Isocarbacyclin derivatives

Abstract: The invention relates to compounds of the following formula (A): wherein R⁷² is a carboxyl group or a salt or ester thereof; R² is H; R³ is H; R⁴ is H, a methyl group or a vinyl group; R⁵ is an unsubstituted linear or branched C₃-C₈ alkyl group or a C₃-C₁₀ cycloalkyl group; n is 1 and m is an integer of 1 to 6. Pharmaceutically acceptable salts thereof are also disclosed.

Description: This invention relates to 3,6,7-trisubstituted-bicyclo[3.3.0]-2-octenes, i . e . 9(0)-methano-Δ 6(9α) -prostaglandins I₁ (isocarbacyclins). Carbacyclins are prostaglandin I₂ analogs resulting from substitution of methylene groups for the oxygen atoms at the 6,9-positions of prostaglandin (to be sometimes abbreviated as PG) I₂ (PGI₂), an in vivo physiologically active substance. Since carbacyclins are chemically more stable than natural prostaglandin I₂ having an enol ether partial structure in the molecule, they are useful as pharmaceuticals such as an anti-thrombotic agent. It was recently discovered that isocarbacyclins, a double bond isomer of carbacyclin, namely 9(0)-methano-Δ 6(9α) -prostaglandins I₁, show the strongest platelet aggregation inhibitory activity among these analogs, and are expected to have application as medicines [see Ikegami et al., Tetrahedron Letters, 33 , 3493 and 3497 (1983)]. Several examples of the production of the 9(0)- methano-Δ 6(9α) -prostaglandin I₁ (isocarbacyclin) have previously been known. The outlines of the methods, key synthetic intermediates used in these examples and the literature references describing them are summarized as follows: (1) Ikegami et al. Testrahedron Letters, 24 , 3493 (1983) and Chemistry Letters, 1069 (1984): (2) Ikegami et al. Tetrahedron Letters, 24 , 3497 (1983) (3) Ikegami et al., J. Chem. Soc., Chemical Communications, 1602 (1984): (4) Shibasaki et al., Tetrahedron Letters, 25 , 5087 (1984): (5) Shibasaki et al., Tetrahhedron Letters, 25 , 1067 (1984): (6) Kojima et al., Chem. Pharm. Bull., 32 , 2866 (1984): (7) Kojima et al., JP-A- 28943/1985: Methods (1) and (5) uses PGE₂ as a starting material, and through several steps, it is converted to a key intermediate, and after further several steps, the final product, isocarbacyclin, is obtained. Methods (2) and (3) require a multiplicity of steps starting from expensive Corey lactone in order to obtain the corresponding starting materials and key intermediates, and the total yield of the final product is not high. According to methods (6) and (7), the final product is obtained only in the form of a DL isomer. Finally, method (4) has the great disadvantage that the total yield is decreased since in the steps from the key intermediate to the final isocarbacyclin, various difficulties arise such as the use of an organic mercury compound, the loss of the regiospecificity of the compounds, and the inclusion of inseparable by-products. The present invention seeks to provide novel 9(0)- methano-Δ 6(9α) -prostaglandins I₁ (isocarbacyclins), namely, 3,6,7-trisubstituted-bicyclo [3.3.0]-2-octenes. Accordingly the present invention provides a compound of the following formula (A): wherein R⁷² is a carboxyl group or a salt or ester thereof; R² and R³ are each hydrogen; R⁴ represents hydrogen, a methyl group or a vinyl group; R⁵ represents an unsubstituted linear or branched C₃-C₈ alkyl group or a C₃-C₁₀ cycloalkyl group; n is 1; and m is an integer of 1 to 6; or a pharmaceutically acceptable salt thereof. A preferred compound of formula (A) is a compound of formula (A'') wherein R¹ is H or a linear or branched C₁-C₁₀ alkyl group, R⁴ is H, a methyl group or a vinyl group, and R⁵ is an unsubstituted linear or branched C₃-C₈ alkyl group or a C₅-C₆ cycloalkyl group or a pharmaceutically acceptable salt thereof. Preferably, in the compound of formula (A'') R¹ is H, R⁴ is H, a methyl group or a vinyl group; R⁵ is an unsubstituted linear or branched C₃-C₈ alkyl group; n is 1 and m is an integer of 1 to 6. Particularly preferred compounds of the invention include 15-deoxy-16-hydroxy-16-methyl-9-(O)-methano-Δ 6(9α) -prostaglandin I₁ of the formula: and 15-deoxy-16-hydroxy-16-vinyl-9-(O)-methano-Δ 6(9α) -prostaglandin I₁ of the formula: Examples of the unsubstituted linear or branched C₃-C₈ alkyl group include propyl, butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl, 2-methylpentyl, 2-methylhexyl and 2,2-dimethylhexyl groups. Of these, butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl and 2-methylpentyl groups are preferred. Examples of the C₃-C₁₀ cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and clycodecyl groups. The cyclopentyl and cyclohexyl groups are preferred. The 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes of formula (A) may be prepared as follows:- The individual steps in Reaction Scheme 1 will be described below. Step 1 (epoxidation) The 3,6,7-trisubstituted-bicyclo[3,3,0]-2-octene used as a starting material in step 1 is represented by formula (V). This compound is known. In formula (V), R²¹ and R³¹ are identical or different, and each represents a tri(C₁-C₇)hydrocarbonsilyl group or a group forming an acetal linkage with the oxygen atom of the hydroxyl group. Preferred examples of the tri(C₁-C₇) hydrocarbonsilyl group include tri(C₁-C₄)alkylsilyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl and t-butyldimethylsilyl groups; diphenyl (C₁-C₄) alkylsilyl groups such as a t-butyldiphenylsilyl group, di(C₁-C₄)-alkylphenylsilyl groups such as a dimethylphenylsilyl group; and a tribenzylsilyl group. The tri(C₁-C₄)alkylsilyl, diphenyl(C₁-C₄)alkylsilyl and phenyldi(C₁-C₄)-alkylsilyl groups are preferred. Among them, t-butyldi- methylsilyl and trimethylsilyl groups are especially preferred. Examples of the group forming an acetal linkage together with the oxygen atom of the hydroxyl group include methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl and 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl groups. The 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl, and 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1,0]hex-4-yl groups are preferred. The 2-tetrahydropyranyl group is especially preferred. It should be understood that these silyl groups and the groups forming an acetal linkage are protective groups for the hydroxyl group. These protective groups can be easily removed under weakly acidic to neutral conditions in the stage of the final product to provide free hydroxyl groups useful in drugs. Hence, protective groups for the hyroxyl group which have such properties may be used instead of the silyl group or the acetal linkage-forming group. Specific preferred examples of these groups may be the same as those given hereinabove with regard to R⁵ in formula (A). In formula (V), n is 1. In step 1, the starting 3,6,7-trisubstituted-bicyclo- [3.3.0]-2-octene is 2,3-epoxidized. Suitable epoxidizing agents that may be used in this step include, for example, hydrogen peroxide, organic peroxides such as t-butyl hydroperoxide and cumene hydroperoxide, and organic acids such as m-chloroperbenzoic acid, perbenzoic acid, mono-peroxyphthalic acid and peracetic acid (oxidizing agents), which are used in the presence of catalysts such as selenium dioxide, tungstic acid, tungstate salts, molybdate salts, vanadium oxide, iron (III)/acetylacetone complex or titanium salts. In view of the fact that the chemical structure of that part of the compound represented by (V) which is to be oxidized is allyl alcohol, t-butyl hydroperoxide, for example, is especially preferably used in the presence of a catalyst such as tungstic acid, a tungstate salt, a molybdate salt (such as molybdenum hexacarbonyl), a vanadium oxide (V) salt (such as vanadyl acetylacetonate) or a titanium salt (such as titanium tetraisopropoxide). In step 1, the starting 3,6,7-trisubstituted-bicyclo- [3,3.0]-2-octene is reacted with the epoxidizing agent (an oxidizing agent and optionally an oxidation catalyst thereof) and an inert organic medium. Stoichiometrically, the starting 3,6,7-trisubstituted- bicyclo[3.3.0]-2-octene and the oxidizing agent react in equimolar proportions. Usually, the reaction is carried out by using 0.5 to 5.0 moles, preferably 0.8 to 3.0 moles, especially preferably 1.0 to 2.0 moles, per mole of the starting 3,6,7-trisubstituted-bicyclo[3.3.0]-2-octene, of the oxidizing agent. Where the oxidation catalyst is used, its amount varies slightly depending upon its kind. Usually, it is used in an amount of 0.001 to 1.2 moles. The reaction temperature, which varies depending upon the kind of the epoxidizing agent (the oxidizing agent and optionally the oxidation catalyst therefor), is usually -100 to 100°C, preferably -78 to 80°C, especially preferably about -20 to 50°C. The reaction time likewise varies depending upon the epoxidizing agent and the reaction temperature. It is usually sufficient that the reaction is carried out for several hours at -20 to 50 °C. The reaction is carried out in the presence of an inert organic medium. Examples of the inert organic medium are saturated hydrocarbons such as pentane, hexane, heptane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, and halogenated hydrocarbons such as methylene chloride and chloroform, The amount of the inert organic medium is one sufficient to cause the reaction to proceed smoothly. Usually, it is used in an amount 1 to 100 times, preferably 2 to 20 times, the volume of the starting material. The resulting reaction mixture is worked up by ordinary methods. For example, a sparingly water-soluble organic solvent such as hexane, pentane, petroleum ether, diethyl ether or ethyl acetate is added to the reaction mixture. Alternatively, the reaction mixture is directly concentrated under reduced pressure, and then the organic solvent is added. The organic mixture obtained is then washed with an aqueous sodium chloride solution as required, and dried over a desiccant such as anhydrous magnesium sulfate, anhydrous sodium sulfate or anhydrous calcium chloride. The organic medium is then concentrated under reduced pressure to form a crude product. As required, the crude product may be purified by purifying means such as column chromatography, thin-layer chromatography, or liquid chromatography. As a result, there is obtained a 3,6,7-trisubstituted-2,3-epoxy- bicyclo[3.3.0]-2-octane of formula (IV'). Step 2 (sulfonylation) The 2,3-epoxy octane of formula (IV') is then sulfonylated in step 2. Sulfonylation is a known reaction, and may be carried out by reacting the 2,3-epoxide with a (C₁-C₁₀) hydrocarbon sulfonyl chloride in the presence of a basic substance in an organic medium Examples of the basic substance used in the above reaction are pyridine, 4-(N,N-dimethylamino)-pyridine, triethylamine, tributylamine and trimethylenediamine. The basic substance is used in an amount of 1.0 to 3.0 moles, preferably 1.2 to 1,5 moles, per mole of the 2,3-epoxide. The organic medium may be the same as the inert organic medium used in step 1. Its amount is one sufficient to cause the reaction to proceed smoothly. Usually, the amount of the organic medium is 1 to 100 times, preferably 2 to 20 times, the volume of the starting compound. Examples of the (C₁-C₁₀)hydrocarbonsulfonyl chloride include methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, naphthalenesulfonyl chloride and camphor-sulfonyl chloride. The amount of the sulfonyl chloride is 1.0 to 2,0 moles, preferably 1.1 to 1.5 moles, per mole of the 2,3-epoxide. The reaction temperature is -100 to 100°C, preferably -78 to 80°C, especially preferably -50 to 30 °C. The reaction time which varies depending upon the reaction temperature is usually several hours at a temperature of -40 to 25°C. After the reaction, the reaction mixture may be worked up, and the product isolated, as in step 1. As a result, a 3,6,7-trisubstituted-2,3-epoxybicyclo[3.3.0]- octane of formula (IV) wherein R⁴, R⁵, R²¹, R³¹ and n are as defined above and R⁶¹ is a (C₁-C₁₀) hydrocarbonsulfonyl group can be obtained. Step 3 (reaction with a solution of an alkali metal or alkaline earth metal anion radical) Step 3 is performed by reacting the 3,6,7-tri-substituted-2,3-epoxybicyclo[3.3.0]octane of formula (IV) obtained in step 2 with a solution of an alkali metal or alkaline earth metal anion radical solution. The alkali metal in the anion radical solution may include lithium, sodium and potassium. Sodium is especially preferred. Calcium is especially preferred as the alkaline earth metal. The amount of the alkali metal or alkaline earth metal used is 1.0 to 20.0 moles, preferably 1.2 to 10.0 moles, per mole of the 3,6,7-trisubstituted-2,3-epoxybicyclo[3.3.0]octane of formula (IV). A preferred solvent for the anion radical solution is, for example, an ether solvent such as diethyl ether, tetrahydrofuran or dimethoxyethane containing liquid ammonia, naphthalene, 1-(N,N-dimethylamino)-naphthalene or 4,4'-di-t-butylbiphenyl in an amount of at least 1 mole per mole of the alkali metal or the alkaline earth metal. Tetrahydrofuran containing liquid ammonia or naphthalene is most preferred. The amount of the solvent may be one sufficient to cause the reaction to proceed smoothly. Usually, its amount is 1 to 100 times, preferably 2 to 20 times, the volume of the starting compound. The reaction temperature is -100 to 100°C, preferably -78 to 50°C, especially preferably -20 to 30°C. The reaction time, which varies depending upon the reaction temperature, is usually within several hours at 0 to 30°C. After the reaction, the reaction mixture is worked up, and the product isolated, as in step 1. As a result, a 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octane of formula (III) is obtained. The 3,6,7-trisubstituted-bicyclo[3.3.0]-2-octene of formula (V) used as the starting material in step 1 can be produced, for example, by the same method as that described in Shibasaki et al., Tetrahedron Letters, 25 , 5087 (1984). This production process is briefly shown by the following Reaction Scheme 2. In accordance with Reaction Scheme 3 shown below, the compound of formula (III) gives useful isocarbacyclins, enantiomers thereof, or mixtures of these in arbitrary ratios. Reaction Scheme 3 will be described below. In formula (III), R²¹ and R³¹ are identical or different and each represents a tri(C₁-C₇)hydrocarbon silyl group or a group forming an acetal linkage together with the oxygen atom of the hydroxyl group. Examples of these groups are the same as those given hereinabove. In formula (III), R⁴ and R⁵ are as defined above. Preferred examples of these groups are the same as those given hereinabove to R⁵ in formula (A). In formula (III), n is 1. In the above reaction, the 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octane of formula (III) is reacted with an organolithium in an organic medium, then with cuprous iodide and further with an organolithium compound of formula (II) in the presence of N-methyl-N-phenylaminotributylphosphonium iodide. The above reaction is carried out in accordance with the method of Y. Tanigawa et al. described in J. Am. Chem. Soc., 100 , 4610 (1978). n-Butyllithium and methyllithium, for example, may be used preferably as the organolithium used in the reaction. The amount of the organolithium is 0.8 to 1.5 times, preferably 1.0 to 1.2 moles, per mole of the 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octane. The reaction temperature is -78°C to 50°C, preferably -40 to 25°C. The reaction time, which varies depending upon the reaction temperature, is, for example, about 30 minutes at 20°C. By this reaction, the 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octane of formula (III) changes to its lithium alkoxide. Thereafter, the resulting lithium alkoxide solution is reacted with cuprous iodide with a solution of an organic copper lithium compound. The amount of cuprous iodide is 0.8 to 1.5 moles, preferably 1.0 to 1.2 moles, per mole of the compound of formula (III). The reaction temperature is -100 to 50°C, preferably -78 to 25°C. The reaction time, which varies depending upon the reaction temperature, is about 30 minutes at 20°C. An organic liquium compound of the following formula (II) Li(CH₂ R⁷¹ (II) wherein R⁷¹ represents a functionalized group convertible into carboxyl group and m is and integer of 1 to 6, is further added to the resulting organic copper lithium compound solution, and the reaction is carried out. Examples of functionalized groups convertible into carboxyl group include C₂-C₆ unsaturated hydocarbon groups such as vinyl, ethynyl and phenyl groups are mentioned first. The vinyl groups is most preferred in order to convert the reaction product into a 9(0)-methano-Δ 6(9α) -prostaglandin I₁ (isocarbacyclin) [M. Shibasaki et al., Tetrahedron Letters, 25 , 5087 (1984)]. In this case, m is preferably 2. A further example of a functionalized group convertible into carboxyl group is a protected hydroxyl group. The protected hydroxyl group may be the same protected hydroxyl groups as exemplified hereinabove for R²¹ and R³¹. These protected hydroxyl groups are preferred because they can be easily converted into the 9(0)-methano-Δ 6(9α) -prostaglanding I₁ (isocarbacyclin). In this case, m is preferably 4. The functionalized groups well known in the reports such as Tetrahedron Letters 24 , 5571 (1983) [E. J. Corey et al.], Synthesis, 153 (1974) [R. H. De Wolfe] and J. Chem. Soc. Chem. Comm., 207 (1980) [B. T. Golding et al.] can be also used as functionalized groups convertible into carboxylic groups. In this case, m is preferably 3. These organic lithium compounds can be easily obtained from the corresponding bromides and iodides by reaction with t-butyllithium or a lithium anion radical solution (such as naphthalene, 1-(N,N-dimethylamino)-naphthalene, 4,4'-di-t-butylbiphenyl, or ammonia). The amount of the organic lithium compound used is 0.8 to 20.0 moles, preferably 1.0 to 10.0 moles, especially preferably 1.2 to 5.0 moles, per mole of the compound of formula (1). The reaction temperature is -100 to 0°C, preferably -78 to -40°C. The reaction time is about 10 to 30 minutes. The reaction is finally carried out by adding N-methyl-N-phenylaminotributylphosphonium iodide. A method of synthesizing this reagent is reported in the above-cited reference of Y. Tanigawa et al. Preferably, this reagent is added in the form of a solution in N,N-dimethylformamide. The amount of this reagent used is 0.8 to 5.0 moles, preferably 1.0 to 3.0 moles, especially preferably 1.1 to 2.0 moles, per mole of the compound of formula (I). The reaction temperature is -100 to 50°C, preferably -78 to 25°C. The reaction time is several hours at 25°C. The reaction using this reagent is carried out in an organic medium from the initial stage. Examples of the organic medium include hexane, benzene, ether, tetrahydrofuran, dimethoxyethane, dioxane, methylene chloride, and N,N-dimethylformamide. They may be used singly or in combination. Hexane, tetrahydrofuran and N,N-dimethylformamide are especially preferred. The amount of the organic medium is 1.0 to 100.0 times, preferably 5.0 to 50.0 times, the volume of the reaction substance. The reaction mixture so obtained is worked up in a usual manner. For example, a sparingly water-soluble organic solvent such as hexane, pentane, petroleum ether, ethyl ether or ethyl acetate is added. The separated organic mixture is washed with an aqueous sodium chloride solution as required, and dried over a desiccant such as anhydrous magnesium sulfate, anhydrous sodium sulfate or anhydrous calcium chloride. The organic medium is then removed under reduced pressure to give a crude product. The crude product, if required, may be purified by purifying means such as column chromatography, thin-layer chromatography, or liquid chromatography. Thus, in accordance with the reactions in Reaction Scheme 3, the compound of formula (A') given above is obtained. By subjecting the compound of formula (A') to deprotection, hydrolysis, esterification and/or salt forming reaction, the groups R²¹, R³¹ and R⁷¹ can be converted to form an isocarbacyclin represented by the following formula (A) wherein R⁷², R², R³, R⁴, R⁵, m and n are as defined above. The deprotection reaction, i . e . the removal of the protective group for the hydroxyl group may be conveniently carried out by using a catalyst such as acetic acid, pyridinium p-toluenesulfonate or a cation exchange resin in a reaction medium such as water, tetrahydrofuran, ethyl ether, dioxane, acetone or acetonitrile if the protective group is a group forming an acetal linkage together with the oxygen atom of the hydroxyl group. The reaction is usually carried out at -78 to +30°C for about 10 minutes to 3 days. If the protective group is a tri-(C₁-C₇)hydrocarbonsilyl group the deprotection reaction can be carried out at the same temperature for the same period of time in the aforesaid reaction solvent in the presence of, for example, acetic acid, tetrabutylammonium fluoride, cerium fluoride, aqueous hydrogen fluoride or pyridine-hydrogen fluoride. When the functionalized groups except those of mentioned above are used, these functionalized groups can be converted into corresponding carboxy-containing groups according to the procedures disclosed in the literature cited hereinbefore for exemplifying the functionalized groups. The compound having the carboxyl group formed as a result of hydrolysis as mentioned above is then subjected, as required, to esterification or a salt-forming reaction to give the corresponding ester or carboxylate salt. The esterification is a known reaction, and can be carried out by reacting the compound with an excessive amount of an alcohol in the presence of an acid catalyst such as p-toluenesulfonic acid, a pyridium salt thereof, sulfuric acid, or a cation exchange resin and a dehydro-condensing agent such as N,N'-dicyclohexylcarbodiimide or isobutyl chloroformate. Methyl-esterification may also be carried out by reacting the compound with an excessive amount of methyl iodide (preferably in the presence of acetonitile as a solvent) in the presence of an organic base such as diisopropylethylamine or diazomethane. The salt-forming reaction is also known per se , and may be carried out by reacting the compound with a nearly-equal amount of a basic compound such as potassium hydroxide, sodium hydroxide or sodium carbonate or ammonia, trimethylamine, monoethanolamine or morpholine by an ordinary method. Thus, an isocarbocyclin of formula (A), its enantiomers or an isomeric mixture thereof in an arbitrary ratio can be produced in accordance with Reaction Scheme 3 from the corresponding starting material. The process for producing the isocarbacyclins in accordance with Reaction Scheme 3 has the great industrial advantage that the starting material can be easily obtained industrially, synthesis of the skeleton of the compounds can be carried out stereospecifically and regiospecifically, the yield of the final product is high, and the final product can be easily isolated. Isocarbacyclins, i.e. 9 (O) methanoΔ 6(9α) -prostaglandins I₁, are useful as medicines for the circulatory system such as an antithrombotic agent, and antilipidemic agent, a hypotensive agent or an antiarterosclerotic agent. The following Examples illustrate the present invention. In the structural formulae given below, ......OZ represents .......OSiMe₂t-Bu, and .....OY, REFERENTIAL EXAMPLE 1 A hexane solution of n-butyllithium (1.56M, 2.72 ml, 4.24 mmoles) was added at 0°C to a solution of (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (1.80 g, 3.54 mmoles) in 50 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. The solution was added to a suspension of cuprous iodide (1.01 g, 5.31 mmoles) cooled at -78°C. The temperature of the mixture was elevated to room temperature, and it was stirred for 30 minutes. Separately, prior to the above procedure, metallic lithium (350 mg, 50.0 mmoles) was added to room temperature to a solution of naphthalene (6.41 g, 50.0 mmoles) in 50 ml of tetrahydrofuran at room temperature. After the mixture was colored, it was cooled to 0°C and stirred for 5 hours, A solution of 4-bromo-1-butene (3.38 g, 25.0 mmoles) in 50 ml of tetrahydrofuran was added dropwise at -78°C to the resulting solution, and the mixture was stirred at -78°C for 5 minutes. The resulting solution was added dropwise at -78°C to the solution prepared by the procedure of the first paragraph, and the mixture was stirred for 10 minutes, A solution of N-methyl-N-phenylaminotributylphosphonium iodide (4.61 g, 10.6 mmoles) in 30 ml of N,N-dimethylformamide was added to the mixture. The cooling bath was removed, and the temperature was elevated. The mixture was then stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with hexane. The resulting organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give a crude product. The crude product was subjected to column chromatography (silica gel treated with triethylamine; hexane/ether=9/1) to give (1S,5S,6S,7R)-3-(4-pentenyl)-6-[(E,3S)-3-t-butyldimethyl- silyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo- [3.3.0]-2-octene (1.16 g, 2.12 mmoles, 60 %). NMR(CDCl₃)δ: 0.03(12H,s), 0.83(21H,m), 1.0-3.1(21H,m), 3.1-4.2(2H,m), 4.6-6.0(6H,m). Thus obtained compound was converted into a corresponding 9(O)-methano-Δ 6(9α) -prostaglandin I₁ according to the same procedure as disclosed in Tetrahedron Letters, 25 , 5087(1984) by M. Shibasaki et al. This product was completely identical with an authentic sample. NMR(CDCl₃)δ: 0.83(3H,m), 1.0-3.3(23H,m), 3.3-4.3(2H,m), 5.20(1H,bs), 5.25-5.5(2H,m), 5.97(3H,bs). IR(liquid film): 3350, 3050, 1710, 1090, 970 cm⁻¹. EXAMPLES 1 AND 2 According to the procedure of Referential Example 1, various kinds of 9(O)-methano-Δ 6(9α) -prostagladin I₁ derivatives listed in the Table below were obtained using corresponding starting materials in the same table. (1S, 2RS, 3RS, 5S, 6S, 7S)-2-hydroxy-3-methylene-6-[(E)-4-butyldimethylsilyloxy-4-methyl-1-octeny]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (69%) and (1S, 2RS, 3RS, 5S, 6S, 7R)-2-hydroxy-3-methylene-6-[(E)-4-t-butyldimethylsiloxy-4-vinyl-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]-octane (74%) were prepared in the same way as Referential Example 2. REFERENTIAL EXAMPLE 2 A solution of 917 mg (1.52 mmoles) of (1S,2RS,-3RS,5S,6S,7R)-3-methanesulfonyloxymethyl-2,3-epoxy-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane obtained in Referential Example 3 in 3 ml of tetrahydrofuran was added to an anion radical solution prepared by reacting naphthalene (1.28 g, 10 mmoles) with sodium (207 mg, 9 mmoles) in 30 ml of tetrahydrofuran at room temperature for 1 hour. The mixture was stirred at room temperature for 10 minutes, and 3.0 g of ammonium chloride was added to the reaction solution. Then, a saturated aqueous solution of ammonium chloride was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give a crude product. It was subjected to column chromatography (silica gel 50 g; hexane/ethyl acetate=19/1) to give (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethysilyloxy-1-octenyl)-7-t-butyldimethy Isilyloxybicyclo-[3.3.0]octane (605 mg, 1.19 mmoles, 78 %). NMR(CDCl₃)δ: 0.05(12H,s), 0.85(21H), 1.0-3.0(16H,m), 3,4-4.5(3H,m), 4.7-5.1(2H,m), 5.2-5.35(2H,m). IR(liquid film): 3350, 3080, 1660, 1255, 1115, 1000, 965, 935, 835, 770 cm⁻¹. MS: 508(M⁺), 491(M-17), 452(M-57). REFERENTIAL EXAMPLE 3 The (1S,2RS,3RS,5S,6S,7R)-3-hydroxymethyl-2,3-epoxy-6-[(E,3S)-3-t-butyldimethylsilyloxy-10-octenyl] 7-t-butyldimethylsilyloxybicyclo[3.3.0 loctane (801 mg, 1.53 mmoles) obtained in Referential Example 4 was dissolved in 3 ml of methylene chloride. The solution was cooled to -25°C, and then triethylamine (170 mg, 1.68 mmoles) and further a solution of methanesulfonyl chloride (193 mg, 1.68 mmoles) in 3 ml of methylene chloride were added. The mixture was stirred for 1 hour. Ice water was added to the reaction mixture, and the entire mixture was then extracted with ethyl acetate. The separated organic layer was washed with an aqueous solution of sodium chloride, dried ove anhydrous magnesium sulfate and concentrated to give (1S,2RS,3RS,5S,6S,7R)-3-methane-sulfonyloxymethyl-2,3-epoxy-6-[(E,3S)-3-t-butyldimethyl-silyloxybicyclo[3.3]octane (917 mg, 1.52 mmoles, 99%) as a nearly pure product. NMR(CDCl₃)δ: 0,04(12H,S), 0.84(21H), 1.0-1.7(8H,m), 1.7-2.7(7H,m), 2.94(3H,s), 3.30(1H,m), 3.6-4.1(2H,m), 4.0-4.6(2H,m), 5.15-5.35(2H,m). IR(liquid film): 3000, 1735, 1355, 1250, 1175, 1115, 1060, 1000, 960, 830, 770 cm⁻¹. MS: 545(M-57), 507, 449. REFERENTIAL EXAMPLE 4 Vanadyl acetylacetonate (10 mg) was added to a solution of 1.0 g (1.97 mmoles) of (1S,5S,6S,7R)-3-hydroxymethyl-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]-2-octene in 8 ml of benzene, and 1 ml (3.0 mmoles) of a 3.0M 1,2-dichloroethane solution of anhydrous t-butyl hydroperoxide was added to the mixture at room temperature. The resulting mixture was heated under reflux for 20 minutes. The reaction mixture was cooled and concentrated. The resulting crude product was subjected to silica gel column chromatography (silica gel 50 g; hexane/ethyl acetate=6/1) to give (1S,2RS,3RS,5S,6S,7R) 3-hydroxymetbyl-2,3-epoxy-6-[(E,3S)-3-t-butyldimethyl-silyoxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo-[3,3,0]octane (912 mg, 1.74 mmoles, 88 %). NMR(CDCl₃ )δ: 0.04(12H,s), 0.85(21H), 1.0-1.6(8H,m), 1.6-2.7(8H,m) , 3.31(1H,m) , 3.67(3H,s), 3.4-4.1(2H,m), 5.15-5.35(2H,m). IR(liquid film): 3440, 3000, 1255, 1115, 1060, 1000, 965, 860, 830, 770 cm⁻¹. MS: 525(M+1), 507(M-17), 467(M-57), 449.

Claims: A compound of the following formula (A): wherein R⁷² is a carboxyl group or a salt or ester thereof; R² is H; R³ is H; R⁴ is H, a methyl group or a vinyl group; R⁵ is an unsubstituted linear or branched C₃-C₈ alkyl group or a C₃-C₁₀ cycloalkyl group; n is 1 and m is an integer of 1 to 6; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 of the following formula: wherein R¹ is H or a linear or branched C₁-C₁₀ alkyl group, R⁴ is H, a methyl group or a vinyl group, and R⁵ is an unsubstituted linear or branched C₃-C₈ alkyl group or a C₅-C₆ cycloalkyl group or a pharmaceutically acceptable salt thereof. A compound or salt according to claim 2 wherein R¹ is H, R⁴ is H, a methyl group or a vinyl group; R⁵ is an unsubstituted linear or branched C₃-C₈ alkyl group; n is 1 and m is an integer or 1 to 6. A compound according to any one of claims 1 to 3 which is 15-deoxy-16-hydroxy-16-methyl-9(O)-methano-Δ 6(9α) -prostaglandin I₁ of the formula: A compound according to any one of claims 1 to 3 which is 15-deoxy-16-hydroxy-16-vinyl-9(O)-methano-Δ 6(9α) -prostaglandin I₁ of the formula:

Inventors: KUROZUMI SEIZI, KUROZUMI, SEIZI
Applicants: TEIJIN LTD, TEIJIN LIMITED
Application year: 1986
Main classification: C07C405
IPC codes: C07F7, C07C405, C07D303, C07F9