JPH07330752A - Difluoroprostacyclins - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as a therapeutic agent and a preventive for cardiovascular diseases, showing excellent inhibitory action on blood platelet aggregation and antithrombotic action and excellent in chemical stability. CONSTITUTION:A compound of formula I [A is ethy(ny)lene or vinylene; R is a 4-10C (branched) alkyl, an alkenyl, an alkynyl, a (substituted) aralkyl, a (substituted) 3- to 8-membered cycloalkyl] or its salt such as sodium 5-{(1S,5R,6 R,7R)-2-oxo-4,4-difluoro-7-hydroxy-6[(3S,5S)3-hydroxy-methyl-E-1 nonenyl]bicyclo[3.3.0]octan-3ylidene}pentanoate. The compound of formula I is obtained by introducing an omega chain to a compound of formula II (R<1> and R<2> are each a protecting group), fluorinating the resultant substance to give a compound of formula III (R<3> is shown as R<1>), adding an alpha chain to the compound to give a compound of formula IV (R<4> is an alkyl), then deprotecting the compound of formula IV and hydrolyzing its ester.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel difluoroprostacyclins. More specifically, it relates to 7,7-difluoroprostacyclin having two fluorine atoms at the 7-position of prostacyclin.

[0002]

2. Description of the Related Art Natural prostacyclin (PGI)
₂ ) is a local hormone that has strong physiological activities in vivo, such as platelet aggregation inhibitory activity, vasodilatory activity, and cytoprotective effect, and is an important factor that regulates its cell function in vivo. However, natural prostacyclin has a vinyl ether bond which is very easily decomposed in the molecule, and therefore is easily inactivated under neutral or acidic conditions (half-life of 10.4 in aqueous solution at pH 7.48).
5 minutes). For this reason, attempts have been made to develop them as pharmaceuticals, but in many cases, the range of application of the pharmaceuticals is limited due to chemical instability. Therefore, the development of a chemically stable prostacyclin derivative having the same physiological activity as that of the natural type has been intensively studied both inside and outside.

Prostacyclines having a fluorine atom at the 7-position have also been reported (JP-A-56-501319, JP-A-57-165382, JP-A-57-57).
171988, JP-A-61-91136,
JP-A-62-482, JP-A-5-9184, JP-B-3-14030, JP-B-3-4727
2 gazette, Japanese Patent Publication No. 1-24147 gazette). In addition,
In the following general description, the position numbers of carbon atoms in prostacyclins and intermediates thereof are represented by the position numbers of carbon atoms of the corresponding natural prostacyclin, unless otherwise specified. Therefore, for example, the 7-position means the position corresponding to the 7-position of natural prostacyclin regardless of the presence or absence of the α chain and its length.

Regarding prostacyclins having two or more fluorine atoms, Japanese Patent Publication No. 56-501319 discloses prostacyclins in which the 2-, 4-, 7- and 10-positions are fluorinated. However, the physical property data is
Only the specific optical rotation is described for 10,10-difluoro-13,14-dehydroprostacyclin, and no physiological activity data is described for any of the compounds. Of these prostacyclins having two or more fluorine atoms, compounds whose physiological activity has been revealed are 10,10-difluoro-13,14-
Dehydroprostacyclin only. Above special table Sho 5
No. 6-501319, the inventor of the invention described in J. F
Ried and co-workers have reported on vasodilatory action, platelet aggregation inhibitory action, chemical stability, etc. Me
d. Chem. , 23, 234 (1980), Pro
c. Natl. Acad. Sci. USA, 77, 68
46 (1980) and Thromb. Res. 23, 38
7 (1981).

[0005]

On the other hand, in the case of prostacyclins having two fluorine atoms at the 7-position, a synthesis example of 7,7-difluoro-13,14-dehydroprostacyclin is described in the above-mentioned JP-A-56-501319. Although it is described in the publication, it uses a synthetic method that is considered to be extremely difficult in practice, and neither physical property data nor physiological activity data is described, and as far as the inventors know, there is no subsequent report. . In addition, among the difluoroprostacyclins, there is no synthetic example in which the 13th and 14th positions of the ω chain are other than the dehydro type, and the 16th to 20th positions are derivatives other than the n-pentyl group, for example, a branched alkyl group, No synthetic examples of derivatives of alkenyl group, alkynyl group, aralkyl group, cycloalkyl group, etc.

7,7-Difluoro-13,14 described in the synthesis example of the above Japanese Patent Publication No. 56-501319.
-Dehydroprostacyclin is prepared from cyclopentadiene and dichloroketene as starting materials, and 7,7-difluoro-13,14-dehydroprostaglandin F is first prepared.
It is manufactured by cyclizing after synthesizing ₂ . According to this method, the synthesis of the starting material 7,7-difluoro-13,14-dehydroprostaglandin F ₂ requires a number of steps and is very difficult. In particular, 7,7-difluoro-13,14-dehydroprostaglandin F is produced by reacting corresponding hemiacetal having two electron-withdrawing fluorine atoms as adjacent groups with 5-triphenylphosphonopentanoic acid.
_In the Wittig reaction for synthesizing ₂ , unlike the usual case, the reaction yield is significantly lowered due to the strong electron-withdrawing effect of the fluorine atom, and it is practically difficult to obtain the target product. In addition, the cyclization reaction of 7,7-difluoro-13,14-dehydroprostaglandin F ₂ has two electron-withdrawing fluorine atoms adjacent to the olefin at the reaction site. Unlike the cyclization reaction of gin F ₂ compounds, the reactivity is extremely low and the reaction takes a long time,
There are problems such as low reaction yield, and this is a difficult process in practice.

As described above, the physical property data and physiological activity data of the 7,7-difluoroprostacyclins have not been specifically known so far, and it was not considered that this compound was actually synthesized. .

[0008]

SUMMARY OF THE INVENTION
-Study of synthesizing difluoroprostacyclin, and then its physical properties and physiological activity were measured to examine its usefulness as a drug, and it has the same physiological activity as natural prostacyclin and is chemically stable. Studies were conducted to find difluoroprostacyclins. As a result, the present inventor has developed a method for synthesizing 7,7-difluoroprostacyclin different from the above synthetic method, and based on the method, synthesizing a novel difluoroprostacyclin, has a high physiological activity, and has a chemical property. We found stable difluoroprostacyclins. The present invention is the following invention relating to these 7,7-difluoroprostacyclins.

Difluoroprostacyclins represented by the following general formula (1), lower alkanol esters thereof,
Or a compound which is a pharmaceutically acceptable salt thereof. A preventive or therapeutic agent for cardiovascular diseases, which comprises the above compound as an active ingredient.

[0010]

[Chemical 2]

(In the general formula (1), A: an ethylene group, a vinylene group, or an ethynylene group; R: a linear or branched alkyl group having 4 to 10 carbon atoms, an alkenyl group, an alkynyl group, or a substituent It represents an aralkyl group which may have or a 3- to 8-membered ring cycloalkyl group which may have a substituent.)

Among the difluoroprostacyclins represented by the above general formula (1), the following compounds are preferable in view of physiological activity and chemical stability. A compound in which A is an ethynylene group and R is an n-pentyl group (provided that the hydroxyl group at the 15-position is facing down toward the paper surface) is described in JP-A-56-501319 (however,
There is no physical property data or physiological activity data).

In the above general formula (1), the direction of the hydroxyl group at the 15-position may be downward (S arrangement) or upward (R arrangement) with respect to the plane of the paper as represented by the wavy line. As will be described later, in the conventional prostacyclins, the hydroxyl group at the 15-position is directed downward (S) in order to exert physiological activity.
However, in the compound of the present invention, the hydroxyl group at the 15-position has a high physiological activity even when it is directed upward (R configuration) with respect to the paper surface. As A, a vinylene group or an ethynylene group is preferable, and a vinylene group is particularly preferable.

R is preferably a linear or branched alkyl group, an alkenyl group or an alkynyl group (hereinafter collectively referred to as a chain hydrocarbon group), and among them, a branched chain hydrocarbon as described later. Groups are preferred.
The chain hydrocarbon group has 4 to 10 carbon atoms, and particularly 5
~ 8 are preferred.

When R is a chain hydrocarbon group, it is more preferable that the straight chain portion excluding the branch has 5 to 6 carbon atoms.
In addition, at least one (preferably 1
(3) unsaturated double bond or unsaturated triple bond. The branched portion is preferably a methyl group or an ethyl group, and particularly preferably a methyl group. Two or more branched portions may be present, and preferably one or two. Also, the two branched moieties may be bonded to one carbon atom. Further, the bonding position of the branched portion is preferably 1-position to 3-position of the chain hydrocarbon group, and particularly 1-position.
Second place is preferred. Further, in that case, it is preferable that the unsaturated double bond or unsaturated triple bond is present at the 3-position or later.

Specific R includes the following chain hydrocarbon groups. n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-decyl group, 1-methylpentyl group, 1,1-dimethylpentyl group, 1-methylhexyl group, 2-methylpentyl group, 2
-Methylhexyl group, 3-pentenyl group, 1-methyl-
3-pentenyl group, 1-methyl-3-hexenyl group,
1,1-dimethyl-3-pentenyl group, 1,1-dimethyl-3-hexenyl group, 2-methyl-3-pentenyl group, 2-methyl-3-hexenyl group, 3-pentynyl group, 1-methyl-3 -Pentynyl group, 1-methyl-3-
Hexynyl group, 2-methyl-3-pentynyl group, 2-methyl-3-hexynyl group, 1,1-dimethyl-3-pentynyl group, 1,1-dimethyl-3-hexynyl group.

Of the above chain hydrocarbon groups, preferred are 2-methylpentyl group, 1-methylhexyl group and 2
-Methylhexyl group, 1,1-dimethylpentyl group, 1
-Methyl-3-pentynyl group, 1-methyl-3-hexynyl group, and 1,1-dimethyl-3-hexynyl group. In particular, 2-methylhexyl group and 1-methyl-3-
Hexynyl groups are preferred.

R may be an alkyl group or a cycloalkyl group in addition to the chain hydrocarbon group, and the number of carbon atoms thereof is preferably 10 or less. Next to the above-mentioned chain hydrocarbon group, R is preferably an aralkyl group which may have a substituent. The aralkyl group is preferably an aralkyl group having a phenyl group and having 4 or less carbon atoms (preferably 1 to 2). Particularly, benzyl group and phenethyl group are preferable. The phenyl group in them may have a substituent such as an alkyl group (preferably having a carbon number of 4 or less), a halogenated methyl group and a halogen atom. As this substituent, an alkyl group having 1 to 2 carbon atoms and a halogen atom are particularly preferable. The alkyl group portion of the aralkyl group may have a branch. Particularly, a benzyl group having a methyl group at the 1-position and a phenethyl group are preferable. Moreover, when R is a cycloalkyl group, a cyclopentyl group and a cyclohexyl group are preferable. The cycloalkyl group may have the same substituent as described above. Examples of these aralkyl groups and cycloalkyl groups are shown below.

(3-methylphenyl) methyl group, (3-
(Chlorophenyl) methyl group, (3-fluorophenyl)
Methyl group, (3-bromophenyl) methyl group, {(3-
Trifluoromethyl) phenyl} methyl group, 1- (3-
Methylphenyl) ethyl group, 1- (3-chlorophenyl) ethyl group, 1-{(3-trifluoromethyl) phenyl} ethyl group, 1- (3-fluorophenyl) ethyl group, 1- (3-bromophenyl) Ethyl group, 2- (3-
Methylphenyl) ethyl group, 2- (3-chlorophenyl) ethyl group, 2-{(3-trifluoromethyl) phenyl} ethyl group, 2- (3-fluorophenyl) ethyl group, 2- (3-bromophenyl) Ethyl group, 1-methyl-2- (3-methylphenyl) ethyl group.

1-methyl-2- (3-chlorophenyl)
Ethyl group, 1-methyl-2-{(3-trifluoromethyl) phenyl} ethyl group, 1-methyl-2- (3-fluorophenyl) ethyl group, 1-methyl-2- (3-bromophenyl) ethyl Group, benzyl group, cyclopentyl group, 3-methylcyclopentyl group, 3-chlorocyclopentyl group, 3-fluorocyclopentyl group, 3-trifluoromethylcyclopentyl group, cyclohexyl group, 3
-Methylcyclohexyl group, 3-chlorocyclohexyl group, 3-fluorocyclohexyl group, 3-trifluoromethylcyclohexyl group.

Since the compound represented by the general formula (1) has an asymmetric carbon in its structure, various stereoisomers,
Although optical isomers exist, the compounds of the present invention include all these stereoisomers, optical isomers and mixtures thereof.

The lower alkanol ester of the difluoroprostacyclin represented by the general formula (1) is the difluoroprostacyclin represented by the general formula (1).
It is an ester formed by the reaction of the carboxyl group at the position with the lower alkanol. The lower alkanol is an alkanol having 4 or less carbon atoms, and particularly preferably an alkanol having 1 to 2 carbon atoms. Specific lower alkanols include, for example, methanol, ethanol, n-propanol,
i-propanol, n-butanol, i-butanol,
t-butanol and the like. This lower alkanol ester of difluoroprostacyclin is useful as a synthetic intermediate for the corresponding difluoroprostacyclin, and is also useful as a prodrug showing physiological activity as the corresponding difluoroprostacyclin in vivo. it is conceivable that.

The pharmaceutically acceptable salt of the difluoroprostacyclin represented by the general formula (1) is a salt of this carboxyl group moiety and a basic substance, in which the hydrogen atom of the carboxyl group is replaced with a cation. It is a compound. Examples of this cation include NH ₄ ⁺ , tetramethylammonium, monomethylammonium, dimethylammonium, trimethylammonium, benzylammonium, phenethylammonium, morpholium cation,
Ammonium cations such as monoethanol ammonium, tris cation, piperidinium cation, Na
Alkali metal cations such as ⁺ and K ⁺ , 1 / 2Ca ²⁺ ,
There are cations of metals other than alkali metals, such as 1 / 2Mg ²⁺ , 1 / 2Zn ²⁺ , and 1 / 3Al ³⁺ . Preferred cations are sodium and potassium ions.

The 7,7-difluoro-13,14-dehydroprostacyclin described in JP-A-56-501319 is a ethynylene group and R is an n-pentyl group in the general formula (1). It is a compound (however, the hydroxyl group at the 15-position is downward). The present inventor synthesized this compound by the method described below and measured its chemical stability and its physiological activity. As a result, this compound had almost the same chemical stability as the other compounds of the present invention (very high stability as compared with natural prostacyclin).
However, the physiological activity was insufficient, and it was extremely low as compared with natural prostacyclin.

On the other hand, the other compounds of the present invention have extremely high chemical stability as compared with natural prostacyclin. Regarding the physiological activity, the other compounds of the present invention have higher physiological activity than natural prostacyclin, those having substantially the same physiological activity, and those not equal to natural prostacyclin (however, Superior to the compounds described in the publication). Among them, when R is the above-mentioned preferred branched chain hydrocarbon group, it has substantially the same to high physiological activity as that of natural prostacyclin. Further, the aralkyl group having a substituent has the second highest activity. Examples of the compound of the present invention include IC immediately after preparation in the test described below in Activity Test Example 1.
The value of _{50 is} the value of IC ₅₀ immediately after the preparation of PGI ₂ Na (2.
A compound having a value of 30 times or less, particularly 10 times or less, of 1) is preferable. In addition, more preferably, a compound having an IC ₅₀ value 24 hours after the preparation, which is 30 times or less, and particularly 10 times or less the IC ₅₀ value (2.1) immediately after the preparation of PGI ₂ Na is preferable.

Another feature of the compound of the present invention is that it has high physiological activity even when the hydroxyl group at the 15-position is oriented upward (R configuration) with respect to the paper surface as described above.
In the case of prostaglandins and prostacyclins, it has been conventionally considered that the hydroxyl group at the 15-position needs to face downward (S configuration) with respect to the paper surface in order to have high physiological activity. In fact, the conventional compound in which the hydroxyl group at the 15-position is upward (R configuration) with respect to the paper surface has substantially no physiological activity. On the other hand, in the present invention, 1
Even if the compound in which the 5th-position hydroxyl group is oriented upward (R configuration) with respect to the paper surface, the 15th-position hydroxyl group is oriented downward (S).
It has a physiological activity equivalent to or close to that of the compound.

The compounds of the present invention are, for example, Japanese Patent Application Nos. 6-20450 and 6-46853 of the present inventors.
Can be produced by the method described in No. For example, Core
After introducing the ω chain using y lactone as a starting material,
It is converted to difluoro Corey lactone with ω chain by fluorination. After adding the α-chain unit, dehydration, conversion reaction to carboxylic acids by deprotection or oxidation,
If desired, the difluoroprostacyclin can be synthesized by subjecting it to deprotection of the hydroxyl group, hydrolysis of the ester, or salt formation reaction of the carboxylic acid. Alternatively, Corey lactone is used as a starting material, and difluoro C is obtained by fluorination.
Convert to orey lactone. After adding the α-chain unit, dehydration is performed, and conversion reaction to carboxylic acids by deprotection or oxidation is performed. After deprotection of the hydroxyl group at the 13-position, the ω chain is introduced, and if desired, deprotection of the hydroxyl group, hydrolysis of the ester, or salt formation reaction of the carboxylic acid can be performed to synthesize difluoroprostacyclin.

The general scheme for synthesizing the compounds of the present invention is shown below. R ^{1 to} R ³ represent a triorganosilyl group, a tetrahydropyranyl group, and other hydroxyl group-protecting groups. R ⁴ represents a group that can be converted into a carboxyl group such as an alkyl group. The reaction from the compound in the top row to the compound in the second row is fluorination, the reaction from the compound in the second row to the compound in the third row is addition of α chain unit, and the reaction from the compound in the third row to the fourth step is To the compound (the compound of the present invention) represents a reaction such as deprotection. The reaction from the compound on the left to the compound on the right represents the introduction of the ω chain.

[0029]

[Chemical 3]

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

[0031]

【Example】

[Reference Example 1] 1- (4-iodobutyl) -4-methyl-2,6,7-
Synthesis of trioxabicyclo [2.2.2] octane.

E. J. Corey et al., Tetrahed
ron Letters, 24, 5571 (1983)
It was synthesized as follows in the same manner as described in 1. Three
-Methyl-3-hydroxymethyl oxetane 4.21 g
5 ml of pyridine in methylene chloride (20 ml) solution of
-Add 12.2 g of iodopentanoic acid chloride at 0 ° C and add 2
Stir for hours. It was poured into aqueous sodium hydrogen carbonate, extracted with methylene chloride, and then purified by silica gel column chromatography to obtain 13.0 g of the corresponding ester. This ester 6.2
To a solution of 4 g of anhydrous methylene chloride (20 ml) at -15 ° C.
Then, boron trifluoride etherate (0.62 ml) was added, and the mixture was stirred at -15 ° C for 4 hours, 0 ° C for 2 hours, and room temperature for 1 hour. After adding 2.79 ml of triethylamine at 0 ° C., the reaction solution was concentrated and purified by silica gel column chromatography to obtain 5.42 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.80 (s, 3H), 1.5-
1.9 (m, 6H), 3.17 (t, J = 7.2Hz, 2H), 3.89 (s, 6H).

Reference Example 2 (1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-
Synthesis of (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one.

Hexamethyldisilazane (6.84 ml)
Tetrahydrofuran (hereinafter referred to as THF) (90 m
l) n-butyllithium (1.56M
Hexane solution) (19.1 ml) and then stirred for 30 minutes to prepare a lithium hexamethyldisilazide solution.
In this solution, (1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6- (t
-Butyldimethylsiloxy) methyl-bicyclo [3.
3.0] Octane-3-one 10 g of THF (20 m
l) The solution was added dropwise at -78 ° C and stirred for 60 minutes. Next, a solution of 9.37 g of N-fluorobenzenesulfonimide in THF (40 ml) was added at -78 ° C. -78 ° C
After stirring for 60 minutes, the temperature was raised, the mixture was stirred at room temperature for 30 minutes, poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Silica gel column chromatography (ethyl acetate: hexane =
Purification by 1: 8-1: 4) gave 9.46 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 6H), 0.88
(m, 9H), 1.4-1.8 (m, 6H), 2.0-3.1 (m, 4H), 3.4-5.3 (m, 8H)
. ¹⁹ F-NMR (CDCl ₃ , ppm): -179 (m).

Reference Example 3 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
Synthesis of 6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one.

136 mg (1 mmol) of anhydrous zinc chloride was synthesized in Reference Example 2 (1S, 5R, 6R, 7R) -2-
Oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one 194
After adding a solution of mg of THF (3 ml) at room temperature and cooling to −78 ° C., lithium diisopropylamide (1M T was added).
1 ml of HF solution) was added and stirred for 20 minutes. To this solution, 236 mg of N-fluorobenzenesulfonimide
(0.75 mmol) was added at -78 ° C, and the mixture was stirred for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain 126 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.06 (m, 6H), 0.89
(m, 9H), 1.2-2.3 (m, 8H), 2.6-2.7 (m, 1H), 3.09 (m, 1H), 3.4-
3.9 (m, 4H), 4.23 (m, 1H), 4.64 (m, 1H), 5.12 (m, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): -94 (m), -115 (m). Mass spectrum: 406 (M ⁺ ).

Reference Example 4 (1S, 5R, 6R, 7R) -2-Oxa-3- {4-
(4-methyl-2,6,7-trioxabicyclo [2.
2.2] Octanyl) butylidene} -4,4-difluoro-6- (t-butyldimethylsiloxy) methyl-7-
(2-Tetrahydropyranyloxy) bicyclo [3.
3.0] Synthesis of octane.

1- (4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane synthesized in Reference Example 1 195 mg of anhydrous ether (5
ml) solution was cooled to −78 ° C., 0.87 ml of t-butyllithium (1.48M pentane solution) was added,
The mixture was stirred at -78 ° C for 2 hours. In addition, (1S, 5R, 6R, 7R) -2-oxa-4,4-synthesized in Reference Example 3 was added.
Difluoro-7- (2-tetrahydropyranyloxy)
-6- (t-Butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one 209 mg of an ether solution (2 ml) was added at -78 ° C, and then -78 ° C.
The mixture was stirred for 1 hour at −60 ° C. for 1 hour. It was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and then concentrated under reduced pressure.

Methylene chloride (2 ml) was added to the residue, triethylamine (0.53 ml) and methanesulfonyl chloride (0.14 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hr. It was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) to obtain 263 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 6H), 0.8-
2.9 (m, 28H), 3.4-4.7 (m, 14H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 (m), -115 (m).

[Reference Example 5] 5- (1S, 5R, 6R, 7R) -2-oxa-4,4
Synthesis of methyl-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate.

Synthesized in Reference Example 4 (1S, 5R, 6R,
7R) -2-oxa-3- {4- (4-methyl-2,
6,7-Trioxabicyclo [2.2.2] octanyl) butylidene} -4,4-difluoro-6- (t-butyldimethylsiloxy) methyl-7- (2-tetrahydropyranyloxy) bicyclo [3. 3.0] Octane 2
To a solution of 63 mg of dimethoxyethane (5 ml), 0.5 ml of 10% sodium hydrogensulfate aqueous solution was added at 0 ° C.
Stir for minutes. The mixture was poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the extract was concentrated under reduced pressure.
136 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. It was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate-hexane (1: 1), and the extract was concentrated under reduced pressure and subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 30-).
1:10) to obtain 191 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 6H), 0.8-
2.9 (m, 25H), 3.67 (s, 3H), 3.4-4.7 (m, 8H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 (m), -115 (m).

Reference Example 6 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0]
Synthesis of octane-3-ylidene] methyl pentanoate.

5- (1S, 5R, 6 synthesized in Reference Example 5
R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0]
Octane-3-ylidene] methyl pentanoate 340 mg
780 μl of tetrabutylammonium fluoride (1M THF solution) was added to a THF (10 ml) solution of 1 at 0 ° C. After stirring at room temperature for 2 hours, the solvent was evaporated and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to obtain 150 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3-2.9 (m, 16H),
3.67 (s, 3H), 3.4-4.7 (m, 8H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 (m), -115 (m).

[Example 1] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate 150 mg benzene (3 ml)
Pyridine 29μl, dimethyl sulfoxide 30μ in the solution
1, trifluoroacetic acid 4 μl and dicyclohexylcarbodiimide 217 mg were added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered, and the filtrate was washed with water and concentrated to obtain the corresponding crude aldehyde product.

37 mg of sodium hydride was added to a solution of 235 mg of dimethyl (4S) -4-methyl-2-oxooctanylphosphonate in dimethoxyethane (5 ml) to obtain 1
Stir for 0 minutes. To this solution was added a solution of the crude aldehyde above in dimethoxyethane (3 ml) at 0 ° C., the mixture was stirred at room temperature for 30 minutes, poured into brine, and extracted with ethyl acetate. After concentration by drying, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4-1: 1) to obtain 120 mg of the corresponding enone. This methanol (5m
l) To the solution, 102 mg of cerium chloride heptahydrate and 15 mg of sodium borohydride were added at -40 ° C to 1 at -40 ° C.
The mixture was stirred for 0 minutes and 0 ° C. for 30 minutes, poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate.

After concentration, the residue was dissolved in methanol (5 ml), 5 mg of p-toluenesulfonic acid monohydrate was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After the methanol was distilled off, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added for extraction. The extract was dried, concentrated, and purified by silica gel column chromatography (methylene chloride: acetone = 1: 2) to give 39 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.7 (m, 25H),
3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.5-5.7 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm):-84 (dd, J = 17Hz, 248Hz),-117 (d, J = 2
48Hz). Mass spectrum: 427 (M ⁺⁺ 1).

[Example 2] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Cyclopentyl-3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Example 1 using methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and dimethyl 2-oxo-2-cyclopentylethylphosphonate. The title compound was synthesized by a method similar to.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.1-2.7 (m, 19H),
3.67 (s, 3H), 3.8-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.4-5.7 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm):-84 (dd, J = 17Hz, 250Hz),-117 (d, J = 2
50Hz). Mass spectrum: 401 (M ⁺⁺ 1).

[Example 3] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and 3-methyl-2-oxo-5-
The title compound was synthesized in the same manner as in Example 1 using dimethyl octynylphosphonate.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.8 (m, 21H),
3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.4-5.7 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -117 (m). Mass spectrum: 427 (M ⁺⁺ 1).

[Example 4] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 4
S) -3-Hydroxy-4-methyl-E-1-nonene-
Synthesis of methyl 6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and (3S) -3-methyl-2-oxo-5-octynylphosphonic acid The title compound was synthesized in the same manner as in Example 1 using dimethyl.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.8 (m, 21H),
3.67 (s, 3H), 3.9-4.3 (m, 2H) .4.7-4.9 (m, 2H), 5.4-5.7 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm):-84 (dd, J = 17Hz, 249Hz),-117 (d, J = 2
50Hz). Mass spectrum: 427 (M ⁺⁺ 1).

Example 5 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-E-1-octenyl} bicyclo [3.
3.0] Synthesis of octane-3-ylidene] methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Same as Example 1 with methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and dimethyl 2-oxo-heptenylphosphonate. By the method of
The title compound was synthesized.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.9-2.7 (m, 21H),
3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.5-5.7 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (dd, J = 16Hz, 249Hz),-117 (d, J = 2
49Hz). Mass spectrum: 403 (M ⁺ +1).

Example 6 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of sodium pentanoate (Compound 1).

5-[(1S, 5R, synthesized in Example 1
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3S, 5S) -3-hydroxy-
5-Methyl-E-1-nonenyl} bicyclo [3.3.
0] octane-3-ylidene] methyl pentanoate 139
To 39 mg of ethanol (8 ml) solution was added 0.1N sodium hydroxide (3.39 ml), and the mixture was stirred at room temperature for 14 hours.
Concentration under reduced pressure gave 125 mg of the title compound.

¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 25H), 3.7
-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.5-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 17Hz, 250Hz),-117 (d, J = 250
Hz).

Example 7 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Cyclopentyl-3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of sodium pentanoate (Compound 2).

5-[(1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3S) -3-cyclopentyl-3
-Hydroxy-E-1-propenyl} bicyclo [3.
The title compound was synthesized in the same manner as in Example 6 by using 3.0] octane-3-ylidene] methyl pentanoate.

¹ H-NMR (D ₂ O) δ (ppm): 1.0-2.9 (m, 19H),
3.7-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.4-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm): -84 (dd, J = 17Hz, 250Hz),-117 (d, J = 25
0Hz).

Example 8 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of sodium pentanoate (compound 3).

5-[(1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.
The title compound was synthesized in the same manner as in Example 6 by using 3.0] octane-3-ylidene] methyl pentanoate.

¹ H-NMR (D ₂ O) δ (ppm): 0.7-2.8 (m, 21H), 3.7
-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.3-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm): -84 (m), -117 (m).

Example 9 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 4
S) -3-Hydroxy-4-methyl-E-1-nonene-
Synthesis of sodium 6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate (Compound 4).

5-[(1S, 5R, synthesized in Example 4
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3S, 4S) -3-hydroxy-
The title compound was synthesized in the same manner as in Example 6 by using methyl 4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

¹ H-NMR (D ₂ O) δ (ppm): 0.7-2.8 (m, 21H), 3.7
-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.3-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 17Hz, 250Hz),-117 (d, J = 250
Hz).

[Example 10] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-E-1-octenyl} bicyclo [3.
3.0] Synthesis of octane-3-ylidene] sodium pentanoate (Compound 5).

5-[(1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3S) -3-hydroxy-E-1
-Octenyl} bicyclo [3.3.0] octane-3-
The title compound was synthesized in the same manner as in Example 6 using methyl ylidene] pentanoate.

¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 21H), 3.7
-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.4-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 17Hz, 250Hz),-117 (d, J = 250
Hz).

[Example 11] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4- (3-methylphenyl) -E-1-
Synthesis of methyl butenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Using methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and dimethyl 2-oxo-3- (3-methylphenyl) propylphosphonate. In the same manner as in Example 1, the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4-2.9 (m, 12H),
2.33 (m, 3H), 3.67 (s, 3H), 3.89 (m, 1H), 4.32 (m, 1H), 4.7-4.
9 (m, 2H), 5.5-5.8 (m, 2H), 7.0-7.2 (m, 4H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (dd, J = 12Hz, 253Hz),-116 (d, J = 2
53Hz).

[Example 12] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 4R
S) -3-Hydroxy-4-methyl-E-1-octene-6-ynyl} bicyclo [3.3.0] octane-3-
Ylidene] Synthesis of methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and (3RS) -3-methyl-2-
Using dimethyl oxo-5-heptinylphosphonate,
Synthesis was carried out in the same manner as in Example 1 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.9-2.8 (m, 19H),
3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.5-4.7 (m, 2H), 5.5-5.7 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -117 (m). Mass spectrum: 413 (M ⁺ +1).

[Example 13] 5-[(1S, 5R, 6R, 7R) -2-oxa-4
4-difluoro-7-hydroxy-6-{(3R, 4R
S) -3-Hydroxy-4-methyl-E-1-nonene-
Synthesis of methyl 6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and (3RS) -3-methyl-2-
Using dimethyl oxo-5-octynylphosphonate,
It was synthesized in the same manner as in Example 1 and was isolated as a less polar isomer than the title compound of Example 3 using silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain the title compound. .

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.9-2.8 (m, 21H),
3.68 (s, 3H), 3.9-4.3 (m, 2H), 4.8-4.9 (m, 2H), 5.6-5.8 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 to -84 (m), -116 to -117 (m).

Example 14 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3R, 4
S) -3-Hydroxy-4-methyl-E-1-nonene-
Synthesis of methyl 6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and (3S) -3-methyl-2-oxo-5-octynylphosphonic acid Synthesized in the same manner as in Example 1 using dimethyl, and isolated as a less polar isomer than the title compound of Example 4 using silica gel column chromatography (hexane: ethyl acetate = 1: 2). The title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.0-2.7 (m, 21H),
3.68 (s, 3H), 3.9-4.3 (m, 2H), 4.8-4.9 (m, 2H), 5.6 (m, 2H)
. ¹⁹ F-NMR (CDCl ₃ , ppm):-84 (dd, J = 17Hz, 254Hz),-116 (d, J = 2
54Hz).

Example 15 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4- (3-methylphenyl) -E-1-
Synthesis of pentenyl} bicyclo [3.3.0] octane-3-ylidene] methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Using methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and dimethyl 2-oxo-3- (3-methylphenyl) butylphosphonate. In the same manner as in Example 1, the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3-2.9 (m, 14H),
2.33 (m, 3H), 3.67 (s, 3H), 3.86 (m, 1H), 4.30 (m, 1H), 4.7-4.
9 (m, 2H), 5.5-5.8 (m, 2H), 7.0-7.3 (m, 4H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -116 (m).

Example 16 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4- (3-chlorophenyl) -E-1-
Synthesis of pentenyl} bicyclo [3.3.0] octane-3-ylidene] methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Using methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and dimethyl 2-oxo-3- (3-methylphenyl) butylphosphonate. In the same manner as in Example 1, the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3-2.9 (m, 14H),
3.67 (s, 3H), 3.93 (m, 1H), 4.45 (m, 1H), 4.7-5.1 (m, 2H), 5.5
-5.9 (m, 2H), 7.0-7.5 (m, 4H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -117 (m).

Example 17 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3R, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 6
6R, 7R) -2-Oxa-4,4-difluoro-7-
Using methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate and dimethyl (4S) -4-methyl-2-oxooctanylphosphonate. Example 1
Was synthesized in the same manner as in 1. and was isolated by silica gel column chromatography (hexane: ethyl acetate = 1: 2) as a less polar isomer than the title compound of Example 1,
30 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.7 (m, 25H),
3.68 (s, 3H), 3.9-4.0 (m, 1H), 4.1-4.2 (m, 1H), 4.8-4.9 (m, 2
H), 5.6-5.7 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , ppm):-84 (dd, J = 17Hz, 254Hz),-116 (d, J = 2
54Hz).

Example 18 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4- (3-methylphenyl) -E-1-
Synthesis of sodium butenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate (Compound 6).

5-[(1S, 5 synthesized in Example 11
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3-hydroxy-4
The title compound was synthesized in the same manner as in Example 6 by using methyl-(3-methylphenyl) -E-1-butenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

¹ H-NMR (D ₂ O) δ (ppm): 1.4-2.9 (m, 15H), 3.8
-4.4 (m, 2H), 4.7-4.9 (m, 2H), 5.5-5.8 (m, 2H), 7.0-7.2 (m, 4
H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 12Hz, 253Hz),-116 (d, J = 253)
Hz).

[Example 19] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 4R
S) -3-Hydroxy-4-methyl-E-1-octene-6-ynyl} bicyclo [3.3.0] octane-3-
Ylidene] Synthesis of sodium pentanoate (Compound 7).

5-[(1S, 5 synthesized in Example 12
R, 6R, 7R) -2-Oxa-4,4-difluoro-
Using methyl 7-hydroxy-6-{(3S, 4RS) -3-hydroxy-4-methyl-E-1-octene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate And synthesized in the same manner as in Example 6,
The title compound was obtained.

¹ H-NMR (D ₂ O) δ (ppm): 0.7-2.8 (m, 19H), 3.7
-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.3-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm): -84 (m), -117 (m).

Example 20 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3R, 4R
S) -3-Hydroxy-4-methyl-E-1-nonene-
Synthesis of sodium 6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate (Compound 8).

5-[(1S, 5 synthesized in Example 13
R, 6R, 7R) -2-Oxa-4,4-difluoro-
Methyl 7-hydroxy-6-{(3R, 4RS) -3-hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate was used. Then, the title compound was synthesized in the same manner as in Example 6.

¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 22H), 3.9
-4.1 (m, 2H), 4.5-5.0 (m, 2H), 5.5-5.6 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm): -83 to -84 (m), -116 to -117 (m).

[Example 21] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3R, 4
S) -3-Hydroxy-4-methyl-E-1-nonene-
Synthesis of sodium 6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate (Compound 9).

5-[(1S, 5 synthesized in Example 14
R, 6R, 7R) -2-Oxa-4,4-difluoro-
Methyl 7-hydroxy-6-{(3R, 4S) -3-hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate was used. Then, the title compound was synthesized in the same manner as in Example 6.

¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 22H), 3.9
-4.1 (m, 2H), 4.5-5.0 (m, 2H), 5.5-5.6 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 17Hz, 248Hz),-117 (d, 248H
z).

Example 22 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4- (3-methylphenyl) -E-1-
Synthesis of sodium pentenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate (Compound 10).

5-[(1S, 5 synthesized in Example 15
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3-hydroxy-4
Synthesized in the same manner as in Example 6 using methyl-(3-methylphenyl) -E-1-pentenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate to obtain the title compound. It was

¹ H-NMR (D ₂ O) δ (ppm): 1.3-2.9 (m, 17H), 3.8
-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.5-5.8 (m, 2H), 7.0-7.3 (m, 4
H). ¹⁹ F-NMR (D ₂ O, ppm): -84 (m), -116 (m).

Example 23 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4- (3-chlorophenyl) -E-1-
Synthesis of sodium pentenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate (Compound 11).

5-[(1S, 5 synthesized in Example 16
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3-hydroxy-4
Methyl-(3-chlorophenyl) -E-1-pentenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate was synthesized in the same manner as in Example 6 to obtain the title compound. .

¹ H-NMR (D ₂ O) δ (ppm): 1.3-2.9 (m, 14H), 3.7
-4.5 (m, 2H), 4.7-5.1 (m, 2H), 5.5-5.9 (m, 2H), 7.0-7.5 (m, 4
H). ¹⁹ F-NMR (D ₂ O, ppm): -84 (m), -117 (m).

[Example 24] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3R, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of sodium pentanoate (Compound 12).

5-[(1S, 5 synthesized in Example 17
R, 6R, 7R) -2-Oxa4,4-difluoro-
7-Hydroxy-6-{(3R, 5S) -3-hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.
The title compound was synthesized in the same manner as in Example 6 by using 3.0] octane-3-ylidene] methyl pentanoate. ¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.8 (m, 25H), 3.9-4.2
(m, 2H), 4.5-5.0 (m, 2H), 5.5-5.6 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm): -84 (dd, J = 17Hz, 248Hz),-117 (d, J = 248)
Hz).

[Example 25] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-1-octynyl} bicyclo [3.3.
Synthesis of methyl [0] octane-3-ylidene] pentanoate.

<Step 1> (1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S)
-3-t-butyldimethylsiloxy-1-octynyl}
-Synthesis of bicyclo [3.3.0] octane-3-one.

Fried et al.'S method (Tetrahedr
on Letters, 3899 (1973)) synthesized (1S, 5R, 6R, 7R) -2-oxa-7.
-Hydroxy-6-{(3S) -3-hydroxy-1-
Octynyl} -bicyclo [3.3.0] octane-3-
The one was t-butyldimethylsilylated with imidazole, t-butyldimethylsilyl chloride in dimethylformamide to give (1S, 5R, 6R, 7R) -2-oxa-7-t-butyldimethylsiloxy-6- {(3S)
-3-t-butyldimethylsiloxy-1-octynyl}
-Bicyclo [3.3.0] octane-3-one was synthesized.

To a solution of hexamethyldisilazane (615 μl) in THF (8 ml) was added 1.66 ml of n-butyllithium (1.56 M, hexane solution) at −78 ° C., and the mixture was stirred for 30 minutes and lithium hexamethyldisilazane was added. A zido solution was prepared. In this solution, (1S, 5R, 6R, 7R)
-2-oxa-7-t-butyldimethylsiloxy-6-
A solution of {(3S) -3-t-butyldimethylsiloxy-1-octynyl} -bicyclo [3.3.0] octane-3-one 1.21 g in THF (10 ml) was added dropwise at -78 ° C for 30 minutes. It was stirred. Next, 930 mg of N-fluorobenzenesulfonimide was added at -78 ° C. -78
After stirring at 15 ° C. for 15 minutes, 0 ° C. for 30 minutes and room temperature for 30 minutes, the mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) gave the title compound (643 mg).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.88
(m, 21H), 1.0-5.4 (m, 16H). _{^{19 F-NMR (CDCl 3,}} ppm): - 178 (dd, 30.1Hz, 52.9Hz).

<Step 2> (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-
Synthesis of {(3S) -3-t-butyldimethylsiloxy-1-octynyl} -bicyclo [3.3.0] octane-3-one.

0.74 ml of n-butyllithium (1.66M, hexane solution) was added to a solution of diisopropylamine (0.18 ml) in THF (2 ml) at -78 ° C, and the mixture was stirred for 30 minutes to obtain a lithium diisopropylamide solution. Prepared. 0.23 g of anhydrous zinc chloride was weighed into another container and synthesized in step 1 (1S, 5R, 6R, 7R)
2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-1-octynyl} -bicyclo [3.3.0] octane-3-one 0.54 g of THF solution (3 ml) was added. This solution was cooled to −78 ° C., and the above lithium diisopropylamide solution was added dropwise at −78 ° C.
Stir for minutes. Next, 0.38 g of N-fluorobenzenesulfonimide was added at -78 ° C. 60 at -78 ° C
After stirring for 30 minutes at room temperature for 30 minutes, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) gave 0.43 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.89
(m, 21H), 1.0-5.4 (m, 15H). ¹⁹ F-NMR (CDCl ₃ , ppm):-92 (dd, J = 25Hz, 280Hz),-113 (d, J = 2
80Hz).

<Step 3> 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-t-butyldimethylsiloxy-6
-{(3S) -3-t-butyldimethylsiloxy-1-
Octynyl} -bicyclo [3.3.0] octane-3-
Ylidene] Synthesis of methyl pentanoate.

1- (4-iodobutyl) -4-methyl-
A solution of 0.29 g of 2,6,7-trioxabicyclo [2.2.2] octane in anhydrous ether (8 ml) was added at -78 ° C.
The mixture was cooled to room temperature, 1.4 ml of t-butyllithium (1.48M, pentane solution) was added, and the mixture was stirred at -78 ° C for 2 hours. This was combined in step 2 (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-t
-Butyldimethylsiloxy-6-{(3S) -3-t-
Butyldimethylsiloxy-1-octynyl} bicyclo [3.3.0] octane-3-one 0.44 g THF
The solution (3 ml) was added at -78 ° C and then 1 at -78 ° C.
The mixture was stirred for 1 hour at −60 ° C. After pouring into sodium bicarbonate water and extracting with ethyl acetate, the extract was washed with saturated saline,
It was concentrated under reduced pressure.

Methylene chloride (3 ml) was added to the residue, triethylamine (0.79 ml) and methanesulfonyl chloride (0.21 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hr. Pour into aqueous sodium hydrogen carbonate, extract with ethyl acetate, concentrate the extract under reduced pressure, and purify by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10), (1S, 5R, 6R, 7R). ) -2-Oxa-3-
{4- (4-Methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butylidene} -4,4-difluoro-7-t-butyldimethylsiloxy-6-
{(3S) -3-t-Butyldimethylsiloxy-1-octynyl} bicyclo [3.3.0] octane 0.39 m
g was obtained.

To this solution of dimethoxyethane (5 ml) was added 0.5 ml of a 10% sodium hydrogensulfate aqueous solution at 0 ° C., and the mixture was stirred for 30 minutes. The mixture was poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate, the extract was concentrated under reduced pressure, 5 ml of methanol and 0.19 g of potassium carbonate were added to the residue, and the mixture was stirred at room temperature for 2 hours. Pour into an aqueous solution of sodium hydrogen carbonate-ethyl acetate-hexane (1:
1), the extract was concentrated under reduced pressure, and subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
30 to 1:10) to obtain 0.29 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03-0.11 (m, 12
H), 0.84-0.95 (m, 18H), 1.1-2.6 (m, 21H), 3.67 (s, 3H), 3.8-
5.0 (m, 4H). ¹⁹ F-NMR (CDCl ₃ , ppm):-83 (dd, J = 17Hz, 249Hz),-115 (d, J = 2
49Hz).

<Step 4> 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-1-octynyl} bicyclo [3.3.
Synthesis of methyl [0] octane-3-ylidene] pentanoate.

5-[(1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-t-butyldimethylsiloxy-6-{(3S) -3
A solution of 284 mg of methyl t-butyldimethylsiloxy-1-octynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate in THF (5 ml) was tetrabutylammonium fluoride (1M, THF solution).
5 ml was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (acetone-methylene chloride) to give the title compound (140 m).
g was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.9-3.0 (m, 21H),
3.66 (s, 3H), 3.8-5.0 (m, 4H). ¹⁹ F-NMR (CDCl ₃ , ppm):-84 (dd, J = 17Hz, 248Hz),-116 (d, J = 2
48Hz).

[Example 26] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-1-octynyl} bicyclo [3.3.
0] Octane-3-ylidene] Synthesis of sodium pentanoate (Compound 13).

5-[(1S, 5 synthesized in Example 25
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3-hydroxy-1
-Octynyl} bicyclo [3.3.0] octane-3-
The title compound was synthesized in the same manner as in Example 6 using methyl ylidene] pentanoate.

¹ H-NMR (D ₂ O) δ (ppm): 0.9-3.0 (m, 21H), 3.7
-5.0 (m, 4H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 17Hz, 250Hz),-116 (d, J = 250
Hz).

Activity Test Example 1 In Vitro Platelet Aggregation Inhibitory Action

The in vitro inhibitory effect on platelet aggregation of the test compound was measured using human platelets. Collect 9 volumes of blood from a healthy person in a plastic container containing 1 volume of 3.8% sodium citrate solution and gently mix by inversion to 100
After centrifugation at 0 rpm for 10 minutes at room temperature, the supernatant was set aside as platelet rich plasma (PRP). 3 more lower layers
After centrifugation at 000 rpm for 15 minutes at room temperature, the supernatant was set aside as platelet poor plasma (PPP). PRP was diluted with PPP so that the platelet count was about 30 × 10 ⁴ / μl. After calibrating the aggregometer, 200 μl of the prepared PRP was heated at 37 ° C. for 1 minute, and 25 μl of a solution prepared by diluting the test compound with physiological saline was added to add 37
Warmed at 1 ° C for 1 minute. Adenosine-5'-diphosphate 1.
25 μl of a 5 sodium (ADP, Sigma) solution was added so that the final concentration was 4 μM, and the change in the transmittance was recorded by an aggregometer. The solution was measured immediately after the test compound was dissolved in physiological saline and after standing for 24 hours at 25 ° C.
After dissolving each of the test compound solutions in physiological saline,
It was diluted with physiological saline before use. As a control, only physiological saline was used. IC ₅₀ (50% inhibitory concentration) is shown in Table 1.
It was shown to.

Aggregation inhibition rate (%) = (1−T / T ₀ ) × 100 T ₀ : Permeability of control T: Permeability of test compound

As shown in Table 1, it was confirmed that the compound of the present invention exhibited an excellent inhibitory effect on platelet aggregation, and the inhibitory effect on platelet aggregation did not decrease even after 24 hours, and was a significantly stabilized compound. It was In addition, in particular, the compounds 1, 6 and 9 of the present invention have an activity close to that of natural prostacyclin, and the compounds 10 and 11 have an activity almost equal to that of natural prostacyclin.
7 has a higher activity than native prostacyclin. Further, in compounds 8, 9, and 12, the hydroxyl group at the 15-position is R
It is a configuration and it is specific that such compounds have activity. In addition, compound 13 has lower activity than the other compounds 1-12.

Compound 13 is shown in Table 56-5013.
7,7-Difluoro-1 described in Japanese Patent No. 19
3,14-dehydroprostacyclin, which was newly synthesized by the synthetic method developed by the present inventors as described in Examples 25 to 26 above. Also, PGI ₂ Na
Shows the sodium salt of natural prostacyclin.

[0147]

[Table 1]

[Activity Test Example 2] In vivo antithrombotic action.

The antithrombotic activity of the test compounds was compared by their effect on inhibiting ADP-induced thrombus formation in hamster cheek pouch microvessels. A method for assessing antithrombotic agents using the hamster cheek pouch is described by Duling et al. (Microvas
circular Research, 1,158 (196
8)), Sim et al. (Arzneim-Forsh./D).
rug Res. , 29, 508 (1979)).

The cheek pouch of a male golden hamster weighing 95-115 g was turned inside out and spread on the Perspex device. The test compound was dissolved in physiological saline and administered through the tail vein. A 1-2 μm diameter micropipette filled with 10 ⁻² M ADP was contacted with a 16-40 μm diameter venule. The rate of thrombus growth is determined by measuring the time required for thrombus formation of 30%, 50%, 90% according to the first-order reaction kinetics, with 100% of the thrombus formation leading to complete blood vessel closure and blood flow arrest. Were determined. The rate of thrombus growth was measured at 5-minute intervals for 1 hour or longer.

The inhibition rate (%) was calculated by the following formula in comparison with the result of control (administration of physiological saline alone). Inhibition rate (%) = (1−S / S ₀ ) × 100 S ₀ : control thrombosis increasing rate S: test compound thrombosis increasing rate

The maximum inhibition rate (%) of the thrombus increasing rate is shown in Table 2. The compound of the present invention showed an excellent antithrombotic effect at a significantly lower concentration as compared with the comparative compound B (veraprost sodium).

[0153]

[Table 2]

[Stability Test Example 1] Stability Test in Aqueous Solution

The test compound was dissolved in ethanol to give 1 mg.
After adjusting the concentration to 1 / ml, dilute with physiological saline to obtain 10 μg.
/ Ml solution was prepared. It was stored at 25 ° C. and the residual rate of the test compound was measured over time. The residual ratio is high performance liquid chromatography (Shimadzu LC9A, SPC-6AU; Mil
ipore805-DS), and quantified by the internal standard (methyl benzoate) method. Column is YMC AM3
12 (ODS) was used, and the eluent was acetonitrile and 1%
A mixed solvent of triethylamine-phosphate buffer (pH 6.3) was used.

Table 3 shows the residual rate and the half-life. As shown in Table 3, it was confirmed that the compound of the present invention exhibits excellent stability in an aqueous solution.

[0157]

[Table 3]

[0158]

INDUSTRIAL APPLICABILITY The difluoroprostacyclins (or salts thereof) of the present invention are compounds having extremely excellent chemical stability as compared with conventional prostacyclins. In addition, the compound of the present invention has a high physiological activity, and in particular, R of compound 1, 3, 4, 7, 9, etc. of the present invention is a straight chain hydrocarbon group having a methyl group in the side chain. The compound has an activity close to or higher than that of natural prostacyclin. In addition, compounds having an aralkyl group such as compounds 6, 10, 11 also have high activity. Further, compounds 8, 9 and 12 in which the hydroxyl group at the 15-position has the R configuration
Has activity close to the corresponding compound in the S configuration. Due to this high physiological activity and extremely high stability, the compound of the present invention has excellent properties as a medicine,
In particular, it is useful as a preventive or therapeutic agent for cardiovascular disease.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshitomi Morisawa 1150 Hazawa-machi, Kanagawa-ku, Yokohama, Kanagawa Prefecture Asahi Glass Co., Ltd. Central Research Laboratory

Claims (7)

[Claims] 1. A difluoroprostacyclin represented by the following general formula (1), a lower alkanol ester thereof,
Or a compound which is a pharmaceutically acceptable salt thereof. [Chemical 1] (In the general formula (1), A: an ethylene group, a vinylene group, or an ethynylene group; R: a linear or branched alkyl group having 4 to 10 carbon atoms, an alkenyl group, an alkynyl group, or a substituent. Represents an optionally substituted aralkyl group or a 3- to 8-membered cycloalkyl group which may have a substituent.) 2. The compound according to claim 1, wherein A is a vinylene group. 3. R is an alkyl group, an alkenyl group or an alkynyl group, which has at least one methyl group at the 1-position or 2-position and has 5 to 6 carbon atoms in the straight chain portion. A compound of Item 1 or 2. 4. R is a 2-methylpentyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 1,1-dimethylpentyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group. Group, or 1,1-dimethyl-3-
The compound of claim 1, 2 or 3 which is a hexynyl group. 5. The compound according to claim 1, 2 or 3, wherein R is a 2-methylhexyl group or a 1-methyl-3-hexynyl group. 6. A benzyl group or a phenethyl group, wherein R may have a methyl group at the 1-position and has a phenyl group having an alkyl group having 1 to 2 carbon atoms or a halogen atom. Compound. 7. A circulatory vessel containing as an active ingredient a compound which is a difluoroprostacyclin selected from 1, 2, 3, 4, 5 or 6, a lower alkanol ester thereof, or a pharmaceutically acceptable salt thereof. A preventive or therapeutic agent for systemic diseases.