³ . R ³ is preferably a hydrogen atom, an alkyl group having 20 or less carbon atoms, a cycloalkyl group having 20 or less carbon atoms, or an aralkyl group having 20 or less carbon atoms. When R ³ is an alkyl group, a cycloalkyl group, or an aralkyl group, it is hydrolyzed in vivo,
Since it can be converted to a physiologically active compound, it is useful as a prodrug. In addition, the type of —OR ³ can be selected to improve the fat solubility of the compound.

Further, the most preferred embodiment when Z is -OR ³ is a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, an isobutoxy group, a cyclohexyloxy group, and a benzyloxy group.

In the present invention, 15-deoxy-15,1
The 5-difluoro PG derivative may form a salt. Examples of the salt include a salt with a base when the 15-deoxy-15,15-difluoroPG derivative has an acidic group such as a carboxyl group (for example, when Z is a hydroxyl group), or 15-deoxy-15,15- When the difluoro PG derivative has a basic group such as an amino group, a salt with an acid is exemplified.

Examples of the salt with a base include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts such as unsubstituted ammonium salts and alkyl-substituted ammonium salts. Is mentioned. As salts with acids, hydrochlorides, sulfates,
Examples thereof include inorganic acid salts such as phosphates, acetates, oxalates, citrates, succinates, and organic acid salts such as p-toluenesulfonate.

Next, 15-deoxy-15,15 of the present invention
A method for producing the 15-difluoro PG derivative will be described. The 15-deoxy-15,15-difluoro PG derivative can be synthesized by combining a skeletal synthesis method similar to a general method for producing PGs and fluorination. Specifically, various 1's mentioned as examples of the compound (1)
The 5-deoxy-15,15-difluoro PG derivative [the following formulas (1a) to (1f)] can be synthesized by the following method.

[0054]

Embedded image

The symbols in the formula have the same meanings as described above, and P ′
-CH (OR ²⁾ is -, or -CH ₂ -, Q '
Is —CH (OR ² ) — or —CH ₂ —. That is, compounds represented by the formulas (1a) to (1f) [hereinafter, described as compounds (1a). ] Is 15-deoxy -15,15- difluoro PGF ₂ alpha following formula is a derivative (2) with a compound represented by [hereinafter referred to as the compound (2). ] As a raw material. However, the symbols in the formula (2) have the same meaning as described above.

[0056]

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[Production Method of Compound (1a)] Compound (1a), which is a 15-deoxy-15,15-difluoro PGE derivative, protects the hydroxyl group at position 11 of compound (2) and then oxidizes the hydroxyl group at position 9 Then, it can be synthesized by deprotecting the 11-position.

[Production method of compound (1b)] The compound (1b), which is a 15-deoxy-15,15-difluoro PGD derivative, is obtained by protecting the 9-position of the compound (2),
It can be synthesized by oxidizing the position and deprotecting the 9 position.

[Production Method of Compound (1c)] Compound (1c), which is a 15-deoxy-15,15-difluoro PGI derivative, is obtained by subjecting compound (2) to a cyclization reaction with, for example, iodine or N-iodosuccinimide. And subjecting it to a dehydroiodination reaction.

[Production method of compound (1d) and compound (1e)] 15-deoxy-15,15-difluoroP
Compound (1d), which is a GA derivative, and 15-deoxy-15,15-difluoroPGB derivative (1
e) can be synthesized by subjecting compound (1a) to a dehydration reaction in the presence of an acid, a base, and other dehydrating agents. Similarly, compound (1f) can be synthesized by subjecting compound (1b) to a dehydration reaction. Compound (2), which is an important starting compound in the above production method, can be synthesized by the following method.

[Production Method of Compound (2)] Corey (C
orey) Using a lactone as a starting material, a fluorination reaction is carried out on a ketone (3) having the following ω chain into which an ω chain has been introduced using a Horner-Emmons reaction to obtain a fluorine atom 2 at the 15-position.
Ω-chain-containing corey lactones (4) are produced. Next, the lactone (4) is reduced to convert it into a lactol (5), and the lactol (5) is reacted with a phosphorane (6) to introduce an α chain, thereby obtaining a compound (2). And If desired, the carboxyl group can be converted to a desired ester, acylamide, thioester,
Converted to amide or the like to obtain compound (2). The phosphoranes (6) are obtained from the phosphonium salts (7).

[0062]

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R ⁹ and Y in the formulas (3) to (7) have the following meanings, and other symbols have the same meanings as described above. R ⁹ : an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, or a dialkylamino group. Y: a halogen atom such as a chlorine atom, a bromine atom and an iodine atom.

The ketone (3) in the method for producing the compound (2) is a known compound except that R ¹ is a specific substituent. The novel ketones (3) in which R ¹ is a specific substituted group can be produced by a method similar to known ketones. For example, ketones (3) can be prepared by reacting a dialkyl 3-substituted-2-oxopropylphosphonate with a corelylactone having a formyl group using a Horner-Emmons reaction.

A fluorination reaction is performed on ketones (3) to obtain ω
Various known fluorination methods can be applied to the chained corely 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 may be fluorinated during the fluorination reaction, it is preferable that the functional group in the ketone (3) is protected by a protecting group in advance. When R ² in the ketones (3) is a hydrogen atom, it is preferable that the carbonyl group at the 15-position is fluorinated by fluorination after protecting with a protecting group, and then deprotected.

The protecting groups for protecting the functional groups in the ketones (3) include triorganosilyl groups, acyl groups, alkyl groups, substituted alkyl groups, aralkyl groups, substituted aralkyl groups, and cyclic groups. Ether groups and the like. As the triorganosilyl group for protecting the functional group in the ketones (3), a group in which three groups selected from an alkyl group, an aryl group, an aralkyl group, and an alkoxy group are bonded to a silicon atom is preferable. A group in which three groups selected from an alkyl group and an aryl group are bonded to three silicon atoms is preferred. Preferred examples thereof include a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triethylsilyl group, a triphenylsilyl group, and a triisopropylsilyl group.

As the acyl group for protecting the functional group in the ketones (3), an acetyl group, a trifluoroacetyl group,
Pivaloyl, benzoyl, p-phenylbenzoyl and the like are preferred. As the acyl group, the same acyl group as R ² in the formula (1) or a different acyl group may be used. When obtaining a 15-deoxy-15,15-difluoro PG derivative (1) having a different acyl group, a desired acyl group may be newly introduced after deprotection of the protecting group.

As the cyclic ether group for protecting the functional group in the ketones (3), a tetrahydropyranyl group or a tetrahydrofuranyl group is preferable. Examples of an alkyl group, an aralkyl group, or a group having a substituent that protects a functional group in the ketones (3) include a methoxymethyl group, a 1-ethoxyethyl group, and a 2-methoxyethoxymethyl group. Examples include an alkoxyalkyl group, a benzyl group, a methoxybenzyl group, and a trityl group.

The above protecting group for a hydroxyl group can be converted into a hydroxyl group by a conventional method. For example, "New Experimental Chemistry Course 1
Synthesis and Reaction of Four Organic Compounds (I), (II), (V) "
(Maruzen), "Protective Groups in Organic Synthesis" (TW Greene,
J. (Wiley & Sons) and the like.

When the ketones (3) are fluorinated to produce the corely lactones (4) with an ω chain, it is preferable to fluorinate using a fluorinating agent. The fluorination reaction is preferably performed in an inert solvent. Further, the fluorination may be performed in the presence of a base. The reaction temperature of the fluorination reaction is usually preferably about -150 ° C to + 100 ° C, particularly preferably -80 ° C to + 60 ° C.

As the fluorinating agent used in the fluorination reaction, a known or well-known nucleophilic fluorinating agent can be used. For example, a nucleophilic fluorinating agent described in "Fluorine Chemistry" by Koya Kitazume, Takashi Ishihara and Takeo Taguchi (Kodansha Scientific) can be used. Specifically, trifluoro (substituted amino) sulfur compounds, tetrafluorophenylphosphorane, fluoroalkylamine reactants such as diethylamine-chlorotrifluoroethene adduct and diethylamine-hexafluoropropene adduct, HF-pyridine and HF- Hydrogen fluoride amine complexes such as triethylamine, silicon tetrafluoride, sulfur tetrafluoride, potassium fluoride,
Examples thereof include metal fluorides such as cesium fluoride and silver fluoride, and ammonium salts and phosphonium salts such as tetrabutylammonium fluoride, tetraethylammonium fluoride and tetrabutylphosphonium fluoride. In general, the amount of the fluorinating agent is preferably about 0.5 to 20 times the weight of the ketone (3), particularly preferably 1 to 5 times.
Double weight is preferred.

In the fluorination reaction of the ketone (3) with the fluorinating agent, the carbonyl group in the ketone (3) can be directly fluorinated. In the fluorination reaction, the carbonyl group of the ketones (3) may be preliminarily derivatized to give an oxime, hydrazone, thioacetal, diazo compound, or the like in order to increase reactivity or suppress side reactions. These derivatization methods are described in Olah et al. (Synlett., 594, 1990, Synl.
ett. , 425, 1994), Katzenelle.
nbogen et al. (J. Org. Chem., 5).
1, 3508, 1986), the method of Hiyama et al.
tt. , 909, 1991) and the method of Fujisawa et al.
uorine Chem. , 71, 9, 1995) can be applied.

The method for fluorinating ketones (3) is a method in which ketones (3) are directly fluorinated using a nucleophilic fluorinating agent without derivatization in terms of yield and selectivity. It is preferable to carry out. Particularly preferred nucleophilic fluorinating agents in the method are trifluoro (substituted amino) sulfur compounds, specifically morpholinosulfatrifluoride, piperidinosulfatrifluoride, diethylaminosulfatrifluoride, and dimethylaminosulfur Trifluoride and the like.

As the inert solvent which can be used for the fluorination reaction of the ketone (3), a halogen solvent, an ether solvent, a hydrocarbon solvent, an ester solvent, a polar solvent, or a mixed solvent thereof is preferable. In general, the amount of the inert solvent is preferably about 2 to 500 times, more preferably 5 to 100 times the weight of the ketone (3).

As the halogen-based solvent which can be used for the fluorination reaction of the ketones (3), methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene, dichloropentafluoropropane and the like are preferable. As ether solvents that can be used for the fluorination reaction of ketones (3), diethyl ether, tetrahydrofuran [THF], 1,4-dioxane, dimethoxyethane, diglyme, t-butyl methyl ether, and the like are preferable. Hexane, toluene, benzene, pentane, xylene, petroleum ether, and the like are preferable as the hydrocarbon solvent that can be used in the fluorination reaction of the ketones (3).

As the ester solvent that can be used for the fluorination reaction of the ketones (3), ethyl acetate, butyl acetate and the like are preferable. Examples of polar solvents that can be used for the fluorination reaction of ketones (3) include dimethyl sulfoxide, hexamethylphosphoramide [HMPA], 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)- Pyrimidinone [DMPU], 1,3-dimethyl-2-imidazolidinone [DMI], N, N, N ', N'-tetramethylethylenediamine [TMEDA], and the like are preferable ([] is an abbreviation). Among these, particularly preferred solvents that can be used for the fluorination reaction of ketones (3) are methylene chloride, chloroform, 1,2-dichloroethane, toluene and the like.

As the base that can be used in the fluorination reaction of the ketones (3), amines such as tertiary amines or aromatic amines, and salts of alkali metals or alkaline earth metals are preferable. Specific examples of the base include triethylamine,
Examples include diisopropylethylamine, pyridine, 2,6-lutidine, dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like.

Next, the lactone with ω chain (4) produced by the fluorination reaction of the ketone (3) is reduced to lactol (5). As a method for reducing the ω-chain-attached lactone (4), a method in which a reducing agent is allowed to act in an inert solvent is preferable. The methods include “New Experimental Chemistry Lecture 15 Oxidation and Reduction (II)” (Maruzen), “Experimental Chemistry Lecture 26 (No. 4)
Edition) Organic Synthesis VIII, Asymmetric Synthesis, Reduction, Sugar, Labeled Compounds ”(Maruzen) and the like.

The reduction reaction of the ω-chain-containing lactone (4) is preferably performed using a reducing agent. The amount of the reducing agent is preferably from 0.01 to 50 equivalents, more preferably from 1 to 20 equivalents, based on the ω-chain-attached lactone (4). Reaction temperature is -1
About 50 ° C. to + 100 ° C., particularly preferably −80 ° C. to 0 ° C.

Examples of the reducing agent which can be used in the reduction reaction of the lactones with an ω chain (4) include diisobutylaluminum hydride [DIBAH], dialkylaluminum alkoxide, lithium aluminum hydride, tributyltin hydride, triphenyltin hydride and triethyltin. Silane, trichlorosilane, dimethylphenylsilane, diphenylsilane, sodium borohydride, sodium trimethoxyborohydride, lithium tri (s-butyl) borohydride, potassium tri (s-butyl) borohydride, lithium triethylborohydride , Lithium trisiamyl borohydride, potassium trisiamyl borohydride, zinc borohydride, calcium borohydride, lithium trialkoxyaluminum hydride, bis (2-methoxyethoxy) al hydride Bromide sodium, diborane, disiamylborane, thexylborane and 9-borabicyclo [3.3.1] nonane and the like, diisobutylaluminum hydride [DIBAH], sodium bis (2-
Preferred are sodium methoxyethoxy) aluminum, disiamylborane, or lithium tri (s-butyl) borohydride.

The reduction reaction of the lactone (4) with an ω chain is preferably carried out 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. As the inert solvent, ether solvents, hydrocarbon solvents, or polar solvents described as specific examples in the description of the fluorination reaction are preferable, and diethyl ether, THF, t-butyl methyl ether, and toluene are particularly preferable. . Next, the lactols (5) generated by the reduction reaction of the lactones (4) with an ω chain are reacted with the phosphoranes (6). The configuration of the hydroxyl group present in the lactols (5) is not particularly limited.

The phosphoranes (6) can be produced by reacting the corresponding phosphonium salts (7) with a base in an inert solvent. Usually, phosphoranes (6)
Is subjected to Wittig reaction with lactols (5) without isolation. As the inert solvent and the base, those similar to the Wittig reaction described later are preferably used. As the method, "New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I)" (Maruzen), "Experimental Chemistry Course 19 (4th
Edition) Organic Synthesis I, Hydrocarbon and Halogen Compounds ”(Maruzen)
Etc., the method of Schaaf et al.
Med. Chem. , 22, 1340, 1979).

Z in the phosphoranes (6) and the phosphonium salts (7) has the same meaning as Z in the formula (1), and Z represents a hydroxyl group (that is, -O wherein R ³ is a hydrogen atom).
R ³ ) is preferred. Specific examples of the phosphonium salts (7) include the following compounds.

(4-carboxybutyl) triphenylphosphonium bromide, (4-carboxy-3-oxabutyl) triphenylphosphonium bromide, [4- (N
-Methanesulfonyl) carbamoylbutyl] triphenylphosphonium bromide, [4- (N-benzoyl) carbamoylbutyl] triphenylphosphonium bromide, (4-carboxybutyl) tri (o-tolyl) phosphonium bromide, (4-carboxybutyl) trim (M
-Tolyl) phosphonium bromide, (4-carboxybutyl) tri (p-tolyl) phosphonium bromide.

Phosphoranes (6) formed by reacting phosphonium salts (7) with a base in an inert solvent
Is preferably reacted with the lactols (5) without isolation. The amount of the phosphoranes (6) to be used is preferably about 0.1 to 20 equivalents, more preferably 1 to 10 equivalents, to the lactols (5).

Lactols (5) and phosphoranes (6)
Is a known reaction generally called a Wittig reaction. The reaction of the lactols (5) and the phosphoranes (6) in the present invention can employ the conditions usually used for this Wittig reaction, and it is particularly preferable to carry out the reaction in the presence of a base. It is preferred to carry out. The reaction temperature of the Wittig reaction is usually preferably about -150 ° C to + 200 ° C, particularly preferably -80 ° C to + 100 ° C.

The amount of the base that can be used in the Wittig reaction is usually 1 to 2 with respect to the lactol (5).
About 0 equivalent is suitable, and 2 to 10 equivalent is preferable. In addition, as a base that can be used in the Wittig reaction,
The selection is preferably made in consideration of the acidity of hydrogen bonded to the carbon at the α-position of the phosphorus atom of the phosphonium salt (7), the stability of the phosphorane (6), and the like.

Bases usable in the Wittig reaction include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, 1,5- Diazabicyclo [4.3.0] non-5-ene, 1,8-
Diazabicyclo [5.4.0] undec-7-ene, potassium t-butoxide, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, lithium 2,2,6 , 6-tetramethylpiperidine, lithium bis (trimethylsilyl) amide, sodium diethylamide, sodium bis (trimethylsilyl) amide, potassium 3-aminopropylamide, potassium bis (trimethylsilyl) amide, lithium hydride, sodium hydride, potassium hydride, Sodium methylsulfinyl methylide, n-butyllithium, s-
Butyllithium, t-butyllithium, methyllithium, phenyllithium, lithium naphthalenide, lithium biphenylide, and sodium trityl are preferred.

Further, as the base, potassium carbonate,
Potassium t-butoxide, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium bis (trimethylsilyl) amide, Sodium diethylamide, sodium bis (trimethylsilyl) amide, potassium 3-aminopropylamide, potassium bis (trimethylsilyl) amide, sodium methylsulfinylmethylide are preferred, and potassium t-
Butoxide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and sodium methylsulfinylmethylide are particularly preferred.

The inert solvent usable in the Wittig reaction includes ether solvents, hydrocarbon solvents, polar solvents,
An aqueous solvent, an alcohol solvent, or a mixed solvent thereof is preferable. The amount of the inert solvent used is usually 5 to 100 parts by weight based on 1 part by weight of the lactol (5).
It is preferably about 0 parts by weight, particularly preferably 10 to 100 parts by weight. As specific examples of the ether-based solvent, the hydrocarbon-based solvent, and the polar solvent, the same solvents as the examples in the above-described specific examples of the inert solvent that can be used for the fluorination reaction are preferable. As the aqueous solvent, water or a mixed solvent of water and an alcohol solvent is preferable. As the alcohol solvent, methanol, ethanol, t-butanol, t-amyl alcohol and the like are preferable. Examples of ether solvents include diethyl ether, THF, 1,2-dimethoxyethane,
t-Butyl methyl ether or toluene is preferred.

Lactols (5) and phosphoranes (6)
When a compound in which Z in the phosphoranes (6) is a hydroxyl group is used in the reaction with, a compound of the formula (2) in which Z is a hydroxyl group is obtained. When it is desired to obtain a compound of the formula (2) in which Z is a group other than a hydroxyl group, it is preferable to convert the compound of the formula (2) in which Z is a hydroxyl group.

However, a method in which Z in the phosphoranes (6) is a group other than a hydroxyl group may be used to produce a compound of the formula (2) in which Z is other than a hydroxyl group.
The method includes the following example. That is, when Z is -N
HcOR ⁴ or -NHSO ₂ with R ⁵ a is a phosphonium salt (7), to convert it into phosphoranes (6), -NHCOR ⁴ in the resulting phosphorane compound (6)
And a hydrogen atom bonded to the nitrogen atom of —NHSO ₂ R ⁵
May be converted to metal ions. When the phosphoranes (6) converted to metal ions and the lactols (5) are reacted by the Wittig reaction described below, the corresponding portions in the reaction products are metal ions. The metal ion is a metal ion (for example, an alkali metal ion or an alkaline earth metal ion) derived from a base used when converting the phosphonium salt (7) into the phosphorane (6), and the phosphorane containing the metal ion In (6), the compound of formula (2) can be synthesized by converting the metal ion portion into a hydrogen atom by a treatment such as hydrolysis.

The 15- represented by the formula (2) or (1)
The deoxy-15,15-difluoro PG derivative can convert the Z moiety to another Z if necessary. For example, when Z is a hydroxyl group, the carboxylic acid (-
COZ) can be converted to esters, salts of carboxylic acids, N-acylamides, amides, thioesters, and the like.

As a method for esterifying the carboxylic acid (—COZ), for example, a method described in “Shin Jikken Kagaku Koza 14 Synthesis and Reaction of Organic Compounds (II)” (Maruzen) can be employed. For example, esterification by condensation with alcohols or phenols, esterification with an O-alkylating agent, esterification using alkenes or alkynes,
Examples include esterification using dialkyl sulfates and halogenated hydrocarbons.

As a method for converting the carboxylic acid (—COZ) of the compound (1) in which Z is a hydroxyl group into an N-acylamide or an amide, for example, the method of Titherley et al. (J. Chem. Soc., 85, 1673) , 19
04), the method of Lynch et al. (Can. J. Che.
m. , 50, 2143, 1972), Davidson
(J. Am. Chem. Soc., 80, 37).
6, 1958) can be employed. Further, a method of converting a carboxylic acid (—COZ) of the compound (1) in which Z is a hydroxyl group into an acid halide or an active ester and then directly performing a condensation reaction with an amide or a sulfonamide, or a reaction with an amine. And then once converted to amides, followed by acylation or sulfonylation.

A method for converting the compound (1) in which Z is a hydroxyl group into thioesters is described in "New Experimental Chemistry Course 14".
"Synthesis and Reaction of Organic Compounds (III)" (Maruzen), "Protective Groups in Organic Synthesis" (TW Greene, J. Wiley & S.)
ons) or the like. For example, Z
Is a carboxylic acid (-COZ) of the compound (1) wherein
Is converted into an acid halide or an active ester, and then reacted with a thiol to form a thioester group.

In the method for producing the compound (1a), as a method for oxidizing the hydroxyl group at the 9-position, a known oxidation reaction can be employed.
-1), (I-2) "(Maruzen)," Experimental Chemistry Course 23 "
(4th edition) Organic Synthesis V "(Maruzen) and the like. As the oxidation method, chromic acid oxidation and oxidation with dimethyl sulfoxide are preferable.
Preferred are es oxidation, Collins oxidation, oxidation with pyridinium chlorochromate, and Swern oxidation. In the method for producing the compound (1b), the same oxidation reaction as described above can be employed as the method for oxidizing the hydroxyl group at the 11-position.

Compound (1c) when it is a 15-deoxy-15,15-difluoro PGI ₂ derivative is
15-deoxy -15,15- difluoro PGF ₂ alpha derivative (2) can be synthesized by cyclizing. The cyclization reaction is carried out by (method 1) cyclization using iodine, N-iodosuccinimide or N-bromosuccinimide, and then dehydrohalogenation in the presence of a base, (method 2) mercury A method of obtaining a cyclized intermediate with a compound and then reducing the mercury compound can be employed.

The base in (Method 1) includes triethylamine, diisopropylethylamine, pyridine,
N-methylmorpholine, 1,5-diazabicyclo [4.
An amine base such as [3.0] non-5-ene or 1,8-diazabicyclo [5.4.0] undec-7-ene is preferred.

In addition, 15-deoxy-15,15-
The difluoro PGE derivative is dehydrated to give 15-deoxy-1
A method for preparing a 5,15-difluoro PGA derivative or a 15-deoxy-15,15-difluoro PGB derivative,
The 15-deoxy-15,15-difluoro PGD derivative is dehydrated to give 15-deoxy-15,15-difluoro P
Various known dehydration reactions can be employed as a method for preparing a GJ derivative. The dehydration reaction is preferably performed in the presence of a dehydrating agent, and particularly preferably a known dehydrating agent is used.
The dehydration reaction can be carried out by the method described in "New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I)" (Maruzen).

For example, the dehydration reaction is preferably carried out using an acid, a base, a halogenating agent, a sulfonating agent or an esterifying agent, a drying agent and the like. Hydrochloric acid, sulfuric acid, acetic acid,
One or more selected from amines such as sodium hydroxide, potassium hydroxide, pyridine, triethylamine and diisopropylethylamine, phosphoryl chloride, thionyl chloride, methanesulfonyl chloride, acetic anhydride, acetyl chloride, and phosphorus pentoxide are used.

Specific examples of the compound (1) are described below, but it should not be construed that the invention is limited thereto. [Specific examples of 15-deoxy-15,15-difluoro-PGE ₂ derivative] 15-deoxy-15,15-difluoro-PGE ₂ methyl ester, 15-deoxy-15,15
15-difluoro-PGE ₂ ethyl ester, 15-deoxy-15,15-difluoro-PGE ₂ isopropyl ester, 16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₂ methyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGE ₂ ethyl ester, 16- (3,5
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GE ₂ isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₂ methyl ester,
16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGE ₂ ethyl ester, 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GE _2- isopropyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-
17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₂ ethyl ester, 16- (3-
Chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE
₂ isopropyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₂ methyl ester, 16- (3-trifluoromethylphenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₂ ethyl ester,
16- (3-trifluoromethylphenoxy) -15-
Deoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₂ isopropyl ester,
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₂
Methyl ester, 16-phenoxy-15-deoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₂ ethyl ester, 16-phenoxy-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₂ isopropyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGE
_2- methyl ester, 17-phenyl-15-deoxy-
15,15-difluoro-18,19,20-trinor PGE ₂ ethyl ester, 17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinor PGE ₂ isopropyl ester, 15-deoxy-15, 15-difluoro-13,14-dihydroPG
E ₂ methyl ester, 15-deoxy-15,15-difluoro-13,14-dihydroPGE ₂ ethyl ester, 15-deoxy-15,15-difluoro-13,
14-dihydro PGE ₂ isopropyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
E ₂ methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₂ ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3,4-
Dichlorophenoxy) -15-deoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGE ₂ methyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₂ Isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₂
Ethyl ester, 16- (3-chlorophenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGE
_2- isopropyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,2
0-tetranor PGE ₂ methyl ester, 16- (3-
Trifluoromethylphenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGE
₂ isopropyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ methyl ester, 16-phenoxy-15-deoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGE ₂ ethyl ester, 16-
Phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₂ isopropyl ester, 17-phenyl-15-deoxy-15,15-difluoro-13,13
14-dihydro-18,19,20-trinor PGE ₂
Methyl ester, 17-phenyl-15-deoxy-1
5,15-difluoro-13,14-dihydro-18,
19,20-trinor PGE ₂ ethyl ester, 17-
Phenyl-15-deoxy-15,15-difluoro-
13,14-dihydro-18,19,20-trinor P
GE ₂ isopropyl ester.

15-Deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GE _2- methyl ester, 15-deoxy-15,15-
Difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ ethyl ester, 15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₂ isopropyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ methyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ ethyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3,4-dichlorophenoxy) -1
5-deoxy-15,15-difluoro-3-oxa-
17,18,19,20-tetranor PGE ₂ ethyl ester, 16- (3,4-dichlorophenoxy) -15
-Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3-chlorophenoxy) -15
Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGE ₂ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ ethyl ester,
16- (3-chlorophenoxy) -15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₂ isopropyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGE ₂
Methyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-
3-oxa-17,18,19,20-tetranor PG
E ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16-phenoxy-1
5-deoxy-15,15-difluoro-3-oxa-
17,18,19,20-tetranor PGE ₂ methyl ester, 16-phenoxy-15-deoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGE ₂ ethyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ isopropyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-3-oxa-18,19,20-trinor PGE ₂ methyl ester, 17-phenyl-15
-Deoxy-15,15-difluoro-3-oxa-1
8,19,20-trinor PGE ₂ ethyl ester, 1
7-phenyl-15-deoxy-15,15-difluoro-3-oxa-18,19,20-trinor PGE ₂
Isopropyl ester, 15-deoxy-15,15-
Difluoro-11-pivaloyl PGE ₂ methyl ester, 15-deoxy-15,15-difluoro-11-
Pivaloyl PGE ₂ ethyl ester, 15-deoxy-
15,15-Difluoro-11-pivaloyl PGE ₂ isopropyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranor PGE ₂
Methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-11
-Pivaloyl-17,18,19,20-tetranor P
GE _2- ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-
11-pivaloyl-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20
-Tetranor PGE ₂ methyl ester, 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-11-pivaloyl-17,18,19,
20-tetranor PGE ₂ ethyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-11-pivaloyl-17,1
8,19,20-tetranor PGE ₂ isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-11-pivaloyl
-17,18,19,20-tetranor PGE_Two Methyl
Ester, 16- (3-chlorophenoxy) -15-de
Oxy-15,15-difluoro-11-pivaloyl-
17,18,19,20-tetranor PGE_Two Ethyl et
Stele, 16- (3-chlorophenoxy) -15-deo
Xy-15,15-difluoro-11-pivaloyl-1
7,18,19,20-tetranor PGE_Two Isopropyl
Ester, 16- (3-trifluoromethylphenoxy)
B) -15-deoxy-15,15-difluoro-11
-Pivaloyl-17,18,19,20-tetranor P
GE_Two Methyl ester, 16- (3-trifluoromethyl
Rufenoxy) -15-deoxy-15,15-diflu
Oro-11-pivaloyl-17,18,19,20-te
Tranor PGE_Two Ethyl ester, 16- (3-trif
(Fluoromethylphenoxy) -15-deoxy-15,1
5-difluoro-11-pivaloyl-17,18,1
9,20-tetranor PGE _Two Isopropyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-11-pivaloyl-17,1
8,19,20-tetranor PGE ₂ methyl ester,
16-phenoxy-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-
Tetranor PGE ₂ ethyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranor PGE
_2- isopropyl ester, 17-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-1
8,19,20-trinor PGE ₂ methyl ester, 1
7-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-18,19,20-trinor P
GE _2- ethyl ester, 17-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-1
8,19,20-trinor PGE ₂ isopropyl ester.

15-deoxy-15,15-difluoroPGE ₂ 1,11-lactone, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE
₂ 1,11-lactone, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-
17,18,19,20-tetranor PGE ₂ 1,11
-Lactone, 16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₂ 1,11-lactone, 1
6- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-17,18,19,
20-tetranor PGE ₂ 1,11-lactone, 16-
Phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₂ 1,1
1-lactone, 17-phenyl-15-deoxy-1
5,15-difluoro-18,19,20-trinor P
GE ₂ 1,11-lactone.

15-Deoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₂ , 16
-(3,5-dichlorophenoxy) -15-deoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₂ , 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₂ , 16-
(3-chlorophenoxy) -15-deoxy-15,1
5-difluoro-17,18,19,20-tetranor PGE ₂ , 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₂ , 16-phenoxy-15-deoxy-15,15-difluoro-
17,18,19,20- tetranor PGE _2.

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGE
_2, 15-deoxy--15,15- difluoro-13
14-dihydro-PGE _2, 16- (3,5- dichlorophenoxy) -15-deoxy -15,15- difluoro-13,14-dihydro-tetranor-PGE _2, 16- (3, 4-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₂ , 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE
₂ , 16- (3-trifluoromethylphenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGE
₂ .

16-phenoxy-15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ , 17-phenyl-15-deoxy-15,15-difluoro-13,
14-dihydro-18,19,20-trinor PGE
_2, 15-deoxy -15,15- difluoro-3-oxa-tetranor-PGE _2,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ , 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGE ₂ , 16- (3-chlorophenoxy)
-15- deoxy -15,15- difluoro-3-oxa-tetranor-PGE _2.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-3-oxa-17,18,19,
20-tetranor PGE ₂ , 16-phenoxy-15-
Deoxy-15,15-difluoro-13,14-dihydro-3-oxa-17,18,19,20-tetranor PGE ₂ , 17-phenyl-15-deoxy-15
15-difluoro-13,14-dihydro-3-oxa-18,19,20-trinor PGE ₂ , N-methanesulfonyl-15-deoxy-15,15-difluoro-
17,18,19,20-tetranor PGE ₂ carboxamide, N-methanesulfonyl-16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₂
Carboxamide, N-methanesulfonyl-16- (3,
4-dichlorophenoxy) -15-deoxy-15,1
5-difluoro-tetranor-PGE _{2-carboxamide.}

[0121] N- methanesulfonyl-16- (3-chlorophenoxy) -15-deoxy -15,15- difluoro tetranor-PGE _{2-carboxamide,} N- methanesulfonyl-16- (3- Trifluoromethylphenoxy) -15-deoxy-1
5,15-difluoro-tetranor-PGE _{2-carboxamide,} N- methanesulfonyl-16-phenoxy-15-deoxy -15,15- difluoro tetranor-PGE
_{2-carboxamide,} N- methanesulfonyl-17-phenyl-15-deoxy -15,15- difluoro -1
8,19,20-trinor PGE ₂ carboxamide, 1
1,15-dideoxy-15,15-difluoro-PG
E ₂ methyl ester, 11,15-dideoxy-15,
15-Difluoro-PGE ₂ ethyl ester.

11,15-dideoxy-15,15-difluoro-PGE ₂ isopropyl ester, 16-
(3,5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₂ methyl ester, 16- (3,
5-dichlorophenoxy) -11,15-dideoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₂ ethyl ester, 16- (3,5-dichlorophenoxy) -11,15-dideoxy-15,
15-difluoro-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3,4-dichlorophenoxy) -11,15-dideoxy-15,
15-difluoro-17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3,4-dichlorophenoxy) -11,15-dideoxy-15,15-
Difluoro-17,18,19,20-tetranor PG
E ₂ ethyl ester.

16- (3,4-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3-chlorophenoxy) -11,
15-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₂ methyl ester,
16- (3-chlorophenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₂ ethyl ester, 16- (3-
(Chlorophenoxy) -11,15-dideoxy-15,
15-difluoro-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-
15,15-Difluoro-17,18,19,20-tetranor PGE ₂ ethyl ester.

16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16-phenoxy-11,15-dideoxy- 15,15-difluoro-17,18,1
9,20-tetranor PGE ₂ methyl ester, 16-
Phenoxy-11,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGE
_2- ethyl ester, 16-phenoxy-11,15-dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₂ isopropyl ester,
17-phenyl-11,15-dideoxy-15,15
-Difluoro-18,19,20-trinor PGE ₂ methyl ester, 17-phenyl-11,15-dideoxy-15,15-difluoro-18,19,20-trinor PGE ₂ ethyl ester.

17-phenyl-11,15-dideoxy-15,15-difluoro-18,19,20-trinor PGE ₂ isopropyl ester, 11,15-dideoxy-15,15-difluoro-13,14-dihydroPGE ₂ Methyl ester, 11,15-dideoxy-1
5,15-difluoro-13,14-dihydroPGE ₂
Ethyl ester, 11,15-dideoxy-15,15
-Difluoro-13,14-dihydroPGE ₂ isopropyl ester, 16- (3,5-dichlorophenoxy)
-11,15-dideoxy-15,15-difluoro-
13,14-dihydro-17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3,5-dichlorophenoxy) -11,15-dideoxy-15,1
5-difluoro-13,14-dihydro-17,18,
19,20-tetranor PGE ₂ ethyl ester.

16- (3,5-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3,4-
Dichlorophenoxy) -11,15-dideoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ methyl ester, 16- (3,4-dichlorophenoxy) -11,1
5-dideoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
E ₂ ethyl ester, 16- (3,4-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20
-Tetranor PGE ₂ isopropyl ester, 16-
(3-chlorophenoxy) -11,15-dideoxy-
15,15-difluoro-13,14-dihydro-1
7,18,19,20-tetranor PGE ₂ methyl ester, 16- (3-chlorophenoxy) -11,15-
Dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₂
Ethyl ester.

16- (3-chlorophenoxy) -11,
15-dideoxy-15,15-difluoro-13,1
4-dihydro-17,18,19,20-tetranor P
GE _2- isopropyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ methyl ester, 16- (3-trifluoromethylphenoxy) -1
1,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ isopropyl ester, 16-phenoxy-11,15-dideoxy-
15,15-difluoro-13,14-dihydro-1
7,18,19,20-tetranor PGE ₂ methyl ester, 16-phenoxy-11,15-dideoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₂ ethyl ester.

16-phenoxy-11,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20-tetranor PGE ₂ isopropyl ester, 17-phenyl-11,15-dideoxy-15,15-difluoro-13,14-dihydro-
18,19,20-trinor PGE ₂ methyl ester,
17-phenyl-11,15-dideoxy-15,15
-Difluoro-13,14-dihydro-18,19,2
0-trinor PGE ₂ ethyl ester.

17-phenyl-11,15-dideoxy-15,15-difluoro-13,14-dihydro-1
8,19,20-trinor PGE ₂ isopropyl ester, 11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GE _2- methyl ester, 11,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₂ ethyl ester, 11
, 15-Dideoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGE ₂
Isopropyl ester, 16- (3,5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3,5 -Dichlorophenoxy) -11,15-dideoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGE ₂ ethyl ester.

16- (3,5-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-3
-Oxa-17,18,19,20-tetranor PGE
_2- isopropyl ester, 16- (3,4-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE _2- methyl ester, 16- (3 4-dichlorophenoxy) -11,15-dideoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGE ₂ ethyl ester, 16- (3,4
-Dichlorophenoxy) -11,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₂ isopropyl ester,
16- (3-chlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ methyl ester,
16- (3-chlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ ethyl ester.

16- (3-chlorophenoxy) -11,
15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ isopropyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro -3-oxa-17,18,19,20-tetranor PGE ₂ methyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₂ ethyl ester, 16-
(3-trifluoromethylphenoxy) -11,15-
Dideoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGE ₂ isopropyl ester, 16-phenoxy-11,15-dideoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ methyl ester,
16-phenoxy-11,15-dideoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGE ₂ ethyl ester.

16-phenoxy-11,15-dideoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₂ isopropyl ester, 17-phenyl-11,15-dideoxy-1
5,15-difluoro-3-oxa-18,19,20
-Trinor PGE ₂ methyl ester, 17-phenyl-
11,15-dideoxy-15,15-difluoro-3
-Oxa-18,19,20-trinor PGE ₂ ethyl ester, 17-phenyl-11,15-dideoxy-
15,15-difluoro-3-oxa-18,19,2
0-trinor PGE ₂ isopropyl ester, 11,1
5-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₂ , 16- (3,5
-Dichlorophenoxy) -11,15-dideoxy-1
5,15-difluoro-17,18,19,20-tetranor PGE ₂ .

16- (3,4-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₂ , 16-
(3-chlorophenoxy) -11,15-dideoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₂ , 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGE
_2, 16-phenoxy -11,15- dideoxy -1
5,15-difluoro-17,18,19,20-tetranor PGE ₂ , 17-phenyl-11,15-dideoxy-15,15-difluoro-18,19,20-trinor PGE ₂ , 11,15-dideoxy 15,15
- difluoro-13,14-dihydro-PGE _2.

16- (3,5-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₂ , 16- (3,4-dichlorophenoxy)
-11,15-dideoxy-15,15-difluoro-
13,14-dihydro-17,18,19,20-tetranor PGE ₂ , 16- (3-chlorophenoxy) -1
1,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₂ , 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18 , 19,20
-Tetranor PGE ₂ , 16-phenoxy-11,15
-Dideoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGE
_2, 17-phenyl -11,15- dideoxy -15,
15-difluoro-13,14-dihydro-18,1
9,20-trinor PGE ₂ .

11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ , 16- (3,5-dichlorophenoxy) -11,15-dideoxy-15, 15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₂ , 16- (3,4-dichlorophenoxy) -1
1,15-dideoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGE
_2, 16- (3-chlorophenoxy) -11,15- dideoxy -15,15- difluoro-3- oxa -1
7,18,19,20-tetranor PGE ₂ , 16-
(3-trifluoromethylphenoxy) -11,15-
Dideoxy-15,15-difluoro-13,14-dihydro-3-oxa-17,18,19,20-tetranor PGE ₂ , 16-phenoxy-11,15-dideoxy-15,15-difluoro-13,14- Dihydro-3-oxa-17,18,19,20-tetranor P
GE ₂ .

17-phenyl-11,15-dideoxy-15,15-difluoro-13,14-dihydro-3
-Oxa-18,19,20-trinor PGE ₂ , N-
Methanesulfonyl-11,15-dideoxy-15,1
5-difluoro-17,18,19,20-tetranor PGE ₂ carboxamide, N-methanesulfonyl-16
-(3,5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,
20-tetranor PGE ₂ carboxamide, N-methanesulfonyl-16- (3,4-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₂ carboxamide, N-methanesulfonyl-16- (3-chlorophenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₂
Carboxamide, N-methanesulfonyl-16- (3-
(Trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₂ carboxamide, N-methanesulfonyl-16-phenoxy-11,15-dideoxy-15,15-difluoro-17,18,19,20-
Tetranor PGE ₂ carboxamide, N-methanesulfonyl-17-phenyl-11,15-dideoxy-1
5,15-difluoro-18,19,20-trinor P
GE ₂ carboxamide.

[Specific Examples of 15-Deoxy-15,15-difluoro-PGE ₁ Derivative] 15-Deoxy-15,15
15-difluoro-PGE ₁ methyl ester, 15-deoxy-15,15-difluoro-PGE ₁ ethyl ester, 15-deoxy-15,15-difluoro-PG
E ₁ isopropyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3,5-dichlorophenoxy) −
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₁ ethyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGE ₁ isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₁ methyl ester,
16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGE ₁ ethyl ester, 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GE ₁ isopropyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-
17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₁ ethyl ester, 16- (3-
Chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE
₁ isopropyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-trifluoromethylphenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₁ ethyl ester,
16- (3-trifluoromethylphenoxy) -15-
Deoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₁ isopropyl ester,
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₁
Methyl ester, 16-phenoxy-15-deoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₁ ethyl ester, 16-phenoxy-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₁ isopropyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGE
₁ methyl ester, 17-phenyl-15-deoxy-
15,15-difluoro-18,19,20-trinor PGE ₁ ethyl ester, 17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinor PGE ₁ isopropyl ester, 15-deoxy-15, 15-difluoro-13,14-dihydroPG
E ₁ methyl ester, 15-deoxy-15,15-difluoro-13,14-dihydroPGE ₁ ethyl ester, 15-deoxy-15,15-difluoro-13,
14-dihydro PGE ₁ isopropyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
E ₁ methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18 , 19,20
-Tetranor PGE ₁ isopropyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₁ methyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁ Ethyl ester, 16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
E ₁ Isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁
Ethyl ester, 16- (3-chlorophenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGE
_1- isopropyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,2
0-tetranor PGE ₁ methyl ester, 16- (3-
Trifluoromethylphenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGE
₁ isopropyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGE ₁ methyl ester, 16-phenoxy-15-deoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGE ₁ ethyl ester, 16-
Phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁ isopropyl ester, 17-phenyl-15-deoxy-15,15-difluoro-13,13
14-dihydro-18,19,20-trinor PGE ₁
Methyl ester, 17-phenyl-15-deoxy-1
5,15-difluoro-13,14-dihydro-18,
19,20-trinor PGE ₁ ethyl ester, 17-
Phenyl-15-deoxy-15,15-difluoro-
13,14-dihydro-18,19,20-trinor P
GE ₁ isopropyl ester.

15-Deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GE ₁ methyl ester, 15-deoxy-15,15-
Difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ ethyl ester, 15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₁ isopropyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₁ methyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₁ ethyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₁ isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3,4-dichlorophenoxy) -1
5-deoxy-15,15-difluoro-3-oxa-
17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3,4-dichlorophenoxy) -15
-Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGE ₁ isopropyl ester, 16- (3-chlorophenoxy) -15
Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₁ ethyl ester,
16- (3-chlorophenoxy) -15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₁ isopropyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGE ₁
Methyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-
3-oxa-17,18,19,20-tetranor PG
E ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ isopropyl ester, 16-phenoxy-1
5-deoxy-15,15-difluoro-3-oxa-
17,18,19,20-tetranor PGE ₁ methyl ester, 16-phenoxy-15-deoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGE ₁ ethyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ isopropyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-3-oxa-18,19,20-trinor PGE ₁ methyl ester, 17-phenyl-15
-Deoxy-15,15-difluoro-3-oxa-1
8,19,20-trinor PGE ₁ ethyl ester, 1
7-phenyl-15-deoxy-15,15-difluoro-3-oxa-18,19,20-trinor PGE ₁
Isopropyl ester, 15-deoxy-15,15-
Difluoro-11-pivaloyl PGE ₁ methyl ester, 15-deoxy-15,15-difluoro-11
Pivaloyl PGE ₁ ethyl ester, 15-deoxy-
15,15-Difluoro-11-pivaloyl PGE ₁ isopropyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranor PGE ₁
Methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-11
-Pivaloyl-17,18,19,20-tetranor P
GE ₁ ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-
11-pivaloyl-17,18,19,20-tetranor PGE ₁ isopropyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20
-Tetranor PGE ₁ methyl ester, 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-11-pivaloyl-17,18,19,
20-tetranor PGE ₁ ethyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-11-pivaloyl-17,1
8,19,20-tetranor PGE ₁ isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-11-pivaloyl-
17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-11-pivaloyl-1
7,18,19,20-tetranor PGE ₁ isopropyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-11
-Pivaloyl-17,18,19,20-tetranor P
GE ₁ methyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3-trimethyl Fluoromethylphenoxy) -15-deoxy-15,1
5-difluoro-11-pivaloyl-17,18,1
9,20-tetranor PGE ₁ isopropyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-11-pivaloyl-17,1
8,19,20-tetranor PGE ₁ methyl ester,
16-phenoxy-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-
Tetranor PGE ₁ ethyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranor PGE
_1- isopropyl ester, 17-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-1
8,19,20-trinor PGE ₁ methyl ester, 1
7-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-18,19,20-trinor P
GE ₁ ethyl ester, 17-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-1
8,19,20-trinor PGE ₁ isopropyl ester.

15-deoxy-15,15-difluoroPGE ₁ 1,11-lactone, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE
₁ 1,11-lactone, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-
17,18,19,20-tetranor PGE ₁ 1,11
-Lactone, 16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₁ 1,11-lactone, 1
6- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-17,18,19,
20-tetranor PGE ₁ 1,11-lactone, 16-
Phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE _11, 1
1-lactone.

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGE
₁ 1,11-lactone, 15-deoxy-15,15-
Difluoro-17,18,19,20-tetranor PG
E _1, 16- (3,5- dichlorophenoxy) -15
Deoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₁ , 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE
₁ , 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-
Tetranor PGE ₁ , 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₁ .

16-phenoxy-15-deoxy-1
5,15-difluoro-17,18,19,20-tetranor PGE ₁ , 17-phenyl-15-deoxy-1
5,15-difluoro-18,19,20-trinor P
GE ₁ , 15-deoxy-15,15-difluoro-1
3,14- dihydro PGE _1, 16- (3,5- dichlorophenoxy) -15-deoxy -15,15- difluoro-13,14-dihydro -17,18,19,20
-Tetranor PGE ₁ , 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-
13,14-dihydro-17,18,19,20-tetranor PGE ₁ , 16- (3-chlorophenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGE
₁ .

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₁ , 16-phenoxy-15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20- tetranor PGE _1, 17-phenyl-15-deoxy -15,15- difluoro -13
14-dihydro-18,19,20-trinor PGE
_1, 15-deoxy -15,15- difluoro-3-oxa-tetranor-PGE _1,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₁ , 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGE ₁ .

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20- tetranor PGE _1, 16-
(3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-
3-oxa-17,18,19,20-tetranor PG
E _1, 16- phenoxy-15-deoxy--15,15
-Difluoro-13,14-dihydro-3-oxa-1
7,18,19,20-tetranor PGE ₁ , 17-phenyl-15-deoxy-15,15-difluoro-1
3,14-dihydro-3-oxa-18,19,20-
Trinor PGE ₁ , N-methanesulfonyl-15-deoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₁ carboxamide, N-methanesulfonyl-16- (3,5-dichlorophenoxy) -1
5-deoxy-15,15-difluoro-17,18,
19,20-tetranor PGE ₁ carboxamide.

N-methanesulfonyl-16- (3,4-
Dichlorophenoxy) -15-deoxy-15,15-
Difluoro-17,18,19,20-tetranor PG
E ₁ carboxamide, N-methanesulfonyl-16-
(3-chlorophenoxy) -15-deoxy-15,1
5-difluoro-17,18,19,20-tetranor PGE ₁ carboxamide, N-methanesulfonyl-16
-(3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₁ carboxamide, N-methanesulfonyl-16-phenoxy-15-deoxy-15,
15-difluoro-17,18,19,20-tetranor PGE ₁ carboxamide, N-methanesulfonyl-1
7-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinor PGE ₁ carboxamide, 11,15-dideoxy-15,15-difluoro-PGE ₁ methyl ester.

11,15-dideoxy-15,15-difluoro-PGE ₁ ethyl ester, 11,15-dideoxy-15,15-difluoro-PGE ₁ isopropyl ester, 16- (3,5-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₁ methyl ester, 16- (3,5-dichlorophenoxy) -11,
15-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₁ ethyl ester,
16- (3,5-dichlorophenoxy) -11,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₁ isopropyl ester,
16- (3,4-dichlorophenoxy) -11,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₁ methyl ester, 16-
(3,4-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₁ ethyl ester, 16- (3,
4-dichlorophenoxy) -11,15-dideoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₁ isopropyl ester.

16- (3-chlorophenoxy) -11,
15-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₁ methyl ester,
16- (3-chlorophenoxy) -11,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGE ₁ ethyl ester, 16- (3-
(Chlorophenoxy) -11,15-dideoxy-15,
15-difluoro-17,18,19,20-tetranor PGE ₁ isopropyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-
15,15-difluoro-17,18,19,20-tetranor PGE ₁ isopropyl ester.

16-phenoxy-11,15-dideoxy-15,15-difluoro-17,18,19,20
-Tetranor PGE ₁ methyl ester, 16-phenoxy-11,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGE ₁ ethyl ester, 16-phenoxy-11,15-dideoxy-15,15 -Difluoro-17,18,19,20-
Tetranor PGE ₁ isopropyl ester, 17-phenyl-11,15-dideoxy-15,15-difluoro-18,19,20-trinor PGE ₁ methyl ester, 17-phenyl-11,15-dideoxy-15
15-difluoro-18,19,20-trinor PGE
₁ ethyl ester, 17-phenyl-11,15-dideoxy-15,15-difluoro-18,19,20-
Trinor PGE ₁ isopropyl ester.

11,15-dideoxy-15,15-difluoro-13,14-dihydroPGE ₁ methyl ester, 11,15-dideoxy-15,15-difluoro-13,14-dihydroPGE ₁ ethyl ester,
1,15-dideoxy-15,15-difluoro-1
3,14-dihydroPGE ₁ isopropyl ester, 1
6- (3,5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3,5- Dichlorophenoxy)
-11,15-dideoxy-15,15-difluoro-
13,14-dihydro-17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3,5-dichlorophenoxy) -11,15-dideoxy-15,1
5-difluoro-13,14-dihydro-17,18,
19,20-tetranor PGE ₁ isopropyl ester.

16- (3,4-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3,4-dichlorophenoxy) -11,15-dideoxy-15,15
-Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGE ₁ ethyl ester, 16-
(3,4-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁ isopropyl ester, 16- (3-chlorophenoxy)- 1
1,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-chlorophenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18 , 19,2
0-tetranor PGE ₁ ethyl ester, 16- (3-
(Chlorophenoxy) -11,15-dideoxy-15,
15-difluoro-13,14-dihydro-17,1
8,19,20-tetranor PGE ₁ isopropyl ester.

16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-
Tetranor PGE ₁ methyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-1
7,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3-trifluoromethylphenoxy)-
11,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₁ isopropyl ester, 16-phenoxy-11,15-dideoxy-15,15-difluoro-
13,14-dihydro-17,18,19,20-tetranor PGE ₁ methyl ester, 16-phenoxy-1
1,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₁ ethyl ester, 16-phenoxy-1
1,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGE ₁ isopropyl ester.

17-phenyl-11,15-dideoxy-15,15-difluoro-13,14-dihydro-1
8,19,20-trinor PGE ₁ methyl ester, 1
7-phenyl-11,15-dideoxy-15,15-
Difluoro-13,14-dihydro-18,19,20
-Trinor PGE ₁ ethyl ester, 17-phenyl-
11,15-dideoxy-15,15-difluoro-1
3,14-dihydro-18,19,20-trinor PG
E ₁ isopropyl ester, 11,15-dideoxy-
15,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₁ methyl ester, 11,
15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ ethyl ester, 11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19, 20-tetranor PGE ₁ isopropyl ester.

16- (3,5-dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-3
-Oxa-17,18,19,20-tetranor PGE
₁ methyl ester, 16- (3,5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3 5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ isopropyl ester, 16- (3,4
-Dichlorophenoxy) -11,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₁ methyl ester, 16-
(3,4-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₁ ethyl ester,
16- (3,4-dichlorophenoxy) -11,15-
Dideoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGE ₁ isopropyl ester.

16- (3-chlorophenoxy) -11,
15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-chlorophenoxy) -11,
15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ ethyl ester, 16- (3-chlorophenoxy) -11,
15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ isopropyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro -3-oxa-17,18,19,20-tetranor PGE ₁ methyl ester, 16- (3-trifluoromethylphenoxy) -11,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGE ₁ ethyl ester, 16-
(3-trifluoromethylphenoxy) -11,15-
Dideoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGE ₁ isopropyl ester.

16-phenoxy-11,15-dideoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGE ₁ methyl ester,
16-phenoxy-11,15-dideoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGE ₁ ethyl ester, 16-phenoxy-11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GE ₁ isopropyl ester, 17-phenyl-11,
15-dideoxy-15,15-difluoro-3-oxa-18,19,20-trinor PGE ₁ methyl ester, 17-phenyl-11,15-dideoxy-15,
15-difluoro-3-oxa-18,19,20-trinor PGE ₁ ethyl ester, 17-phenyl-1
1,15-dideoxy-15,15-difluoro-3-
Oxa-18,19,20-trinor PGE ₁ isopropyl ester.

11,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGE
₁ , 16- (3,5-dichlorophenoxy) -11,1
5-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGE ₁ , 16- (3,4
-Dichlorophenoxy) -11,15-dideoxy-1
5,15-difluoro-17,18,19,20-tetranor PGE ₁ , 16- (3-chlorophenoxy) -1
1,15-dideoxy-15,15-difluoro-1
7,18,19,20- tetranor PGE _1, 16-
(3-trifluoromethylphenoxy) -11,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₁ , 16-phenoxy-1
1,15-dideoxy-15,15-difluoro-1
7,18,19,20- tetranor PGE _1.

17-phenyl-11,15-dideoxy-15,15-difluoro-18,19,20-trinor PGE ₁ , 11,15-dideoxy-15,15-difluoro-13,14-dihydroPGE ₁ , 16 −
(3,5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁ , 16
-(3,4-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE ₁ , 1
6- (3-chlorophenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-
17, 18, 19, 20-tetranor PGE ₁ , 16-
(3-trifluoromethylphenoxy) -11,15-
Dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGE
₁ .

16-phenoxy-11,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20-tetranor PGE ₁ , 17-
Phenyl-11,15-dideoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinor PGE ₁ , 11,15-dideoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGE ₁ , 16- (3,5-dichlorophenoxy) -11,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGE ₁ , 16- (3,4- Dichlorophenoxy)-
11,15-dideoxy-15,15-difluoro-3
-Oxa-17,18,19,20-tetranor PGE
_1, 16- (3-chlorophenoxy) -11,15- dideoxy -15,15- difluoro-3- oxa -1
7,18,19,20- tetranor PGE _1.

16- (3-trifluoromethylphenoxy) -11,15-dideoxy-15,15-difluoro-13,14-dihydro-3-oxa-17,18,
19,20-tetranor PGE ₁ , 16-phenoxy-
11,15-dideoxy-15,15-difluoro-1
3,14-dihydro-3-oxa-17,18,19,
20-tetranor PGE ₁ , 17-phenyl-11,1
5-dideoxy-15,15-difluoro-13,14
- dihydro-3-oxa-18,19,20-trinor PGE _1, N-methanesulfonyl -11,15- dideoxy -15,15- difluoro -17,18,19,2
0-tetranor PGE ₁ carboxamide, N-methanesulfonyl-16- (3,5-dichlorophenoxy) -1
1,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGE ₁ carboxamide, N-methanesulfonyl-16- (3,4-dichlorophenoxy) -11,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GE ₁ carboxamide.

N-methanesulfonyl-16- (3-chlorophenoxy) -11,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GE ₁ carboxamide, N-methanesulfonyl-16
(3-trifluoromethylphenoxy) -11,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGE ₁ carboxamide, N-methanesulfonyl-16-phenoxy-11,15-dideoxy-15,15-difluoro-17,18,19,
20-tetranor PGE ₁ carboxamide, N-methanesulfonyl-17-phenyl-11,15-dideoxy-15,15-difluoro-18,19,20-trinor PGE ₁ carboxamide.

[Specific Examples of 15-Deoxy-15,15-difluoro-PGD ₂ Derivatives]
15-difluoro-PGD ₂ methyl ester, 15-deoxy-15,15-difluoro-PGD ₂ ethyl ester, 15-deoxy-15,15-difluoro-PG
D ₂ isopropyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3,5-dichlorophenoxy) −
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ ethyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₂ isopropyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-Difluoro-17,18,19,20-tetranor PGD ₂ methyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ ethyl ester,
16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₂ isopropyl ester, 16-
(3-chlorophenoxy) -15-deoxy-15,1
5-difluoro-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₂ isopropyl ester, 16-
(3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₂ methyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-trifluoromethylphenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ isopropyl ester, 16-phenoxy-15-deoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD ₂ methyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,2
0-tetranor PGD ₂ ethyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ isopropyl ester, 17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGD
₂ methyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGD
_2- ethyl ester, 17-phenyl-15-deoxy-
15,15-difluoro-18,19,20-trinor PGD ₂ isopropyl ester, 15-deoxy-1
5,15-difluoro-13,14-dihydroPGD ₂
Methyl ester, 15-deoxy-15,15-difluoro-13,14-dihydroPGD ₂ ethyl ester,
15-deoxy-15,15-difluoro-13,14
-DihydroPGD ₂ isopropyl ester, 16-
(3,5-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₂ methyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
D ₂ ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3,4-
Dichlorophenoxy) -15-deoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₂ methyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₂ ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₂ Isopropyl ester, 16- (3-chlorophenoxy)-
15-deoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
D ₂ methyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₂
Isopropyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20
-Tetranor PGD ₂ methyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGD
_2- isopropyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₂ methyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₂ ethyl ester, 16-phenoxy-15-deoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₂ isopropyl ester,
17-phenyl-15-deoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinor PGD ₂ methyl ester, 17-phenyl-15-
Deoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinor PGD ₂ ethyl ester, 17-phenyl-15-deoxy-15,15-
Difluoro-13,14-dihydro-18,19,20
-Trinor PGD ₂ isopropyl ester, 15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGD ₂ methyl ester.

15-Deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD ₂ ethyl ester, 15-deoxy-15,15-
Difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3
5-dichlorophenoxy) -15-deoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGD ₂ methyl ester, 16- (3,5
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGD ₂ ethyl ester, 16- (3,5-
Dichlorophenoxy) -15-deoxy-15,15-
Difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3
4-dichlorophenoxy) -15-deoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGD ₂ methyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3,4-dichlorophenoxy) -1
5-deoxy-15,15-difluoro-3-oxa-
17,18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGD ₂ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGD ₂ ethyl ester,
16- (3-chlorophenoxy) -15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₂ isopropyl ester,
16- (3-trifluoromethylphenoxy) -15-
Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGD ₂ methyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGD ₂
Ethyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-
3-oxa-17,18,19,20-tetranor PG
D ₂ isopropyl ester, 16-phenoxy-15-
Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGD ₂ methyl ester, 16-phenoxy-15-deoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGD ₂ ethyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ isopropyl ester, 17-phenyl-15-deoxy-
15,15-difluoro-3-oxa-18,19,2
0-trinor PGD ₂ methyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-3-oxa-18,19,20-trinor PGD ₂ ethyl ester, 17-phenyl-15
-Deoxy-15,15-difluoro-3-oxa-1
8,19,20-trinor PGD ₂ isopropyl ester, 15-deoxy-15,15-difluoro-9-pivaloyl PGD ₂ methyl ester, 15-deoxy-1
5,15-difluoro-9-pivaloyl PGD ₂ ethyl ester, 15-deoxy-15,15-difluoro-
9-pivaloyl PGD ₂ isopropyl ester, 16-
(3,5-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-9-pivaloyl-17,18,
19,20-tetranor PGD ₂ methyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3,5-dichlorophenoxy)
-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₂
Isopropyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-
9-pivaloyl-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20 -Tetranor PGD ₂ ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₂ isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-9-pivaloyl-
17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-1
7,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-17,
18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3-trifluoromethylphenoxy)
-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₂
Methyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-
9-pivaloyl-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20 -Tetranor PGD ₂ isopropyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-9-pivaloyl-17,18,
19,20-tetranor PGD ₂ methyl ester, 16
-Phenoxy-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₂ ethyl ester, 16-phenoxy-15
-Deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₂ isopropyl ester, 17-phenyl-15-deoxy-1
5,15-difluoro-9-pivaloyl-18,19,
20-trinor PGD ₂ methyl ester, 17-phenyl-15-deoxy-15,15-difluoro-9-pivaloyl-18,19,20-trinor PGD ₂ ethyl ester, 17-phenyl-15-deoxy-15,1
5-difluoro-9-pivaloyl-18,19,20-
Trinor PGD ₂ isopropyl ester.

15-deoxy-15,15-difluoroPGD ₂ 1,9-lactone, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ 1,
9-lactone, 16- (3,4-dichlorophenoxy)
-15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ 1,9-lactone, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-
Tetranor PGD ₂ 1,9-lactone, 16- (3-trifluoromethylphenoxy) -15-deoxy-1
5,15-difluoro-17,18,19,20-tetranor PGD ₂ 1,9-lactone, 16-phenoxy-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ 1,9-lactone, 17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinor PGD ₂ 1,9
-Lactone.

15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ , 16
-(3,5-dichlorophenoxy) -15-deoxy-
15,15-difluoro-17,18,19,20-tetranor PGD ₂ , 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ , 16-
(3-chlorophenoxy) -15-deoxy-15,1
5-difluoro-17,18,19,20-tetranor PGD ₂ , 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ , 16-phenoxy-15-deoxy-15,15-difluoro-
17,18,19,20- tetranor PGD _2.

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGD
_2, 15-deoxy--15,15- difluoro-13
14-dihydro-PGD _2, 16- (3,5- dichlorophenoxy) -15-deoxy -15,15- difluoro-13,14-dihydro-tetranor-PGD _2, 16- (3, 4-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₂ , 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD
₂ , 16- (3-trifluoromethylphenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGD
₂ , 16-phenoxy-15-deoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₂ , 17-phenyl-15
- deoxy -15,15- difluoro-13,14-dihydro-18,19,20-trinor PGD _2.

15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD ₂ , 16- (3,5-dichlorophenoxy) -15
-Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGD ₂ , 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₂ , 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD _2, 16- (3- trifluoromethylphenoxy)
-15-deoxy-15,15-difluoro-13,1
4-dihydro-3-oxa-17,18,19,20-
Tetranor PGD ₂ , 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-
3-oxa-17,18,19,20-tetranor PG
D _2, 17-phenyl-15-deoxy -15,15-
Difluoro-13,14-dihydro-3-oxa-1
8,19,20- trinor PGD _2.

N-methanesulfonyl-15-deoxy-
15,15-difluoro-17,18,19,20 tetranor PGD _{2-carboxamide,} N- methanesulfonyl-16- (3,5-dichlorophenoxy) -15-deoxy -15,15- difluoro -17,18,19 ,
20-tetranor PGD ₂ carboxamide, N-methanesulfonyl-16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ carboxamide,
N-methanesulfonyl-16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20- tetranor PGD _{2-carboxamide,} N- methanesulfonyl-16- (3-trifluoromethylphenoxy) -15-deoxy -15,15-
Difluoro-17,18,19,20-tetranor PG
D _{2-carboxamide,} N- methanesulfonyl-16-phenoxy-15-deoxy -15,15- difluoro -
17,18,19,20- tetranor PGD _{2-carboxamide,} N- methanesulfonyl-17-phenyl -15
-Deoxy-15,15-difluoro-18,19,2
0 trinor PGD _{2-carboxamide.}

9,15-dideoxy-15,15-difluoro-PGD ₂ methyl ester, 9,15-dideoxy-15,15-difluoro-PGD ₂ ethyl ester, 9,15-dideoxy-15,15-difluoro-
PGD ₂ isopropyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD ₂ methyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3,5-dichloro) Phenoxy)
-9,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ isopropyl ester.

16- (3,4-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ methyl ester, 16- (3,4-dichlorophenoxy) -9,1
5-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ ethyl ester,
16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₂ isopropyl ester,
16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₂ methyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD ₂ ethyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ isopropyl ester.

16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro- 17,18,19,20-tetranor PGD ₂ isopropyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGD ₂ methyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂ ethyl ester, 16-phenoxy-9,15-dideoxy-
15,15-Difluoro-17,18,19,20-tetranor PGD ₂ isopropyl ester.

17-phenyl-9,15-dideoxy-
15,15-difluoro-18,19,20-trinor PGD ₂ methyl ester, 17-phenyl-9,15-
Dideoxy-15,15-difluoro-18,19,2
0-trinor PGD ₂ ethyl ester, 17-phenyl-9,15-dideoxy-15,15-difluoro-1
8,19,20-trinor PGD ₂ isopropyl ester, 9,15-dideoxy-15,15-difluoro-
13,14-dihydro-PGD ₂ methyl ester, 9,1
5-dideoxy-15,15-difluoro-13,14
- dihydro PGD ₂ ethyl ester, 9,15- dideoxy -15,15- difluoro-13,14-dihydro-PGD ₂ isopropyl ester.

16- (3,5-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₂ ethyl ester, 16-
(3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3,4-dichlorophenoxy)
-9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₂ ethyl ester, 16-
(3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20-tetranor PGD ₂ isopropyl ester.

16- (3-chlorophenoxy) -9,1
5-dideoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
D ₂ methyl ester, 16- (3-chlorophenoxy)
-9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18 , 19,20
-Tetranor PGD ₂ isopropyl ester, 16-
(3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3-trifluoromethylphenoxy) ) -9,15-Dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-
Tetranor PGD ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-
15,15-difluoro-13,14-dihydro-1
7,18,19,20-tetranor PGD ₂ isopropyl ester.

16-phenoxy-9,15-dideoxy-15,15-difluoro-13,14-dihydro-1
7,18,19,20-tetranor PGD ₂ methyl ester, 16-phenoxy-9,15-dideoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₂ ethyl ester, 16-phenoxy-9,15-dideoxy-15,
15-difluoro-13,14-dihydro-17,1
8,19,20-tetranor PGD ₂ isopropyl ester, 17-phenyl-9,15-dideoxy-15,
15-difluoro-13,14-dihydro-18,1
9,20-trinor PGD ₂ methyl ester, 17-phenyl-9,15-dideoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinor PGD ₂ ethyl ester, 17-phenyl-9, Fifteen
-Dideoxy-15,15-difluoro-13,14-
Dihydro-18,19,20-trinor PGD ₂ isopropyl ester.

9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ methyl ester, 9,15-dideoxy-
15,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₂ ethyl ester, 9.1
5-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro -3-oxa-17,18,19,20-tetranor P
GD ₂ methyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3 , 5-Dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ isopropyl ester.

16- (3,4-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGD ₂
Methyl ester, 16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD ₂ ethyl ester, 16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ isopropyl ester, 16- (3 -Chlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ methyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy- 15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17 , 18,19,20-tetranor PGD ₂ isopropyl ester.

16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD ₂ methyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-
Difluoro-3-oxa-17,18,19,20-tetranor PGD ₂ ethyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₂ isopropyl ester,
16-phenoxy-9,15-dideoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGD ₂ methyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-3
-Oxa-17,18,19,20-tetranor PGD
_2- ethyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-3-oxa-17,
18,19,20-tetranor PGD ₂ isopropyl ester.

17-phenyl-9,15-dideoxy-
15,15-difluoro-3-oxa-18,19,2
0-trinor PGD ₂ methyl ester, 17-phenyl-9,15-dideoxy-15,15-difluoro-3
-Oxa-18,19,20-trinor PGD ₂ ethyl ester, 17-phenyl-9,15-dideoxy-1
5,15-difluoro-3-oxa-18,19,20
-Trinor PGD ₂ isopropyl ester, 9,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₂ , 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD ₂ , 16- (3,4-dichlorophenoxy) -9,
15-dideoxy-15,15-difluoro-17,1
8,19,20- tetranor PGD _2.

16- (3-chlorophenoxy) -9,1
5-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ , 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-
Tetranor PGD ₂ , 16-phenoxy-9,15-dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₂ , 17-phenyl-9,
15-dideoxy-15,15-difluoro-18,1
9,20-trinor PGD ₂ , 9,15-dideoxy-
15,15-difluoro-13,14-dihydroPGD
₂ , 16- (3,5-dichlorophenoxy) -9,15
-Dideoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGD
₂ .

16- (3,4-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₂ , 16- (3-chlorophenoxy) -9,
15-dideoxy-15,15-difluoro-13,1
4-dihydro-17,18,19,20-tetranor P
GD _2, 16- (3- trifluoromethylphenoxy)
-9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₂ , 16-phenoxy-9,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20-tetranor PGD ₂ , 17-
Phenyl-9,15-dideoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinor PGD ₂ , 9,15-dideoxy-15,15-difluoro-3-oxa-17,18, 19,20- tetranor PGD _2.

16- (3,5-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGD
₂ , 16- (3,4-dichlorophenoxy) -9,15
-Dideoxy-15,15-difluoro-3-oxa-
17, 18, 19, 20-tetranor PGD ₂ , 16-
(3-chlorophenoxy) -9,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₂ , 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-1
5,15-difluoro-13,14-dihydro-3-oxa-17,18,19,20-tetranor PGD ₂ ,
16-phenoxy-9,15-dideoxy-15,15
-Difluoro-13,14-dihydro-3-oxa-1
7,18,19,20-tetranor PGD ₂ , 17-phenyl-9,15-dideoxy-15,15-difluoro-13,14-dihydro-3-oxa-18,19,
20-trinor PGD _2.

N-methanesulfonyl-9,15-dideoxy-15,15-difluoro-17,18,19,2
0 tetranor PGD _{2-carboxamide,} N- methanesulfonyl-16- (3,5-dichlorophenoxy) -
9,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₂ carboxamide, N-methanesulfonyl-16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-
Difluoro-17,18,19,20-tetranor PG
D _{2-carboxamide,} N- methanesulfonyl-16-
(3-chlorophenoxy) -9,15-dideoxy-1
5,15-difluoro-tetranor-PGD _{2-carboxamide,} N- methanesulfonyl-16- (3-trifluoromethylphenoxy) -9,
15-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₂ carboxamide,
N-methanesulfonyl-16-phenoxy-9,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₂ carboxamide, N-methanesulfonyl-17-phenyl-9,15-dideoxy-15,15-difluoro-18,19,20-trinor PGD ₂ carboxamide.

[Specific examples of 15-deoxy-15,15-difluoro-PGD ₁ derivative] 15-deoxy-15,15
15-difluoro-PGD ₁ methyl ester, 15-deoxy-15,15-difluoro-PGD ₁ ethyl ester, 15-deoxy-15,15-difluoro-PG
D ₁ isopropyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3,5-dichlorophenoxy) −
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ ethyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₁ isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ methyl ester,
16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₁ ethyl ester, 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD ₁ isopropyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-
17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,2
0-tetranor PGD ₁ ethyl ester, 16- (3-
Chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD
₁ isopropyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-trifluoromethylphenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ ethyl ester,
16- (3-trifluoromethylphenoxy) -15-
Deoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₁ isopropyl ester,
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁
Methyl ester, 16-phenoxy-15-deoxy-
15,15-difluoro-17,18,19,20-tetranor PGD ₁ ethyl ester, 16-phenoxy-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ isopropyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGD
₁ methyl ester, 17-phenyl-15-deoxy-
15,15-difluoro-18,19,20-trinor PGD ₁ ethyl ester, 17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinor PGD ₁ isopropyl ester, 15-deoxy-15, 15-difluoro-13,14-dihydroPG
D ₁ methyl ester, 15-deoxy-15,15-difluoro-13,14-dihydroPGD ₁ ethyl ester, 15-deoxy-15,15-difluoro-13,
14-dihydroPGD ₁ isopropyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
D ₁ methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18 , 19,20
-Tetranor PGD ₁ isopropyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₁ methyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₁ Ethyl ester, 16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
D ₁ isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₁
Ethyl ester, 16- (3-chlorophenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGD
_1- isopropyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,2
0-tetranor PGD ₁ methyl ester, 16- (3-
Trifluoromethylphenoxy) -15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGD
₁ isopropyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₁ methyl ester, 16-phenoxy-15-deoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₁ ethyl ester, 16-
Phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₁ isopropyl ester, 17-phenyl-15-deoxy-15,15-difluoro-13,
14-dihydro-18,19,20-trinor PGD ₁
Methyl ester, 17-phenyl-15-deoxy-1
5,15-difluoro-13,14-dihydro-18,
19,20-trinor PGD ₁ ethyl ester, 17-
Phenyl-15-deoxy-15,15-difluoro-
13,14-dihydro-18,19,20-trinor P
GD ₁ isopropyl ester.

15-Deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD ₁ methyl ester, 15-deoxy-15,15-
Difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ ethyl ester, 15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₁ isopropyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGD ₁ methyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGD ₁ ethyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGD ₁ isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3,4-dichlorophenoxy) -1
5-deoxy-15,15-difluoro-3-oxa-
17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3,4-dichlorophenoxy) -15
-Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGD ₁ isopropyl ester, 16- (3-chlorophenoxy) -15
Deoxy-15,15-difluoro-3-oxa-1
7,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGD ₁ ethyl ester,
16- (3-chlorophenoxy) -15-deoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₁ isopropyl ester.

16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGD ₁
Methyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-
3-oxa-17,18,19,20-tetranor PG
D ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ isopropyl ester, 16-phenoxy-1
5-deoxy-15,15-difluoro-3-oxa-
17,18,19,20-tetranor PGD ₁ methyl ester, 16-phenoxy-15-deoxy-15,1
5-difluoro-3-oxa-17,18,19,20
-Tetranor PGD ₁ ethyl ester, 16-phenoxy-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ isopropyl ester.

17-phenyl-15-deoxy-15,
15-difluoro-3-oxa-18,19,20-trinor PGD ₁ methyl ester, 17-phenyl-15
-Deoxy-15,15-difluoro-3-oxa-1
8,19,20-trinor PGD ₁ ethyl ester, 1
7-phenyl-15-deoxy-15,15-difluoro-3-oxa-18,19,20-trinor PGD ₁
Isopropyl ester, 15-deoxy-15,15-
Difluoro-9-pivaloyl PGD ₁ methyl ester,
15-deoxy-15,15-difluoro-9-pivaloyl PGD ₁ ethyl ester, 15-deoxy-15,
15-Difluoro-9-pivaloyl PGD ₁ isopropyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3,5-dichlorophenoxy)
-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁
Ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-9-
Pivaloyl-17,18,19,20-tetranor PG
D ₁ isopropyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3,4 -Dichlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15. 15-Difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁ isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15,15-difluoro-9-pivaloyl-
17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-1
7,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-9-pivaloyl-17,
18,19,20-tetranor PGD ₁ isopropyl ester, 16- (3-trifluoromethylphenoxy)
-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-trifluoromethylphenoxy)
-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁
Ethyl ester, 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-
9-pivaloyl-17,18,19,20-tetranor PGD ₁ isopropyl ester, 16-phenoxy-1
5-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranor PGD ₁ methyl ester, 16-phenoxy-15-deoxy-1
5,15-difluoro-9-pivaloyl-17,18,
19,20-tetranor PGD ₁ ethyl ester.

16-phenoxy-15-deoxy-1
5,15-difluoro-9-pivaloyl-17,18,
19,20-tetranor PGD ₁ isopropyl ester, 17-phenyl-15-deoxy-15,15-difluoro-9-pivaloyl-18,19,20-trinor PGD ₁ methyl ester, 17-phenyl-15-deoxy-15, 15-difluoro-9-pivaloyl-1
8,19,20-trinor PGD ₁ ethyl ester, 1
7-phenyl-15-deoxy-15,15-difluoro-9-pivaloyl-18,19,20-trinor PG
D ₁ isopropyl ester.

15-deoxy-15,15-difluoroPGD _{11, 9} -lactone, 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ 1,
9-lactone, 16- (3,4-dichlorophenoxy)
-15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD _{11, 9} -lactone, 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-
Tetranor PGD ₁ 1,9-lactone, 16- (3-trifluoromethylphenoxy) -15-deoxy-1
5,15-difluoro-17,18,19,20-tetranor PGD _{11, 9} -lactone, 16-phenoxy-
15-deoxy-15,15-difluoro-17,1
8,19,20- tetranor PGD ₁ 1,9-lactone, 17-phenyl-15-deoxy -15,15- difluoro-18,19,20-trinor PGD ₁ 1, 9
-Lactone.

15-Deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ , 16
-(3,5-dichlorophenoxy) -15-deoxy-
15,15-difluoro-17,18,19,20-tetranor PGD ₁ , 16- (3,4-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20- tetranor PGD _1, 16-
(3-chlorophenoxy) -15-deoxy-15,1
5-difluoro-17,18,19,20-tetranor PGD ₁ , 16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₁ , 16-phenoxy-15-deoxy-15,15-difluoro-
17, 18, 19, 20-tetranor PGD ₁ .

17-phenyl-15-deoxy-15,
15-difluoro-18,19,20-trinor PGD
_1, 15-deoxy--15,15- difluoro-13
14-dihydroPGD ₁ , 16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₁ , 16- (3, 4-dichlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₁ , 16- (3-chlorophenoxy) -15
-Deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD
₁ , 16- (3-trifluoromethylphenoxy) -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGD
₁ .

16-phenoxy-15-deoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20- tetranor PGD _1, 17-phenyl-15-deoxy -15,15- difluoro -13
14-dihydro-18,19,20-trinor PGD
_1, 15-deoxy -15,15- difluoro-3-oxa-17,18,19,20 tetranor PGD _1,
16- (3,5-dichlorophenoxy) -15-deoxy-15,15-difluoro-3-oxa-17,1
8,19,20-tetranor PGD ₁ , 16- (3,4
-Dichlorophenoxy) -15-deoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGD _1, 16- (3- chlorophenoxy)
-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ , 1
6- (3-trifluoromethylphenoxy) -15-deoxy-15,15-difluoro-13,14-dihydro-3-oxa-17,18,19,20-tetranor PGD ₁ , 16-phenoxy-15-deoxy -15
15-difluoro-13,14-dihydro-3-oxa-17,18,19,20-tetranor PGD ₁ , 17
-Phenyl-15-deoxy-15,15-difluoro-13,14-dihydro-3-oxa-18,19,2
0-trinor PGD ₁ .

N-methanesulfonyl-15-deoxy-
15,15-difluoro-17,18,19,20 tetranor PGD _{1-carboxamide,} N- methanesulfonyl-16- (3,5-dichlorophenoxy) -15-deoxy -15,15- difluoro -17,18,19 ,
20-tetranor PGD ₁ carboxamide, N-methanesulfonyl-16- (3,4-dichlorophenoxy)-
15-deoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ carboxamide,
N-methanesulfonyl-16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₁ carboxamide, N-methanesulfonyl-16- (3-trifluoromethylphenoxy) -15-deoxy-15,15-
Difluoro-17,18,19,20-tetranor PG
D ₁ carboxamide, N-methanesulfonyl-16-phenoxy-15-deoxy-15,15-difluoro-
17,18,19,20-tetranor PGD ₁ carboxamide, N-methanesulfonyl-17-phenyl-15
-Deoxy-15,15-difluoro-18,19,2
0-trinor PGD ₁ carboxamide.

9,15-dideoxy-15,15-difluoro-PGD ₁ methyl ester, 9,15-dideoxy-15,15-difluoro-PGD ₁ ethyl ester, 9,15-dideoxy-15,15-difluoro-
PGD ₁ isopropyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD ₁ methyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3,5-dichloro) Phenoxy)
-9,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₁ isopropyl ester.

16- (3,4-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-1
7,18,19,20-tetranor PGD ₁ methyl ester, 16- (3,4-dichlorophenoxy) -9,1
5-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ ethyl ester,
16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₁ isopropyl ester,
16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20
-Tetranor PGD ₁ methyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD ₁ ethyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ isopropyl ester.

16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro- 17,18,19,20-tetranor PGD ₁ isopropyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGD ₁ methyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₁ ethyl ester, 16-phenoxy-9,15-dideoxy-
15,15-Difluoro-17,18,19,20-tetranor PGD ₁ isopropyl ester.

17-phenyl-9,15-dideoxy-
15,15-difluoro-18,19,20-trinor PGD ₁ methyl ester, 17-phenyl-9,15-
Dideoxy-15,15-difluoro-18,19,2
0-trinor PGD ₁ ethyl ester, 17-phenyl-9,15-dideoxy-15,15-difluoro-1
8,19,20-trinor PGD ₁ isopropyl ester, 9,15-dideoxy-15,15-difluoro-
13,14-dihydroPGD ₁ methyl ester, 9.1
5-dideoxy-15,15-difluoro-13,14
- dihydro PGD ₁ ethyl ester, 9,15- dideoxy -15,15- difluoro-13,14-dihydro-PGD ₁ isopropyl ester.

16- (3,5-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₁ ethyl ester, 16-
(3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20-tetranor PGD ₁ isopropyl ester, 16- (3,4-dichlorophenoxy)
-9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-
Difluoro-13,14-dihydro-17,18,1
9,20-tetranor PGD ₁ ethyl ester, 16-
(3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20-tetranor PGD ₁ isopropyl ester.

16- (3-chlorophenoxy) -9,1
5-dideoxy-15,15-difluoro-13,14
-Dihydro-17,18,19,20-tetranor PG
D ₁ methyl ester, 16- (3-chlorophenoxy)
-9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18 , 19,20
-Tetranor PGD ₁ isopropyl ester, 16-
(3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-trifluoromethylphenoxy) ) -9,15-Dideoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-
Tetranor PGD ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-
15,15-difluoro-13,14-dihydro-1
7,18,19,20-tetranor PGD ₁ isopropyl ester.

16-phenoxy-9,15-dideoxy-15,15-difluoro-13,14-dihydro-1
7,18,19,20-tetranor PGD ₁ methyl ester, 16-phenoxy-9,15-dideoxy-1
5,15-difluoro-13,14-dihydro-17,
18,19,20-tetranor PGD ₁ ethyl ester, 16-phenoxy-9,15-dideoxy-15,
15-difluoro-13,14-dihydro-17,1
8,19,20-tetranor PGD ₁ isopropyl ester, 17-phenyl-9,15-dideoxy-15,
15-difluoro-13,14-dihydro-18,1
9,20-trinor PGD ₁ methyl ester, 17-phenyl-9,15-dideoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinor PGD ₁ ethyl ester, 17-phenyl-9, Fifteen
-Dideoxy-15,15-difluoro-13,14-
Dihydro-18,19,20-trinor PGD ₁ isopropyl ester.

9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ methyl ester, 9,15-dideoxy-
15,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₁ ethyl ester, 9.1
5-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ isopropyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro -3-oxa-17,18,19,20-tetranor P
GD ₁ methyl ester, 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3 , 5-Dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ isopropyl ester.

16- (3,4-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGD ₁
Methyl ester, 16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD ₁ ethyl ester, 16- (3,4-dichlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ isopropyl ester, 16- (3 -Chlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ methyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy- 15,15-difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3-chlorophenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17 , 18,19,20-tetranor PGD ₁ isopropyl ester.

16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor P
GD ₁ methyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-
Difluoro-3-oxa-17,18,19,20-tetranor PGD ₁ ethyl ester, 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₁ isopropyl ester,
16-phenoxy-9,15-dideoxy-15,15
-Difluoro-3-oxa-17,18,19,20-
Tetranor PGD ₁ methyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-3
-Oxa-17,18,19,20-tetranor PGD
₁ ethyl ester, 16-phenoxy-9,15-dideoxy-15,15-difluoro-3-oxa-17,
18,19,20-tetranor PGD ₁ isopropyl ester.

17-phenyl-9,15-dideoxy-
15,15-difluoro-3-oxa-18,19,2
0-trinor PGD ₁ methyl ester, 17-phenyl-9,15-dideoxy-15,15-difluoro-3
-Oxa-18,19,20-trinor PGD ₁ ethyl ester, 17-phenyl-9,15-dideoxy-1
5,15-difluoro-3-oxa-18,19,20
-Trinor PGD ₁ isopropyl ester, 9,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₁ , 16- (3,5-dichlorophenoxy) -9,15-dideoxy-15,15
-Difluoro-17,18,19,20-tetranor P
GD _1, 16- (3,4-dichlorophenoxy) -9,
15-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ .

16- (3-chlorophenoxy) -9,1
5-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ , 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-15,15-difluoro-17,18,19,20-
Tetranor PGD ₁ , 16-phenoxy-9,15-dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₁ , 17-phenyl-9,
15-dideoxy-15,15-difluoro-18,1
9,20-trinor PGD ₁ , 9,15-dideoxy-
15,15-difluoro-13,14-dihydroPGD
₁ , 16- (3,5-dichlorophenoxy) -9,15
-Dideoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGD
₁ .

16- (3,4-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₁ , 16- (3-chlorophenoxy) -9,
15-dideoxy-15,15-difluoro-13,1
4-dihydro-17,18,19,20-tetranor P
GD _1, 16- (3- trifluoromethylphenoxy)
-9,15-dideoxy-15,15-difluoro-1
3,14-dihydro-17,18,19,20-tetranor PGD ₁ , 16-phenoxy-9,15-dideoxy-15,15-difluoro-13,14-dihydro-
17,18,19,20- tetranor PGD _1, 17-
Phenyl-9,15-dideoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinor PGD ₁ , 9,15-dideoxy-15,15-difluoro-3-oxa-17,18, 19,20-tetranor PGD ₁ .

16- (3,5-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-3-
Oxa-17,18,19,20-tetranor PGD
₁ , 16- (3,4-dichlorophenoxy) -9,15
-Dideoxy-15,15-difluoro-3-oxa-
17,18,19,20- tetranor PGD _1, 16-
(3-chlorophenoxy) -9,15-dideoxy-1
5,15-difluoro-3-oxa-17,18,1
9,20-tetranor PGD ₁ , 16- (3-trifluoromethylphenoxy) -9,15-dideoxy-1
5,15-difluoro-13,14-dihydro-3-oxa-17,18,19,20-tetranor PGD ₁ ,
16-phenoxy-9,15-dideoxy-15,15
-Difluoro-13,14-dihydro-3-oxa-1
7,18,19,20-tetranor PGD ₁ , 17-phenyl-9,15-dideoxy-15,15-difluoro-13,14-dihydro-3-oxa-18,19,
20-trinor PGD ₁ .

N-methanesulfonyl-9,15-dideoxy-15,15-difluoro-17,18,19,2
0-tetranor PGD ₁ carboxamide, N-methanesulfonyl-16- (3,5-dichlorophenoxy)-
9,15-dideoxy-15,15-difluoro-1
7,18,19,20- tetranor PGD _{1-carboxamide,} N- methanesulfonyl-16- (3,4-dichlorophenoxy) -9,15- dideoxy -15,15-
Difluoro-17,18,19,20-tetranor PG
D ₁ carboxamide, N-methanesulfonyl-16-
(3-chlorophenoxy) -9,15-dideoxy-1
5,15-difluoro-tetranor-PGD _{1-carboxamide,} N- methanesulfonyl-16- (3-trifluoromethylphenoxy) -9,
15-dideoxy-15,15-difluoro-17,1
8,19,20-tetranor PGD ₁ carboxamide,
N-methanesulfonyl-16-phenoxy-9,15-
Dideoxy-15,15-difluoro-17,18,1
9,20-tetranor PGD ₁ carboxamide, N-methanesulfonyl-17-phenyl-9,15-dideoxy-15,15-difluoro-18,19,20-trinor PGD ₁ carboxamide.

Since the fluorine-containing PG derivative represented by the formula (1) has an asymmetric carbon in its structure, there are various stereoisomers and optical isomers.
The G derivative includes all these stereoisomers, optical isomers and mixtures thereof.

The fluorine-containing PG derivative represented by the formula (1) has various effects related to pain and inflammation, in addition to a vasodilatory effect, a bronchodilator effect, a gastric acid secretion inhibitory effect, a gastric mucosal protective effect, a uterine contractile effect, and the like. Since it has an action, it can be used as a blood flow improving agent, a therapeutic agent for gastric ulcer, an agent for inducing labor, and the like. In addition, other than central nervous system action, sleep-inducing action, platelet aggregation inhibitory action, etc., it can affect various actions related to allergy, immune reaction, and inflammation. It is useful as a prodrug. Further, the fluorine-containing PG derivative represented by the formula (1) of the present invention is also useful as a therapeutic agent for osteoporosis, an anticancer agent, a therapeutic agent for neurogenic inflammation, an analgesic agent, and an antiallergic agent.

Further, the fluorine-containing PG derivative represented by the formula (1) of the present invention can exert a remarkable action based on the structure having two fluorine atoms at the 15-position. That is, the conventional P
Since it has higher selectivity for the receptor in vivo than the G derivative, it is possible to expect excellent drug efficacy while preventing side effects with a small amount of administration. In addition, since it has excellent chemical stability, it can be administered by oral administration, and since it can be stably present in blood, it has excellent effect continuity.

[0243]

The present invention will be described in more detail with reference to specific examples, but the present invention is not limited to these examples. In addition,
Examples 1-14, 18-20, 23, and 26-2 below
8 is a reference example, and Examples 15 to 17, 21, 22, 24,
25 and 29 are examples.

[Example 1] (1S, 5R, 6R, 7R) -2
-Oxa-7-benzoyloxy-6-[(1E) -4
Synthesis of-(3-chlorophenoxy) -3-oxo-1-butenyl] -bicyclo [3.3.0] octan-3-one dimethyl 2-oxo-3- (3-chlorophenoxy) -propylphosphonate 26 .5 g of THF (260 ml)
3.39 g of lithium chloride and 10.9 ml of triethylamine were added to the solution under ice cooling. After stirring for 15 minutes, (1
A solution of 18.1 g of (S, 5R, 6R, 7R) -6-formyl-7-benzoyloxy-2-oxa-bicyclo [3.3.0] octan-3-one in methylene chloride (65 ml) was added. After stirring at 0 ° C. for 1 hour, the reaction solution was poured into a 1/1 (volume ratio) mixture of a saturated aqueous solution of ammonium chloride / ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried and concentrated. This was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
(1/3 to 2/1 (volume ratio)) to give the title compound 1
9.8 g were obtained. ¹ H-NMR (CDCl ₃ ): δ 2.2-2.9 (m, 6H), 4.67 (s, 2H), 5.09 (m, 1
H), 5.34 (m, 1H), 6.56 (d, J = 15.9Hz, 1H), 6.73-6.97 (m, 4H),
7.18 (m, 1H), 7.44 (m, 2H), 7.58 (m, 1H), 7.97 (m, 2H).

[Example 2] (1S, 5R, 6R, 7R) -2
-Oxa-7-benzoyloxy-6-[(1E)-
3,3-difluoro-4- (3-chlorophenoxy)-
1-butenyl] -bicyclo [3.3.0] octane-3
Synthesis of -one (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E) -3,3-
19.8 g of morpholinosulfatrifluoride was added to a solution of 5.00 g of difluoro-4- (3-chlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one in 150 ml of methylene chloride. Added at ° C. After stirring at room temperature for 180 hours, pour into saturated aqueous sodium bicarbonate,
Extracted with ethyl acetate. The extract was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2 /
1 (volume ratio)) to give 3.47 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ 2.2-3.0 (m, 6H), 4.13 (m, 2H), 5.09 (m, 1
H), 5.30 (m, 1H), 5.87 (dt, J = 15.6,11.2Hz, 1H), 6.15 (m, 1H
H), 6.72 (m, 1H), 6.84 (m, 1H), 6.97 (m, 1H), 7.18 (m, 1H), 7.4
. 1 (m, 2H), 7.55 (m, 1H), 7.96 (m, 2H) 19 F-NMR (CDCl 3): - 104.1 (m).

[Example 3] (1S, 5R, 6R, 7R) -2
-Oxa-7-hydroxy-6-[(1E) -3,3-
Synthesis of difluoro-4- (3-chlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one (1S, 5R, 6R, 7R) -2-oxa- synthesized in Example 2. 7-benzoyloxy-6-[(1E) -3,3-
3.47 g of difluoro-4- (3-chlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one was dissolved in 40 ml of methanol, 645 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. did. With acetic acid
After H was adjusted to 7, water was added, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2 to 2/3 (volume ratio)) to obtain 2.69 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ 2.0-2.8 (m, 6H), 4.09-4.21 (m, 3H), 4.9
5 (m, 1H), 5.84 (dt, J = 15.6,11.2Hz, 1H), 6.07 (m, 1H), 6.81
. (m, 1H), 6.91 (m, 1H), 7.01 (m, 1H), 7.23 (m, 1H) 19 F-NMR (CDCl 3): - 103.7 (m).

Example 4 (1S, 5R, 6R, 7R) -2
-Oxa-3,7-dihydroxy-6-[(1E)-
3,3-difluoro-4- (3-chlorophenoxy)-
Synthesis of 1-butenyl] -bicyclo [3.3.0] octane (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E) -3,3- Difluoro-4- (3-chlorophenoxy) -1-butenyl]
-Bicyclo [3.3.0] octan-3-one 1.57
g of THF (50 ml) at −78 ° C. in toluene solution of diisobutylaluminum hydride (1M, 17.5 m
l) and stirred for 30 minutes, then water (20 ml), 1
N hydrochloric acid (40 ml) was added, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 to 3/2 (volume ratio)) to obtain 1.26 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ 2.0-2.6 (m, 6H), 2.89-3.10 (m, 1H), 3.9
8 (m, 1H), 4.18 (m, 2H), 4.66 (m, 1H), 5.57-5.67 (m, 1H), 5.79
(m, 1H), 6.11 (m, 1H), 6.81 (m, 1H), 6.92 (m, 1H), 6.99 (m, 1
. H), 7.22 (m, 1H) 19 F-NMR (CDCl 3): - 103.4 (m).

Example 5 16- (3-chlorophenoxy)
-15-deoxy-15,15-difluoro-17,1
Synthesis of 8,19,20-tetranor PGF ₂ α-isopropyl ester A suspension of 6.21 g of 4-carboxybutyltriphenylphosphonium bromide in 80 ml of THF was dissolved in a toluene solution of potassium bis (trimethylsilyl) amide (0.5 ml).
M, 56 ml) and stirred at room temperature for 30 minutes. (1S, 5R, 6R, 7R) -2-oxa synthesized in Example 4
1.26 g of 3,7-dihydroxy-6-[(1E) -3,3-difluoro-4- (3-chlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane
An HF (30 ml) solution was added at −20 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by adding water, washed with diethyl ether, the aqueous layer was made acidic, and extracted with ethyl acetate.
After drying, the solvent was distilled off to obtain 1.56 g of a crude carboxylic acid. To a solution of 1.56 g of the synthesized carboxylic acid crude product in acetone (14 ml), 1,8-diazabicyclo [5.4.
0] 4.28 g of undec-7-ene and 5.38 g of 2-iodopropane were added and stirred for 17 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated saline solution, a 3% aqueous citric acid solution and a sodium bicarbonate solution, dried and concentrated. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 (volume ratio)) to give the title compound 0.91.
g was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.22 (d, J = 6.4 Hz, 6H), 1.6-2.8 (m, 14
H), 4.03 (m, 1H), 4.18 (t, J = 11.7Hz, 2H), 4.21 (m, 1H), 4.99
(m, 1H), 5.38 (m, 1H), 5.78 (dt, J = 15.6,11.2Hz, 1H), 6.10
(m, 1H), 6.81 (m, 1H), 6.92 (m, 1H), 6.98 (m, 1H), 7.21 (m, 1
^{. H) 19 F-NMR (} CDCl 3): - 103.3 (m).

Example 6 16- (3-chlorophenoxy)
-15-deoxy-15,15-difluoro-17,1
8,19,20- tetranor PGF synthesized 16- (3-chlorophenoxy) in Synthesis Example 5 of ₂ alpha -15
-Deoxy-15,15-difluoro-17,18,1
A 0.2 N sodium hydroxide aqueous solution (11.3 ml) was added to a solution of 440 mg of 9,20-tetranor PGF ₂ α-isopropyl ester in ethanol (13 ml), and the mixture was stirred at room temperature for 22 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and washed with toluene. After adjusting the pH to 1 by adding 2N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to obtain 423 mg of the title compound. _{^{1 H-NMR (CDCl 3)}} : δ 1.6-2.5 (m, 14H), 4.04 (m, 1H), 4.14-4.
20 (m, 3H), 5.38 (m, 2H), 5.78 (dt, J = 15.6,11.2Hz, 1H), 6.09
(m, 1H), 6.81 (m, 1H), 6.92 (m, 1H), 6.98 (m, 1H), 7.21 (m, 1
^{. H) 19 F-NMR (} CDCl 3): - 103.4 (m).

Example 7 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20
Synthesis of -tetranor PGF ₂ α-isopropyl ester (1S, 5R, 6R, 7R) -6-formyl-7-benzoyloxy-2-oxa-bicyclo [3.3.0] octan-3-one and 2-oxo- The title compound was synthesized from dimethyl 3-phenoxy-propylphosphonate in the same manner as in Examples 1 to 5. ¹ H-NMR (CDCl ₃ ): δ 1.22 (d, J = 6.4 Hz, 6H), 1.59 (m, 1H), 1.6
6 (m, 2H), 1.83 (m, 1H), 2.0-2.4 (m, 7H), 2.47 (m, 1H), 4.02
(m, 1H), 4.19 (t, J = 11.5Hz, 2H), 4.19 (m, 1H), 4.99 (m, 1H),
5.38 (m, 2H), 5.80 (dt, J = 15.6,11.2Hz, 1H), 6.10 (m, 1H), 6.
91 (m, 2H), 7.00 (m, 1H), 7.30 (m, 2H) 19 F-NMR (CDCl 3): -. 103.7 (m).

The spectrum data of the compound synthesized in each step of Example 7 is as follows. (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E) -4-phenoxy-3-oxo-1-butenyl] -bicyclo [3.3.0] octane-3 -On ¹ H-NMR (CDCl ₃ ): δ 2.29 (ddd, J = 15.6, 4.9, 0.2 Hz, 1 H), 2.4
5-2.51 (m, 1H), 2.60 (dt, J = 15.6,6.6Hz, 1H), 2.83-2.95 (m, 1H
3H), 4.67 (s, 2H), 5.08 (td, J = 4.6,1.7Hz, 1H), 5.31 (m, 1H),
6.60 (dd, J = 15.6,1.0Hz, 1H), 6.84-6.87 (m, 2H), 6.91 (dd, J
= 15.6,7.8Hz, 1H), 6.98 (t, J = 7.3Hz, 1H), 7.25-7.29 (m, 2
H), 7.44 (t, J = 7.3Hz, 2H), 7.58 (dt, J = 7.3,1.2Hz, 1H), 7.97
(dd, J = 8.3,1.2Hz, 2H).

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3. 0] Octane-3-one ¹ H-NMR (CDCl ₃ ): δ 2.2-2.9 (m, 6H), 4.17 (t, J = 11.5 Hz, 2
H), 5.09 (m, 1H), 5.29 (m, 1H), 5.89 (dt, J = 15.6,11.0Hz, 1
H), 6.15 (m, 1H), 6.85 (d, J = 7.8Hz, 2H), 6.99 (t, J = 7.3Hz, 1
H), 7.27 (m, 2H), 7.41 (m, 2H), 7.55 (t, J = 7.3Hz, 1H), 7.97
. (d, J = 7.3Hz, 2H) 19 F-NMR (CDCl 3): - 104.0 (m).

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.
3.0] Octane-3-one ¹ H-NMR (CDCl ₃ ): δ 2.0-2.8 (m, 6H), 4.09 (m, 1H), 4.20 (t, J
= 11.5Hz, 2H), 4.94 (m, 1H), 5.84 (dt, J = 15.6,11.2Hz, 1H),
6.07 (m, 1H), 6.91 (d, J = 7.8Hz, 2H), 7.02 (t, J = 7.3Hz, 1H),
^{. 7.31 (m, 2H) 19} F-NMR (CDCl 3): - 103.6 (m).

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3 .0] octane ¹ H-NMR (CDCl ₃ ): δ 1.8-2.9 (m, 6H), 3.96 (m, 1H), 4.19 (t, J
= 11.5Hz, 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 = 8.3Hz, 2H), 7.00 (m, 1H), 7.
30 (t, J = 7.8Hz, 2H) 19 F-NMR (CDCl 3): -. 103 (m).

Example 8 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20
- synthesized in Synthesis Example 7 of tetranor PGF ₂ alpha 16- phenoxy-15-deoxy-1
Using 5,15-difluoro-17,18,19,20-tetranor PGF ₂ α-isopropyl ester, the title compound was synthesized in the same manner as in Example 6. ¹ H-NMR (CDCl ₃ ): δ 1.60 (m, 1 H), 1.67
(M, 2H), 1.83 (m, 1H), 2.0-2.5
(M, 8H), 2.47 (m, 1H), 4.03 (m,
1H), 4.18 (t, J = 11.7 Hz, 2H),
4.18 (m, 1H), 5.36 (m, 2H), 5.8
0 (dt, J = 15.8, 10.5 Hz, 1H), 6.
09 (m, 1H), 6.91 (m, 2H), 6.99
(M, 1H), 7.29 (m, 2H). ¹⁹ F-NMR (CDCl ₃ ): -103.7 (m).

[Example 9] (1S, 5R, 6R, 7R) -2
Synthesis of -oxa-7-benzoyloxy-6- [4- (3-chlorophenoxy) -3-oxobutyl] -bicyclo [3.3.0] octan-3-one Synthesized in Example 1 (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E) -4- (3
-Chlorophenoxy) -3-oxo-1-butenyl]-
Bicyclo [3.3.0] octan-3-one 4.08 g
Was added to a solution of 5% Pd-C (580 ml) in ethyl acetate (80 ml).
mg), and the mixture was suspended in a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite and concentrated. The concentrate was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 (volume ratio)) to obtain 3.89 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ 1.68 (m, 1H), 1.81 (m, 1H), 2.13 (m, 1H),
2.35-2.52 (m, 3H), 2.68 (m, 1H), 2.78-2.95 (m, 3H), 4.56 (s,
2H), 5.10 (dt, J = 1.0,6.0Hz, 1H), 5.20 (ddd, J = 2.9,3.3,6.0
Hz, 1H), 6.74 (m, 1H), 6.85 (m, 1H), 6.97 (m, 1H), 7.19 (m, 1
H), 7.43 (m, 2H), 7.55 (m, 1H), 7.97 (m, 2H).

Example 10 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-1
Synthesis of 3,14-dihydro-17,18,19,20-tetranor PGF ₂ α-isopropyl ester (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6- [4 synthesized in Example 9. -(3-chlorophenoxy) -3-oxobutyl] -bicyclo [3.3.
0] Octane-3-one to give the title compound in the same manner as in Examples 2-5. ¹ H-NMR (CDCl ₃ ): δ 1.22 (d, J = 6.4 Hz, 6H), 1.43 (m, 2H), 1.6
5-1.75 (m, 4H), 1.9-2.5 (m, 10H), 3.95 (m, 1H), 4.10 (m, 2H),
4.20 (m, 1H), 5.00 (m, 1H), 5.41 (m, 2H), 6.82 (m, 1H), 6.93
. (m, 1H), 6.99 (m, 1H), 7.22 (m, 1H) 19 F-NMR (CDCl 3): - 105.7 (m).

The spectral data of the compound synthesized in each step of Example 10 is as follows. (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6- [3,3-difluoro-4- (3-chlorophenoxy) butyl] -bicyclo [3.3.0] octane-3 -On ¹ H-NMR (CDCl ₃ ): δ 1.68 (m, 2H), 2.2-2.5 (m, 6H), 2.72 (m, 1
H), 2.94 (dd, J = 18.3,10.7Hz, 1H), 4.11 (t, J = 11.5Hz, 2H),
5.12 (dt, J = 5.7,1.0Hz, 1H), 5.27 (m, 1H), 6.78 (ddd, J = 5.9,
2.5,1.7Hz, 1H), 6.90 (t, J = 2.2Hz, 1H), 7.01 (m, 1H), 7.21
(t, J = 8.1Hz, 1H), 7.44 (t, J = 7.7Hz, 2H), 7.54 (m, 1H), 7.99
^{. (m, 2H) 19 F} -NMR (CDCl 3): - 106.1 (m).

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6- [3,3-difluoro-4-
(3-chlorophenoxy) butyl] -bicyclo [3.
3.0] Octane-3-one ¹ H-NMR (CDCl ₃ ): δ 1.55-1.68 (m, 2H), 1.89 (m, 1H), 2.1-2.
6 (m, 6H), 2.85 (dd, J = 18.8,11.2Hz, 1H), 4.05 (m, 1H), 4.10
(m, 2H), 4.98 (ddd, J = 7.1,6.8,2.2Hz, 1H), 6.81 (ddd, 8.3,
1.7,1.0Hz, 1H), 6.92 (t, J = 2.2Hz, 1H), 7.01 (m, 1H), 7.23
. (t, J = 8.3Hz, 1H) 19 F-NMR (CDCl 3): - 106.0 (m).

Example 11 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-1
3,14- dihydro tetranor-PGF ₂ synthesized 16- (3-chlorophenoxy) in Synthesis Example 10 of alpha -1
5-deoxy-15,15-difluoro-13,14-
Dihydro-17,18,19,20-tetranor PGF
_The title compound was synthesized from 2α-isopropyl ester in the same manner as in Example 6. ¹ H-NMR (CDCl ₃ ): δ 1.41 (m, 2H), 1.65-2.40 (m, 14H), 3.95
(m, 1H), 4.10 (t, J = 11.6Hz, 2H), 4.17 (m, 1H), 5.40 (m, 2H),
6.81 (m, 1H), 6.92 (m, 1H), 7.00 (m, 1H), 7.22 (m, 1H) 19 F-NMR (CDCl 3): -. 105.8 (m).

Example 12 Synthesis of 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranor PGF ₂ α-isopropyl ester (1S, 5R, 6R, 7R) -6-Formyl-7-benzoyloxy-2-oxa-bicyclo [3.3.0] octan-3-one and dimethyl 2-oxo-3-phenoxy-propylphosphonate from Examples 1, 9, 2 The title compound was synthesized in the same manner as in Examples 5 to 5. ¹ H-NMR (CDCl ₃ ): δ 1.23 (d, J = 6.4 Hz, 6H), 1.4-2.5 (m, 18
H), 3.95 (m, 1H), 4.10-4.94 (m, 3H), 5.00 (m, 1H), 5.42 (m, 2
. H), 6.92 (m, 2H), 7.01 (m, 1H), 7.31 (m, 2H) 19 F-NMR (CDCl 3): - 105.7 (m).

The spectrum data of the compound synthesized in each step of Example 12 is as follows. (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6- (4-phenoxy-3-oxobutyl) -bicyclo [3.3.0] octan-3-one ¹ H-NMR (CDCl ₃ ): δ 1.74 (m, 2H), 2.13 (m, 1H), 2.32-2.52
(m, 3H), 2.66 (m, 1H), 2.80-2.93 (m, 3H), 4.57 (s, 2H), 5.09
(m, 1H), 5.20 (m, 1H), 6.85 (d, J = 7.8Hz, 2H), 6.99 (t, J = 7.3H
z, 1H), 7.28 (m, 2H), 7.43 (m, 2H), 7.55 (t, J = 7.3Hz, 1H), 7.9
8 (d, J = 7.3Hz, 2H).

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6- (3,3-difluoro-
4-phenoxybutyl) -bicyclo [3.3.0] octan-3-one ¹ H-NMR (CDCl ₃ ): δ 1.67 (m, 2H), 2.18-2.54 (m, 6H), 2.72
(m, 1H), 2.94 (dd, J = 18.3,10.5Hz, 1H), 4.13 (t, J = 11.5Hz, 2
H), 5.11 (m, 1H), 5.26 (m, 1H), 6.89 (d, J = 7.8Hz, 2H), 7.01
(t, J = 7.3Hz, 1H), 7.30 (m, 2H), 7.44 (m, 2H), 7.56 (m, 1H), 7.
99 (d, J = 7.3Hz, 2H) 19 F-NMR (CDCl 3): -. 105.9 (m).

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6- (3,3-difluoro-4-phenoxybutyl) -bicyclo [3.3.0] octane-
3-one ¹ H-NMR (CDCl ₃ ): δ 1.47-1.68 (m, 2H), 1.89 (m, 1H), 2.0-2.
2 (m, 3H), 2.32 (dt, J = 15.1,5.9Hz, 1H), 2.51-2.60 (m, 2H),
2.84 (dd, J = 18.8,11.0Hz, 1H), 4.09 (m, 1H), 4.13 (t, J = 11.5
Hz, 2H), 4.98 (m, 1H), 6.92 (d, J = 8.3Hz, 2H), 7.02 (t, J = 7.3H
. z, 1H), 7.32 ( t, J = 7.8Hz, 2H) 19 F-NMR (CDCl 3): - 105.9 (m).

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6- (3,3-difluoro-
4-phenoxybutyl) -bicyclo [3.3.0] octane ¹ H-NMR (CDCl ₃ ): δ 1.4-2.5 (m, 10H), 3.95 (m, 1H), 4.12 (t,
J = 11.5Hz, 2H), 4.68 (m, 1H), 5.54-5.67 (m, 1H), 6.92 (d, J =
. 7.8Hz, 2H), 7.01 ( t, J = 7.3Hz, 1H), 7.31 (t, J = 7.8Hz, 2H) 19 F-NMR (CDCl 3): - 105.6 (m).

[0266] [Example 13] 16-phenoxy-15-deoxy -15,15- difluoro-13,14-dihydro-17,18,19,20 tetranor PGF ₂ alpha synthesized 16-phenoxy in Synthesis Example 12 of - 15-deoxy-
15,15-difluoro-13,14-dihydro-1
The title compound was synthesized from 7,18,19,20-tetranor PGF ₂ α-isopropyl ester in the same manner as in Example 6. ¹ H-NMR (CDCl ₃ ): δ 1.4-2.4 (m, 18H), 3.96 (m, 1H), 4.12 (t,
11.7Hz, 2H), 4.17 (m, 1H), 5.40 (m, 2H), 6.92 (m, 2H), 7.00
. (m, 1H), 7.30 (m, 2H) 19 F-NMR (CDCl 3): - 105.7 (m).

Example 14 9- (t-butyldimethylsilyl) -16-phenoxy-15-deoxy-15,15
-Difluoro-17,18,19,20-tetranor P
Synthesis of GF ₂ α-isopropyl ester 16-phenoxy-15-deoxy-1 synthesized in Example 7
0.29 g of 5,15-difluoro-17,18,19,20-tetranor PGF ₂ α-isopropyl ester was dissolved in 2 ml of N, N-dimethylformamide, and 47.7 mg of imidazole and 96.5 mg of t-butyldimethylsilyl chloride were added. The mixture was added under ice cooling and stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate: hexane (1: 1) was added.
(Volume ratio) The mixture was extracted with a mixed solvent. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 10: 1 to 1: 1 (volume ratio)) to obtain 0.26 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ0.03 (s, 6H), 0.86 (s, 9H), 1.21 (d, J = 6.3
Hz, 6H), 1.56 (m, 1H), 1.65 (m, 2H), 1.76 (m, 1H), 2.0-2.5 (m,
8H), 4.00 (m, 1H), 4.11 (m, 1H), 4.17 (t, J = 11.3Hz, 2H), 4.98
(m, 1H), 5.39 (m, 2H), 5.76 (m, 1H), 6.01 (m, 1H), 6.90 (m, 2
. H), 6.98 (m, 1H), 7.28 (m, 2H) 19 F-NMR (CDCl 3): - 103.2 (m).

Example 15 9- (t-butyldimethylsilyl) -16-phenoxy-15-deoxy-15,15
-Difluoro-17,18,19,20-tetranor P
Synthesis of GD ₂ isopropyl ester 9- (t-butyldimethylsilyl)-synthesized in Example 14
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGF ₂
170 mg of α-isopropyl ester in methylene chloride 3 m
1M, molecular sieve 4A (powder) 850m
g and 194 mg of pyridinium chlorochromate were added under ice-cooling, followed by stirring for 3 hours. After filtering the insoluble matter, the filtrate was concentrated and purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 10: 1 to 5: 1 (volume ratio)) to obtain 154 mg of the title compound. ¹ H-NMR (CDCl ₃ ): δ0.01 (s, 6H), 0.83 (s, 9H), 1.17 (d, J = 6.1
Hz, 6H), 1.57 (m, 2H), 1.9-2.4 (m, 8H), 2.53 (m, 1H), 2.64 (d
d, J = 18.5,7.0Hz, 1H), 4.07 (m, 1H), 4.16 (m, 2H), 4.95 (m, 1
H), 5.31 (m, 2H), 5.83 (dt, J = 15.2,11.3Hz, 1H), 6.08 (m, 1
H), 6.87 (d, J = 7.5Hz, 2H), 6.96 (t, J = 7.5Hz, 1H), 7.26 (t, J =
^{. 7.5Hz, 2H) 19 F-} NMR (CDCl 3): - 103.5 (m).

Example 16 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,2
Synthesis of 0-tetranor PGD ₂ isopropyl ester 9- (t-butyldimethylsilyl)-synthesized in Example 15
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor PGD ₂
152 mg of isopropyl ester was added to acetonitrile
The solution was dissolved in 7 ml, and 0.54 ml of a 46% hydrofluoric acid solution was added under ice cooling, followed by stirring for 3 hours. Saturated aqueous sodium bicarbonate was slowly added, and the mixture was extracted with ethyl acetate. After concentration, silica gel column chromatography (elution solvent: hexane: ethyl acetate =
Purification by 1: 1) afforded 69 mg of the title compound. ¹ H-NMR (CDCl ₃ ): δ 1.22 (d, J = 6.3 Hz, 6H), 1.62 (m, 2H), 2.02
(m, 1H), 2.1-2.5 (m, 8H), 2.75 (m, 1H), 4.16 (m, 1H), 4.22 (m,
2H), 4.98 (m, 1H), 5.34 (m, 2H), 5.90 (dt, J = 16.2,11.2Hz, 1
. H), 6.17 (m, 1H), 6.91 (m, 2H), 7.01 (m, 1H), 7.29 (m, 2H) 19 F-NMR (CDCl 3): - 103.4 (m).

Example 17 16- (3-chlorophenoxy) -15-deoxy-15,15-difluoro-1
Synthesis of 7,18,19,20-tetranor PGD ₂ isopropyl ester 16- (3-chlorophenoxy) -15 synthesized in Example 5
-Deoxy-15,15-difluoro-17,18,1
The title compound was synthesized from 9,20-tetranor PGF ₂ α-isopropyl ester in the same manner as in Examples 14 to 16. ¹ H-NMR (CDCl ₃ ): δ 1.22 (d, J = 6.4 Hz, 6H), 1.62 (m, 2H), 2.0
3 (m, 1H), 2.1-2.5 (m, 8H), 2.76 (m, 1H), 4.17 (m, 1H), 4.22
(m, 2H), 4.99 (m, 1H), 5.36 (m, 2H), 5.86 (dt, J = 16.0,11.2H
z, 1H), 6.15 (m, 1H), 6.82 (m, 1H), 6.93 (m, 1H), 6.99 (m, 1H),
^{. 7.22 (m, 1H) 19} F-NMR (CDCl 3): - 103.7 (m).

The spectrum data of the compound synthesized in each step of Example 17 is as follows. 9-(t-butyldimethylsilyl) -16-(3-chlorophenoxy) -15-deoxy -15,15- difluoro tetranor-PGF ₂ alpha
Isopropyl ester ¹ H-NMR (CDCl ₃ ): δ0.02 (s, 6H), 0.87 (s, 9H), 1.21 (d, J = 6.4
Hz, 6H), 1.5-2.5 (m, 12H), 4.01 (m, 1H), 4.12 (m, 1H), 4.17
(t, J = 11.4Hz, 2H), 4.99 (m, 1H), 5.37 (m, 2H), 5.76 (m, 1H),
6.01 (m, 1H), 6.83 (m, 1H), 6.93 (m, 1H), 7.00 (m, 1H), 7.23
^{. (m, 1H) 19 F} -NMR (CDCl 3): - 103.4 (m).

9- (t-butyldimethylsilyl) -16
-(3-chlorophenoxy) -15-deoxy-15,
15-Difluoro-17,18,19,20-tetranor PGD ₂ isopropyl ester ¹ H-NMR (CDCl ₃ ): δ0.01 (s, 6H), 0.85 (s, 9H), 1.19 (d, J = 6.3)
Hz, 6H), 1.57-2.6 (m, 12H), 4.04 (m, 1H), 4.16 (m, 2H), 4.95
(m, 1H), 5.34 (m, 2H), 5.80 (m, 1H), 6.06 (m, 1H), 6.86 (m, 1
. H), 6.95 (m, 1H), 6.99 (m, 1H), 7.25 (m, 1H) 19 F-NMR (CDCl 3): - 103.5 (m).

[Example 18] (1S, 5R, 6R, 7R)-
2-oxa-7-tetrahydropyranyloxy-6-
[(1E) -3,3-difluoro-4-phenoxy-1
-Butenyl] -bicyclo [3.3.0] octane-3-
Synthesis of ON (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0 4.6 g of octane-3-one is dissolved in methylene chloride (20 ml), and 2.0 ml of 3,4-dihydro-2H-pyran and p-toluenesulfonic acid monohydrate (270 g) are dissolved therein at room temperature.
mg) was added. After stirring for 20 minutes, 5 drops of pyridine were added, and the mixture was further diluted with diethyl ether (100 ml) and washed twice with brine (30 ml). The organic layer was dried and concentrated, and the obtained crude product was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1).
(Volume ratio)) to give 5.5 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ1.47-1.75 (m, 6H), 2.12-2.20 (m, 1H),
2.38-2.81 (m, 5H), 3.48 (m, 1H), 3.80 (m, 1H), 3.97-4.21 (m,
3H), 4.66 (m, 1H), 4.97 (m, 1H), 5.82 (m, 1H), 6.08 (m, 1H),
6.89 (m, 2H), 7.01 (m, 1H), 7.30 (m, 2H). ¹⁹ F-NMR (CDCl ₃ ): -105.4 (m).

[Example 19] (1S, 5R, 6R, 7R)-
2-oxa-3-hydroxy-7-tellorahydropyranyloxy-6-[(1E) -3,3-difluoro-4-
Phenoxy-1-butenyl] -bicyclo [3.3.0]
Synthesis of octane (1S, 5R, 6R, 7R) -2-oxa-7-tetrahydropyranyloxy-6-[(1
E) 5.4 g of 3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octan-3-one was dissolved in THF (30 ml), and -78 was added thereto.
A toluene solution of diisobutylaluminum hydride (1.0 M, 30.0 ml) was added at ° C., and the mixture was stirred for 30 minutes. Then, methanol (2 ml) and 1N hydrochloric acid (20 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2 to 2/3 (volume ratio)) to obtain 4.7 g of the title compound. . ¹ H-NMR (CDCl ₃ ): δ1.40-2.22 (m, 10H), 2.35-2.84 (m, 2H),
2.96 (m, 1H), 3.44 (m, 1H), 3.68-4.22 (m, 4H), 4.58-4.71 (m,
2H), 5.57 (m, 1H), 5.81 (m, 1H), 6.16 (m, 1H), 6.91 (m, 2H), 7.
00 (m, 1H), 7.29 (m, 2H). ¹⁹ F-NMR (CDCl ₃ ): -107.0 (m).

Example 20 16-phenoxy-15-deoxy-15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor P
Synthesis of GF ₂ α To a suspension of 20.3 g of 4-carboxybutyltriphenylphosphonium bromide in 100 ml of THF was added a solution of potassium bis (trimethylsilyl) amide in toluene (0.
5M, 95 ml) and stirred at room temperature for 1 hour. Example 1
(1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7-tellorahydropyranyloxy-
A solution of 4.7 g of 6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] in 24 ml of THF was added at 0 ° C., and the mixture was stirred for 3 hours. . The reaction was stopped by adding ice water, washed with diethyl ether, and the aqueous layer was acidified, and then extracted with ethyl acetate. After the extract was dried, the solvent was distilled off, and the crude carboxylic acid obtained was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 (volume ratio)) to obtain 4.7 g of the title compound. Was. ¹ H-NMR (CDCl ₃ ): δ1.49-1.94 (m, 10H), 2.06-2.34 (m, 8H),
2.56 (m, 1H), 3.44 (m, 1H), 3.80 (m, 1H), 4.08-4.21 (m, 3H),
4.64 (m, 1H), 5.38 (m, 2H), 5.83 (m, 1H), 6.14 (m, 1H), 6.91
(m, 2H), 6.99 (m, 1H), 7.29 (m, 2H). ¹⁹ F-NMR (CDCl ₃ ): -103.3 (m).

Example 21 16-phenoxy-15-deoxy-15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor P
Synthesis of GE ₂ 16-phenoxy-15-deoxy-synthesized in Example 20
15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor PGF ₂
α45.0 mg was dissolved in methylene chloride (12 ml). There, sodium acetate (300.0 mg) at room temperature
And 980.6 mg of pyridinium chlorochromate were added, followed by stirring for 2 hours. The reaction solution was filtered through celite, washed with diethyl ether, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 24/1 (volume ratio)) to give 200 mg of the title compound. I got ¹ H-NMR (CDCl ₃ ): δ1.37-1.77 (m, 8H), 2.01-2.42 (m, 8H), 2.
66-2.84 (m, 2H), 3.47 (m, 1H), 3.79 (m, 1H), 4.02-4.26 (m, 3
H), 4.68 (m, 1H), 5.29-5.43 (m, 2H), 5.93 (m, 1H), 6.22 (m, 1
. H), 6.91 (m, 2H), 7.00 (m, 1H), 7.29 (m, 2H) 19 F-NMR (CDCl 3): - 103.6 (m).

Example 22 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,2
Synthesis of 0-tetranor PGE ₂ 16-phenoxy-15-deoxy-synthesized in Example 21
15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor PGE ₂
45 mg was dissolved in acetone (2 ml). There 1
After adding 0.5 ml of an aqueous solution of N hydrochloric acid and stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate and washed with water. After drying, the solvent was distilled off, and the resulting crude product was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 1/1 (volume ratio)) to obtain 23 mg of the title compound. ¹ H-NMR (CDCl ₃ ): δ 1.62 (m, 2H), 2.05 (m, 2H), 2.15-2.22 (m,
2H), 2.27 (t, J = 7.3Hz, 2H), 2.37 (dd, J = 6.4Hz, 7.3Hz, 2H),
2.55 (m, 1H), 2.76 (dd, J = 6.8Hz, 18.6Hz, 1H), 4.15 (m, 1H),
4.21 (t, J = 11.2Hz, 2H), 5.29 (m, 1H), 5.39 (m, 1H), 5.90 (dt,
J = 11.2Hz, 15.6Hz, 1H), 6.17 (ddd, J = 2.0Hz, 8.3Hz, 15.6Hz,
1H), 6.91 (dd, J = 1.0Hz, 7.8Hz, 2H), 7.01 (t, J = 7.3Hz, 1H),
7.30 (m, 2H). ¹⁹ F-NMR (CDCl ₃ ): -103.3 (m).

Example 23 16-phenoxy-15-deoxy-15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor P
Synthesis of GF ₂ α-isopropyl ester 16-phenoxy-15-deoxy-synthesized in Example 20
15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor PGF ₂
200 mg of α was added to a solution of acetone (1 ml) in 1,8-diazabicyclo [5.4.0] undec-7-ene 0.17.
Then, 0.17 ml of 2-iodopropane was added, and the mixture was stirred at 30 ° C for 7 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated saline solution, a 3% aqueous citric acid solution and an aqueous sodium bicarbonate solution, dried and concentrated, and then purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/3). 180 mg of the title compound were obtained. ¹ H-NMR (CDCl ₃ ): δ 1.21 (d, J = 6.1 Hz, 6H), 1.23-1.93 (m, 10
H), 2.06-2.32 (m, 8H), 2.58 (m, 1H), 3.43 (m, 1H), 3.81 (m, 1
H), 4.05-4.21 (m, 3H), 4.64 (m, 1H), 4.99 (m, 1H), 5.40 (m, 2
H), 5.81 (m, 1H), 6.14 (m, 1H), 6.89 (m, 2H), 7.00 (m, 1H), 7.2
9 (m, 2H). ¹⁹ F-NMR (CDCl ₃ ): -103.2 (m).

Example 24 16-phenoxy-15-deoxy-15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor P
Synthesis of GE ₂ isopropyl ester 16-phenoxy-15-deoxy-synthesized in Example 23
15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor PGF ₂
180 mg of α-isopropyl ester in methylene chloride (4
ml). There, celite at room temperature (300m
g) and 289 mg of pyridinium chlorochromate were added, and the mixture was stirred as it was for 3 hours. After the reaction solution was filtered through celite, washed with diethyl ether, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1 (volume ratio)). 130 mg of the title compound were obtained. ¹ H-NMR (CDCl ₃ ): δ 1.21 (d, J = 6.4 Hz, 6H), 1.50-1.74 (m, 8
H), 2.02-2.40 (m, 8H), 2.71-2.82 (m, 2H), 3.45 (m, 1H), 3.79
(m, 1H), 4.04-4.26 (m, 3H), 4.67 (m, 1H), 4.99 (m, 1H), 5.28
(m, 1H), 5.38 (m, 1H), 5.89 (m, 1H), 6.21 (m, 1H), 6.91 (m, 2
. H), 7.00 (m, 1H), 7.29 (m, 2H) 19 F-NMR (CDCl 3): - 103.7 (m).

Example 25 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,2
Synthesis of 0-tetranor PGE ₂ isopropyl ester 16-phenoxy-15-deoxy-synthesized in Example 24
15,15-difluoro-11-tetrahydropyranyloxy-17,18,19,20-tetranor PGE ₂
The title compound was synthesized from isopropyl ester in the same manner as in Example 22. ¹ H-NMR (CDCl ₃ ): δ 1.21 (d, J = 6.4 Hz, 6H), 1.63 (m, 2H), 2.02
-2.40 (m, 8H), 2.71-2.82 (m, 2H), 4.05-4.26 (m, 3H), 4.97
(m, 1H), 5.31 (m, 1H), 5.40 (m, 1H), 5.91 (m, 1H), 6.21 (m, 1
H), 6.91 (m, 2H), 7.01 (m, 1H), 7.31 (m, 2H). ¹⁹ F-NMR (CDCl ₃ ): -103.4 (m). [Example 26] (1S, 5R, 6R) -2-oxa-6-
[(1E) -3,3-difluoro-4-phenoxy-1
-Butenyl] -bicyclo [3.3.0] octane-3-
Synthesis of ON (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [synthesized in Example 7 [3.3.0] To a solution of 2.15 g of octane-3-one in methylene chloride (20 ml) was added 2.43 g of 4-dimethylaminopyridine, and 1.83 ml of phenoxychlorothionocarbonate was added dropwise. After stirring at room temperature for 2 hours, the obtained pale yellow suspension was poured into saturated aqueous sodium hydrogen carbonate solution (30 ml) and extracted with ethyl acetate. After drying and concentration, silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/1)
And purified by (1S, 5R, 6R, 7R) -2-oxa-
7-phenoxythionocarbonyloxy-6-[(1
E) 2.96 g of -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octan-3-one were obtained. ¹ H-NMR (CDCl ₃ ): δ 2.3-3.0 (m, 6H), 4.21 (t, J = 11.4 Hz, 2H),
5.02 (m, 1H), 5.50 (m, 1H), 5.92 (m, 1H), 6.15 (m, 1H), 6.8-6.
9 (m, 3H), 7.02 (m, 2H), 7.2-7.4 (m, 5H) 19 F-NMR (CDCl 3): -. 104 (m).

(1S, 5R, 6R, 7R) -2-oxa-7-phenoxythionocarbonyloxy-6-[(1
E) To a solution of 2.96 g of 3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octan-3-one in 65 ml of toluene, 30 mg of azobisisobutyronitrile, 5.19 ml of tributyltin hydride was added, and the mixture was heated under reflux. Thirty minutes later, 5.19 ml of tributyltin hydride was added, and the mixture was further heated under reflux for 30 minutes. After allowing to cool, the mixture was concentrated under reduced pressure, and silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/1).
Purification in 1) gave 0.36 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ1.57 (m, 1H), 1.72 (m, 2H), 2.2-2.3 (m, 2
H), 2.7-3.1 (m, 3H), 4.16 (t, J = 11.6Hz, 2H), 5.01 (m, 1H), 5.
75 (m, 1H), 6.14 (m, 1H), 6.90 (d, J = 8.0Hz, 2H), 6.99 (m, 1H),
7.29 (t, J = 8.0Hz, 2H) 19 F-NMR (CDCl 3): -. 103 (m).

Example 27 (1S, 5R, 6R) -2-oxa-6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octane Synthesis of -3-ol (1S, 5R, 6R) -2-oxa- synthesized in Example 26
6-[(1E) -3,3-difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octane-
Dissolve 0.36 g of 3-one in 3 ml of toluene, and add
After cooling to ℃, 1.39 ml of diisobutylaluminum hydride was added dropwise. After stirring for 30 minutes, 10 ml of saturated saline was added, and the mixture was extracted three times with ethyl acetate (10 ml). After drying over anhydrous magnesium sulfate and concentration under reduced pressure, 340 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ): δ1.4-1.7 (m, 4H), 1.9-3.0 (m, 4H), 4.17
(t, J = 11.6Hz, 2H), 4.76 (m, 1H), 5.57 (m, 1H), 5.75 (m, 1H),
6.17 (m, 1H), 6.91 (m, 2H), 6.99 (m, 1H), 7.29 (m, 2H) 19 F-NMR (CDCl 3): -. 104 (m).

Example 28 16-Phenoxy-11,15
-Dideoxy-15,15-difluoro-17,18,
19,20- tetranor PGF ₂ Synthesis of 4-carboxybutyl triphenylphosphonium bromide 1.94g of α After drying under vacuum, was synthesized in Example 27 (1S, 5R, 6R) -2- oxa-6 - [( 1E)
-3,3-Difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octan-3-ol 3
18 mg of THF was added to 40 mg to prepare a suspension.

17.5 ml of a toluene solution of potassium bistrimethylsilylamide (0.5 M) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Synthesized in Example 27 (1S,
5R, 6R) -2-oxa-6-[(1E) -3,3-
Difluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octan-3-ol 340 mg of T
An HF (11 ml) solution was added at -5 ° C and the mixture was stirred for 3 hours. 20 ml of water was added, and the mixture was extracted twice with ether (15 ml). 20 ml of a 5% citric acid solution was added to the aqueous layer, and extracted three times with ethyl acetate (20 ml). The extract was dried and concentrated. Purification by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 2/3) gave 390 mg of the title compound. ¹ H-NMR (CDCl ₃ ): δ1.4-2.4 (m, 14H), 4.1-4.2 (m, 3H), 5.40
(m, 2H), 5.67 (m, 1H), 6.19 (m, 1H), 6.92 (m, 2H), 6.99 (m, 1
. H), 7.29 (m, 2H) 19 F-NMR (CDCl 3): - 104 (m).

Example 29 16-phenoxy-11,15
-Dideoxy-15,15-difluoro-17,18,
Synthesis of 19,20-tetranor PGE ₂ 16-phenoxy-11,15-dideoxy-15,15-difluoro-17,18,19, synthesized in Example 28
20-tetranor PGF ₂ α of dichloromethane (4.3
ml) The solution was cooled on ice and molecular sieve 4A (powder)
836 mg, followed by pyridinium chlorochromate 16
7 mg was added. After stirring for 40 minutes, silica gel column chromatography (hexane / ethyl acetate = 4/1)
１／1/1, then only ethyl acetate) to give 38.9 mg of the title compound. ¹ H-NMR (CDCl ₃ ): δ 1.6-2.5 (m, 13 H), 3.02 (m, 1 H), 4.18 (t, J
= 11.4Hz, 2H), 5.40 (m, 2H), 5.77 (m, 1H), 6.24 (m, 1H), 6.91
. (m, 2H), 7.00 (m, 1H), 7.29 (m, 2H) 19 F-NMR (CDCl 3): - 104 (m).

[0286]

The present invention provides a PG derivative having two fluorine atoms at the 15-position, which is a PG derivative useful as a pharmaceutical. The PG derivative of the present invention is a compound that can be easily produced by applying a known production method.

The PG derivative has various effects related to pain and inflammation, as well as a vasodilatory effect, a bronchodilator effect, a gastric acid secretion inhibitory effect, a gastric mucosal protective effect, a uterine contractile effect, and the like. Agent, a therapeutic agent for gastric ulcer, a labor-inducing agent and the like. In addition, since it can affect various actions related to central nervous system action, sleep-inducing action, platelet aggregation inhibitory action, allergy, immune response, and inflammation, it is used as a drug that regulates or prevents these actions. sell. It is also useful as a prodrug of a drug having these effects. In addition, the PG of the present invention
Derivatives are excellent compounds that can exhibit pharmacological activity selectivity based on their structure and drug durability based on chemical stability.

Claims (11)

[Claims] 1. A derivative of 15-deoxy-15,15-difluoroprostaglandin E, 15-deoxy-1
Derivatives of 5,15-difluoroprostaglandin D,
Derivatives of 15-deoxy-15,15-difluoroprostaglandin I, derivatives of 15-deoxy-15,15-difluoroprostaglandin A, derivatives of 15-deoxy-15,15-difluoroprostaglandin B, and 15 A 15-deoxy-15,15-difluoroprostaglandin derivative selected from derivatives of -deoxy-15,15-difluoroprostaglandin J, or a salt thereof (provided that 13,14-dihydro-1
Except 5-deoxy -15,15- difluoromethyl-20-methyl-prostaglandin E ₁ methyl ester. ). 2. Derivatives of 15-deoxy-15,15-difluoroprostaglandin E and 15-deoxy-15,15-difluoroprostaglandin selected from 15-deoxy-15,15-difluoroprostaglandin D Derivatives or salts thereof (13,1
Excluding 4-dihydro-15-deoxy-15,15-difluoro-20-methylprostaglandin E ₁ methyl ester. ). 3. The 15-deoxy-15,15-difluoroprostaglandin derivative according to claim 1, wherein the 15-deoxy-15,15-difluoroprostaglandin derivative is represented by the following formula (1): Salt (however, A
Is an ethylene group, P is -CO-, Q is -CH (OH)-,
X is -CH ₂ -, Z is OCH _3, R ¹ is n- hexyl group, and, except for the compound solid and broken lines of the overlapped portion is a single bond. ). Embedded image 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-. Overlap between solid and dashed line: single bond, cis double bond, or trans double bond. R ¹ : an alkyl group having 3 to 8 carbon atoms, substituted 3 carbon atoms
An alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a substituted alkenyl group having 3 to 8 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, a substituted alkynyl group having 3 to 8 carbon atoms,
C3-8 cycloalkyl group, substituted C3
~ 8 cycloalkyl groups, aralkyl groups, substituted aralkyl groups, aryloxyalkyl groups, or substituted aryloxyalkyl groups. P and Q: each independently —CO—, —CH (OR ² )
— Or —CH ₂ —, and P and Q are simultaneously —CO
But not -CH (OR ² )-(wherein R ² independently represents a hydrogen atom or an acyl group). In addition, one of R ² and Z may form a single bond together. ^{Z: -OR 3, -NHCOR 4,} -NHSO 2 R 5, -
SR ⁶ or -NR ⁷ R ^8,. Further, one of R ² and Z may form a single bond together (provided that R 2 is
³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ each independently represent a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, An alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, an aralkyl group, or a substituted aralkyl group. ). 4. A is an ethylene group or a vinylene group.
The 15-deoxy-15,15-difluoroprostaglandin derivative according to claim 3, or a salt thereof. 5. The method according to claim 3, wherein X is --CH _2-.
15. The 15-deoxy-15,15-difluoroprostaglandin derivative or a salt thereof according to item 1. 6. The 15-deoxy-15,15-difluoroprostaglandin derivative according to claim 3, wherein R ² is a hydrogen atom, or a salt thereof. 7. The 15-deoxy-15,15-difluoroprostaglandin derivative according to claim ³ , wherein Z is —OR ³ , or a salt thereof. 8. P is --CO--, and Q is --CH--
And (OR ² ) — or —CH ₂ —.
15-deoxy-15,15 according to 5, 6, or 7
-A difluoroprostaglandin derivative or a salt thereof. 9. P is —CH (OR ² ) — or —CH ₂ —
And Q is -CO-.
The 15-deoxy-15,15-difluoroprostaglandin derivative according to 6 or 7, or a salt thereof. 10. The 15-deoxy-15,15- according to claim 3, 4, 5, 6, 7, 8, or 9 wherein R ¹ is an aryloxyalkyl group or a substituted aryloxyalkyl group. A difluoroprostaglandin derivative or a salt thereof. 11. The method according to claim 3, wherein R ¹ is a phenoxymethyl group, a 3-chlorophenoxymethyl group, a 3,5-dichlorophenoxymethyl group, or a 3- (trifluoromethyl) phenoxymethyl group. , 6, 7, 8, or 9, the 15-deoxy-15,15-difluoroprostaglandin derivative, or a salt thereof.