JPH0952890A - Interphenylene-type difluoroprostacyclins - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent physiological activity and stability of platelet aggregation suppressing activity and vasodilation activity, etc., and useful as a preventive or a treating agent, etc., for circulatory diseases, comprising a specific interphenylene-type difluoro prostacyclin. SOLUTION: This new interphenylene-type difluoroprostacyclin (a lower alkanol ester or its salt) is expressed by the formula[ A is ethylene, vinylene or ethynylene; R is a 4-10C alkyl, an alkenyl, an alkynyl, a (substituted) aralkyl or a 3-8 membered cycloalkyl ]. The compound has an excellent physiological activity and stability of platelet aggregation suppressing activity, vasadilation activity and cell protecting action, etc., and is useful as a preventive and a treating agent, etc., of circulatory diseases. The compound is obtained by transferring Corey lactone to difluoro Corey lactone by fluoridizing Corey lactone and adding an α-chain unit thereto, then dehydrating, thus transferring to a carboxylic acid by deprotecting or oxidizing, and further introducing an ω-chain onto its 13th position.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to novel difluoroprostacyclins. More specifically, it relates to interphenylene type 7,7-difluoroprostacyclins having two fluorine atoms at the 7-position of prostacyclin and a benzene ring in the α chain.

[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 studied diligently at home and abroad.

Prostacyclins having a fluorine atom at the 7-position have also been reported (Tokusho 56-501319,
JP-A-57-165382, JP-A-57-17198
8, JP-A-61-91136, JP-A-62-482, JP-A-5-9184, JP-B-3-14030, and JP-B-3-
47272, Japanese Patent Publication No. 1-24147). In the following general description, the position numbers of carbon atoms in prostacyclins and their intermediates 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 the prostacyclins having two or more fluorine atoms, see Japanese Patent Publication No. 56-501319, 2
Fluorinated prostacyclins at the 4th, 7th and 10th positions are described, but the physical property data is 1
Only the specific optical rotation is described for 0,10-difluoro-13,14-dehydroprostacyclin, and no physiological activity data is described for any compound.

Of these prostacyclins having two or more fluorine atoms, the only compound of which physiological activity has been revealed is 10,10-difluoro-13,14-dehydroprostacyclin. The above special table Sho 56-50
1319, the inventor of the invention. Fried et al.
Regarding vasodilatory action, platelet aggregation inhibitory action, chemical stability, etc., J. Med. Chem. , 23, 234 (1
980), Proc. Natl. Acad. Sci. U
SA, 77, 6846 (1980) and Thromb. R
es. 23, 387 (1981).

[0006]

On the other hand, in the case of prostacyclins having two fluorine atoms at the 7-position, the synthesis example of 7,7-difluoro-13,14-dehydroprostacyclin is described in the above-mentioned JP-A-56-501319. Although the synthetic method which is considered to be very difficult in practice is used, the physical property data and the physiological activity data are not described, and as far as the inventors know, there is no subsequent report. In addition, in difluoroprostacyclins, one of the ω chains
There are no synthetic examples other than the dehydro type at the 3 and 14 positions, and derivatives other than the n-pentyl group at the 16 to 20 positions, such as branched alkyl groups, alkenyl groups, alkynyl groups,
No synthetic examples of derivatives of aralkyl groups, cycloalkyl groups and the like are known. Examples of prostacyclins having a benzene ring in the α chain include Arzneim-For
sh / Drug Res. , 40 (II), Nr8,930
Although the compound described in (1990) is known, a synthetic example of a prostacyclin derivative having a fluorine atom at the 7-position and a benzene ring in the α chain is not known at all.

The 7,7-difluoro-13,14-dehydroprostacyclin described in the synthesis example of Japanese Patent Publication No. 56-501319 mentioned above is prepared by first using cyclopentadiene and dichloroketene as starting materials. After synthesis of 13,14-dehydroepiandrosterone prostaglandin F _2, it is prepared by cyclization. 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, a corresponding hemiacetal having two electron-withdrawing fluorine atoms as adjacent groups is treated with 5-triphenylphosphonopentanoic acid to give 7,7-difluoro-13,14-dehydroprostaglandin. Unlike the usual case, the Wittig reaction for synthesizing F ₂ remarkably lowers the reaction yield due to the strong electron-withdrawing effect of the fluorine atom, making it practically difficult to obtain the desired product. Besides,
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 type ₂ ,
This is a practically difficult process because of its extremely low reactivity, long reaction time, and low reaction yield.

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. .

[0010]

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 the novel interphenylene type 7,7-difluoroprostacyclin.

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

[0012]

Embedded image

(However, in the general formula (1), A: ethylene group, vinylene group or ethynylene group, R: linear or branched alkyl group, alkenyl group or alkynyl group having 4 to 10 carbon atoms, substituted Represents an aralkyl group which may have a group, or a 3- to 8-membered cycloalkyl group.)

Among the interphenylene type difluoroprostacyclins represented by the above general formula (1), the following compounds are preferable in view of physiological activity and chemical stability.

In the above general formula, A is preferably a vinylene group or an ethynylene group, and particularly preferably a vinylene group.

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 preferably has 5 to 8 carbon atoms.

When R is a chain hydrocarbon group, the number of carbon atoms in the straight chain portion excluding the branch is preferably 4-10, and more preferably 5-6. Further, the straight-chain portion may have one 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 the 1st to 3rd positions of the chain hydrocarbon group, and particularly preferably the 1st to 2nd positions. 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 other than a 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.
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.

Further, 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-fluoro Cyclohexyl 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 interphenylene type difluoroprostacyclin represented by the general formula (1) is a lower alkanol and the 1-position carboxyl group of the interphenylene type difluoroprostacyclin represented by the general formula (1). Is an ester formed by the reaction. The lower alkanol is an alkanol having 4 or less carbon atoms, and particularly preferably an alkanol having 1 to 2 carbon atoms. Specific examples of the lower alkanol include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol and t-butanol.

The lower alkanol ester of the interphenylene type difluoroprostacyclin is useful as a synthetic intermediate for the corresponding interphenylene type difluoroprostacyclin, and becomes the corresponding interphenylene type difluoroprostacyclin in the living body. It is also considered to be useful as a prodrug that exhibits physiological activity.

The pharmaceutically acceptable salt of the interphenylene type difluoroprostacyclin represented by the general formula (1) is a salt of this carboxyl group moiety and a basic substance, and the hydrogen atom of the carboxyl group is a cation. Is a compound substituted with. Examples of this cation include NH
₄ ^+, tetramethylammonium, monomethyl ammonium, dimethyl ammonium, trimethyl ammonium,
Benzyl ammonium, phenethyl ammonium, morpholium cation, monoethanol ammonium, tris cation, ammonium cation such as piperidinium cation, alkali metal cation such as Na ⁺ and K ⁺ , 1 / 2Ca ²⁺ , 1 / 2Mg ²⁺ , 1/2 Zn ²⁺ , 1 /
There are cations of metals other than alkali metals such as 3Al ³⁺ . Preferred cations are sodium and potassium ions.

The compound of the present invention has extremely high chemical stability as compared with natural prostacyclin. Regarding the physiological activity, the compound of the present invention has almost the same physiological activity as that of natural prostacyclin. In vivo, it is not easily decomposed by metabolism such as β-oxidation, is stable, and is highly orally absorbable. Therefore, it is very useful as a medicine.

The compounds of the present invention are, for example, Japanese Patent Application No. 6-20450, Japanese Patent Application No. 6-46853, Japanese Patent Application No. 6-71097, Japanese Patent Application No. 6-80641 and Japanese Patent Application No. 6-
283857 and the method described in Japanese Patent Application No. 7-24400. For example, using a Corey lactone as a starting material, an ω chain is first introduced, and then fluorination is performed to convert the ω chain to a difluoro Corey lactone.
After adding the α-chain unit, dehydration, conversion reaction to carboxylic acid by deprotection or oxidation is performed, and if desired, deprotection of hydroxyl group, hydrolysis of ester, or salt formation reaction of carboxylic acid to give an interphenylene type Difluoroprostacyclins can be synthesized. Or Co
Using rey lactone as a starting material, it is converted into difluoro Corey lactone by fluorination. An α-chain unit is added to this, followed by dehydration, and then conversion reaction to carboxylic acid by deprotection or oxidation. 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 is carried out to synthesize the interphenylene type difluoroprostacyclin.

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.

[0032]

【Example】

[Reference Example 1] (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxymethyl) -bicyclo [3.3 .0] Octane-3-one synthesis.

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
-Butyldimethylsiloxymethyl) -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), 0.8
8 (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 2] (1S, 5R, 6R, 7R)
2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxymethyl) -bicyclo [3.3.0] octane-3
-On synthesis.

136 mg (1 mmol) of anhydrous zinc chloride was synthesized in Reference Example 1 (1S, 5R, 6R, 7R) -2-
Oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxymethyl) -bicyclo [3.3.0] octan-3-one 19
4 mg of THF (3 ml) solution was added at room temperature, and the temperature was -78 ° C.
After cooling to 1, 1 ml of lithium diisopropylamide (1M THF solution) was added, and the mixture was stirred for 20 minutes. 236 mg of N-fluorobenzenesulfonamide was added to this solution.
(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 3] (1S, 5R, 6R, 7R)
2-Oxa-3- (3-methoxycarbonylbenzylidene) -4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxymethyl) -bicyclo [3.3.0] ] Octane synthesis.

1.3-g of (3-methoxycarbonylbenzyl) triphenylphosphonium chloride was added to anhydrous THF.
(5 ml), 1M sodium hexamethyldisilazide THF solution (2.8 ml), and refluxed for 1 hour.
(1S, 5R, 6R, 7R) synthesized in Reference Example 2-2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxymethyl) -bicyclo [3.3.0] octane-3-one 203 mg anhydrous THF solution (2 ml ) Was added at room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. Purify by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) to give the title compound 115.
mg was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 6H), 0.8
-2.9 (m, 19H), 3.67 (s, 3H), 3.4-5.6 (m, 8H), 7.1-8.7 (m, 4
H).

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

Synthesized in Reference Example 3 (1S, 5R, 6R,
7R) -2-oxa-3- (3-methoxycarbonylbenzylidene) -4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxymethyl) -bicyclo [3.3 .0] Octane 11
To a solution of 5 mg of THF (10 ml) was added 350 μl of tetrabutylammonium fluoride (1M THF solution).
Added at ° 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 90 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3-2.9 (m, 10
H), 3.67 (s, 3H), 3.4-5.5 (m, 8H), 7.1-8.7 (m, 4H).

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

Synthesized in Reference Example 4 (1S, 5R, 6R,
7R) -2-oxa-3- (3-methoxycarbonylbenzylidene) -4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane 90 mg Benzene (3m
l) 18 μl of pyridine and 3 of dimethyl sulfoxide
1 μl, trifluoroacetic acid 2.4 μl, and dicyclohexylcarbodiimide 130 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 92 mg of the corresponding crude aldehyde.

A solution of 58 mg of dimethyl (4S) -4-methyl-2-oxooctanylphosphonate in dimethoxyethane (5 ml) was added with 16 mg of sodium hydride (60%).
Was added and stirred for 10 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 drying and concentration, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4-1: 1) to obtain 115 mg of the corresponding enone. To this methanol (5 ml) solution, 176 mg of cerium chloride heptahydrate and 18 mg of sodium borohydride were added at -40 ° C, and -40
After stirring at 0 ° C for 10 minutes and at 0 ° C for 30 minutes, the mixture was 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 the title compound (35 mg).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.7 (m, 19
H), 3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.7-5.2 (m, 2H), 5.5-5.7
(m, 2H), 7.1-8.7 (m, 4H).

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

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

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.8 (m, 15H),
3.67 (s, 3H), 3.9-4.3 (m, 2H) .4.7-5.2 (m, 2H), 5.4-5.7 (m, 2
H), 7.1-8.5 (m, 4H).

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

Synthesized in Example 1 (1S, 5R, 6R,
7R) -2-oxa-3- (3-methoxycarbonylbenzylidene) -4,4-difluoro-7-hydroxy-
6-{(3S, 5S) -3-hydroxy-5-methyl-
E-1-nonenyl} bicyclo [3.3.0] octane 3
0.65 ml of 0.1N sodium hydroxide was added to a 0 mg ethanol (3 ml) solution, and the mixture was stirred at room temperature for 14 hours. Concentration under reduced pressure gave 30 mg of the title compound.

¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 19H),
3.7-4.3 (m, 2H), 4.5-5.7 (m, 4H), 7.0-8.5 (m, 4H).

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

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

¹ H-NMR (D ₂ O) δ (ppm): 0.7-2.8 (m, 15H), 3.
7-4.3 (m, 2H), 4.5-5.7 (m, 2H), 7.0-8.8 (m, 4H).

[Example 5] In vitro inhibitory effect on platelet aggregation.

The in vitro platelet aggregation inhibitory effect 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 37
Warmed at 1 ° C for 1 minute. Add 25 μl of adenosine-5′-sodium diphosphate (ADP, Sigma) solution to a final concentration of 4
The change in transmittance was recorded with an aggregometer in addition to μM. Immediately after dissolving the test compound in physiological saline,
The solution was measured after being left at 24 ° C. for 24 hours. Each solution of the test compound was dissolved in physiological saline and then diluted with physiological saline before use. 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 when physiological saline is added T: Permeability when test compound is added

As shown in Table 1, it can be confirmed that the compound of the present invention exhibits an excellent inhibitory effect on platelet aggregation, and the inhibitory effect on platelet aggregation does not decrease even after 24 hours, and is a significantly stabilized compound. It was In addition to that, in particular, compound 2 of the invention has a higher activity than native prostacyclin.

PGI ₂ Na is a sodium salt of natural prostacyclin.

[0063]

[Table 1]

[Example 6] Stability test in an 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 2 shows the residual rate and the half-life. As shown in Table 2, it was confirmed that the compound of the present invention exhibits excellent stability in an aqueous solution.

[0067]

[Table 2]

[0068]

INDUSTRIAL APPLICABILITY The interphenylene type 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, the compound of the present invention in which R such as the compounds 1 and 2 of the present invention is a linear hydrocarbon group having a methyl group in the side chain is a natural prostacyclin Has an activity close to or higher than. Due to this high physiological activity and extremely high stability, the compound of the present invention has excellent properties as a medicine and is particularly useful as a preventive agent or therapeutic agent for cardiovascular disease.

Claims (7)

[Claims] 1. A compound which is an interphenylene type difluoroprostacyclin represented by the following general formula (1), a lower alkanol ester thereof, or a pharmaceutically acceptable salt thereof. Embedded image (However, 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.) 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 or 2, which is a hexynyl group. 5. The compound according to claim 1 or 2, 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 a phenyl group has an alkyl group having 1 to 2 carbon atoms or a halogen atom, or Compound of 2. 7. A preventive or therapeutic agent for cardiovascular diseases, which comprises a compound selected from 1, 2, 3, 4, 5 or 6 as an active ingredient.