JPH059184A - New prostaglandin derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound having strong platelet- coagulating action and antianginal action and low toxicity, and useful as a preventive and treating agent for circulatory diseases. CONSTITUTION:A prostaglandin I2 compound having a halogen atom on 7-site C atom of natural-type prostaglandin I2 and a cycloalkylene group on the alpha-chain, its ester and its salt expressed by formula I [R<1> is (substituted) 1-10C alkyl, (substituted) 5- or 6-membered cycloalkyl, etc. ; R<2> is H, 1-10C alkyl or cation; one of R<3> and R<4> is H and the other is F or Cl; (k), (l), (m) and (n) are 0-6; 0<=k+n<=4; 1<=l+m<=6], etc., e.g. 2,3-methylene-7alpha-fluoro-17,20- dimethyl PGI2. The compound of formula I can be produced by converting a compound of formula II (R<21> is 1-10C alkyl, etc.; R<31> and R<41> are protecting group other than trimethylsilyl) into the compound of formula III and subjecting the product to fluorination, deprotection and, as necessary, hydrolysis, salt- forming, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel prostaglandin.
I₂ It relates to derivatives. In more detail,
Akira has a cycloalkylene group in the α side chain and has a natural P
GI₂ To the carbon atom corresponding to the 7-position of
Prostaglandin I having a fluorine atom₂ Kind, and
Those prostaglandins I₂ Related to esters and salts
It is something. Below, Prostaglandin I₂ Including
These are prostaglandins I ₂ Collectively referred to as a derivative. It
In addition, the present invention provides these prostaglandins I₂ Derivative
The present invention relates to a medicine as an active ingredient. In addition, the following
Rostaglandin is sometimes abbreviated as PG.

[0002]

_2. Description of the Related Art Natural PGI ₂ is a local hormone produced mainly in the inner wall of blood vessels of arteries in vivo, and has strong physiological activities such as platelet aggregation inhibitory activity.
It is an important factor that regulates the cell function of the living body by vasodilatory activity, etc., and it has been attempted to directly use this as a medicine (PJ Lewis, JO
Grady (PJLewis, JOGrady) et al.
Clinical Pharmacology of Prostacy
clin), Raven Press, NY, 1981).

[0003]

[Problems to be Solved by the Invention] However, natural PGI
_{Since 2} has a vinyl ether bond which is very easily hydrolyzed in the molecule, it is easily deactivated under neutral or acidic conditions, and it cannot be said to be a preferable compound as a drug because of its chemical instability.

Therefore, a chemically stable synthetic PGI ₂ derivative having a physiological activity similar to that of natural PGI ₂ has been earnestly studied both inside and outside. Among them, examples in which fluorine atoms are introduced into various sites have been reported (“Organic Synthesis Society”, Volume 42, 794 (1984)), and a 7-fluoro PGI ₂ derivative having fluorine introduced in the 7-position is also reported. Reported (JP-A-57-171)
988, JP-A-60-243079, etc.). In addition, a PGI ₂ derivative in which a cycloalkyl group is introduced into the ω side chain has been reported for enhancing drug efficacy and improving stability (Japanese Patent Laid-Open No. Sho 5).
9-163365 bulletin etc.).

However, there have been no reports of PGI ₂ and its derivatives having a cycloalkylene group introduced into the α side chain.

[0006]

Means for Solving the Problems As a result of earnest research and development, the present inventor has introduced a cycloalkylene group into the α side chain of PGI ₂ and has a halogen atom at the carbon atom corresponding to the natural 7-position. It was found that the introduction of the antibacterial agent has a strong platelet aggregation-inhibiting effect and an antianginal effect and is highly stable. The halogen atom is preferably a fluorine atom,
The number is preferably one.

The present invention provides the following prostaglandin I ₂
Derivatives and their use as pharmaceuticals.

[0008] the carbon atoms which correspond to the 7-position of natural type prostaglandin I ₂ a halogen atom, and prostaglandin I ₂ compound having a cycloalkylene group in α-chain,
A novel prostaglandin I ₂ derivative selected from its ester and its salt.

A prostaglandin I ₂ derivative represented by the following formula [I].

[0010]

[Chemical 2]

Where R ^{1 is a} substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an alkenyl group, or an alkynyl group, or a substituted or unsubstituted 5- or 6-membered cycloalkyl group, R ^{2 is a} hydrogen atom , An alkyl group having 1 to 10 carbon atoms, or a cation, R ³ , R ⁴ : the same or different, a hydrogen atom or a protective group, X ¹ , X ² : one is a hydrogen atom, the other is a fluorine atom or a chlorine atom, k , l, m, n: each represents an integer of 0 to 6, and 0 ≦ k + n ≦ 4, 1 ≦ l + m ≦ 6

A medicament containing the prostaglandin I ₂ derivative as an active ingredient.

In the PGI ₂ class of the present invention, a natural PG
₂ of the α chain corresponding to the trimethylene group at the 2-4 position of I 2.
The valent hydrocarbon moiety is a cycloalkylene group having 3 to 8 carbon atoms, or a divalent hydrocarbon group containing a cycloalkylene group having a methylene group or a dimethylene group in at least one bond of the cycloalkylene group, Is preferred.

Examples of the cycloalkylene group include cyclopropylene group, 1,2-cyclobutylene group, 1,3-cyclobutylene group, 1,2-cyclopentylene group, 1,3-cyclopentylene group, 1, A 2-cyclohexylene group, a 1,3-cyclohexylene group, and a 1,4-cyclohexylene group are preferable.

The hydrocarbon group corresponding to the n-pentyl group at the 16th to 20th positions of natural PGI ₂ is composed of various monovalent organic groups. The organic group is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group,
Examples thereof include a substituted aryl group, and an alkyl group, a cycloalkyl-substituted alkyl group, a cycloalkyl group and the like are preferable.
Particularly, a linear or branched alkyl group having 5 to 9 carbon atoms is preferable. Preferred PGI ₂ such present invention is a PGI ₂ compound represented by the formula [I] (R ² is a hydrogen atom).

The PGI _{2 of the} present invention represented by the general formula [I]
In the derivative, R ¹ is a substituted or unsubstituted C 1
10 represents an alkyl group, an alkenyl group, an alkynyl group, or a substituted or unsubstituted 5- or 6-membered cycloalkyl group. Examples of the alkyl group, alkenyl group and alkynyl group having 1 to 10 carbon atoms are methyl, ethyl, n-propyl, iso-propyl, n-butyl, n-pentyl, n-hexyl, 1,1-dimethylpentyl and 2-methyl. Hexyl, 1-methyl-3-pentenyl, 1-methyl-3-hexenyl, 1-methyl
-3-Pentynyl, or 1-methyl-3-hexynyl is preferred. Particularly preferred is an alkyl group having 5 to 9 carbon atoms, and among them, an n-pentyl group, an n-hexyl group, a 2-methylhexyl group and a 1,1-dimethylpentyl group are preferred.

The substituted or unsubstituted 5- or 6-membered cycloalkyl group is substituted with a cyclopentyl group or a methyl, ethyl, propyl, butyl, pentyl, phenoxy, trifluoromethyl or trifluoromethylphenoxy group. A cyclohexyl group or a cyclopentyl group is preferred.

R ² represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or a cation. Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n There may be mentioned linear or branched alkyl groups such as -octyl, n-nonyl and n-decyl. Of these, a methyl group and an ethyl group are preferable.

Examples of the cation include NH ₄ ⁺ , tetramethylammonium, monomethylammonium, dimethylammonium, trimethylammonium, benzylammonium, phenethylammonium, morpholinium cation, monoethanolammonium, tris cation and piperidinium cation. Ammonium cation: Na ⁺ , K ⁺ and other alkali metal cations: 1/2 Ca ²⁺ ,
Examples thereof include divalent or trivalent metal cations such as 1/2 Mg ²⁺ , 1/2 Zn ²⁺ and 1/3 Al ³⁺ . Particularly preferred R ² is a methyl group or sodium ion.

R ³ and R ⁴ represent the same or different hydrogen atoms or protecting groups. Various protecting groups can be adopted as the protecting group. Examples thereof include a silyl group having three alkyl groups, aryl groups or aralkyl groups, an alkanoyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a benzoyl group or a methoxyethoxy group. A trialkylsilyl group in which three alkyl groups are the same or different is preferable, and an alkyl group in which at least one alkyl group has 2 or more carbon atoms is particularly preferable. Specific examples thereof include a dimethyl-t-butylsilyl group, a triethylsilyl group, a diphenyl-t-butyl group and the like, and a dimethyl-t-butylsilyl group is particularly preferable.

^One of X ¹ and X ² represents a hydrogen atom and the other represents a halogen atom. The halogen atom is a fluorine atom or a chlorine atom, and a fluorine atom is particularly preferable. Particularly preferably, X ¹ is a fluorine atom and X ² is a hydrogen atom.

K, l, m and n each represent an integer of 0 to 6, and 1≤l + m≤6 and 0≤k + n≤4.

L and m represent the number of rings of the cycloalkyl group and the number related to the position of the bond. That is, l + m + 2 is the number of carbon atoms constituting the ring of the cycloalkylene group.
The smaller numerical value of l and m represents the position of the bond of the cycloalkylene group. For example, when the smaller one of l and m is 0, it represents a 1,2-cycloalkylene group, and when the smaller one of l and m is 1, it represents a 1,3-cycloalkylene group.

K and n represent the number of methylene groups bonded to the bonds of the cycloalkylene group. Both k and n may be 0.

Each of l and m is preferably 0, 1, 2 or 3. Particularly, l + m is preferably 1 to 4. That is,
The cycloalkylene group is preferably a cyclopropylene group to a cyclohexylene group. Each of k and n is preferably 0, 1, or 2, and in that case, k + n is preferably 0 to 2. Particularly preferably, k + n is 0 or 1.

Further, k + n is preferably smaller as the number of carbon atoms constituting the ring of the cycloalkylene group increases. That is, when l + m + 2 is 3, 0 ≦ k + n ≦ 2, l
When + m + 2 is 4, 0 ≦ k + n ≦ 1, l + m + 2 is 5
In the case of 6, it is preferable that k + n = 0.

Furthermore, the length of the carbon chain corresponding to the trimethylene group at the 2nd to 4th positions of natural PGI ₂ , ie, k + 1
Each of + n + 2 and k + m + n + 2 is preferably 6 or less. Particularly, the smaller one of k + l + n + 2 and k + m + n + 2 is preferably 2 to 4, and the larger one is preferably 3 to 5.

The compound of the present invention represented by the general formula [I] has 6 to 10 asymmetric carbon atoms in its structure and therefore has various stereoisomers. Includes all stereoisomers, optical isomers and mixtures thereof.

The PGI ₂ derivative of the present invention can be synthesized by various methods. The feature of the PGI ₂ derivative of the present invention is that it has a cycloalkylene group in the α chain, and it can be synthesized using a known 7-halo PGI ₂ synthesis method except that point. Also, a general PGI ₂ synthesis method can be applied.

One of the synthetic methods is, as described in detail later, the corresponding 7-halo PGF ₂ α and 7-halo-5,6-dehydro PGF ₂ α (5th, 6th, 7th This is a method of synthesizing by cyclization of the position corresponding to the natural type, the same in the following description) (see the flow sheets of FIGS. 1 and 2 and the description thereof). There is also a method of synthesis using Corey lactone as a starting material. Further, PGI ₂ having a cycloalkylene group in the α chain can be synthesized and then halogenated at the 7-position.

In the case of synthesizing the PGI ₂ derivative of the present invention using Corey lactone as a starting material, it is customary to first introduce the ω chain and then the α chain. However, the α chain may be introduced first. The introduction of halogen atoms can also be carried out in any order with the introduction of these two chains. Corey lactone is used as a starting material in the synthetic method, in which a halogen atom is introduced before introducing both α chain and ω chain, and then the remaining chain is introduced, and after introducing α chain and ω chain, halogen atom is introduced. (7-halo PGF ₂ α and 7-halo-5,6-dehydro PGF ₂
There is a method via α). The former method uses 7-halo P
There are a method of passing through GF ₂ α and a method of not passing through it.

The outline of (1) to (3) will be described below as an example of the method of first introducing the ω chain and then introducing the α chain using Corey lactone as a starting material. The case where the halogen atom is a fluorine atom will be described.

(1) Corey lactone with ω chain is fluorinated to synthesize a corresponding fluoroketone. Fluorination is
There are methods such as first introducing a hydroxyl group into the carbon atom at the position where a fluorine atom should be introduced and then introducing a fluorine atom with a fluorinating agent such as dimethylaminosulfur trifluoride, and making the lactone an enolate and reacting with XeF _2. .

Next, an α chain is introduced into the fluoroketone.
The basic reaction of introducing an α chain into a lactone by direct methyleneation is known (T. Okazoe, K. Takai, K. Oshima, K. Utimoto,
J. Org. Chem., 52, 4410, 1987), this method can be applied. Further, fluorolactone is reduced to fluoro hemiacetal, and α chain is introduced by Wittig reaction to synthesize the compound [VII] (7-fluoro PGF ₂ α) described later,
After that, cyclization can be performed in the same manner as described below to synthesize the desired product. For the Wittig reaction, see, for example, EJCorey, N.
M.Weinshenker, TKSchaaf, W.Huber, J.Am.Chem.Soc., 9
See 1,5675,1969 and so on.

(2) Corey lactone with ω chain is reduced to lactol, and then α chain is introduced by Wittig reaction.
A hydroxyl group is introduced at the position to synthesize the compound [VII] described later. After that, the target compound can be synthesized from the compound [VII] as described below.

(3) Corey lactone with ω chain (cyclopentanones with ω chain can also be used as a starting material)
Cyclopentanecarbaldehyde was synthesized from it and reacted with acetylide, which is the α chain, to give 7-hydroxy-5,6-
Dehydro PGF ₂ α is synthesized. After that, the compound is fluorinated (see the fluorination of the flow sheet of FIGS. 1 and 2) to give the compound [IV] (7-fluoro-5,6-dehydro PGF ₂ α) described below, and the target compound Can be synthesized.

Below, 7-halo PGF ₂ α and 7-halo-5,6-
Synthetic method via dehydro PGF ₂ α, and 7-halo PGF ₂ α or 7-halo-without starting Corey lactone
The method for synthesizing 5,6-dehydro PGF ₂ α will be described in detail. In the description, the 7th-position halogen atom is a fluorine atom.

The compound of the present invention represented by the general formula [I] is produced by the method shown in the flow sheets shown in FIGS. 1 and 2 (the final product in this flow sheet is represented by the formula [I ']). Compound). FIG. 1 is a flow sheet (No. 1) up to the synthesis of the compound represented by the formula [IV], and FIG. 2 is a compound represented by the formula [I '] from the synthesis of the compound represented by the formula [IV]. Is the flow sheet up to (2).

However, the expressions [II] to
Each symbol in the compound represented by [VI] and the formula [I ′] has the following meaning. R ¹ , k, l, m, n: R ¹ , k, l, in the formula [I]
Same as m and n. R ²¹ : a C _{1 to} C ₁₀ alkyl group. R ³¹ and R ⁴¹ : Protecting groups other than the same or different trimethylsilyl groups. R ⁵ : a protective group different from R ³¹ and R ⁴¹ other than the trimethylsilyl group.

That is, the compound of the formula [II] is converted into the compound [III] by the method described in the patent of the present applicant (Japanese Patent Laid-Open No. 61-10551) and then fluorinated ( Compound [IV]), deprotection (compound [V]), cyclization (compound [VI]), deprotection, optionally hydrolysis, salt formation and the like to give the compound of the above formula [I ′] The compound can be prepared.

In the above formula [III], R ⁵ is a tri (C ₁ -C ₇ ) hydrocarbon silyl group other than the trimethylsilyl group, or a group which forms an acetal bond with the oxygen atom of the hydroxyl group. As the tri (C ₁ -C ₇ ) hydrocarbon silyl group, a triethylsilyl group is particularly preferable. As the group that forms an acetal bond together with the oxygen atom of the hydroxyl group, 2-tetrahydropyranyl group and 2-tetrahydrofuranyl group are particularly preferable.

R ³¹ and R ⁴¹ are R other than a trimethylsilyl group.
It is a protecting group different from ⁵ , and a tri (C ₁ -C ₇ ) hydrocarbon silyl group is preferable. Tri (C ₁ ~C ₇₎ such tri (C ₁ ~ of the hydrocarbon silyl group t- butyldimethylsilyl group
Preferred examples include a C ₄ ) alkylsilyl group, a diphenyl (C ₁ -C ₄ ) alkylsilyl group such as a t-butyldiphenylsilyl group, and a tribenzylsilyl group. A t-butyldimethylsilyl group is particularly preferable.

The fluorination of the compound [III] can be carried out by using a known method (JP-A-60-32718, 59-227888). That is, 1,1,2-trichloro-1,2,2-trifluoroethane, by piperidinosulfur trifluoride, aminosulfur trifluoride-based fluorinating agents such as diethylaminosulfur trifluoride,
It can be preferably carried out in a fluorinated hydrocarbon solvent such as trichlorofluoromethane.

Reaction with a fluorinating agent gives a compound of formula [IV], which is converted to a compound of formula [V] by a known deprotection reaction. Examples of the deprotecting agent include acetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and a cation exchange resin as a catalyst.
For example, it is preferably carried out by using water, methanol, ethanol, or tetrahydrofuran (hereinafter also referred to as THF) in the coexistence of water, methanol, ethanol, etc., ethyl ether, dioxane, acetone, acetonitrile, etc. as a reaction solvent. . The reaction temperature is usually -78 ° C to +
It is carried out in the temperature range of 50 ° C. for about 10 minutes to 3 days.

The compound of the formula [V] can be obtained by the cyclization reaction.
I] compound. This cyclization reaction can basically use a known method, for example, J.Amer.Chem.So.
c., 104, 5842-5844 (1982). That is, the cyclization reaction can be carried out by cyclizing with mercury trifluoroacetate and then hydrogenating with a hydrogenating agent. In addition, JP-A-62-120377
It can also be carried out according to the method described in the publication. That is, the cyclization reaction can be carried out by cyclizing with phenylselenenyl chloride and then removing the phenylselenenyl group using a reducing agent such as tributyltin hydride.

The cyclization can also be carried out according to the method described in US Pat. No. 4,612,380. That is,
The compound of the formula [V] is hydrogenated by a known method (Tetrahedron Letters, 25, 1383 to 1386 (1984)) and the compound represented by the following formula [VII] (provided that R ¹ , R ² , R ³ ,
(R ²¹ , R ³¹ , R ⁴¹ , k, l, m, n are the same as the above definition)
Cyclization with N-iodosuccinimide or iodine, followed by 1,8-diazabicyclo [5.
4.0] -7-Undecene and the like can be used to eliminate hydrogen iodide to carry out the cyclization reaction.

[0047]

[Chemical 3]

The compound of the formula [VI] thus obtained is optionally subjected to a deprotection reaction and / or a hydrolysis reaction and / or an esterification reaction and / or a salt formation reaction to give a prostaglandin of the present invention. An I ₂ derivative [I ′] can be obtained. Removal of the protective group for the hydroxyl group (deprotection reaction) is performed using tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride /
Fluorine-based reagents such as pyridine can be used, but tetrabutylammonium fluoride is particularly preferred. As the reaction solvent, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile and the like can be used, and usually-
It is preferably carried out at a temperature range of 78 ° C to + 50 ° C for about 10 minutes to 3 days.

The hydrolysis reaction of the ester group at the 1-position is carried out by a conventional method, for example, caustic soda, caustic potash, an aqueous solution of calcium hydroxide or a water-alcohol mixed solution, or an alcohol containing sodium methoxide, potassium methoxide or sodium ethoxide. It can be carried out by hydrolyzing with a water mixture. Further, for example, using an enzyme such as lipase in water or a solvent containing water-
It is carried out by treating at a temperature range of 10 ° C to + 60 ° C for about 10 minutes to 24 hours. Post-treatment and purification after the hydrolysis reaction are carried out by a usual method after neutralizing with an acid such as dilute hydrochloric acid or oxalic acid.

The compound having a carboxyl group produced by the above hydrolysis reaction is then subjected to a salt formation reaction to give a corresponding carboxylic acid salt, if necessary. The salt-forming reaction is known per se, and neutralizes a carboxylic acid and an equivalent amount of a basic compound such as sodium hydroxide, potassium hydroxide, or sodium carbonate, or ammonia, trimethylamine, monoethanolamine, morpholine, etc. by a usual method. It is carried out by reacting.
The carboxylic acid salt can also be directly obtained by the hydrolysis reaction of the above ester.

The esterification of the hydroxyl group is carried out by a usual method in which an acid anhydride, an acid halide and the like are reacted in the presence of a base, that is, acetic anhydride, acetyl chloride, benzoyl chloride and the like are reacted in the presence of a base such as pyridine and triethylamine. Achieved easily (New Experimental Chemistry Course Volume 14-II,
1002-1027, edited by The Chemical Society of Japan, Maruzen Co., Ltd.).

The method for synthesizing the compound of the formula [II] which is the starting material of the present invention is not particularly limited, but for example, it is shown in the flow sheets (No. 1 and No. 2) described in FIGS. 3 and 4. It can be synthesized by two methods.

However, in the formulas of FIGS. 3 and 4, M is an organic metal (copper, nickel, zirconium, zinc, aluminum).
Represents a species, R ¹ , R ²¹ , R ³¹ , R ⁴¹ and k, l, m, n
Has the same meaning as in formula [II].

The flow sheet shown in FIG. 3 (No. 1)
The method described in the literature (Tetrahedron Letters, Volume 23,
4057 (1982)). Further, in the method of the flow sheet (part 2) shown in FIG. 4, a method of adding an alkenyl metal reactant to an enone and capturing it with a trimethylsilyl group is known (J. Am. Chem. Soc., 97). roll,
107 (1975)), the obtained silyl ether is a known method (J.
Am.Chem.Soc., Vol. 95, 3310 (1973)) can be converted into the compound represented by the formula [II].

The aldehydes represented by the formula [VIII] used here are novel compounds. The method for synthesizing this compound is not particularly limited, but for example, it is synthesized by the method shown in the flow sheets (Nos. 1 to 5) shown in FIGS. 5 to 9.

However, the flow sheet of FIG. 5 (No. 1)
Is a flow sheet when k and n are 0 in the formula [VIII]. The flow sheet (No. 2) of FIG. 6 is a flow sheet when k is O and n is 1 in the formula [VIII]. The flow sheet (part 3) of FIG. 7 is a flow sheet when k is 2, l is 1, m and n are 0 in the formula [VIII]. The flow sheet (part 4) of FIG. 8 is a flow sheet when k and l are 1 and m and n are 0 in the formula [VIII]. The flow sheet (No. 5) of FIG. 9 is a flow sheet when k and n are 0, l is 1 and m is 2 in the formula [VIII].

The compound [I] of the present invention and salts thereof have strong platelet aggregation inhibitory action and antianginal action, and weak toxicity, so that thrombosis, angina pectoris, myocardial infarction, arteriosclerosis, etc. It is effective in the prevention and treatment of.

The results of the pharmacological test of the compound of the present invention are as follows.

Inhibitory Action on Platelet Aggregation Citrated blood was obtained from guinea pigs (Hartley system) by heart blood sampling. The blood was centrifuged at 120 G for 10 minutes to separate the supernatant platelet-rich plasma. Bone nephelometry (GVR Bone: Nature, 19
Vol. 4, p. 927, 1962), using an aggregometer.

In the in vitro experiment, a test compound was added to platelet-rich plasma and incubated for 10 minutes, and then adenosine diphosphate (1 μM) was added to induce platelet aggregation. After the addition of adenosine diphosphate,
Expressed by the maximum rate of change in translucency within 5 minutes (maximum aggregation rate),
The results are shown at 50% inhibitory concentration.

In the ex vivo experiment, the test compound was dissolved in ethanol, suspended in 0.5% tragacanth solution or 1% β-cyclodextrin solution, and orally administered. Administration 3
Platelet-rich plasma was prepared from blood obtained by heart blood sampling 0 minutes later, and platelet aggregation was measured as in the case of in vitro. The results are shown in Table 1.

In Table 1 and the following tables, the abbreviations of compounds and solvents are as follows. In addition, the following compound F (natural prostaglandin I ₂ ) was used as a compound for comparison.

Compound A: 2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ sodium salt synthesized in Example 1. Compound B-b: a highly polar one of (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester synthesized in Example 3. Compound C: (1S ^* , 3R ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester synthesized in Example 4. Compound Da: 2,4-methylene-7α-, synthesized in Example 7
Fluoro-17,20-dimethyl PGI ₂ methyl ester having a low polarity. Compound Db; 2,4-methylene-7α-, synthesized in Example 7
Highly polar of fluoro-17,20-dimethyl PGI ₂ methyl ester. Compound E-a; 2,4-methylene-7α-, synthesized in Example 7
Fluoro-17,20-dimethyl PGI ₂ sodium salt having a low polarity. Compound E-b; 2,4-methylene-7α-, synthesized in Example 7
Highly polar of fluoro-17,20-dimethyl PGI ₂ sodium salt. Compound F; natural PGI ₂ . Solvent X: 0.5% tragacanth solution. Solvent Y: 1% β-cyclodextrin solution.

[0064]

[Table 1]

As shown in Table 1, the compounds of the present invention are
It has a strong inhibitory activity on platelet aggregation.

Antianginal activity (vasopressin-induced ST depression inhibitory effect) Vasopressin (0.2 IU / kg) was administered from the femoral vein of a male rat (Dongryu strain) anesthetized with pentobarbital, and at intervals of 30 seconds for 5 minutes after the administration. The electrocardiogram was recorded for 5 seconds, and the ST depression degree (average of 5 beats) on the electrocardiogram was calculated. The test compound was dissolved in ethanol and administered intravenously 2 minutes before vasopressin loading, or after dissolution in ethanol
The cells were suspended in 0.5% tragacanth solution or 1% β-cyclodextrin solution and orally administered 30 minutes before vasopressin loading.

Test compound administration group and untreated control group (5 for each group)
For example, a two-way analysis of variance for ST drop
The presence or absence of the ST depression inhibitory action of the test compound was determined. The results are shown in Table 2.

[0068]

[Table 2]

As shown in Table 2, the compounds of the present invention have a strong antianginal activity.

Acute toxicity To 5 male ddy mice (body weight 25 to 32 g) per group,
A predetermined dose of the test compound, which was dissolved in a small amount of ethanol and then diluted with a 1% β-cyclodextrin aqueous solution, was orally administered, and the presence or absence of death was observed for 7 days after the administration.
Table 3 shows the dose and the number of dead animals in 5 animals.

[0071]

[Table 3]

As shown in Table 3, the compounds of the present invention are
Very low toxicity.

The compound of the present invention is administered orally or parenterally such as subcutaneously, intramuscularly, intravenously, transdermally, and rectally. Examples of the dosage form for oral administration include solid preparations such as tablets, granules, powders and capsules, and liquid preparations such as emulsions, solutions, suspensions, syrups and elixirs.

In the form of tablets, for example, excipients such as lactose, starch, crystalline cellulose and polyvinylpyrrolidone; binders such as carboxymethylcellulose and methylcellulose; disintegration of sodium alginate, sodium hydrogen carbonate, sodium lauryl sulfate and the like. It can be molded by an ordinary method using an agent or the like. Granules and powders can likewise be formed by the usual methods using the above-mentioned excipients and the like.

Capsules can be obtained, for example, by dissolving a compound of the present invention in a vegetable oil such as coconut oil and filling a gelatin soft capsule with a solution obtained.

The preparations for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions or emulsions, and aseptic solid preparations to be dissolved in a sterile solvent for injection immediately before use. To be In addition, suppositories for rectal administration,
Examples include pessaries for vaginal administration.

The compound of the present invention can also be used for formulation by forming an inclusion compound with α, β or γ-cyclodextrin or methylated cyclodextrin.

The dose of the compound of the present invention is usually 0.0001 to 1.0 mg / kg per day, 0.0001 to 0.3 mg / kg for intramuscular, subcutaneous or intravenous administration, and 0.0001 to 1.
0 mg / kg is preferred. However, the dose is not limited to this because it varies depending on the age, body weight, degree of symptoms, type of disease, and frequency of administration of the patient.

[0079]

EXAMPLES The present invention will be described in more detail below with reference to Reference Examples, Examples and Formulation Examples, but the present invention is not limited to these examples.

Reference Example 1 Synthesis of 2-bromomethylcyclopropanecarboxylic acid ethyl ester (2-formyl) cyclopropanecarboxylic acid ethyl ester (14.2 g, 0.10 mol) was dissolved in methanol (200 ml),
Cooled to 0 ℃ and sodium borohydride (3.8g, 0.10mol)
Was added and stirred for 20 minutes. After the solvent was distilled off, saturated saline was added, and the mixture was extracted with chloroform. After drying and concentration, silica gel column chromatography (hexane: ethyl acetate =
Purification by 2: 1) gave (2-hydroxymethyl) cyclopropanecarboxylic acid ethyl ester (14.3 g, yield 99%).

(2-Hydroxymethyl) cyclopropanecarboxylic acid ethyl ester (14.3 g, 0.1 mol) was dissolved in N, N-dimethylformamide (150 ml), and triphenylphosphine (25.9 g, 0.1 mol) was added at room temperature. Stir for 10 minutes. After cooling to −20 ° C., bromine (15.8 g, 0.1 mol) was added dropwise over 10 minutes. After 1 hour, the reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ether. Dry,
After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 5: 1) to obtain (2-bromomethyl) cyclopropanecarboxylic acid ethyl ester (15.3 g, yield 74%).

¹ N-NMR (CDCl ₃ ) δ 0.9-1.0 (m, 1H), 1.27
(t, J = 7.6Hz, 3H), 1.3-1.5 (m, 1H), 1.6-1.7 (m, 1H), 1.8-
2.0 (m, 1H), 3.3-3.4 (m, 2H), 4.25 (q, J = 7.6Hz, 2H).

Reference Example 2 Synthesis of 2-bromomethylcyclopropylmethanol (2-Bromomethyl) cyclopropanecarboxylic acid ethyl ester (15.3 g, 74 mmol) was dissolved in ether (50 ml), and lithium aluminum hydride ( 2.8g, 74mmol) of ether (1
(50 ml) and the mixture was stirred at room temperature for 1 hour. 2N-
Hydrochloric acid was added, extracted with ether, dried and concentrated. By column chromatography purification, (2-bromomethyl) cyclopropylmethanol (6.7 g, yield 55%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.6-0.7 (m, 1H), 0.7-0.
8 (m, 1H), 1.0-1.2 (m, 2H), 1.7-1.8 (m, 1H), 3.2-3.6 (m, 4
H).

Reference Example 3 Synthesis of 2-bromomethylcyclopropylmethyl t-butyldimethylsilyl ether (2-bromomethyl) cyclopropylmethanol (6.7 g, 41
mmol) in N, N-dimethylformamide (80 ml),
Imidazole (6.8 g, 0.1 mol) and t-butyldimethylsilyl chloride (9.0 g, 60 mmol) were added at 0 ° C, and the mixture was stirred for 1 hr. Water was added, the mixture was extracted with ether, concentrated to dryness, and purified by silica gel column chromatography to give (2-bromomethyl) cyclopropylmethyl t-butyldimethylsilyl ether (10.5
g, yield 92%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.08 (s, 6H), 0.5-0.6
(m, 1H), 0.7-0.8 (m, 1H), 0.92 (s, 9H), 1.0-1.1 (m, 1H),
1.2-1.3 (m, 1H), 3.3-3.4 (m, 2H), 3.56 (d, J = 5.6Hz, 2H).

Reference Example 4 Synthesis of 2- (4-tetrahydropyranyloxy-2-butynyl) cyclopropylmethyl t-butyldimethylsilyl ether propargyl alcohol tetrahydropyranyl ether
(5.6 g, 40 mmol) was dissolved in THF (80 ml) and cooled to -78 ° C. n-Butyl lithium (27ml, factor = 1.48, 40
ml) was added and 15 minutes later, the temperature was raised to 0 ° C. After 10 minutes, hexamethylphosphoric triamide (hereinafter referred to as HMPT) (1
4.3 g, 80 mmol) was added, and (2-bromomethyl) cyclopropylmethyl t-butyldimethylsilyl ether (11.2
g, 40 mmol) in THF (20 ml) was added, and the mixture was stirred at 0 ° C. for 1 hour.
Stir at room temperature for 3 hours. After adding water, extracting with ether, drying and concentrating, 2-
(4-Tetrahydropyranyloxy-2-butynyl) cyclopropylmethyl t-butyldimethylsilyl ether (5.8 g, yield 43%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00 (s, 6H), 0.4-0.5
(m, 1H), 0.8-1.0 (m, 3H), 0.86 (s, 9H), 1.4-1.9 (m, 6H),
2.2-2.3 (m, 2H), 3.4-3.5 (m, 3H), 3.8-3.9 (m, 1H), 4.15
(d, J = 14Hz, 1H), 4.23 (d, J = 14Hz, 1H), 4.7-4.8 (m, 1H).

Reference Example 5 Synthesis of 2- (4-hydroxy-2-butynyl) cyclopropanecarboxylic acid methyl ester 2- (4-tetrahydropyranyloxy-2-butynyl) cyclopropylmethyl t-butyldimethylsilyl ether ( 5.8g,
17.2 mmol) was dissolved in THF (50 ml), and tetrabutylammonium fluoride (factor = 1.0, THF was added at 0 ° C).
The solution (33 ml, 33 mmol) was added at 0 ° C. and the mixture was stirred for 1 hr. By column chromatography purification, 2- (4-tetrahydropyranyloxy-2-butynyl) cyclopropylmethanol (4.3 g) was obtained.

2- (4-tetrahydropyranyloxy-2-butynyl) cyclopropylmethanol (4.3 g) was added to acetone (30 m
l) and was oxidized to cyclopropanecarboxylic acid with Jones reagent at 0 ° C.

The crude product was dissolved in ether (50 ml) and methyl esterified with diazomethane. The reaction mixture was concentrated, the crude product was dissolved in ethanol (30 ml), pyridinium p-toluenesulfonate (0.5 g) was added, and the mixture was heated to 50 ° C and heated to 1.5.
Stir for hours. Add saturated aqueous sodium hydrogen carbonate solution,
Extracted with dichloromethane. The extract was dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography to give 2- (4-hydroxy-2-butynyl) cyclopropanecarboxylic acid methyl ester (0.7 g).

¹ H-NMR (CDCl ₃ ) δ 0.9-1.0 (m, 1H), 1.1-1.
3 (m, 1H), 1.5-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.4-2.5 (m, 2
H), 3.64 (s, 3H), 4.22 (s, 2H).

Reference Example 6 Synthesis of 2- (4-oxo-2-butynyl) cyclopropanecarboxylic acid methyl ester Ogizalyl chloride (0.78 g, 6.2 mmol) was added to dichloromethane.
It was dissolved in (12 ml) and cooled to -40 ° C. Dimethyl sulfoxide (1.0g, 12.3mmol) in dichloromethane (4ml)
The solution was added dropwise over 10 minutes. After 15 minutes, a solution of 2- (4-hydroxy-2-butynyl) cyclopropanecarboxylic acid methyl ester (0.70 g, 4.1 mmol) in dichloromethane (5 ml) was added dropwise over 15 minutes. After 40 minutes triethylamine (2.5
g, 25 mmol) was added and the temperature was raised to 0 ° C. Water was added, the mixture was extracted with dichloromethane, and the crude product was roughly separated by silica gel column chromatography to obtain 2- (4-oxo-2-butynyl) cyclopropanecarboxylic acid methyl ester (0.32 g).

Reference Example 7 Synthesis of 2- (2-hydroxyethyl) cyclopropylmethyl t-butyldimethylsilyl ether 2-vinylcyclopropylmethyl t-butyldimethylsilyl ether (17.1 g, 81 mmol) in THF (100 ml) Dissolves in
Cooled to 0 ° C. Borane-dimethyl sulfide complex (2.5 g, 33 mmol) was added thereto, and the mixture was stirred for 1 hour. ethanol
(38 ml), 3N-sodium hydroxide (38 ml) and 30% hydrogen peroxide (18.2 ml) were added, and the mixture was stirred for 30 minutes. Saturated saline was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography to give 2- (2-hydroxyethyl) cyclopropylmethyl t-butyldimethylsilyl ether (15.0 g, yield 81%).

¹ H-NMR (CDCl ₃ ) δ 0.00 (s, 3H), 0.05 (s, 3
H), 0.3-0.4 (m, 2H), 0.5-0.6 (m, 1H), 0.91 (s, 9H), 0.9-
1.0 (m, 1H), 1.1-1.2 (m, 1H), 1.81 (dq, J = 14.0,4.7Hz, 1
H), 3.03 (dt, J = 9.4,10.3Hz, 1H), 3.71 (d, J = 4.2Hz, 1H),
3.75 (d, J = 4.2Hz, 1H), 3.94 (dd, J = 10.3,5.1Hz, 1H).

Reference Example 8 Synthesis of 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropylmethyl t-butyldimethylsilyl ether 2- (2-hydroxyethyl) cyclopropylmethyl t-butyldimethylsilyl ether ( 15.0 g, 65 mmol) was dissolved in N, N-dimethylformamide (120 ml), triphenylphosphine (17.3 g, 66 mmol) was added at room temperature, and after 20 minutes, -20
Cooled to ° C. Bromine (10.5 g, 66 mmol) was added over 5 minutes, and the temperature was gradually raised to 0 ° C. The mixture was poured into a saturated sodium hydrogencarbonate aqueous solution and extracted with ether. 2- (2-Bromoethyl) cyclopropylmethyl t-butyldimethylsilyl ether (2.7 g) was obtained by drying over magnesium sulfate and silica gel column chromatography purification.

A THF solution (15 ml) of propargyl alcohol tetrahydropyranyl ether (1.44 g, 10.3 mmol) was cooled to −78 ° C., and n-butyllithium (factor = 1.
5, 6.9 ml, 10.3 mmol) was added, and 15 minutes later, the temperature was raised to 0 ° C. HMPT (3.76 ml, 21 mmol) was added here, and it stirred for 15 minutes. 2- (2-bromoethyl) cyclopropylmethyl
A THF solution of t-butyldimethylsilyl ether (2.73 g, 10.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. The crude product was purified by silica gel column chromatography, 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropylmethyl
t-Butyldimethylsilyl ether (3 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00 (s, 6H), 0.2-0.3
(m, 1H), 0.3-0.4 (m, 1H), 0.6-0.7 (m, 1H), 0.7-0.8 (m, 1
H), 0.87 (s, 9H), 1.4-1.9 (m, 8H), 2.2-2.3 (m, 2H), 3.4-
3.5 (m, 3H), 3.7-3.9 (m, 1H), 4.14 (d, J = 14.0Hz, 1H), 4.2
6 (d, J = 14.0Hz, 1H), 5.76 (t, J = 3.7Hz, 1H).

Reference Example 9 Synthesis of 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropylmethanol 2- (5-Tetrahydropyranyloxy-3-pentynyl) cyclopropylmethyl t-butyldimethylsilyl ether (3 g ,
10 mmol) was dissolved in THF (10 ml), tetrabutylammonium fluoride (factor = 1.0, 12 ml, 12 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. After distilling off the solvent, the residue was purified by silica gel column chromatography to give 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropanemethanol (1.2
g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.2-0.4 (m, 2H), 0.6-0.
8 (m, 1H), 0.88 (t, J = 7.5Hz, 1H), 1.1-1.9 (m, 8H), 2.2-2.4
(m, 2H), 3.3-3.6 (m, 3H), 3.7-3.9 (m, 1H), 4.14 (d, J = 15H
z, 1H), 4.27 (d, J = 15Hz, 1H), 4.76 (s, 1H).

Reference Example 10 Synthesis of 2- (5-hydroxy-3-pentynyl) cyclopropanecarboxylic acid methyl ester The alcohol (0.70 g, 2.9 mmol) synthesized in Reference Example 9 was dissolved in dichloromethane (30 ml), Pyridinium chlorochromate (0.90 g) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered through Celite, concentrated and the aldehyde (0.62g)
Got

Silver nitrite (2 g) dissolved in water (4 ml) in the above aldehyde (0.62 g) and sodium hydroxide (0.93 g)
Was dissolved in water (4 ml), and the mixture was added at 0 ° C. and stirred for 5 minutes. The mixture was filtered through Celite and adjusted to pH 7 with concentrated hydrochloric acid.
After distilling off the solvent, the residue was dissolved in ether (3 ml), and a diazomethane-ether solution was added for methyl esterification. Methyl ester (0.46
g) was obtained.

The above methyl ester compound (0.45 g, 1.5 mmol) was dissolved in ethanol (30 ml), pyridinium p-toluenesulfonate (80 mg, 0.3 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours. Purification by silica gel column chromatography gave the title compound (0.31 g).

¹ H-NMR (CDCl ₃ ) δ 0.8-2.0 (m, 6H), 2.3-2.
5 (m, 3H), 3.68 (s, 3H), 4.25 (s, 2H).

Reference Example 11 Synthesis of 2- (5-oxo-3-pentynyl) cyclopropanecarboxylic acid methyl ester Ogizalyl chloride (0.40 g, 3.1 mmol) was added to dichloromethane.
It was dissolved in (6 ml) and cooled to -40 ° C. Dimethyl sulfoxide (0.52 g, 6.2 mmol) was added to dichloromethane (2 m
What was melt | dissolved in l) was added over 5 minutes, and it stirred for 20 minutes. A solution of 0.37 g (2 mmol) of 2- (5-hydroxy-3-pentynyl) cyclopropanecarboxylic acid methyl ester dissolved in dichloromethane (5 ml) was added, and the mixture was stirred for 30 minutes, and triethylamine (1.7 ml, 12 mmol) was added. After warming to 0 ° C., saturated saline was added, and the mixture was extracted with dichloromethane. It was dried over magnesium sulfate and purified by silica gel column chromatography to obtain the title compound (0.35 g, yield 96%).

Reference Example 12 Synthesis of (1S ^* , 3S ^* )-3- (3-tetrahydropyranyloxy-1-propynyl) cyclopentanecarboxylic acid methyl ester Borane-dimethyl sulfide complex (1.92 ml, 20.2 mmol) A 1M THF solution (20.2 ml, 20.2 mmol) of 2,3-dimethyl-2-butene was added to the THF (18.3 ml) solution at 0 ° C., and the mixture was stirred at the same temperature. After 2 hours, the reaction solution was cooled to -25 ° C and treated with 3-cyclopentenecarboxylic acid methyl ester (2.55 g, 20.2 mmol) in T.
An HF (20 ml) solution was added dropwise and the mixture was stirred at the same temperature. After 1.5 hours, methanol (1.64 ml) was added dropwise, the reaction temperature was raised to 0 ° C., and the mixture was stirred for 1 hour. After the reaction solution was concentrated under reduced pressure and dried,
It was dissolved in THF (20 ml).

Separately, a solution of propargyl tetrahydropyranyl ether (2.83 g, 20.2 mmol) in THF (20 ml) was added to a solution of n-butyllithium in 1.5 M hexane (13.7 ml, 20.6).
mmol) at 0 ° C. and stirred for 1 hour. This solution was added dropwise to the above THF (10 ml) solution at 0 ° C. After this time, the reaction solution was cooled to -78 ° C and the iodine (5.13g, 20.2mmol) in T
An HF (10 ml) solution was added dropwise, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. 2N-sodium hydroxide aqueous solution (12.1 ml),
30% Hydrogen peroxide solution (2.83 ml) was added dropwise, the mixture was stirred for 5 minutes, diluted with ethyl acetate (150 ml), and washed with saturated aqueous sodium thiosulfate solution (150 ml) and saturated brine (150 ml).
The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (2.5
6g, 47.6%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.50-2.10 (m, 12H), 2.8
0-3.02 (m, 2H), 3.48-3.60 (m, 1H), 3.67 (s, 3H), 3.80-3.
92 (m, 1H), 4.18 (d, J = 15Hz, 1H), 4.30 (d, J = 15Hz, 1H), 4.
70-4.80 (m, 1H).

Reference Example 13 Synthesis of (1S ^* , 3S ^* )-3- (3-hydroxy-1-propynyl) cyclopentanecarboxylic acid methyl ester Carboxylic acid methyl ester synthesized in Reference Example 12 (1.0 g,
3.75 mmol) was dissolved in methanol (4 ml) and pyridinium was added.
Add p-toluenesulfonate (100mg, 0.4mmol) and add 50 ℃
It was stirred for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (532 mg, 78.0
%) Was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.60-2.10 (m, 6H), 2.80
-3.02 (m, 2H), 3.68 (s, 3H), 4.24 (s, 2H).

Reference Example 14 Synthesis of (1S ^* , 3S ^* )-3- (3-oxo-1-propynyl) cyclopentanecarboxylic acid methyl ester The compound (1.95 g, 10.7 mmol) synthesized in Reference Example 13 was used. Using the same procedure as in Reference Example 6, the title compound (1.31 g, 67.7
%) Was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.80-2.35 (m, 6H), 2.95
-3.10 (m, 2H), 3.69 (s, 3H), 9.19 (s, 1H).

Reference Example 15 Synthesis of (1S ^* , 3R ^* )-3- (3-tetrahydropyranyloxy-1-propynyl) cyclopentanecarboxylic acid methyl ester Diisopropylamine (16.6 ml, 118.4 mmol) in THF (2
50 ml) solution was added with a 1.5 M hexane solution of n-butyllithium (71.0 ml, 106.6 mmol) at 0 ° C. and stirred for 15 minutes. The compound synthesized in Reference Example 12 after cooling the reaction solution to -70 ° C
A solution of (15.8 g, 59.2 mmol) in THF (60 ml) was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was poured into saturated aqueous ammonium chloride solution (300 ml), and extracted with ether (150 ml × 2). The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1), and the title compound (2.34g, 8.76mmol, The yield was 14.8%) and the raw materials were recovered (8.53 g, yield 54.0%).

¹ H-NMR (CDCl ₃ ) δ 1.50-2.38 (m, 12H), 2.6
0-2.84 (m, 2H), 3.48,3.60 (m, 1H), 3.68 (s, 3H), 3.80-3.
92 (m, 1H), 4.19 (d, J = 15Hz, 1H), 4.30 (d, J = 15Hz, 1H), 4.
75-4.85 (m, 1H).

Reference Example 16 Synthesis of (1S ^* , 3R ^* )-3- (3-hydroxy-1-propynyl) cyclopentanecarboxylic acid methyl ester The compound (2.34 g, 8.76 mmol) synthesized in Reference Example 15 was used. Using the same procedure as in Reference Example 13, the title compound (1.41 g, 7.75
mmol, yield 88.5%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.72-2.35 (m, 6H), 2.62
-2.90 (m, 2H), 3.69 (s, 3H), 4.25 (s, 2H).

Reference Example 17 Synthesis of (1S ^* , 3R ^* )-3- (3-oxo-1-propynyl) cyclopentanecarboxylic acid methyl ester The compound (1.41 g, 7.75 mmol) synthesized in Reference Example 16 was used. Using the same procedure as in Reference Example 6, the title compound (1.08 g, 6.05 mm
ol, yield 77.4%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.80-2.42 (m, 6H), 2.75
-2.95 (m, 2H), 3.70 (s, 3H), 9.19 (s, 1H).

Reference Example 18 Synthesis of 4- (t-butyldimethylsiloxymethyl) -1-cyclohexanecarbaldehyde 1,4-Cyclohexanedimethanol (72.1 g) was dissolved in N, N-dimethylformamide (500 ml). , Imidazole (68.1
g) and t-butyldimethylsilyl chloride (75.4 g) were added, and the mixture was stirred at room temperature for 14 hours. It was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ether, and dried. Purification by silica gel column chromatography gave monosilyl ether (72.5 g).

Next, a solution of oxalyl chloride (18.5 ml) in methylene chloride (480 ml) was added to dimethyl sulfoxide (30.1 ml).
Of methylene chloride (95 ml) was added at -78 ° C. After stirring for 5 minutes, a solution of the above monosilyl ether (50 g) in methylene chloride (190 ml) was added at -78 ° C, and the mixture was further stirred for 30 minutes. Triethylamine (135 ml) was added dropwise at -78 ° C, and the temperature was gradually raised to room temperature. It was poured into 1 liter of water, and the aqueous layer was extracted with methylene chloride. The extracts are combined, washed with brine, dried, concentrated and purified by column chromatography to give the title compound.
(49g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.84-0.85 (m, 9H), 3.37
(m, 2H), 9.58 (s, 1H).

Reference Example 19 4- (2,2-dibromovinyl) -1-cyclohexanemethanol
Synthesis of t-butyldimethylsilyl ether A solution of the aldehyde (57.6 g) synthesized in Reference Example 18 in methylene chloride (600 ml) was added with triphenylphosphine (118
g), carbon tetrabromide (81.9 g) and methylene chloride (200 ml) were added. After stirring for 1 hour, the mixture was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The extract was washed with brine, dried and purified by column chromatography to give the title compound (67.
6g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.86 (s, 9H), 3.4 (m, 2
H).

Reference Example 20 Synthesis of 4- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanemethanol t-butyldimethylsilyl ether Dibromide (62 g) synthesized in Reference Example 19 in THF (500 m
l) solution of n-butyllithium in 1.5M hexane (207m
l) was added and the mixture was cooled to −78 ° C. and paraformaldehyde was added.
(9.34 g) was added, and the mixture was stirred at -20 ° C for 12 hours and at room temperature for 2 hours, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ether. The extract was washed with brine, dried and concentrated. The residue was dissolved in methylene chloride (310 ml), 2,3-dihydropyran (15.7 ml) and p-toluenesulfonic acid (2.97 g) were added, and the mixture was stirred at room temperature for 14 hours. It was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with methylene chloride, dried and concentrated, and purified by column chromatography to obtain the title compound (31.6 g).

¹ H-NMR (CDCl ₃ ) δ 0.86 (s, 9H), 3.37 (m, 2
H), 4.79 (m, 1H).

Reference Example 21 4- (3-tetrahydropyranyloxy-1-propynyl) -1-
Synthesis of cyclohexanemethanol THF of silyl ether (31.6 g) synthesized in Reference Example 20
To the (170 ml) solution was added a 1 M solution of tetrabutylammonium fluoride in THF (94.8 ml) at 0 ° C., the mixture was stirred at room temperature for 14 hr, concentrated, and purified by column chromatography to obtain the title compound (21.3 g).

¹ H-NMR (CDCl ₃ ) δ 4.81 (m, 1H).

Reference Example 22 4- (3-tetrahydropyranyloxy-1-propynyl) -1-
Synthesis of cyclohexanecarbaldehyde Oxalyl chloride (6.38 ml) in methylene chloride (165 ml) was mixed with dimethyl sulfoxide (10.38 ml) in methylene chloride.
The (35 ml) solution was added dropwise at -78 ° C. After stirring for 10 minutes, a solution of the alcohol (16.78 g) synthesized in Reference Example 21 in methylene chloride (65 ml) was added dropwise at -78 ° C, and the mixture was stirred for 30 minutes. Triethylamine (46.3 ml) was added dropwise at -78 ° C, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 30 minutes. After pouring into water and extracting with methylene chloride, the extract is washed with brine, dried and concentrated, and purified by column chromatography to obtain the title compound.
(16.0 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 4.80 (m, 1H), 9.63 (m, 1
H).

Reference Example 23 Synthesis of 4- (3-hydroxy-1-propynyl) -1-cyclohexanecarboxylic acid methyl ester An aqueous solution (45 ml) of silver nitrate (22.7 g) and sodium hydroxide (10.
The aldehyde (16.0 g) synthesized in Reference Example 22 was added to a mixture of an aqueous solution (45 ml) of 5 g) at 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture was filtered through Celite, washed with hot water, and allowed to cool. The mixture was acidified with hydrochloric acid, extracted with ether, and the extract was dried and concentrated. The residue was dissolved in ether (120 ml), and diazomethane (0.5 M ether solution, 13 ml) was added dropwise at 0 ° C.

The reaction mixture was concentrated and the residue was washed with ethanol (100
ml) and pyridinium p-toluenesulfonate
(0.89 g) was added, and the mixture was stirred at 40 ° C for 30 minutes and at 55 ° C for 3.5 hours. It was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried, concentrated, and purified by column chromatography to obtain the title compound (7.42 g).

¹ H-NMR (CDCl ₃ ) δ1.3-2.4 (m, 10H), 3.67
(m, 3H), 4.25 (m, 2H) .IR (CDCl ₃ ) 3600, 3460, 2220, 1720 cm ^-1 .

Reference Example 24 Synthesis of 4- (3-oxo-1-propynyl) cyclohexanecarboxylic acid methyl ester Oxalyl chloride (3.63 ml) in methylene chloride (95 ml) was dissolved in dimethylsulfoxide (5.91 ml) in methylene chloride. (19 ml)
The solution was added at −78 ° C. and stirred for 5 minutes, then, Reference Example 2
Alcohol synthesized in 3 (7.02g) in methylene chloride (38ml)
The solution was added dropwise at -78 ° C and stirred for 30 minutes. Triethylamine (26.4 ml) was added at -78 ° C and the temperature was raised to room temperature.
Stir for minutes. The mixture was poured into water and extracted with methylene chloride. The extract was washed with brine, dried, concentrated, and purified by column chromatography to give the title compound (5.2g).

¹ H-NMR (CDCl ₃ ) δ 1.4-2.5 (m, 10H), 3.68
(m, 3H), 9.19 (m, 1H).

Example 1 2,3-Methylene-7α-fluoro
-17,20-Dimethyl PGI ₂ sodium salt

<Example 1-1> Synthesis of 5,6-dehydro-2,3-methylene-7-hydroxy-17,20-dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether t-butyllithium (factor = 1.5, pentane solution,
2.7 ml, 4.0 mmol) was added to ether (5 ml) at -78 ° C. (1E, 3S, 5S) -3-t-Butyldimethylsiloxy-5-methyl-1-iodo-1-nonene (0.79 g, 2.0 mmol) was added to ether (5
ml) and added dropwise over 10 minutes. 2 hours, -78
After stirring at ° C, pentyl copper (0.26g, 2.0mmol) and H
MPT (0.65g, 4.0mmol) was dissolved in ether (10ml) and
It was added dropwise over 5 minutes.

After 1.5 hours, a solution of (4R) -4-t-butyldimethylsiloxy-2-cyclopentenone (0.40 g, 1.9 mmol) in ether (10 ml) was added thereto, and after 20 minutes, the mixture was heated to -40 ° C. The temperature was raised. Furthermore, 2- (4-oxo-2-butynyl) cyclopropanecarboxylic acid methyl ester (0.32 g, 2.0 mmol)
Of ether (10 ml) was added dropwise over 15 minutes. After stirring for 1 hour at -40 ° C, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. Purification by silica gel column chromatography gave the title compound (0.66 g, yield 53%).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-1.5 (m, 9H), 2.2-2.9 (m, 9H), 3.65 (s, 3
H), 4.0-4.2 (m, 2H), 5.5-5.7 (m, 2H).

<Example 1-2> 5,6-dehydro-2,3-methylene-7-trimethylsiloxy-1
Synthesis of 7,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Alcohol synthesized in Example 1-1 (0.40 g, 0.62 mmol)
Was dissolved in dichloromethane (5 ml) and cooled to 0 ° C. Pyridine (0.50 ml, 6.2 mmol) and chlorotrimethylsilane (0.20 ml, 1.55 mmol) were added here, and post-treatment was carried out. The crude product was dissolved in methanol (6 ml) and cooled to -30 ° C.
Sodium borohydride (78 mg, 2.1 mmol) was added here,
Stir for 40 minutes. Add saturated ammonium chloride solution,
Post-treated.

The crude product was dissolved in pyridine (5 ml) and -1
Cooled to 2 ° C. Chlorotriethylsilane (0.22m
(1, 1.3 mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. A saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with hexane, dried, concentrated, and purified by silica gel column chromatography to obtain the title compound (0.32 g).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.5-
0.7 (m, 6H), 0.7-1.0 (m, 36H), 1.1-1.6 (m, 9H), 1.9-2.7
(m, 7H), 3.63 (s, 3H), 3.8-4.2 (m, 3H), 4.5-4.7 (m, 1H),
5.4-5.6 (m, 2H).

<Example 1-3> 5,6-dehydro-2,3-methylene-7β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9- Synthesis of Triethylsilyl Ether Trimethylsilyl ether (0.3
2 g, 0.39 mmol) was dissolved in 1,1,2-trichloro-1,2,2-trifluoroethane (8 ml) and cooled to 0 ° C. Piperidinosulfur trifluoride (0.062 ml, 0.47 mmol) was added, and the mixture was stirred at room temperature for 5.5 hours. Triethylamine was added, and saturated aqueous potassium carbonate solution was added. The title compound (0.21 g) was obtained by silica gel column chromatography purification.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.5-
0.7 (m, 6H), 0.7-1.0 (m, 36H), 1.1-1.6 (m, 9H), 1.9-2.7
(m, 7H), 3.63 (s, 3H), 3.85 (q, J = 6.5Hz, 1H), 4.1-4.2 (m,
1H), 4.2-4.3 (m, 1H), 5.35 (dd, J = 48,7.5Hz, 1H), 5.4-5.5
(m, 2H). ¹⁹ F-NMR (based on CDCl ₃ and CCl ₃ F) -170.0 ppm (m).

Example 1-4 5,6-Dehydro-2,3-methylene-7β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether Triethylsilyl ether synthesized in Synthesis Example 1-3 (0.2
1 g, 0.27 mmol) was dissolved in ethanol (5 ml), pyridinium p-toluenesulfonate (7 mg, 0.027 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. After drying and concentration, the title compound (9
5 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.8-
1.0 (m, 36H), 1.0-2.0 (m, 13H), 2.4-2.6 (m, 2H), 3.12 (d
d, J = 8.4,11.2Hz, 1H), 3.62 (s, 3H), 4.0-4.2 (m, 2H), 4.2
-4.4 (m, 1H), 5.2-5.5 (m, 3H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.3ppm (dm, J = 47.1Hz).

<Example 1-5> 2,3-Methylene-7β-fluoro-17,20-dimethyl PGF ₂
Synthesis of α-methyl ester 11,15-bis (t-butyldimethyl) silyl ether The compound (95 mg, 0.15 mmol) synthesized in Example 1-4 was dissolved in a mixed solution of benzene (2.5 ml) and cyclohexane (2.5 ml). Then cyclohexene (0.15 ml, 1.5 mmol) and Lindlar's catalyst (20 mg) were added and hydrogenated at 0 ° C. for 1.5 hours.

¹ H-NMR (CDCl ₃ ) δ 0.0-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-2.4 (m, 16H), 3.70 (s, 3H), 4.0-4.2 (m,
2H), 4.3-4.4 (m, 1H), 5.2-5.7 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -167.0ppm (d, J = 48Hz).

<Example 1-6> 2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂
Synthesis of methyl ester 11,15-bis (t-butyldimethyl) silyl ether Olefin synthesized in Examples 1-5 (100 mg, 0.15 mmol)
Was dissolved in acetonitrile (4 ml), N-iodosuccinimide (0.49 g, 2.2 mmol) was added, and the mixture was stirred at 40 ° C. for 24 hours. A 10% aqueous sodium thiosulfate solution was added, the mixture was extracted with dichloromethane, the organic layer was dried, concentrated, and purified by silica gel chromatography to obtain a cyclized product (83 mg).

The cyclized product (83 mg) was dissolved in toluene (5 ml), and 1,8-diazabicyclo [5.4.0] -7-undecene (0.15 ml) was dissolved.
Was added and the mixture was stirred at 110 ° C. for 18 hours. Saturated saline was added, the mixture was extracted with ether, the organic layer was dried, concentrated, and purified by silica gel column chromatography to obtain the title compound (14 mg).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.7-
1.0 (m, 27H), 1.0-1.8 (m, 12H), 2.0-2.2 (m, 1H, H-4), 2.3
-2.4 (m, 1H, H-10), 2.4-2.6 (m, 1H, H-8), 2.7-2.8 (m, 1H, H
-12), 3.62 (s, 3H), 3.8-3.9 (m, 1H, H-11), 4.1-4.2 (m, 1
H, H-15), 4.5-4.6 (m, 2H, H-5, H-9), 5.32 (dd, J = 53,7.5H
z, 1H), 5.4-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -184.0ppm (d, J = 53Hz, 0.5
F), 184.2 ppm (d, J = 51.7Hz, 0.5F).

<Example 1-7> 2,3-Methylene-7α-fluoro-17,20-dimethyl PGI ₂
Synthesis of methyl ester The t-butyldimethylsilyl ether compound (13 mg) synthesized in Example 1-6 was dissolved in THF (1 ml) and tetrabutylammonium fluoride (factor = 1, THF solution, 0.16
ml, 0.16 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours.
A saturated aqueous ammonium sulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried, concentrated, and purified by florisil column chromatography to obtain the title compound (9 mg).

¹ H-NMR (CDCl ₃ ) δ 0.7-1.0 (m, 9H), 1.0-1.
9 (m, 11H), 2.4-2.8 (m, 5H), 3.60 (s, 3H), 3.85 (q, J = 7.5H
z, 1H), 4.10 (q, J = 6.5Hz, 1H), 4.5-4.6 (m, 2H), 5.35 (dm,
1H), 5.5-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -186.0ppm (d, J = 55.0Hz, 0.
5F), -188.0ppm (d, J = 55.5Hz, 0.5F).

<Example 1-8> 2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂
Synthesis of sodium salt The methyl ester (9 mg) synthesized in Example 1-7 was dissolved in ethanol (0.30 ml), and 0.1 N-sodium hydroxide (0.2
8 ml) was added and the mixture was stirred at 25 ° C. for 36 hours. Concentration and drying gave the title compound.

Example 2 4-Homo-2,3-methylene-7α-
Fluoro-17,20-dimethyl PGI ₂ sodium salt

<Example 2-1> 5,6-dehydro-4-homo-2,3-methylene-7-hydroxy-1
7,20-Dimethyl PGE ₂ methyl ester 11,15-bis (t-
Synthesis of butyldimethyl) silyl ether t-butyllithium (factor = 1.5, pentane solution,
2.7 ml, 4.0 mmol) was added to ether (5 ml) at -78 ° C. (1E, 3S, 5S) -3-t-Butyldimethylsiloxy-5-methyl-1-iodo-1-nonene (0.79 g, 2.0 mmol) was added to ether (5
ml) and added dropwise over 10 minutes. 2 hours, -78
After stirring at ° C, pentyl copper (0.26g, 2.0mmol) and HMPT (0.65g, 4.0mmol) were dissolved in ether (10ml),
It was added dropwise over 15 minutes.

After 1.5 hours, a solution of (4R) -4-t-butyldimethylsiloxy-2-cyclopentenone (0.40 g, 1.9 mmol) in ether (10 ml) was added thereto, and after 20 minutes, the mixture was heated to -40 ° C. The temperature was raised. Further here, 2- (5-oxo-3-pentynyl)
Cyclopropanecarboxylic acid methyl ester (0.35g, 2.0m
A solution of (mol) in ether (10 ml) was added dropwise over 15 minutes.
After stirring for 1 hour at -40 ° C, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. Purification by silica gel column chromatography gave the title compound (0.66 g, yield 53%).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-1.5 (m, 11H), 2.1-2.4 (m, 7H), 2.6-2.8
(m, 2H), 3.62 (s, 3H), 4.0-4.2 (m, 2H), 5.5-5.6 (m, 2H).

Example 2-2 5,6-dehydro-4-homo-2,3-methylene-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether In the same manner as in Example 1-2, the alcohol (0.66 g, 1.0 mmol) synthesized in Example 2-1 was used to give the title compound (0.59 g )
Got

Example 2-3 5,6-dehydro-4-homo-2,3-methylene-7β-fluoro-1
Synthesis of 7,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Trimethylsilyl ether (0.5
Using 9 g, 0.70 mmol), fluorination was performed in the same manner as in Example 1-3 to obtain the title compound (0.39 g).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.5-
0.6 (m, 6H), 0.7-1.0 (m, 36H), 1.1-1.6 (m, 11H), 1.8-2.4
(m, 6H), 2.6-2.7 (m, 1H), 3.63 (s, 3H), 3.86 (q, J = 6.5Hz,
1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 5.32 (dd, J = 49,7.5
Hz, 1H), 5.4-5.6 (m, 2H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -169.6ppm (m).

<Example 2-4> 5,6-dehydro-4-homo-2,3-methylene-7β-fluoro-1
Synthesis of 7,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether The triethylsilyl ether (0.3
The title compound (0.24 g) was obtained by the same procedure as in Example 1-4 using 9 g, 0.50 mmol).

Example 2-5 Synthesis of 4-Homo-2,3-methylene-7β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the acetylene (0.24g) synthesized in Example 2-4 and following the same procedure as in Example 1-5, the title compound (0.21g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.0-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-2.4 (m, 18H), 3.65 (s, 3H), 4.0-4.2 (m,
2H), 4.3-4.4 (m, 1H), 5.2-5.7 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -167.2ppm (dm, J = 47.9Hz).

<Example 2-6> Synthesis example of 4-homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Olefin synthesized in 2-5 (0.21g, 0.35mmol)
Using the same procedure as in Example 1-6, the title compound (34 mg)
Got

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-1.8 (m, 13H), 2.0-2.2 (m, 2H), 2.3-2.4
(m, 1H), 2.4-2.6 (s, 1H), 2.7-2.8 (m, 1H), 3.62 (s, 3H),
3.80 (q, J = 7.5Hz, 1H), 4.1-4.2 (m, 1H), 4.5-4.6 (m, 2H),
5.28 (dd, J = 56, 7.5Hz, 1H), 5.4-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.6ppm (d, J = 56Hz).

<Example 2-7> Synthesis of 4-homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester The silyl ether compound (34 mg) synthesized in Example 2-6 was used. Using the same procedure as in Example 1-7, the title compound (24 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.7-1.0 (m, 6H), 0.87
(d, J = 6.3Hz, 3H), 1.0-1.9 (m, 13H), 2.4-3.0 (m, 5H), 3.6
6 (s, 1.5H), 3.67 (s, 1.5H), 3.8- 3.9 (m, 1H), 4.1-4.2
(m, 1H), 4.5-4.7 (m, 1H), 5.40 (d, J = 55Hz, 1H), 5.56 (d, J =
4.1Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -187.0ppm (d, J = 57.0Hz, 0.
5F), -187.3ppm (d, J = 54.7Hz, 0.5F).

<Example 2-8> Synthesis of 4-homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ sodium salt The methyl ester prepared in Example 2-7 (24 mg, 0.06 mmo)
l) was dissolved in ethanol (0.73 ml), 0.1 N-sodium hydroxide (0.68 ml) was added, and the mixture was stirred at 25 ° C. for 48 hours.
Concentration and drying gave the title compound.

[Example 3] (1S ^* , 3S ^* )-2,4-ethylene-7α
-Fluoro-17,20-dimethyl PGI ₂ methyl ester and sodium salt

<Example 3-1> (1S ^* , 3S ^* )-2,4-ethylene-5,6-dehydro-7-hydroxy
Synthesis of -17,20-dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the aldehyde synthesized in Reference Example 14 (1.36 g, 7.56 mmol), the same as in Example 1-1. The title compound (3.07
g, yield 67.2%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.8
0-1.00 (m, 24H), 3.69 (s, 3H), 4.15-4.25 (m, 2H), 5.54-
5.70 (m, 2H).

Example 3-2 (1S ^* , 3S ^* )-2,4-ethylene-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α methyl ester
Synthesis of 11,15-bis (t-butyldimethyl) silyl ether Using the compound (3.07 g, 4.62 mmol) synthesized in Example 3-1, the title compound (2.77) was prepared in the same manner as in Example 1-2. g,
Yield 70.5%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 21H), 0.5
0-0.70 (m, 6H), 0.80-1.00 (m, 30H), 3.68 (s, 3H), 4.15-4.
25 (m, 2H), 5.50-5.70 (m, 2H).

Example 3-3 (1S ^* , 3S ^* )-2,4-ethylene-5,6-dehydro-7β-fluoro
Synthesis of -17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (2.77 g, 3.26 mmol) synthesized in Example 3-2, In the same manner as in Example 1-3, the title compound (2.15 g,
Yield 84.9%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.5
0-0.70 (m, 6H), 0.80-1.00 (m, 30H), 3.68 (s, 3H), 4.15-4.
25 (m, 2H), 5.40-5.70 (m, 3H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -169.0ppm (m).

<Example 3-4> (1S ^* , 3S ^* )-2,4-ethylene-5,6-dehydro-7β-fluoro
Synthesis of -17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound (2.15 g, 2.77 mmol) synthesized in Example 3-3, Example 1- In the same manner as in 4, the title compound (1.13 g,
mmol, yield 61.5%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.8
0-1.00 (m, 24H), 3.68 (s, 3H), 4.08-4.24 (m, 2H), 5.28-
5.56 (m, 3H). ¹⁹ F-NMR (based on CDCl ₃ and CCl ₃ F) -169.0 ppm (m).

<Example 3-5> (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound (1.13 g, 1.70 mmol) synthesized in Example 3-4, the title compound was obtained in the same manner as in Examples 1-5 and 1-6. Low-polarity substance (127 mg, yield 11.2%),
Highly polar substance (67 mg, yield 5.9%).

Low polar compounds ¹ H-NMR (CDCl ₃ ) δ 0.00-0.10 (m, 12H), 0.80-0.90 (m, 24
H), 3.63 (s, 3H), 5.26 (dd, J = 56,9Hz, 1H), 5.50-5.55 (m,
2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -183.4 ppm (dd, J = 56,9Hz).

Highly polar ¹ H-NMR (CDCl ₃ ) δ 0.02 (s, 12H), 0.84-0.88 (m, 24H), 3.
65 (s, 3H), 5.26 (dd, J = 56,9Hz, 1H), 5.50-5.55 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -183.0 ppm (dd, J = 56,9H
z).

<Example 3-6> Synthesis of (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester Among the compounds synthesized in Example 3-5 Low-polarity substance (127 mg,
Using 0.19 mmol), the low polar compound of the title compound (58 mg, yield 70.2%) was obtained by the same procedure as in Example 1-7. Example 3
Highly polar compounds (67mg, 0.10mmol) synthesized in -5
A highly polar product of the title compound (33 mg, yield 75.1%) was obtained by the same procedure as in Example 1-7 using.

Low polar compounds ¹ H-NMR (CDCl ₃ ) δ 0.80-0.95 (m, 6H), 3.67 (s, 3H), 3.80
-3.95 (m, 1H), 4.10-4.20 (m, 1H), 4.55-4.65 (m, 2H), 5.3
5 (dd, J = 56,9Hz, 1H), 5.50-5.60 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) 185.6ppm (dd, J = 56,9Hz).

High polar substance ¹ H-NMR (CDCl ₃ ) δ 0.80-0.95 (m, 6H), 6.67 (s, 3H), 3.80
-3.95 (m, 1H), 4.10-4.20 (m, 1H), 4.50-4.65 (m, 2H), 5.3
5 (dd, J = 56,9Hz, 1H), 5.55-5.60 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -184.9ppm (dd, J = 56,9Hz).

<Example 3-7> Synthesis of (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ sodium salt Of the compounds synthesized in Example 3-6, Low polarity substance (96mg)
Using the same procedure as in Example 1-8, a low polar compound (83 mg) of the title compound was obtained. Using the highly polar compound (87 mg) of the compounds synthesized in Example 3-6 and following the same procedure as in Example 1-8, the highly polar compound (69 mg) of the title compound was obtained.

Low polar ¹ H-NMR (CD ₃ OD) δ 0.92-1.05 (m, 6H), 3.90-4.00 (m, 1H),
4.12-4.25 (m, 1H), 4.58-4.72 (m, 2H), 5.45 (dd, J = 64,8.
4Hz, 1H), 5.56-5.80 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -186.0ppm (d, 64Hz).

Highly polar ¹ H-NMR (CD ₃ OD) δ 0.90-1.05 (m, 6H), 3.88-4.02 (m, 1H),
4.14-4.24 (m, 1H), 4.58-4.70 (m, 2H), 5.45 (dd, J = 64,8.
4Hz, 1H), 5.55-5.80 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -185.4ppm (d, 64Hz).

[Example 4] (1S ^* , 3S ^* )-2,4-ethylene-7α
-Fluoro-17,20-dimethyl PGI ₂ methyl ester

Example 4-1 (1S ^* , 3R ^* )-2,4-ethylene-5,6-dehydro-7-hydroxy
Synthesis of -17,20-dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether The same as in Example 1-1, except that the aldehyde (1.09 g, 6.05 mmol) synthesized in Reference Example 17 was used. The title compound (2.28
g, yield 62.2%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.8
0-1.00 (m, 24H), 3.67 (s, 3H), 4.16-4.30 (m, 2H), 5.50-
5.70 (m, 2H).

Example 4-2 (1S ^* , 3R ^* )-2,4-ethylene-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α methyl ester
Synthesis of 11,15-bis (t-butyldimethyl) silyl ether Using the compound (2.28 g, 3.42 mmol) synthesized in Example 4-1, the title compound (1.98 g,
Yield 68.1%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.10 (m, 21H), 0.5
0-0.65 (m, 6H), 0.28-1.00 (m, 30H), 3.67 (s, 3H), 5.40-5.
60 (m, 2H).

Example 4-3 (1S ^* , 3R ^* )-2,4-ethylene-5,6-dehydro-7β-fluoro
Synthesis of -17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.98 g, 2.33 mmol) synthesized in Example 4-2, The title compound (1.55 g,
Yield 85.4%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.10 (m, 12H), 0.5
0-0.70 (m, 6H), 0.80-1.00 (m, 30H), 3.68 (s, 3H), 5.20-5.
60 (m, 3H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.8ppm (m).

Example 4-4 (1S ^* , 3R ^* )-2,4-ethylene-5,6-dehydro-7β-fluoro
Synthesis of -17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether Example 1-using the compound (1.55 g, 1.99 mmol) synthesized in Example 4-3 The title compound (845m
g, yield 64.0%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.15 (m, 12H), 0.8
5-0.95 (m, 24H), 3.68 (s, 3H), 4.10-4.20 (m, 2H), 5.30-
5.55 (m, 3H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.0ppm (dd, J = 56,9Hz).

<Example 4-5> (1S ^* , 3R ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound (845 mg, 1.27 mmol) synthesized in Example 4-4, the title compound (205 mg, yield 24.3%) was prepared in the same manner as in Example 1-5 and subsequently in Example 1-6. Got

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.8
0-0.95 (m, 24H), 3.67 (s, 3H), 5.30 (dd, J = 56Hz, 1H), 5.5
5-5.60 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.4 ppm (dd, J = 56,9H
z), -182.8ppm (dd, J = 56,9Hz).

<Example 4-6> Synthesis of (1S ^* , 3R ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester Compound synthesized in Example 4-5 (205 mg) , 0.31 mmol) and the same procedure as in Example 1-7 to give the title compound (118 mg, yield 87.5%).

¹ H-NMR (CDCl ₃ ) δ 0.85-1.00 (m, 6H), 3.67
(s, 3H), 3.85-3.95 (m, 1H), 4.15-4.25 (m, 1H), 4.55-4.6
5 (m, 1H), 5.38 (dd, J = 56,9Hz, 1H), 5.55-5.65 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -184.5ppm (dd, J = 56,9Hz),
-185.1ppm (dd, J = 56,9Hz).

[Example 5] 2,4-Ethylene-3α-homo-7α
-Fluoro-17,20-dimethyl PGI ₂ methyl ester

Example 5-1 2,4-Ethylene-3α-homo-5,6-dehydro-7-hydroxy
Synthesis of -17,20-dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the aldehyde (3.68 g, 19.9 mmol) synthesized in Reference Example 24, the same as in Example 1-1. The title compound (5.4
1 g, yield 44%) was obtained.

Example 5-2 2,4-Ethylene-3α-homo-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α methyl ester
Synthesis of 11,15-bis (t-butyldimethyl) silyl ether Using the compound synthesized in Example 5-1 (5.41 g, 7.99 mmol) and following the procedure of Example 1-2, the title compound (4.39 g,
Yield 64%).

¹ H-NMR (CDCl ₃ ) δ 3.67 (s, 3H), 5.4-5.7
(m, 2H).

Example 5-3 2,4-Ethylene-3α-homo-5,6-dehydro-7β-fluoro
Synthesis of -17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound synthesized in Example 5-2 (4.39 g, 5.07 mmol) By the same operation as in Example 1-3, the title compound (2.60 g,
Yield 65%) was obtained.

Example 5-4 2,4-Ethylene-3α-homo-5,6-dehydro-7β-fluoro
Synthesis of -17,20-dimethyl PGF ₂ α-methyl ester 11,15-bis (t-butyldimethyl) silyl ether Example 1-4 was performed using the compound (2.60 g, 3.27 mmol) synthesized in Example 5-3. Following the same procedure as for the title compound (1.31 g,
Yield 59%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 3.67 (m, 3H), 5.45 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -168.4ppm (m), -169.1ppm
(m).

<Example 5-5> Synthesis example of 2,4-ethylene-3α-homo-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound (1.31 g, 1.92 mmol) synthesized in 5-4 and following the same procedure as in Example 1-5 and then Example 1-6, two isomers of the title compound (low polar ( 115 mg, yield
8.8%) and a highly polar substance (102 mg, yield 7.8%)) were obtained.

Low polar substance ¹ H-NMR (CDCl ₃ ) δ 3.67 (s, 3H), 5.54 (m, 1H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.2 ppm (m).

Highly polar ¹ H-NMR (CDCl ₃ ) δ 3.66 (s, 3H), 5.3 (m, 1H), 5.54 (m, 1
H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -182.7 ppm (m).

Example 5-6 Synthesis of 2,4-Ethylene-3α-homo-7α-fluoro-17,20-dimethyl PGI ₂ Methyl Ester Among the compounds synthesized in Example 5-5, low-polar compounds ( 115 mg,
Using 0.17 mmol) and following the same procedure as in Example 1-7, a low polar compound of the title compound (57 mg, yield 75%) was obtained. Example 5-
Using the high polarity substance (102 mg, 0.15 mmol) of the compounds synthesized in 5, the high polarity substance (62 mg, yield 91%) of the title compound was obtained by the same procedure as in Example 1-7.

Low polar compounds ¹ H-NMR (CDCl ₃ ) δ 0.8-2.8 (m, 29H), 3.68 (s, 3H), 3.90
(m, 1H), 4.18 (m, 1H), 4.64 (m, 2H), 5.37 (m, 1H), 5.59
(m, 2H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -184.5 ppm (m).

Highly polar ¹ H-NMR (CDCl ₃ ) δ 0.8-2.8 (m, 29H), 3.66 (s, 3H), 3.90
(m, 1H), 4.15 (m, 1H), 4.4-4.7 (m, 2H), 5.38 (m, 1H), 5.5
8 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -184.8ppm (m).

Reference Example 25 Synthesis of 3- (t-butyldimethylsiloxymethyl) cyclohexanecarbaldehyde Using 1,3-cyclohexanedimethanol (48 g) in the same manner as in Reference Example 18, the title compound (31 g ) Got

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 6H), 0.7-0.9
(m, 9H), 1.0-2.4 (m, 8H), 3.4-3.6 (m, 2H), 9.6 (s, 1H).

Reference Example 26 3- (2,2-dibromovinyl) cyclohexanemethanol
Synthesis of t-butyldimethylsilyl ether Using the compound (14 g) synthesized in Reference Example 25, Reference Example 1
The same operation as in 9 gave the title compound (16 g).

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 6H), 0.7-0.9
(m, 9H), 1.2-1.8 (m, 8H), 3.3-3.5 (m, 2H), 6.2 (m, 1H).

Reference Example 27 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanemethanol t-butyldimethylsilyl ether Using the compound (16 g) synthesized in Reference Example 26, Reference Example 2
The title compound (11.6 g) was obtained in the same manner as in 0.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 6H), 0.8-0.9
(m, 9H), 1.2-2.3 (m, 14H), 3.3-3.4 (m, 2H), 3.4-3.6 (m, 1
H), 3.8-3.9 (m, 1H), 4.1-4.3 (m, 2H), 4.8-4.9 (m, 1H).

Reference Example 28 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanemethanol Using the compound (11.6 g) synthesized in Reference Example 27, and in the same manner as in Reference Example 21, The title compound (7.8 g) was obtained.

Reference Example 29 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanecarbaldehyde Using the compound (7.8 g) synthesized in Reference Example 28, Reference Example 2
The same operation as in 2 gave the title compound (6.0 g).

¹ H-NMR (CDCl ₃ ) δ 1.2-2.4 (m, 14H), 3.4-
3.6 (m, 1H), 3.8-3.9 (m, 1H), 4.2-4.4 (m, 2H), 4.8-4.9
(m, 1H), 9.6 (m, 1H).

Reference Example 30 Synthesis of 3- (3-hydroxy-1-propynyl) cyclohexanecarboxylic acid methyl ester Using the compound (9 g) synthesized in Reference Example 29, Reference Example 23
The title compound (3.8 g) was obtained by the same operation as described above.

¹ H-NMR (CDCl ₃ ) δ 1.2-2.4 (m, 8H), 3.7 (s,
3H), 4.2-4.3 (m, 2H).

Reference Example 31 Synthesis of 3- (3-oxo-1-propynyl) cyclohexanecarboxylic acid methyl ester Using the compound (3.8 g) synthesized in Reference Example 30, Reference Example 2
The same operation as in 4 gave the title compound (3.1 g).

¹ H-NMR (CDCl ₃ ) δ 1.2-2.6 (m, 8H), 3.7 (s,
3H), 9.2 (m, 1H).

Example 6 2,4-Propylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester

Example 6-1 2,4-Propylene-5,6-dehydro-7-hydroxy-17,20-
Synthesis of dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the aldehyde (0.92 g) synthesized in Reference Example 31 and following the same procedure as in Example 1-1, the title compound (1.50 g) got.

<Example 6-2> 2,4-Propylene-5,6-dehydro-7-trimethylsiloxy
Synthesis of -17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.50 g) synthesized in Example 6-1, Example 1 The title compound (1.47 g) was obtained by the same operation as that for -2.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 21H), 0.5
0-0.70 (m, 6H), 0.80-1.00 (m, 33H), 3.58 (s, 3H), 3.98-4.
15 (m, 2H), 5.32-5.60 (m, 2H).

<Example 6-3> 2,4-Propylene-5,6-dehydro-7β-fluoro-17,20-
Synthesis of dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.47 g) synthesized in Example 6-2, the same procedure as in Example 1-3 was performed. By operation, the title compound (0.90 g) was obtained.

¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.5 ppm
(m).

Example 6-4 2,4-Propylene-5,6-dehydro-7β-fluoro-17,20-
Synthesis of dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound (0.90 g) synthesized in Example 6-3, the same procedure as in Example 1-4 was conducted. The title compound (488 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.12 (m, 12H), 0.8
0-1.00 (m, 24H), 3.61 (s, 3H), 4.00-4.18 (m, 2H), 5.22-
5.54 (m, 2H). ¹⁹ F-NMR (based on CDCl ₃ and CCl ₃ F) -168.6 ppm (m).

<Example 6-5> 2,4-Propylene-7α-fluoro-17,20-dimethyl PGI
Synthesis of _2- methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound (488 mg) synthesized in Example 6-4, the same as in Example 1-5 and subsequently in Example 1-6. The two isomers of the title compound (low polar (53 mg) and high polar (4 mg)
8 mg)) was obtained.

Low polar compounds ¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.80-0.90 (m, 24
H), 3.59 (s, 3H), 5.22 (dd, J = 57.9,9Hz, 1H), 5.42-5.48
(m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.9ppm (dd, J = 60,10H
z).

Highly polar ¹ H-NMR (CDCl ₃ ) δ 0.00-0.15 (m, 12H), 0.78-0.90 (m, 24
H), 3.61 (s, 3H), 5.22 (dd, J = 60,9Hz, 1H), 5.42-5.48 (m,
2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.4ppm (dd, J = 60,10H
z).

<Example 6-6> 2,4-propylene-7α-fluoro-17,20-dimethyl PGI
Synthesis of ₂ methyl ester Using the low polar compound (53 mg) among the compounds synthesized in Example 6-5, the low polar compound (27 mg) of the title compound was obtained in the same manner as in Example 1-7. . Example 6
Using the highly polar compound (48 mg) among the compounds synthesized in -5,
By the same operation as in Example 1-7, highly polar compounds (2
5 mg) was obtained.

Low polar ¹ H-NMR (CDCl ₃ ) δ 0.88-0.96 (m, 6H), 3.65 (s, 3H), 3.82
-4.00 (m, 1H), 4.16-4.24 (m, 1H), 4.46-4.52 (m, 1H), 4.6
0-4.70 (m, 1H), 5.38 (dd, J = 57,9Hz, 1H), 5.56-5.64 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -184.8ppm (dm, J = 57Hz),-
186.8ppm (dm, J = 57Hz).

Highly Polar Compound ¹ H-NMR (CDCl ₃ ) δ 0.88-0.92 (m, 6H), 3.65 (s, 3H), 3.82
-4.00 (m, 1H), 4.16-4.24 (m, 1H), 4.46-4.52 (m, 1H), 4.6
0-4.70 (m, 1H), 5.38 (dd, J = 58,10Hz, 1H), 5.58-5.62 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -184.2ppm (dm, J = 58Hz),-
184.4ppm (dm, J = 58Hz).

Reference Example 32 Synthesis of 3- (t-butyldimethylsiloxymethyl) cyclobutanecarbaldehyde 1,3-Cyclobutanedimethanol
The title compound (3.61 g) was obtained by the same procedure as in Reference Example 18 using (4.11 g).

¹ H-NMR (CDCl ₃ ) δ 0.07-0.13 (m, 6H), 0.96
(s, 9H), 1.98-2.60 (m, 5H), 2.98-3.15 (m, 1H), 3.51 (d, J
= 5.4Hz, 0.5H), 3.61 (d, J = 5.4Hz, 0.5H), 9.67 (d, J = 3.2H
z, 0.5H), 9.79 (d, J = 3.2Hz, 0.5H).

Reference Example 33 3- (2,2-dibromovinyl) cyclobutanemethanol t-
Synthesis of Butyldimethylsilyl Ether Using the compound (3.61 g) synthesized in Reference Example 32 and following the procedure of Reference Example 19, the title compound (5.35 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.04 (s, 3H), 0.06 (s, 3
H), 0.90 (s, 9H), 1.80-2.50 (m, 5H), 2.90-3.20 (m, 1H),
3.50 (d, J = 5.1Hz, 0.5H), 3.62 (d, J = 5.1Hz, 0.5H), 6.44
(d, J = 8.4Hz, 0.5H).

Reference Example 34 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclobutanemethanol t-butyldimethylsilyl ether Reference Example 20 was prepared using the compound (5.35 g) synthesized in Reference Example 33. The title compound (3.82 g) was obtained by the same procedure as described above.

¹ H-NMR (CDCl ₃ ) δ 0.04 (s, 3H), 0.07 (s, 3
H), 0.90 (s, 9H), 1.42-2.60 (m, 11H), 2.80-3.10 (m, 1H),
3.48-3.60 (m, 3H), 3.78-3.94 (m, 1H), 4.15-4.38 (m, 2H),
4.78-3.84 (m, 1H).

Reference Example 35 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclobutanemethanol Using the compound (3.82 g) synthesized in Reference Example 34 and following the same procedure as in Reference Example 21, The title compound (2.07 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.40-2.65 (m, 11H), 2.8
5-3.18 (m, 1H), 3.50-3.70 (m, 3H), 3.78-3.90 (m, 1H), 4.
15-4.38 (m, 2H), 4.75 -5.05 (m, 1H).

Reference Example 36 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclobutanecarbaldehyde By the same procedure as in Reference Example 22 using the compound (2.07 g) synthesized in Reference Example 35. The title compound (1.96 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.40-1.90 (m, 6H), 2.18
-2.55 (m, 4H), 2.95-3.18 (m, 2H), 3.46-3.60 (m, 1H), 3.7
3-3.90 (m, 1H), 4.12-4.36 (m, 2H), 4.76 (m, 1H), 9.65 (d,
2.2Hz, 0.5H), 9.77 (d, 2.2Hz, 0.5H).

Reference Example 37 Synthesis of Methyl 3- (3-hydroxy-1-propynyl) cyclobutanecarboxylate Using the compound (1.96 g) synthesized in Reference Example 36, the procedure of Reference Example 23 was repeated. A compound (1.24 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 2.25-2.26 (m, 4H), 2.90
-3.10 (m, 1H), 3.12-3.28 (m, 1H), 3.68 (s, 1.5H), 3.70
(s, 1.5H), 4.27 (m, 1H).

Reference Example 38 Synthesis of methyl 3- (3-oxo-1-propynyl) cyclobutanecarboxylate Using the compound (1.24 g) synthesized in Reference Example 37, the same procedure as in Reference Example 24 was carried out. The compound (803 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ 2.36-2.53 (m, 2H), 2.60
-2.75 (m, 2H), 3.20-3.45 (m, 2H), 3.70 (s, 3H), 9.21 (s, 1
H).

Example 7 2,4-Methylene-7α-fluoro
-17,20-Dimethyl PGI ₂ methyl ester and sodium salt

Example 7-1 Synthesis of 2,4-methylene-5,6-dehydro-7-hydroxy-17,20-dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether The title compound (1.60 g) was obtained by the same procedure as in Example 1-1, using the compound (803 mg) synthesized in Reference Example 38.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 12H), 0.80-0.
95 (m, 24H), 3.66 (m, 3H), 5.50-5.70 (m, 2H).

Example 7-2 2,4-methylene-5,6-dehydro-7-trimethylsiloxy-1
Synthesis of 7,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.60 g) synthesized in Example 7-1, Example 1- The same operation as in 2 gave the title compound (1.54 g).

¹ H-NMR (CDCl ₃ ) δ 0-0.2 (m, 12H), 0.45-1.
00 (m, 48H), 3.73 (m, 3H), 3.82-3.95 (m, 1H), 4.10-4.25
(m, 2H), 4.55-4.80 (m, 2H), 5.40-5.70 (m, 2H).

Example 7-3 2,4-Methylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9- Synthesis of triethylsilyl ether Using the compound (1.54 g) synthesized in Example 7-2 and following the same procedure as in Example 1-3, the title compound (1.17 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.20 (m, 12H), 0.50-
1.0 (m, 33H), 3.73 (s, 1.5H), 3.75 (s, 1.5H), 3.85-3.95
(m, 1H), 4.10-4.20 (m, 1H), 4.21-4.35 (m, 1H), 5.35 (dm,
J = 46.6Hz, 1H), 5.50 (m, 2H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -170.1ppm (m).

<Example 7-4> of 2,4-methylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether The title compound (717 mg) was obtained by the same procedure as in Example 1-4 using the compound (1.17 g) synthesized in Synthesis Example 7-3.

¹ H-NMR (CDCl ₃ ) δ 0-0.15 (m, 12H), 0.75-
0.95 (m, 24H), 3.71 (s, 1.5H), 3.73 (s, 1.5H), 4.08-4.20
(m, 2H), 4.30-4.41 (m, 1H), 5.40-5.50 (m, 2H), 5.47 (dm,
J = 46.6Hz, 1H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -168.2ppm (m).

<Example 7-5> 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂
Synthesis of methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound (717 mg) synthesized in Example 7-4, the same procedure as in Example 1-5 and then in Example 1-6 was performed. By operation, the title compound (251 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.10 (m, 12H), 0.75-
0.95 (m, 24H), 3.66 (s, 1.5H), 3.69 (s, 1.5H), 3.75-3.90
(m, 1H), 4.10-4.20 (m, 1H), 4.48-4.80 (m, 2H), 5.30 (dm,
J = 56.5Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -183.8ppm (dd, J = 56.5,7.5
Hz), -184.2ppm (dd, J = 56.5,7.5Hz).

<Example 7-6> 2,4-Methylene-7α-fluoro-17,20-dimethyl PGI ₂
Synthesis of methyl ester Using the compound (251 mg) synthesized in Example 7-5, the title compound (132 mg) was obtained in the same manner as in Example 1-7.
Furthermore, the obtained compound (132 mg) was subjected to high performance liquid chromatography (silica, hexane: ethanol = 96:
4) was used to separate the two isomers, and
mg) and a highly polar substance (67 mg) were obtained.

Low polar substances ¹ H-NMR ((CD ₃ ) ₂ CO) δ 0.80-0.90 (m, 6H), 3.55-3.60 (m, 1
H), 3.60 (s, 3H), 3.80-3.95 (m, 1H), 4.05-4.15 (m, 2H),
4.55-4.68 (m, 2H), 5.41 (dd, J = 60,8.3Hz, 1H), 5.50-5.71
(m, 2H). ¹⁹ F-NMR ((CD ₃ ) ₂ CO, CCl ₃ F standard) -184.8 ppm (dd, J = 60,
8.1Hz).

Highly polar ¹ H-NMR ((CD ₃ ) ₂ CO) δ 0.80-0.90 (m, 6H), 3.50-3.60 (m, 2
H), 3.65 (s, 3H), 3.80-3.98 (m, 1H), 4 03-4.15 (m, 2H),
4.58-4.66 (m, 1H), 4.70-4.80 (m, 1H), 5.44 (dd, J = 60,8.3
Hz, 1H), 5.50-5.70 (m, 2H). ¹⁹ F-NMR ((CD ₃ ) ₂ CO, CCl ₃ F standard) -184.8ppm (dd, J = 60,
8.3Hz).

<Example 7-7> 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂
Synthesis of sodium salt Of the compounds synthesized in Example 7-6, low-polar compounds (158 mg)
Was dissolved in ethanol (9.1 ml), 0.1N-sodium hydroxide aqueous solution (3.94 ml) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was water (0.45 ml).
Was dissolved in acetonitrile and acetonitrile (13.8 ml) was added with stirring. The precipitated white solid was filtered off and dried to give the title compound of low polarity (1
28 mg) was obtained.

Using the highly polar compound (188 mg) of the compounds synthesized in Example 7-6 and by the same procedure, the highly polar compound (156 mg) of the title compound was obtained.

Low polar ¹ H-NMR (CD ₃ OD) δ 0.94-1.05 (m, 6H), 1.18-1.85 (m, 10
H), 2.03-2.19 (m, 2H), 2.33-3.20 (m, 7H), 3.86-4.00 (m,
1H), 4.14-4.25 (m, 1H), 4.60-4.75 (m, 2H), 5.45 (dd, J = 6
0,8.4Hz, 1H), 5.55-5.78 (m, 2H). ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard) -186.2ppm (d, J = 60Hz).

Highly polar ¹ H-NMR (CD ₃ OD) δ 0.95-1.05 (m, 6H), 1.18-1.82 (m, 10
H), 2.00-2.20 (m, 2H), 2.50-2.78 (m, 5H), 3.00-3.20 (m,
1H), 3.30-3.40 (m, 1H), 3.90-4.00 (m, 1H), 4.15-4.25
(m, 1H), 4.63-4.72 (m, 1H), 4.86-4.94 (m, 1H), 5.46 (dd,
J = 60,8.4Hz, 1H), 5.57-5.80 (m, 2H). ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard) -186.0ppm (d, J = 60Hz).

Reference Example 39 Synthesis of methyl 3- (3-hydroxy-1-propynyl) cyclobutylacetate The compound (2.07 g) synthesized in Reference Example 35 was converted into methylene chloride (3
It was dissolved in 0 ml), triethylamine (1.67 ml) and methanesulfonyl chloride (0.79 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (20 ml) was added to the reaction solution, the organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (50 ml) and water (10 ml), potassium cyanide (0.78 g) was added, and the mixture was stirred at 80 ° C. for 7 hr. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ether (20 ml × 2). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.

The residue obtained was washed with water (25 ml) and ethanol (25 ml).
l) and add potassium hydroxide (807 mg),
Stir for 5 hours. The mixture was adjusted to pH 2 by adding concentrated sulfuric acid, saturated with sodium chloride, and extracted with methylene chloride (30 ml × 2). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in benzene (10 ml), methanol (2 ml) and concentrated sulfuric acid (1 drop) were added, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.33 g).

¹ H-NMR (CDCl ₃ ) δ 1.70-1.90 (m, 1H), 1.95
-2.10 (m, 1H), 2.18-2.35 (m, 1H), 2.35-2.60 (m, 3H), 2.7
5-3.14 (m, 2H), 3.65 (s, 1.5H), 3.66 (s, 1.5H), 4.23-4.3
0 (m, 2H).

Reference Example 40 Synthesis of Methyl 3- (3-oxo-1-propynyl) cyclobutylacetate Using the compound (1.33 g) synthesized in Reference Example 39, the same procedure as in Reference Example 24 was conducted. A compound (1.26 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.88-2.00 (m, 1H), 2.05
-2.20 (m, 1H), 2.35-2.75 (m, 4.5H), 2.85-3.28 (m, 1.5H),
3.66 (s, 3H), 9.20 (d, J = 7.3Hz, 1H).

Example 8 1α-Homo-2,3-methylene-7
α-Fluoro-17,20-dimethyl PGI ₂ methyl ester

Example 8-1 1α-Homo-2,3-methylene-5,6-dehydro-7-hydroxy-17,20-dimethyl PGE ₂ methyl ester 11,15-
Synthesis of (t-butyldimethyl) silyl ether Using the compound (840 mg) synthesized in Reference Example 40 and following the procedure of Example 1-1, the title compound (1.68 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.15 (m, 12H), 0.7
5-0.93 (m, 24H), 3.65 (s, 3H), 4.10-4.20 (m, 2H), 5.50-
5.68 (m, 2H).

Example 8-2 1α-Homo-2,3-methylene-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α methyl ester
Synthesis of 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.68 g) synthesized in Example 8-1, the same procedure as in Example 1-2 was conducted to give the title compound. (1.58g) was obtained.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.18 (m, 12H), 0.5
0-0.68 (m, 6H), 0.72-1.00 (m, 33H), 3.65 (s, 3H), 3.82-4.
98 (m, 1H), 4.07-4.21 (m, 2H), 4.55-4.76 (m, 2H), 5.40-
5.68 (m, 2H).

Example 8-3 1α-Homo-2,3-methylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-
Synthesis of bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.58 g) synthesized in Example 8-2 and following the same procedure as in Example 1-3, the title compound (1.22 g) Got

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 12H), 0.50-0.
70 (m, 6H), 0.75-0.98 (m, 33H), 3.65 (s, 3H), 4.03-4.18
(m, 2H), 5.30-5.60 (m, 3H). ¹⁹ F-NMR (based on CDCl ₃ and CCl ₃ F) -168.4 ppm (m).

Example 8-4 1α-Homo-2,3-methylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-
Synthesis of bis (t-butyldimethyl) silyl ether The title compound (753 mg) was obtained by the same procedure as in Example 1-4, using the compound (1.22 g) synthesized in Example 8-3.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 12H), 0.75-0.
93 (m, 24H), 3.65 (s, 3H), 4.03-4.18 (m, 2H), 5.30-5.57
(m, 3H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -168.1 ppm (m).

Example 8-5 Synthesis Example of 1α-homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether The title compound (241 mg) was obtained in the same manner as in Example 1-5 and then in Example 1-6 using the compound (753 mg) synthesized in 8-4.

¹ H-NMR (CDCl ₃ ) δ 0-0.15 (m, 12H), 0.70-
0.95 (m, 24H), 3.62 (s, 3H), 3.70-3.86 (m, 1H), 4.12 (m, 1
H), 4.50-4.80 (m, 2H), 5.27 (dm, J = 56.7Hz, 1H), 5.48-5.
54 (m, 2H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -182.9 ppm (m).

<Example 8-6> Synthesis of 1α-homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester The compound (241 mg) synthesized in Example 8-5 was used. Then, the title compound (144 mg) was obtained in the same manner as in Example 1-7.

¹ H-NMR (CDCl ₃ ) δ 0.85-1.00 (m, 6H), 3.65
(s, 1.5H), 3.66 (s, 1.5H), 3.85-4.02 (m, 1H), 4.10-4.20
(m, 2H), 4.60-4.90 (m, 2H), 5.26 (dd, J = 60,8.4Hz, 0.5H),
5.54-5.76 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -183.7ppm (dd, J = 60,8.1H
z), -184.1ppm (dd, J = 60,8.1Hz).

Formulation Example 1 Gastric dissolution capsule (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester (50 mg) was dissolved in ethanol (10 ml), and this was dissolved in mannitol (18.5). Mix with g, dry through a 30 mesh screen for 90 minutes at 30 ° C.
It was passed through a mesh sieve.

Aerosil (microfine silica) 200 mg was added to the powder to obtain No. 3 hard gelatin capsule 100.
Filled into individual pieces, 0.5mg per capsule (1S ^* , 3S ^* )-2,
A gastric capsule containing 4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester was obtained.

<Formulation Example 2> Injection 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂
Dissolve 0.5 mg of methyl ester in 5 ml of ethanol, sterilize through a bacteria-retaining filter, and add 0.1 ml per 1 ml ampoule.
Ampoules were sealed containing 10 μg of 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester. The contents of the ampoule should be a suitable solvent, such as pH.
Use it as an injection by diluting it to 1 ml with 8.6 Tris-HCl buffer.

<Formulation Example 3> Lyophilization agent for injection 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂
To a solution of methyl ester 50 mg, α-cyclodextrin 1.6 g and distilled water 10 ml, citric acid 10 mg, lactose 50 g
And 800 ml of distilled water are added and dissolved, and the total volume is made up to 1 liter with distilled water. Thereafter, after sterile filtration according to a conventional method, 1 ml each was filled in an ampoule, and freeze-dried to obtain a freeze-dried preparation for injection.

[0294]

INDUSTRIAL APPLICABILITY The novel PGI ₂ derivative of the present invention is a weakly toxic compound having a strong platelet aggregation inhibitory action and antianginal action, and is useful for preventing thrombosis, angina pectoris, myocardial infarction, arteriosclerosis and the like. Effective for treatment.

[Brief description of drawings]

FIG. 1 is a synthetic flow sheet of the compound [I ′] of the present invention (No. 1)

FIG. 2 is a synthesis flow sheet of the compound [I ′] of the present invention (No. 2)

FIG. 3 is a synthesis flow sheet of the starting material [II] of the compound of the present invention (No. 1)

FIG. 4 is a synthesis flow sheet of the starting material [II] of the compound of the present invention (No. 2)

FIG. 5: Synthesis flow sheet of aldehydes [III] (Part 1)

FIG. 6: Synthesis flow sheet of aldehydes [III] (Part 2)

FIG. 7: Synthesis flow sheet of aldehydes [III] (Part 3)

FIG. 8: Synthesis flow sheet of aldehydes [III] (Part 4)

FIG. 9: Synthesis flow sheet of aldehydes [III] (Part 5)

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Arata Yasuda             1150 Hazawa-machi, Kanagawa-ku, Yokohama-shi, Kanagawa             Asahi Glass Co., Ltd. Central Research Laboratory (72) Inventor Taku Yamamoto             1-7-9-203 Kaminita, Toyonaka-shi, Osaka (72) Inventor Takekazu Fujitani             13-20 Miharadai, Sakai City, Osaka Prefecture (72) Inventor Kazu Hosoki             1-5-20 Ueno Nishi, Toyonaka City, Osaka Prefecture

Claims (12)

[Claims] 1. A natural prostaglandin I have a halogen atom to a carbon atom corresponding to the 7-position of _2, and prostaglandin I ₂ compound having a cycloalkylene group in α-chain, an ester, and salts thereof, A novel prostaglandin I ₂ derivative selected from Wherein the naturally occurring prostaglandins carbon atoms corresponding to the 7-position of the I ₂ having a fluorine atom, yet the α-chain corresponding to the trimethylene group at the 2-position and 4-position of natural prostaglandin I ₂ The divalent hydrocarbon moiety is cyclopropylene group, 1,2-cyclobutylene group, 1,3-cyclobutylene group, 1,
2-cyclopentylene group, 1,3-cyclopentylene group, 1,2-
A carbonization selected from a cyclohexylene group, a 1,3-cyclohexylene group, a 1,4-cyclohexylene group, and a divalent group in which a methylene group or a dimethylene group is bonded to at least one bond of these cycloalkylene groups. The prostaglandin I ₂ derivative according to claim 1, which is a hydrogen group. 3. A novel prostaglandin I ₂ derivative represented by the following formula [I]. [Chemical 1] Here, R ¹ : a substituted or unsubstituted C 1-10 alkyl group, an alkenyl group, or an alkynyl group, or a substituted or unsubstituted 5- or 6-membered cycloalkyl group, R ² : a hydrogen atom, a carbon number 1 to 10 alkyl groups or cations, R ³ , R ^{4 are the} same or different and are hydrogen atoms or protective groups, X ¹ , X ² : one is a hydrogen atom, the other is a fluorine atom or a chlorine atom, k, l, m, n: each represents an integer of 0 to 6, and 0 ≦ k + n ≦ 4, 1 ≦ l + m ≦ 6 4. The prostaglandin I ₂ derivative according to claim 3, wherein ^one of X ¹ and X ² is a hydrogen atom and the other is a fluorine atom. 5. k and n each represent an integer of 0 to 2,
l and m each represent an integer of 0 to 4, and 0 ≦ k +
n ≦ 2, 1 ≦ l + m ≦ 4, k + l + n ≦ 4, k + m + n
The prostaglandin I ₂ derivative according to claim 3, wherein ≦ 4. 6. X ¹ is a fluorine atom, X ² is a hydrogen atom, R ² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
And a group selected from alkali metal ions, R ³ ,
The prostaglandin I ₂ derivative according to claim 3, wherein each R ⁴ is a hydrogen atom, and R ¹ is a linear or branched alkyl group having 5 to 9 carbon atoms. 7. R ¹ is n-pentyl group, n-hexyl group, 2-
The prostaglandin I ₂ derivative according to claim 6, which is an alkyl group selected from a methylhexyl group and a 1,1-dimethylpentyl group. 8. The number of carbon atoms (l + m + 2) constituting the ring of the α-chain cycloalkylene group is 3 to 6, and the cycloalkylene group is a cyclopropylene group, a 1,2-cyclobutylene group, 1, 3-cyclobutylene group, 1,2-cyclopentylene group, 1,3-cyclopentylene group, 1,2-cyclohexylene group, 1,3-cyclohexylene group, and 1,4-cyclohexylene group Is a cycloalkylene group, and when l + m + 2 is 3, 0 ≦ k + n ≦ 2, and l + m + 2 is 4
In case of 0 ≦ k + n ≦ 1, and in case of 1 + m + 2 being 5-6, k +
The prostaglandin I ₂ derivative according to claim 6, wherein n = 0. 9. 2,3-methylene -7α- fluoro -17,20- dimethyl PGI _2, 4-homo-2,3-methylene -7α- fluoro -1
7,20-Dimethyl PGI ₂ , 2,4-ethylene-7α-fluoro
-17,20-Dimethyl PGI ₂ , 2,4-ethylene-3α-homo-7
α-fluoro-17,20-dimethyl PGI ₂ , 2,4-propylene-7α-fluoro-17,20-dimethyl PGI ₂ , 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂ , 1α-
Homo-2,3-methylene-7α-fluoro-17,20-dimethyl P
GI _2, lower alkyl esters of these PGI _2, and sodium salts or potassium salts of these PGI ₂ prostaglandin I ₂ derivative selected from. 10. A prostaglandin I ₂ derivative selected from 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂ , its methyl ester, and its sodium salt. 11. A medicine comprising a prostaglandin I ₂ derivative selected from any one of claims 1, 3, 9 and 10 as an active ingredient. 12. A preventive and / or therapeutic agent for cardiovascular diseases, which comprises a prostaglandin I ₂ derivative selected from any one of claims 1, 3, 9, and 10 as an active ingredient.