JPH0455416B2 - - Google Patents

Description

[Detailed description of the invention]

[Technical field] The present invention relates to a novel prostaglandin I ₂ analog compound and its use as a circulation-improving drug such as blood flow improvement, antithrombotic drug, or anti-inflammatory drug. [Prior art] Prostaglandin I ₂ (hereinafter referred to as PGI ₂ ) is known as a natural physiologically active substance, and has the structure shown by the following formula, Its chemical name is (5Z, 13E)-(9α, 11α15S)-
6,9-epoxy-11,15-dihydroxyprosta-5,13-dienoic acid. PGI ₂ exists in the arterial wall and has a strong platelet aggregation inhibiting effect and a peripheral arterial smooth muscle relaxing effect [Nature, 263 , 663 (1976)]. PGI ₂ , which exhibits such an effect, is useful for the prevention and treatment of cerebral thrombosis, myocardial infarction, and acute angina pectoris induced by accelerated platelet aggregation and increased thrombotic tendency, and is useful for the prevention and treatment of arteriosclerotic diseases. It is expected that it will be applicable, and it is expected that it will be developed as a so-called blood flow improving drug or antithrombotic drug. Furthermore, prostaglandins including PGI ₂ are known to have gastric mucosal protective effects and gastric mucosal blood flow increasing effects ['83 Inflammation Seminar ``Prostaglandin'' proceedings, p. 50 (sponsored by the Japanese Society of Inflammation)]. PGI ₂ is expected to be applicable to the prevention and treatment of gastrointestinal ulcers, such as gastric ulcers. However, PGI ₂ is a very unstable substance, which poses an obstacle to its practical application as a pharmaceutical. In order to solve this problem, research has been carried out on stable analogues in which the oxygen atom between the 6th and 9th carbon atoms of PGI ₂ is replaced with a carbon atom. OP−41483 [Unexamined Japanese Patent Publication 1973-
130543] Carbacycline compounds represented by the general formula (), 9(O)-meta-Δ ⁶ -PGI ₁ represented by the chemical formula () [JP-A-56-32436]
Both are chemically stable PGI ₂ analogs. In addition, 9(O)-methano- ^{Δ 6(9} 〓 ⁾ -prostaglandin I ₁ (isocarbacycline) in which the 5-position double bond of 9(O)-methanoprostacyclin (carbacyclin) was moved to the 6(9α) position Cyclin, chemical formula ()) is also chemically stable enough and has been reported as a PGI ₂ analog compound with strong physiological activity [JP-A-59-137445]. [OP-41483 A=cyclopentyl] [Objective and Summary of the Invention] The present inventors have conducted extensive research with the aim of providing a prostaglandin I ₂ analogue compound that is stable and has excellent pharmacological properties, with almost no decomposition occurring at room temperature, and as a result, a novel The present invention has been completed by creating a prostaglandin I ₂ analogue compound, and discovering that the compound has strong platelet aggregation inhibiting, hypotensive, vasodilatory, and antiulcer effects, as well as low toxicity. I've reached it. That is, the present invention is based on the general formula () [In the formula, R ¹ represents a hydrogen atom, a methyl group, or an ethyl group, and A represents a cyclohexyl group, 1-methyl-
Represents a 3-hexynyl group or 1-methylhexyl group, the double bond between the carbon atoms at the 4th and 5th positions is E or Z, or a mixture thereof, and the asymmetric center in the substituent represented by A is the R-configuration or the S-configuration, or a mixture thereof. ] and drugs containing it as an _active ingredient. The compound of the present invention has shown strong platelet aggregation inhibiting, hypotensive, vasodilating, and antiulcer effects in animal experiments. This platelet aggregation inhibitory effect and vasodilatory effect indicate that this compound has the purpose of preventing and treating various circulatory disorders such as cerebral thrombosis, myocardial infarction, acute angina pectoris, and peripheral circulatory disorders caused by accelerated platelet aggregation and arteriosclerosis in humans. This suggests that it is an excellent blood flow improving or antithrombotic drug. In addition, the anti-inflammatory action suggests that it is an excellent anti-inflammatory drug for the prevention and treatment of gastrointestinal ulcers such as gastric ulcers in humans. In animal experiments, the compound of the present invention had low toxicity, which suggests that it is an excellent drug with high safety. [Specific description of the invention] (Compound of the present invention) Prostaglandin I ₂ provided by the present invention
Specific examples of related compounds include 3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclohexyl-trans-1'-propenyl)- 7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (compound A) and its ethyl ester (compound A'),
3-(4'-carboxy-1'-butenyl)-6(S)-
(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-nonen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0 ] Oct-2-ene (compound B) and its ethyl ester (compound B'), 3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-4' (
RS)
-Methyl-trans-1'-nonenyl)-7(R)-
Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]
These include oct-2-ene (compound D) and its ethyl ester (compound D'), as well as non-toxic acid salts of these compounds, and clathrates of these compounds with cyclodextrin. (Drug) An effective administration method for clinically applying the compound of the present invention as a blood flow improving drug, antithrombotic drug, antihypertensive drug, and antitussive drug is oral or parenteral administration, with a single dose of 0.01 μg to 100 mg. Preferably 0.01μg~
It is desirable to administer 1 mg once or several times a day. However, the exact dosage will depend on the patient's age, weight, symptoms, route of administration, and frequency of administration. Solid formulations for oral administration include tablets, pill powders and granules. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as semidigestible starch, potato starch, alginic acid, mannite or lactose. The formulations may contain additives other than diluents in a conventional manner, for example lubricants such as magnesium stearate. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, or elixirs and, in addition to commonly used inert diluents, may contain adjuvants such as wetting agents, suspension aid,
Contains sweeteners, flavoring agents, aromatics or preservatives.
Also included for oral administration are capsules of absorbable materials, such as gelatin, with or without one or more active substances and diluents or excipients. Solid preparations for rectal administration consist of at least one inert base containing one or more active substances, such as cocoa butter, Macrogold, Wichiepsol, processed in a manner known per se. Includes suppositories. Further examples include ointments and the like as external application agents. Products for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.
Non-aqueous solvents or suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of disinfectants or by irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in a sterile injection solvent immediately before use. (Synthesis method) The compound of the present invention represented by the general formula () is already known, for example, as described in [45th Organic Synthesis Symposium (sponsored by Japan Society of Organic Synthesis Chemistry) Abstracts, pages 51-54] along with its synthesis method. It can be produced by the route shown below using the compound () as a starting material. [In the formula, A is the same as defined above. ^R2 represents a methyl group or an ethyl group, Si〓 represents a -t-butyldimethylsilyl group, and THP represents a tetrahydro-2-pyranyl group. ] Compound () is R ³ ₃ P ⁺ CH ₂ CH ₂ CH ₂ CO ₂ R ² X ⁻ [wherein R ² is the same as defined above] in compound (). R ³ is carbon number 1
-4 represents an alkyl group or a phenyl group, and X represents a halogen atom such as chlorine or bromine. ] It can be obtained by reacting with a Witteitsch reagent obtained by treating with a base. As a base, sodium hydride, potassium hydride or potassium tert
-Butoxide is preferred. The amount of Uiteitzch reagent is 1 to 10 equivalents, preferably 1 equivalent to the starting compound.
~5 equivalents. As the reaction solvent, dimethyl sulfoxide or ethers such as tetrahydrofuran and dimethoxyethane are preferred. The reaction temperature is −78
℃~50℃, preferably -20℃~30℃. Compound () is obtained by treating compound () with 1 to 10 equivalents, preferably 1 to 3 equivalents, of a fluorine compound such as tetra-n-butylammonium fluoride or cesium fluoride. The reaction is usually carried out in an ether such as tetrahydrofuran or ethyl ether at a reaction temperature of 0 to 30°C.
It lasts from 10 minutes to 3 days. Compound () oxidizes the hydroxymethyl group of compound () to form an aldehyde, which is then converted into (R ⁴
O) ₂ P(O)CH ₂ C(O)-A [in the formula, A is the same as the above definition. R ⁴ represents an alkyl group having 1 to 3 carbon atoms. ]
It is obtained by reacting with the Witteitsch reagent obtained by treating with a base. When oxidizing a hydroxymethyl group, an oxidation method using an amine/pyridine-sulfur trioxide complex/dimethyl sulfoxide system that oxidizes a primary alcohol to an aldehyde is particularly preferably used. Reactive leaves usually 10℃~40℃
It is carried out at a temperature range of 1 minute to 2 hours. The amount of the oxidizing agent is preferably 2 to 100 equivalents relative to the raw material compound (2). The aldehyde thus obtained is preferably subjected to the next Witteig reaction without being purified. The base used in the Witteig reaction is preferably sodium hydride, potassium hydride or potassium tert-butoxide. The amount of reagent is 1 to 10 equivalents, preferably 1 to 5 equivalents relative to the aldehyde. The reaction solvent is preferably an ether such as tetrahydrofuran or dimethoxyethane, and the reaction is carried out at a temperature of -20°C to 50°C for about 5 minutes to 24 hours. These compounds () to () can be purified by conventional purification means such as column chromatography, thin layer chromatography, and liquid chromatography. Compound () can be obtained by reducing compound (). The reducing reagent is preferably one that does not reduce ^COOR2 , such as trialkylborohydride such as sodium borohydride, zinc borohydride, diphenyltin hydride or lithium tri-sec-butylborohydride, and 2,6-di-tert. -butyl-4-methylbuenol-modified di-
iso-butyl aluminum hydride, or 1,
Examples include lithium aluminum hydride modified with 1'-bi-2-naphthol and a lower alcohol such as ethanol. Examples of the reaction solvent include lower alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and aromatic hydrocarbons such as benzene or toluene. The amount of reducing reagent used is based on the raw material compounds α and β.
- preferably 0.5 to 30 equivalents relative to the unsaturated compound,
Particularly preferred is 1 to 10 equivalents. The reaction temperature is -
The temperature is 150°C to 80°C, preferably -100°C to 30°C.
The reaction solution thus obtained may be post-treated according to a commonly used method. For example, the reaction solution is poured into dilute hydrochloric acid, dilute sulfuric acid or saturated ammonium chloride aqueous solution, hexane, pentane, petroleum ether,
Extract with an organic solvent that is sparingly soluble in water such as ethyl ether, benzene or toluene, wash the resulting extract with brine, and dry with a desiccant such as anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous potassium carbonate, etc. , the organic solvent is distilled off under reduced pressure to obtain a crude product. The crude product can be purified by purification means such as column chromatography, thin layer chromatography, liquid chromatography, etc., if desired. The product thus obtained can be further subjected to deprotection reaction, separation of diastereomers, hydrolysis reaction, and salt formation reaction, if necessary. Removal of the protective group for the hydroxyl group is preferably carried out using acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin as a catalyst, and using water, tetrahydrofuran ethyl ether, dioxane, acetone, acetonitrile, etc. as a solvent. be done. The reaction is usually carried out at a temperature range of -78°C to 80°C for about 10 minutes to 3 days. The thus obtained product is subjected to column chromatography, thin layer chromatography, separation of diastereomers based on the 15-position hydroxyl group produced by the reduction reaction, as necessary.
It can be purified by purification means such as liquid chromatography. The hydrolysis reaction of the carboxylic acid ester group is carried out at -10°C to 100°C in a single or mixed solution of water, methanol, or ethanol containing caustic soda or caustic potassium.
1 minute to 24 hours at a temperature range of -10°C to 60°C in water or a water-containing solution using oxygen, such as reverse, for 1 minute to 24 hours.
done in time. The product after the hydrolysis reaction can be purified by the same purification means as described above. The present invention will be explained in more detail with reference to Examples below. In the examples, the unit of the NMR δ scale represents "ppm". (Synthesis of compound) Example 1 Sodium hydride 216mg under algol atmosphere
(9.0 mmol) was suspended in 10 ml of dimethyl sulfoxide and stirred at 50°C for 30 minutes. The solution was cooled to 20°C, and 4.11 g of (3-ethoxycarbonyl)propyltriphenylphosphonium bromide was added to the solution.
(9.0 mmol) in dimethyl sulfoxide (7 ml) was added dropwise. After stirring for 30 minutes, 3-formyl-6(R)-tert-butyldimethylsiloxy-7
(R)-Tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene (1) 1.14g
(3.0 mmol) in dimethyl sulfoxide (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with ether, dried over MgSO ₄ and concentrated under reduced pressure to obtain a crude product. This was subjected to column chromatography (ethyl ether/hexane = 3/
2) to produce 3-(4'-ethoxycarbonyl-
1'-butenyl)-6(R)-tert-butyldimethylsiloxy-7(R)-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene (compound 2)
1.37g was obtained. Yield 97%. IR (neat); 1735, 1135, 1020, ^{835cm -1} . NMRδ (CDC1 ₃ ); 5.90, (d, 0.9H, J=11
Hz), 5.4 to 5.6 (m, 1H), 4.9 to 5.4 (m, 1H),
4.4-4.7 (m, 1H), 4.05 (q, 2H, J=7
Hz), 1.20 (t, 3HJ=7Hz), 0.89 (s, 9H),
0.05 (s, 6H). Example 2 1.30 g (2.7 mmol) of compound (2) was dissolved in 30 ml of tetrahydrofuran, and 4 ml (40 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added thereto at room temperature. After stirring at room temperature for 5 hours and at 0° C. overnight, the mixture was poured into an aqueous NaHCO ₃ solution and extracted with ethyl ether. The extract was dried with MgSO ₄ and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (ethyl ether/hexane = 2/1) to give 3-(4'-ethoxycarbonyl-1'-butenyl)- 936 mg of 6(R)-hydroxy-7(R)-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene (compound 3) was obtained. Yield 95%. IR (neat); 3450, 1730, 1370, 1350, 810cm ^-
1 . NMRδ (CDC1 ₃ ); 5.83 (d, 0, 9H, J = 11
Hz), 5.5 to 5.7 (m, 1H), 5.0 to 5.5 (m, 1H),
4.11 (q, 2H, J = 7Hz), 1.28 (t, 3H, J
=7Hz). Example 3 Alcohol (3) 60mg under argon atmosphere
(0.16 mmol) was dissolved in 0.8 ml of triethylamine and 0.5 ml of dimethyl sulfoxide, and added to this at room temperature.
A solution of 534 mg of SO ₃ -pyridine complex in dimethyl sulfoxide (2 ml) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into ice water and extracted with ethyl ether.
After drying with MgSO ₄ and concentrating, crude aldehyde (4) was obtained. Under argon atmosphere, 13 mg of sodium hydride (60
%, 0.32 mmol) suspended in tetrahydrofuran,
A solution of 82 mg (0.35 mmol) of dimethyl (2-cyclohexyl-2-oxoethyl)phosphonate in tetrahydrofuran (2 ml) was added at room temperature. After stirring for 30 minutes, a solution of the above crude aldehyde (4) in tetrahydrofuran (2 ml) was added, and the mixture was further stirred for 1 hour. The reaction solution was poured into ice water, extracted with ethyl ether, dried over MgSO ₄ , and the solvent was distilled off to obtain a crude product. This was purified by thin layer chromatography (hexane/ethyl ether = 1/1), and α,
66 mg of a β-unsaturated carbonyl compound (compound 5) was obtained. Yield 86%. IR (neat); 1735, 1680, 1665, 1625cm ^-1 . NMR (CDC1 ₃ ); 6.0-7.1 (m, 2H), 5.81 (d,
0.9H, J=11Hz), 5.5~5.7 (m, 1H), 5.0~
5.5 (m, 1H), 4.4-4.7 (m, 1H), 4.08 (q,
2H, J = 7Hz), 1.25 (t, 3H, J = 7Hz). Example 4 The following compound was synthesized by the same operation as in Example 3. Table 1 shows the yield and spectral data.

[Table] Example 5 α,β-unsaturated ketone (compound 5) 60mg
(0.13 mmo1) in 5 ml of methanol, -78℃
A solution of 6.0 mg of sodium borohydride in methanol (1 ml) was added thereto. After 1 hour, the reaction solution was reduced to -20
The temperature was raised to ℃ and further stirred for 1 hour. After adding acetone to stop the reaction, the mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl ether, and concentrated under reduced pressure to obtain crude alcohol (6). This crude alcohol was dissolved in a 65% acetic acid aqueous solution, and the mixture was heated and stirred at 50°C for 2 hours. After cooling the reaction solution, it was poured into an aqueous NaHCO ₃ solution, extracted with ethyl acetate, dried over MgSO ₄ and the solvent was distilled off to obtain a crude product. This was purified using thin layer chromatography, and 15α was purified as a highly polar component.
-29 mg of diol compound (7) was obtained. Yield 59%. IR (neat); 3450, 1730cm ^-1 . NMRδ (CDC1 ₃ ); 5.90 (d, 0.9H, J=11
Hz), 4.9-5.8 (m, 4H), 4.5-4.8 (m, 1H),
4.07 (q, 2H, J = 7Hz), 1.25 (t, 3H, J
=7Hz). Example 6 The following compound was obtained by the same operation as in Example 5. Table 2 shows the yield and spectral data.

[Table] Example 7 15α-diol (compound 7) 29mg
(0.075 mmol) was dissolved in 2 ml of ethanol, and 1 ml of 5% sodium hydroxide aqueous solution was added at room temperature.
Stir for hours. After the reaction was completed, the reaction mixture was carefully neutralized with 5N hydrochloric acid to finally adjust the pH to 4 to 3. This was extracted with ethyl acetate, dried over MgSO ₄ , and then the solvent was distilled off to obtain a crude product. This was purified using a neutral silica gel capillary column to obtain 23 mg of carboxylic acid (A).
Yield 85%. IR (neat); 3350, 1700cm ^-1 . NMRδ (CDC1 ₃ ); 6.29 (d, 0.1H, J=15
Hz), 6.10 (d, 0.9H, J=11Hz), 5.4-5.7
(m, 3H), 3.5-5.4 (m, 1H), 3.7-3.9 (m,
2H), 3.0-3.2 (m, 1H). Mass m/z; 342, 324. Example 8 The following compound was synthesized in the same manner as in Example 7. Table 3 shows the yield and spectral data.

[Table] (Drug production) Example 9 3-(4'-carboxy-1'-butenyl)-6(S)-3'(S)-hydroxy-3'-cyclohexyl-trans-1 dissolved in 5 ml of ethanol '-Propenyl-7(R)-hydroxy-(1S,5S)-cis-
Bicyclo[3.3.0]oct-2-ene (compound A)
5mg, carboxymethylcellulose calcium
After mixing and drying 0.2 g of silicon dioxide, 20 mg of magnesium stearate, 0.2 g of magnesium stearate, and 5 g of mannitrate, add mannitto to make 10 g, mix well until homogeneous, and then directly compress into tablets using a mortar using a conventional method. Tablets containing 50 μg of active substance in the tablet
Got 100 tablets. Example 10 For Compound A', Compound B, Compound B', Compound D, and Compound D', 100 tablets each containing 50 μg of the active substance were obtained by the same procedure as in Example 9. Example 11 3-(4'-ethoxycarbonyl-1'-butenyl)
-6(S)-3'(S)-hydroxy-3'-cyclohexyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]
70 mg of α-cyclodextrin clathrate of oct-2-ene (compound A') [Content of compound A' 5
mg] Carboxymethyl cellulose calcium 0.2
g, 20 mg of silicon dioxide, 0.2 g of magnesium stearate, and dried mannitol to make 10 g, mixed well until homogeneous, and then directly compressed into tablets using a conventional method to make 100 tablets containing 50 μg of active substance in each tablet.
Got the lock. Example 12 3-(4'-carboxy-1'-butenyl)-6(S)
-3'(S)-hydroxy-4'(RS)-methyl-trans-1'-nonen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0 ] 70 mg of β-cyclodextrin clathrate compound of oct-2-ene (compound B) [content of compound B: 5 mg], 0.23 g of magnesium stearate and lactose were added to make 2.3 g, and the mixture was thoroughly mixed until homogeneous. 100 capsules containing 50 μg of active substance in each capsule were obtained by filling into No. 3 gelatin capsules in a conventional manner. (Physiological activity) Example 1 - Platelet aggregation inhibitory effect - (Experimental method) Healthy adult male (22~
Blood was collected from 23) early in the morning on an empty stomach. 50 ml of blood was collected using a syringe containing a 3.8% aqueous sodium citrate solution, immediately agitated by inversion, and then centrifuged at 200 xg for 15 minutes. PRP supernatant (platelet rich blood)
The residue was further centrifuged at 2000 xg for 15 minutes, and the supernatant was collected as PPP (platelet-poor blood plasma) and used in experiments. Put 250 μl of PRP in a cuvette, add 5 μl of a 1% ethanol aqueous solution or 1% ethanol aqueous solution of the compound of the present invention, and
After a minute incubation, aggregation inducing agent (ADP)
was added, and the aggregation process was recorded using an aggregometer (Sienco). The lowest concentration of ADP (2-10 μM) that gave maximum aggregation was used for each platelet. The platelet aggregation inhibition rate was calculated using the following formula. Inhibition rate = AB/A x 100 A: Maximum aggregation rate when solvent is added (1% ethanol aqueous solution) B: Maximum aggregation rate when the compound of the present invention is added The platelet aggregation inhibiting effect of the compound of the present invention is determined by the IC ₅₀ value. Therefore, it is as shown in Table 4.

[Table] Example 2 - Anti-ulcer effect - (Experimental method) 18 male Wistar rats (weight 250-280 g)
After an hourly fast, the abdomen was opened under ether anesthesia, the pylorus was ligated, and gastric juice was collected 4 hours later under fasting and water deprivation. After centrifuging this gastric juice at 3000 rpm for 10 minutes, the gastric juice volume, pH, and acidity were measured. Acidity was determined to PH0.7 with 0.1N NaOH using an automatic titrator (Toa Denpa Kogyo).
It was calculated by the following formula. Titration amount required for 1ml sample (0.1N NaOH)/0.1N HC1
Titration amount required for 1 ml (0.1N NaOH) x 0.1 (N) x 1000 (mEq/1) The gastric acid secretion suppression rate was calculated using the following formula. Suppression rate = AB/A x 100 A: Amount of gastric acid secretion in the control group B: Amount of gastric acid secretion in the drug group Table 5 shows the results of administering the test drug subcutaneously immediately after pylorus ligation.

[Table] Example 14 Alcohol (3) 100mg under Angone atmosphere
(0.27 mmol) was dissolved in 5.0 ml of triethylamine and 3.6 ml of dimethyl sulfoxide, and added to this at room temperature.
A solution of 2.7 g of SO ₃ -pyridine complex in dimethyl sulfoxide (8 ml) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into ice water and extracted with ethyl ether.
After drying with MgSO ₄ and concentrating, crude aldehyde (4) was obtained. Sodium hydroxide 12 mg (60
%, 0.3mmo1) suspended in tetrahydrofuran,
Under ice cooling, 93 mg of dimethyl 3(S)-(3-methyl-2-oxo-5-octynyl)phosphonate
(0.38 mmol) in tetrahydrofuran (5 ml) was added. After stirring for 30 minutes, a solution of the above crude aldehyde (4) in tetrahydrofuran (3 ml) was added.
The mixture was further stirred for 1 hour under ice cooling. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl ether, dried over MgSO ₄ , and then the solvent was distilled off to obtain a crude product. This was purified by column chromatography (hexane/ethyl ether = 1/1),
α,β-unsaturated carbonyl compound (compound 8)
Obtained 112 mg. Yield 86%. IR (neat); 1730, 1688, 1668, 1625cm ^-1 . NMR (CDC1 ₃ ); 5.9-7.1 (m, 2H), 5.88 (d,
1H, J=11Hz), 5.0~5.7 (m, 2H), 4.4~
4.7 (m, 1H), 4.08 (q, 2H, J=7Hz),
0.9~1.4 (m, 9H). Example 15 The following compound was synthesized by the same operation as in Example 14. Table 6 shows the yield and spectral data.

[Table] Example 16 α,β-unsaturated ketone (compound 8) 821 mg
(1.70mmo1) was dissolved in 5ml of methanol, and the mixture was heated at -40℃.
Then 65 mg of sodium borohydride was added. After 1 hour, the reaction solution was heated to -20°C and further stirred for 1 hour. After adding acetone to stop the reaction, the mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl ether, and concentrated under reduced pressure to obtain crude alcohol (9).
Dissolve this crude alcohol in 65% acetic acid aqueous solution,
The mixture was heated and stirred at 50°C for 2 hours. After cooling the reaction solution,
Pour into NaHCO ₃ aqueous solution, extract with ethyl acetate,
The crude product was obtained by drying with MgSO ₂ and evaporating the solvent.
This was purified by silica gel column chromatography, and the highly polar component was 15α-diol (10).
Obtained 313 mg. Yield 46%. IR (neat); 3360, 1730cm ^-1 . Massm/z; 400, 382, 271, 234, 117, 81. Example 17 The following compound was obtained by the same operation as in Example 16. Table 7 shows the yield and spectral data.

[Table] Example 18 15α-diol (compound 10) 24mg
(0.06 mmol) was dissolved in 1 ml of ethanol, and 1 ml of 5% sodium hydroxide aqueous solution was added at room temperature.
Stir for hours. After the reaction was completed, the mixture was carefully neutralized with 5N hydrochloric acid, and the pH was finally adjusted to 4 to 5. This was extracted with ethyl acetate, dried over _MgSO4 , and the solvent was distilled off.
A crude product was obtained. This was purified by high performance liquid chromatography to obtain 13 mg of carboxylic acid (11). Yield 58
%. IR (neat); 3350, 2930, 1705cm ^-1 . NMRδ (CDC1 ₃ , 270MHz); 6.00 (d, 1H,
J = 11.9Hz), 5.56 (m, 3H), 5.38 (m,
1H), 3.98 (m, 1H), 3.78 (m, 1H), 3.08
(broad s, 1H), 1.0-2.9 (m, 21H), 0.95
(d, 3H, J=6.8Hz). Example 19 The following compound was obtained by the same operation as in Example 18. Table 8 shows the yield and spectral data.

[Table] Example 20 Add 86mg (0.23mmo1) of carboxylic acid to a solution of diazomethane in ethyl ether under ice cooling, and at the same temperature.
Stir for 20 minutes. After adding formic acid to decompose excess diazomethane, saturated aqueous NaHCO ₃ solution was added, and the mixture was extracted with ethyl ether. After drying with MgSO ₄ , the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography to obtain 81 mg of methyl ester. yield
91%. IR (neat); 3350, 2910, 1735, 1460, 1265cm
^-1 . NMRδ (CDC1 ₃ ); 5.89 (d, 1H, J = 11Hz),
5.0-5.6 (m, 4H), 3.70 (s, 3H). Example 21 The following compound was obtained by the same operation as in Example 20. Table 9 shows the yield and spectral data.

[Table] Experimental Example 3 - Platelet aggregation inhibitory effect - In the same manner as in Experimental Example 1, the platelet aggregation inhibitory effect of the following compounds was measured. The results are shown in Table 10.

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a methyl group, or an ethyl group, A represents a cyclohexyl group, a 1-methyl-3-hexynyl group, or a 1-methylhexyl group, and carbon atoms at the 4th and 5th positions The double bond between is E
or Z, or a mixture thereof, and the asymmetric center in the substituent represented by A is R-configuration or S-configuration,
or a mixture thereof. ] A prostaglandin I ₂ analog compound or a non-toxic salt of its acid, or a cyclodextrin clathrate thereof. 2 General formula [In the formula, R ¹ represents a hydrogen atom, a methyl group, or an ethyl group, A represents a cyclohexyl group, a 1-methyl-3-hexynyl group, or a 1-methylhexyl group, and carbon atoms at the 4th and 5th positions The double bond between is E
or Z, or a mixture thereof, and the asymmetric center in the substituent represented by A is R-configuration or S-configuration,
or a mixture thereof. ] A platelet aggregation inhibitor comprising a prostaglandin I ₂ analogue compound or a non-toxic salt thereof, or a cyclodextrin clathrate thereof as an active ingredient. 3 General formula [In the formula, R ¹ represents a hydrogen atom, a methyl group, or an ethyl group, A represents a cyclohexyl group, a 1-methyl-3-hexynyl group, or a 1-methylhexyl group, and carbon atoms at the 4th and 5th positions The double bond between is E
or Z, or a mixture thereof, and the asymmetric center in the substituent represented by A is R-configuration or S-configuration,
or a mixture thereof. An anti-inflammatory agent containing as an active ingredient a prostaglandin I ₂ analog compound or a non-toxic salt of its acid, or a cyclodextrin clathrate thereof.