JPH0748345A - Fluorine-containing prostaglandin analog - Google Patents

Abstract

PURPOSE:To obtain a new fluorine-containing prostaglandin analog having excellent safety and durability of activity, useful as a prodrug of PGE0 and converted to the corresponding PGE0 by the hydrolysis in the body to exhibit bio-activity. CONSTITUTION:The fluorine-containing prostaglandin analog expressed by the formula I [R<1> is residue obtained by removing carboxyl group from carboxylic acid; R<2> is H or residue obtained by removing OH from alcohol; R<3> and R<4> are H or OH-protecting group; R<5> is (substituted) <=10C hydrocarbon group], especially a compound expressed by the formula II, e.g. methyl-9- acetoxy-14-fluoro-11alpha,15S-dihydroxy-13,14-dihydroprost-8-en-1-oate. The compound of the formula I can be produced e.g. by reacting a 2-cyclopenten-1-one compound of the formula III with an alkyl metal compound.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel fluorine-containing prostaglandin analog having excellent stability and durability of activity.

[0002]

2. Description of the Related Art Prostaglandins (hereinafter referred to as PG) are physiologically active substances derived from polyunsaturated fatty acids. 1960 PGE ₁ , PGE ₂ , PGE ₃ , PG
Since the structures of six types of F ₁ α, PGF ₂ α, and PGF ₃ α were determined, the discovery of PG analogs was made one after another, and their physiological activities were also revealed one after another.

In particular, PGE ₁ , PGE ₂ and its derivatives are known to induce biochemical and physiological effects in various mammals. PGE ₁ contracts smooth muscle of the vas deferens of the mammalian male reproductive system and contracts uterine smooth muscle in the female reproductive system. It also stimulates the contraction of gastrointestinal smooth muscle, suppresses gastric juice secretion, and affects the tracheal smooth muscle of the respiratory tract. Furthermore, PGE ₁ inhibits platelet aggregation and, in the cardiovascular system, its action on vascular smooth muscle makes it a vasodilator.

Therefore, PGE ₁ and its homologues are expected to have wide clinical applications, and it is predicted that drugs of these PGs will play a large role in the future (Sim, AK).
Arzneim-Forsch / Drug Res., 1206 (1986)).

In another document, it is predicted that the drugs of these PG analogs have a large role, and PG analogs are typical of local hormones, which are locally produced as necessary, and Because they are hormones that act locally, these PG-related drugs are called autacoids.
It is considered necessary to carry out chemical modification taking into account the characteristics and chemical properties of

Examples of PG analogs include methyl 9-
Acetoxy -11α, 15S- Dihydroxyprosta -8,13E-
Diene-1-oate, methyl 9,11α, 15S-triacetoxyprosta-8,13E-diene-1-oate, methyl 9,
15R-diacetoxy -11α-hydroxyprosta -8,13E-
Diene-1-oate, methyl 9,15 S-diacetoxy-11
α-Hydroxyprosta-8,13E-diene-1-oate and the like are known (Japanese Patent Publication No. 60-33827).

Meanwhile, in the study of prostaglandins
It has been reported that 13,14-dihydro-PGE ₁ (PGE ₀ ) has a high inhibitory effect on platelet aggregation (J. Westw.
ick, J. Pharmacol., 58, 297 (1976)). For example, the ability of PGE ₀ to inhibit platelet aggregation induced by ADP is said to be as strong as PGE ₁ .

[0008]

However, natural prostaglandins (1) generally lack chemical stability,
It has drawbacks such as (2) a high metabolic rate in the body and (3) various side effects. In particular, PGE ₁ is
PGA that is unstable under both acidic and basic conditions, eliminates the 11-position hydroxyl group, and has no biological activity
Will be converted into a type compound.

An object of the present invention is to provide a PG analog which retains such high PG physiological activity and overcomes chemical instability.

[0010]

The present invention provides the following formula (1):
Is a novel fluorine-containing prostaglandin analog represented by. This fluorine-containing prostaglandin analog is PGE
Are useful as prodrugs of ₀ class, it exhibits an altered biological activity PGE ₀ class corresponding undergo hydrolysis in vivo.

[0011]

[Chemical 3]

[In the formula (1), R ^{1 to} R ⁵ represent the following. R ¹ : A residue obtained by removing a carboxyl group from carboxylic acids. R ² : A hydrogen atom or a residue obtained by removing a hydroxyl group from alcohols. R ³ and R ⁴ : each independently a hydrogen atom or a hydroxyl-protecting group. R ⁵ : a hydrocarbon group having 10 or less carbon atoms which may have a substituent. ]

In the formula (1), the wavy bond representing the bond between the ring and the R ³ O group and the wavy bond representing the bond between the ring and the side chain (ω chain) are on the plane of the ring. On the other hand, it represents a bond which may be directed upward or downward. Similarly, the wavy bond representing the bond between the R ⁴ O group and the side chain carbon atom indicates that the side chain carbon atom which is the asymmetric carbon atom may have any configuration. Further, in the following, a bond indicated by a dotted line indicates a downward bond, and a wedge-like bond indicates an upward bond.

The compound represented by the formula (1) includes a ring and a side chain (ω chain) group in which the bond between the ring and the R ³ O group and the bond between the R ⁴ O group and the side chain carbon atom are downward. Compounds having an upward bond with are preferred. This preferable compound is represented by the following formula (2). The bond of the waveform representing the bond between the fluorine atom and the side chain carbon atom in the side chain may have any configuration in the side chain carbon atom which is the asymmetric carbon atom (that is, the direction of the bond hand). Can be either).

[0015]

[Chemical 4]

The novel fluorine-containing prostaglandin analog of the present invention represented by the formula (1) (hereinafter referred to as PG analog)
In, R ¹ represents a residue of a carboxylic acid in which the hydroxyl group at the 9-position is esterified, excluding the carboxyl group, particularly a monovalent hydrocarbon group. This hydrocarbon group may have a substituent. The number of carbon atoms of this hydrocarbon group is preferably 8 or less, particularly 6 or less, but is not necessarily limited to this. The hydrocarbon group may be an aromatic hydrocarbon group, an aromatic nucleus-substituted aliphatic hydrocarbon group, an alicyclic hydrocarbon group, or an alicyclic hydrocarbon group-substituted aliphatic hydrocarbon group,
Aliphatic hydrocarbon groups are preferred. As the aliphatic hydrocarbon group, an alkyl group having 6 or less carbon atoms is preferable. More preferably, it is an alkyl group having 4 or less carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a pentyl group.

R ² is a hydrogen atom or represents a residue obtained by removing a hydroxyl group from alcohols, particularly a monovalent hydrocarbon group. This hydrocarbon group may have a substituent. .
The number of carbon atoms of this hydrocarbon group is preferably 20 or less, particularly preferably 10 or less, but not limited to this. As this hydrocarbon group, an aromatic nucleus-substituted aliphatic hydrocarbon group,
It may be an alicyclic hydrocarbon group or an alicyclic hydrocarbon group-substituted aliphatic hydrocarbon group, but an aliphatic hydrocarbon group is preferred. As the aliphatic hydrocarbon group, an alkyl group having 20 or less carbon atoms is preferable. More preferably, it is an alkyl group having 8 or less carbon atoms, particularly 6 or less carbon atoms. Examples of the alkyl group include an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a pentyl group.

R ³ and R ⁴ each independently represent a hydrogen atom or a hydroxyl-protecting group. As the hydroxyl-protecting group, there are commonly used protecting groups such as TW Grenne, P.
rotective Group in Organic Synthesis, 1981. John W
iley & Sons) are preferable, and examples thereof include a triorganosilyl group, an acyl group and an ether type protecting group.

Specific protective groups include, for example, triorganosilyl groups such as trimethylsilyl group, t-butyldimethylsilyl group, diphenylmethylsilyl group, dimethylisopropylsilyl group and biphenylmethylsilyl group, acetyl group, propionyl group, Acyl group such as benzoyl group, or methyl group, benzyl group, methoxybenzyl group, trityl group, dimethoxytrityl group, methoxymethyl group, methoxyethoxymethyl group, trimethylethoxymethyl group, ethoxyethyl group, tetrahydropyranyl group, tetrahydrofuran There are ether-based protecting groups such as a nyl group.

R ⁵ is a hydrocarbon group having 10 or less carbon atoms which may have a substituent, and a hydrocarbon group portion excluding the substituent, that is, a skeleton portion is an aliphatic hydrocarbon having 1 to 8 carbon atoms. It is preferably a group or an alicyclic hydrocarbon group having 3 to 10 ring members. The aliphatic hydrocarbon group may be linear or branched, and may be an aliphatic hydrocarbon group having an unsaturated bond, that is, an alkenyl group or an alkynyl group. Moreover, an unsaturated bond may be present in the ring of the alicyclic hydrocarbon group.

In the case of an aliphatic hydrocarbon group having a substituent,
The substituent is, for example, a halogen atom, an alkoxy group which may be substituted with a halogen atom, a nitrile group, a carboxyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms, or an alicyclic carbon atom which may have a substituent. There are a hydrogen group, a cycloalkyloxy group which may have a substituent, a phenyl group which may have a substituent and a phenoxy group. The alkoxy group as the substituent preferably has 6 or less carbon atoms, and the alicyclic hydrocarbon group and the cycloalkyloxy group as the substituent preferably have 4 to 7 ring members.

When the alicyclic hydrocarbon group as a skeleton or the alicyclic hydrocarbon group as a substituent, a cycloalkyloxy group, a phenyl group or a phenoxy group has a substituent, the substituent is In addition to the above, it may be an alkyl group which may be further substituted with a halogen atom. The alkyl group preferably has 6 or less carbon atoms, and particularly preferably 4 or less carbon atoms. In addition, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

R ⁵ is preferably substituted with a linear or branched alkyl group, alkenyl group, alkynyl group or alkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom. A cycloalkyl group having 4 to 7 ring members, or a cycloalkyl group (which may be substituted with an alkyl group), an alkoxy group, a phenyl group, or a phenoxy group having 1 carbon atom.
~ 5 alkyl groups. The halogen atom is preferably a fluorine atom. The alkyl group as a substituent of the cycloalkyl group is preferably an alkyl group having 4 or less carbon atoms, that is, a lower alkyl group. This alkoxy group is also preferably an alkoxy group having 4 or less carbon atoms, that is, a lower alkoxy group.

Most preferably, R ⁵ is a linear or branched alkyl group having 4 to 7 carbon atoms, a cycloalkyl group having 5 to 6 ring members, or 1 to 4 carbon atoms substituted with a phenoxy group. Is an alkyl group.

Examples of R ⁵ are as follows.
R ⁵ is not limited to these.

Propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, 1-methylbutyl group,
2-methylbutyl group, 2-methylhexyl group, 1-methylpentyl group, 1,1-dimethylpentyl group, 6-methyl-5-heptenyl group, 1-methyl-3-pentynyl group, 1-methyl-3-hexynyl group Group, 1,1-difluoropentyl group, 1-fluoropentyl group, cyclopropyl group, cyclobutyl group.

Cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, 3-methylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl,
3-pentylcyclopentyl group, 4-propylcyclohexyl group, benzyl group, 2-phenylethyl group, phenoxymethyl group, 2-phenoxyethyl group, 1-phenoxy-1-methylethyl group, 2-methoxyethyl group, 2 -Ethoxyethyl group.

Of these, preferred R ⁵ is butyl group, pentyl group, hexyl group, (R)-or (S) -2-methylhexyl group, 1-methylpentyl group, 1-methylbutyl group, 1,1 -Dimethylpentyl group, 6-methyl-5-heptenyl group, 1-methyl-3-pentynyl group, 1-methyl-3-hexynyl group, 1,1-difluoropentyl group, 1-fluoropentyl group, 2-phenoxyethyl group Group, 1-phenoxy-1-methylethyl group, and 2-methoxyethyl group.

The PG analog of the present invention represented by the formula (1) has various stereoisomers because it has an asymmetric carbon at the 11th, 12th, 14th and 15th positions as described above. However, the present invention may be any PG analog thereof or a mixture thereof. However, it is preferably a compound having the stereostructure of the formula (2) as described above.

The compound represented by the formula (1) can be produced, for example, by reacting a 2-cyclopenten-1-one represented by the following formula (3) with an alkyl metal compound. This alkyl metal compound can be obtained by reacting a halogen-containing compound represented by the following formula (4) with a metal compound.

[0031]

[Chemical 5]

[Wherein R ²² and R ²³ in the above formula (3) have the same meanings as the corresponding R ² and R ^{3 in} the formula (1), or
It is a group that can be converted into the corresponding R ² and R ³ . ]

[0033]

[Chemical 6]

[In the above formula (4), R ²⁴ and R ²⁵ are represented by the formula (1)
The corresponding R ^4, R ⁵ and either synonymous or a corresponding R ^4, group which can be converted into R ^5, X is a halogen atom. ]

Specifically, for example, a substituted 1-iodoalkane represented by the formula (4) is reacted with an alkyllithium to give a substituted 1-lithioalkane, and then a trialkylphosphine-iodine. It is reacted with a copper (I) chloride complex to give an organolithiocuprate. Then, this organolithiocuprate substituted 2-cyclopentene-1
-On, 1,4 conjugated addition reaction, and then quenching the reaction mixture with carboxylic acid anhydride or carboxylic acid halide.

Organolithiocuprate can be prepared by the method described in the literature (Organic Reactions, vol.38, chapter 2.), and as the ligand, tri (dialkylamino) phosphine having 6 to 12 carbon atoms and 3 to 12 carbon atoms are used as ligands. Trialkylphosphine and dialkyl sulfide having 2 to 12 carbon atoms are preferable. Particularly, tri (dimethylamino) phosphine, tri (n-butyl) phosphine, diisopropyl sulfide, dimethyl sulfide and the like are preferable.

Further, a substituted 1-iodoalkane represented by the above formula (4) is reacted with alkyllithium to form a substituted 1-lithioalkane, and then a trialkylphosphine-copper iodide (I ) In addition to a method of reacting with a complex to form an organolithiocuprate, a substituted 1-haloalkane represented by the formula (4) is prepared from magnesium as a Grignard reaction agent, and by using this and an inorganic copper reagent. Similarly, the compound represented by the formula (1) can be produced by carrying out a 1,4 conjugate addition reaction and then quenching the reaction mixture with a carboxylic acid anhydride or a carboxylic acid halide.

As the reaction solvent for the 1,4 conjugate addition reaction and the subsequent quenching, ether, tetrahydrofuran, a mixed solvent of ether-tetrahydrofuran, a mixed solvent of pentane-tetrahydrofuran, a mixed solvent of pentane-ether and the like can be used. preferable. The reaction temperature may be −70 ° C. to the solvent reflux temperature, but a temperature of −70 ° C. to room temperature is usually adopted.

The compound represented by the formula (4) can be produced, for example, as follows. That is, N-bromosuccinimide or a compound represented by the formula (5)
It can be produced by reacting a reactant obtained by adding hydrogen fluoride-pyridine to N-iodosuccinimide or the like in an inert solvent such as ether, tetrahydrofuran, dioxane, or dichloromethane. This reaction is -78 ° C
It can be carried out using a reaction temperature in the range of to solvent reflux, but is usually carried out in the range of 0 ° C to room temperature.

[0040]

[Chemical 7]

[In the above formula (5), R ²⁴ and R ²⁵ have the same meanings as the corresponding R ⁴ and R ^{5 in} the formula (1), or
It is a group that can be converted into the corresponding R ⁴ and R ⁵ . ]

The compound of formula (1) in which R ³ or R ⁴ is a hydroxyl-protecting group is optionally deprotected. The deprotection reaction can be carried out under ordinary reaction conditions. For example, when the protecting group is a triorganosilyl group, tetrabutylammonium fluoride or hydrofluoric acid is used, and when the protecting group is a tetrapyranyl group, Is p-toluenesulfonic acid,
Pyridinium p-toluenesulfonate, hydrofluoric acid, etc. can be used. As the reaction solvent, a mixed solvent such as acetonitrile-water, tetrahydrofuran-water, ether-water, or an inert solvent such as tetrahydrofuran can be used, and the reaction temperature is in the range of -70 ° C to the solvent reflux temperature. To be

Examples of the carboxylic acid anhydride or carboxylic acid halide used as a quenching agent include, for example,
The following compounds can be used: Acetic anhydride, propionic anhydride, butyric anhydride, pentanoic anhydride, hexanoic anhydride, acetyl chloride, propionyl chloride, butanoyl chloride, pentanoyl chloride.

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

[0045]

【Example】

[Reference Example 1] Synthesis of (3S) -1-iodo-2-fluoro-3- (t-butyldimethylsiloxy) octane

N-iodosuccinimide (2.70 g, 12.0 mmo
l) was dissolved in ether (10 ml), cooled to 0 ° C. and hydrofluoric acid-pyridine (9.75 ml) was added. After stirring for 30 minutes, (3S)
-3- (t-Butyldimethylsiloxy) -1-octene (1.70 g, 10.
0 mmol) was dissolved in ether (30 ml) and added. After stirring at 0 ° C to room temperature for 15 hours, the mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated, dissolved in N, N-dimethylformamide (10 ml), added with imidazole (1.36 g, 20 mmol) and t-butyldimethylsilyl chloride (1.80 g, 12 mmol), and added at 0 ° C. 15
Stir for hours. After post-treatment by a conventional method, it was purified by silica gel column chromatography to give the title compound (0.70 g)
Got

¹ H-NMR (CDCl ₃ ) δ 0.0 (6H, s), 0.9 (12H, s +
t), 1.2-2.2 (8H, m), 4.0-4.2 (1H, m), 5.0-5.5 (3H, m).

Reference Example 2 Synthesis of (3S, 5S) -1-iodo-2-fluoro-3- (t-butyldimethylsiloxy) -5-methylnonane

In Reference Example 1, instead of (3S) -3- (t-butyldimethylsiloxy) -1-octene, (3S, 5S) -3- (t-butyldimethylsiloxy) -5-methyl-1- The title compound (yield 40%) was obtained by the same procedure as in Reference Example using nonene.

¹ H-NMR (CDCl ₃ ) δ 0.0 (6H, s), 0.9 (15H, s +
t + t), 1.2-2.2 (9H, m), 4.0-4.2 (1H, m), 5.0-5.5 (3H, m).

Example 1 Synthesis of methyl 9-acetoxy-14-fluoro-11α, 15S-dihydroxy-13,14-dihydroprosta-8-en-1-oate

(3S) -1-Iodo-2-fluoro-3- (t-butyldimethylsiloxy) octane (1.00 g, 2.83 mmol) was dissolved in ether (5 ml) and cooled to -78 ° C. t-Butyllithium (f = 1.60, hexane solution, 3.94 ml, 6.3 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hr, then tributylphosphine-copper (I) iodide complex (1.05 g, 2.8 mmol) and tributyl were added. Add a solution of phosphine (0.68 ml, 2.8 mmol) in ether (5 ml).
It was added dropwise over 20 minutes. After stirring at -78 ° C for 1 hour, (4
An ether solution (10 ml) of (R) -t-butyldimethylsiloxy-2- (6-carbomethoxyhexyl) -2-cyclopenten-1-one (1.02 g, 2.9 mmol) was added dropwise over 20 minutes. 30 at the same temperature
For 30 minutes at -30 to -20 ℃, and then acetic anhydride (0.85 m
(1, 8.5 mmol) was added dropwise, and the mixture was stirred from 0 ° C. to room temperature for 15 hours.

A saturated aqueous ammonium sulfate solution (50 ml) was added, the organic phase was separated, and then the aqueous phase was extracted with ether.
The organic phases were collected, washed with saturated brine, dried over magnesium sulfate, and concentrated by filtration. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain an adduct.

This adduct was dissolved in acetonitrile (10 ml), 40% hydrofluoric acid aqueous solution (5 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hr. 20% aqueous potassium carbonate solution
(50 ml) and methylene chloride (50 ml) were poured into the mixture. The methylene chloride layers were collected, dried and concentrated with magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1.1 g).

¹ H-NMR (CDCl ₃ ) δ 0.9 (3H, t, J = 7Hz), 1.2-
3.1 (29H, m + s (δ 2.1,3H)), 3.6 (3H, s), 4.0-4.3 (2H, m),
5.0-5.2 (1H, m).

Example 2 Methyl 9-acetoxy-14-fluoro-11α, 15S-dihydroxy-17S, 20-dimethyl-13,14-dihydroprosta-8-
Synthesis of en-1-oate

In Example 1, instead of (3S) -1-iodo-2-fluoro-3- (t-butyldimethylsiloxy) octane, (3S, 5S) -1-iodo-2-fluoro-3- (t The title compound was obtained by the same procedure as in Example 1 using -butyldimethylsiloxy) -5-methylnonane (yield 27%).

¹ H-NMR (CDCl ₃ ) δ 0.8-0.95 (6H, m), 1.1-
3.1 (30H, m + s (δ 2.1,3H)), 3.65 (3H, s), 4.0-4.3 (2H,
m), 5.0-5.3 (1H, m).

Example 3 Butyl 9-acetoxy-14-fluoro-11α, 15S-dihydroxy-17S, 20-dimethyl-13,14-dihydroprosta-8-
Synthesis of en-1-oate

In Example 1, instead of (3S) -1-iodo-2-fluoro-3- (t-butyldimethylsiloxy) octane, (3S, 5S) -1-iodo-2-fluoro-3- (t -Butyldimethylsiloxy) -5-methylnonane, (4R) -t-butyldimethyl instead of (4R) -t-butyldimethylsiloxy-2- (6-carbomethoxyhexyl) -2-cyclopenten-1-one Using siloxy-2- (6-carbobutoxyhexyl) -2-cyclopenten-1-one and by the same procedure as in Example 1, the title compound was obtained (yield 32%).

¹ H-NMR (CDCl ₃ ) δ 0.8-0.95 (9H, m), 1.1-
3.1 (34H, m + s (δ 2.1,3H)), 4.2 (2H, q, J = 7Hz), 4.0-4.3
(2H, m), 4.8-5.1 (1H, m).

Example 4 Synthesis of butyl 9-acetoxy-14-fluoro-11α, 15S-dihydroxy-13,14-dihydroprosta-8-en-1-oate

In Example 1, instead of (4R) -t-butyldimethylsiloxy-2- (6-carbomethoxyhexyl) -2-cyclopenten-1-one, (4R) -t-butyldimethylsiloxy-2- ( 6-carbobutoxyhexyl) -2-cyclopentene-
The title compound was obtained by the same procedure as in Example 1 using 1-one (yield 53%).

¹ H-NMR (CDCl ₃ ) δ 0.9 (6H, m), 1.2-3.1 (33
H, m + s (δ 2.1,3H)), 4.1 (2H, q), 4.0-4.3 (2H, m), 5.1-
5.3 (1H, m).

[0065]

[Effect of the Invention The novel fluorine-containing PGE ₀ such is obtained, the fluorine-containing PGE ₀ class are considered to be useful as high PG prodrug stability.

Claims (6)

[Claims] 1. A fluorine-containing prostaglandin analog represented by the following formula (1). [Chemical 1] [In the formula (1), R ^{1 to} R ⁵ represent the following. R ¹ : A residue obtained by removing a carboxyl group from carboxylic acids. R ² : A hydrogen atom or a residue obtained by removing a hydroxyl group from alcohols. R ³ and R ⁴ : each independently a hydrogen atom or a hydroxyl-protecting group. R ⁵ : a hydrocarbon group having 10 or less carbon atoms which may have a substituent. ] 2. R ¹ is an alkyl group having 6 or less carbon atoms, R ² is a hydrogen atom or an alkyl group having 8 or less carbon atoms, and R ⁵ is a direct alkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom. A chain or branched alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group having 4 to 7 ring members which may be substituted with an alkyl group, or an alkoxy group, a phenyl group or a phenoxy group The compound of claim 1, which is an alkyl group having 1 to 5 carbon atoms. 3. R ¹ is a linear or branched alkyl group having 4 to 7 carbon atoms, a cycloalkyl group having 5 to 6 ring members, or a C 1 to C substituted with a phenoxy group.
The compound of claim 1 or 2, which is an alkyl group of 4. 4. A fluorine-containing prostaglandin analog represented by the following formula (2). [Chemical 2] [In the formula (2), R ^{1 to} R ⁵ represent the following. R ¹ : A residue obtained by removing a carboxyl group from carboxylic acids. R ² : A hydrogen atom or a residue obtained by removing a hydroxyl group from alcohols. R ³ and R ⁴ : each independently a hydrogen atom or a hydroxyl-protecting group. R ⁵ : a hydrocarbon group having 10 or less carbon atoms which may have a substituent. ] 5. R ¹ is an alkyl group having 6 or less carbon atoms, R ² is a hydrogen atom or an alkyl group having 8 or less carbon atoms, and R ⁵ is a direct alkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom. A chain or branched alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group having 4 to 7 ring members which may be substituted with an alkyl group, or an alkoxy group, a phenyl group or a phenoxy group The compound according to claim 4, which is an alkyl group having 1 to 5 carbon atoms. 6. R ⁵ is a linear or branched alkyl group having 4 to 7 carbon atoms, a cycloalkyl group having 5 to 6 ring members, or 1 to 1 carbon atoms substituted with a phenoxy group.
The compound of claim 4 or 5, which is an alkyl group of 4.