JPH0141143B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is a novel 6-nitroprostaglandin
Class E ₁ relates to its manufacturing method and drugs containing it as an active ingredient. Natural prostaglandins are known as local hormones with high biological and pharmacological activity, and therefore many studies have been conducted on their derivatives. Among natural prostaglandins, prostaglandin E ₁ has strong platelet aggregation inhibitory and vasodilatory effects, and is expected to have clinical application. Recently, 6-oxoprostaglandin E ₁ , which is considered to be a derivative of prostaglandin E ₁ , has been discovered as one of the arachidonic acid metabolites in vivo.
Its unique physiological activity has attracted attention. From this point of view, various studies have been conducted on various 6-oxoprostaglandin E ₁ derivatives and 6-hydroxyprostaglandin E ₁ derivatives. As a result of intensive research aimed at introducing a functional group into the 6-position of prostaglandin E ₁ , the present inventor found that
Prostaglandin with a nitro group introduced at the 6th position
The present invention was achieved by successfully synthesizing an E ₁ derivative. Moreover, the obtained compound exhibits a platelet aggregation inhibiting effect, and is therefore a drug that controls vascular activity, such as antianginal pectoris, vasodilation, lowering blood pressure, antimyocardial infarction, antithrombotic, antiarteriosclerotic, and suppressing metastasis of malignant tumors. The present invention further provides a method for producing the above-mentioned novel 6-nitroprostaglandin E ₁ . That is, the present invention provides the following formula [] [In the formula, R ¹ represents a hydrogen atom, a C ₁ to _{C 10} alkyl group, a 5- to 6-membered alicyclic group, a phenyl group, or a pharmaceutically acceptable cation, and R ² and
R ³ is the same or different, hydrogen atom, tri(C ₁
~ _C6 ) represents a hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and ^R4 is a linear or branched alkyl group that may contain a _C4 to _C8 oxygen atom. , a 5- to 6-membered alicyclic group, or a ( _C1 - _C2 ) alkyl group substituted with a 5- to 6-membered alicyclic group. ] 6-nitroprostaglandin E class ₁ , which is a compound represented by the above, its stereoisomer, or a mixture thereof in any proportion, and a method for producing the same, and a drug containing the same as an active ingredient. In the above formula [], R ¹ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a 5- to 6-membered alicyclic group, a phenyl group, or a pharmaceutically acceptable cation. C ₁
~ _C10 alkyl groups include methyl group, ethyl group,
Examples include propyl group, butyl group, t-butyl group, hexyl group, decyl group, etc., but methyl group and ethyl group are preferable. Examples of 5- to 6-membered alicyclic groups include cyclopentyl and cyclohexyl groups, and pharmaceutically acceptable cations include alkali metal ions such as sodium and potassium, calcium, ammonium, ethanolamine, diethanolamine, and morpholine. are mentioned, but sodium ion is preferred. Particularly preferable R ¹ is a hydrogen atom, a methyl group, or a sodium ion. R ² and R ³ are the same or different, a hydrogen atom,
Represents a tri(C ₁ -C ₆ ) hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. Examples of the tri( _C1 - _C6 ) hydrocarbon-silyl group include trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group,
Examples include t-butyldiphenylsilyl group, and t-butyldimethylsilyl group is particularly preferred.
Groups that form an acetal bond with the oxygen atom of a hydroxyl group include, for example, a methoxymethyl group, a 1-
Ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group or 6 ,6-dimethyl-3-oxa-2-oxo-bicyclo[3,1,0]hex-4-yl group, and 2-tetrahydropyranyl group is particularly preferred. These silyl groups and groups forming acetal bonds are to be understood as protecting groups for hydroxyl groups. These protecting groups can be easily removed under mildly acidic to neutral conditions to give the final product, the free hydroxyl group, which is useful as a drug. Hydrogen atoms are particularly preferred as R ² and R ³ . R ⁴ is a linear or branched alkyl group which may contain a C ₄ to C ₈ oxygen atom, a 5 to 6 membered alicyclic group, or a 5 to 6 membered alicyclic group substituted ( _C1 - _C2 ) represents an alkyl group. Examples of the linear or branched alkyl group that may contain a _C4 to _C8 oxygen atom include a 2-ethoxyethyl group, a pentyl group, a hexyl group, a 2-hexyl group,
Examples include a 2-methylhexyl group, a heptyl group, an octyl group, and preferably a pentyl group, a hexyl group, a 2-hexyl group, a 2-methylhexyl group, and the like. Examples of the 5- to 6-membered alicyclic group include a cyclopentyl group and cyclohexyl group; examples of the (C ₁ to C ₂ ) alkyl group substituted with a 5- to 6-membered alicyclic group include a cyclopentylmethyl group, a cyclohexylmethyl group, and a 2- cyclopentylethyl group, 2-cyclohexylethyl group, 1-cyclopentylethyl group,
Examples include 1-cyclohexylethyl group. As ^R4 , 2-ethoxyethyl group, pentyl group, hexyl group, 2-hexyl group, 2-methylhexyl group, cyclopentyl group, cyclohexyl group, cyclopentylmethyl group, and cyclohexylmethyl group are particularly preferable. Furthermore, natural prostaglandin E ₁ is a particularly useful derivative because it has the configuration shown in the above formula [], but the present invention also includes its stereoisomers or mixtures thereof in arbitrary proportions. . The following three types of stereoisomers can be mainly cited, taking into consideration the production method described below. That is, the following formulas ['], []ent, and []'ent. [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as defined above. ] Specific examples of the 6-nitroprostaglandin E ₁ represented by the above formula [ ] provided by the present invention include the compounds shown below. 01 6-nitroprostaglandin E ₁ 02 6-nitro-18-oxaprostaglandin
E ₁ 03 20-methyl-6-nitroprostaglandin
E ₁ 04 17,20-dimethyl-6-nitroprostaglandin E ₁ 05 16,17,18,19,20-pentanol-15-cyclohexyl-6-nitroprostaglandin
E ₁ 06 16,17,18,19,20-pentanol-15-cyclopentyl-6-nitroprostaglandin
E ₁ 07 17,18,19,20-Tetranor-16-cyclohexyl-6-nitroprostaglandinE ₁ 08 15-Epimers of compounds of 01) to 07) 09 Enantiomers of compounds of 01) to 08) 10 Methyl esters of compounds 01) to 09) 11 Ethyl esters of compounds 01) to 09) 12 Sodium salts of compounds 01) to 09) 13 Hydroxyl groups (11th and 15th positions) of compounds 01) to 11) )
Examples include, but are not limited to, ethers protected with a t-butyldimethylsilyl group and/or a 2-tetrahydropyranyl group. The 6-nitroprostaglandin E type ₁ of the present invention has the following formula [] [In the formula, R ²¹ represents a tri(C ₁ -C ₆ ) hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] 4-Substituted-2-cyclopentenones or their enantiomers represented by the following formula [] [In the formula, R ³¹ represents a tri(C ₁ to _{C 6} ) hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and Y is an iodine atom, a phenylthio group, or a (C ₁ to C ₅ ) It represents an alkyl-substituted ethynyl group or a cyano group, and R ⁴ is as defined above. ] Organocopper lithium compound or its enantiomer, or a mixture thereof in any proportion;
Conjugate addition reaction in an aprotic organic solvent,
Next, the following formula [] [In the formula, R ¹¹ is a C ₁ to C ₁₀ alkyl group, 5 to 6
represents a member alicyclic group or phenyl group. ] Reacted with nitroolefins represented by
By subjecting it to deprotection and/or hydrolysis and/or salt formation reaction as necessary, the following formula [] [In the formula, R ¹ , R ² , R ³ , and R ⁴ are the same as defined above. ] It is possible to produce 6-nitroprostaglandin E ₁ , which is a compound represented by the following, its stereoisomer, or a mixture thereof in any proportion. The 4-substituted-2-cyclopentenones represented by the above formula [], which are the starting materials of the present invention, are known substances and are easily available. Since the production method of the present invention uses a reaction that proceeds stereospecifically, from the starting material having the configuration represented by the above formula [], the compound of the above formula [] and/or the above formula []' can be obtained. Furthermore, compounds of the formula []ent and/or []'ent can be obtained from a starting material having a configuration opposite to that of the above formula [],
Starting from an optical mixture of arbitrary proportions, a mixture of corresponding proportions is obtained. In the above formula [], ^R21 represents a tri( _C1 - _C6 ) hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and the same groups as mentioned for ^R2 are preferred. However, t-butyldimethylsilyl group and 2-tetrahydropyranyl group are particularly preferred. In the method of the present invention, the organocopper lithium compound represented by the above formula [], which is the other raw material compound, its enantiomer, or a mixture thereof in any proportion can be prepared by a method known per se [e.g.
GHPosner, Organic Reaction, vol. 19 , 1
(1972)] or by a method separately proposed by the present inventors. That is,
This is a method of reacting a corresponding organolithium compound with a cuprous salt, and in this method, the compound represented by the formula [] is reacted with a trivalent phosphorus compound, for example, trialkylphosphine, as an organocopperlithium compound. (e.g. triethylphosphine,
complexes with tri-n-butylphosphine, etc.), trialkyl phosphites (e.g., trimethylphosphite, triethylphosphite, triisopropylphosphite, tri-n-butylphosphite, etc.), or hexamethylphosphorustriamide, etc. It may also be used as The method of the present invention is carried out by reacting a 4-substituted-2-cyclopentenone represented by the above formula [] with an organocopper lithium compound represented by the above formula [] in the presence of an aprotic inert organic medium. It will be done. The 4-substituted-2-cyclopentenone and the organocopper lithium compound react in equimolar terms stoichiometrically, but usually 0.5 to 1 mole per mole of the 4-substituted-2-cyclopentenone. This is carried out using an organocopper lithium compound in an amount of 2.0 mol, particularly preferably 1.5 mol. The reaction temperature is -120°C to 0°C, particularly preferably -
A temperature range of about 90°C to -30°C is adopted. The reaction time varies depending on the reaction temperature, but is usually between -78°C and -20°C.
A reaction time of about 1 hour at ℃ is sufficient. The reaction is carried out in the presence of an organic medium. An inert aprotic organic medium is used that is liquid at the reaction temperature and does not react with the reaction reagents. Such aprotic inert organic medium includes:
For example, saturated hydrocarbons such as pentane, hexane, and heptane, aromatic hydrocarbons such as benzene, toluene, and xylene, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and other hexamethylphosphorics. These include so-called aprotic polar solvents such as triamide (HMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), dimethylsulfoxide, sulfolane, and N-methylpyrrolidone. It is also possible to use a mixed solvent of the above solvents. Further, as the aprotic inert organic medium, the inert medium used for producing the organocopper lithium compound can also be used as it is.
That is, in this case, the reaction may be carried out by adding the 4-substituted-2-cyclopentenones into the reaction system in which the organocopper lithium compound was produced. The amount of organic medium used is sufficient as long as it allows the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the raw materials, preferably 2 to 30 times the volume. In the method of the present invention, an alkenyl group, which is an organic group of the organocopper lithium compound, is added to the 3-position of the 4-substituted-2-cyclopentenone through the previous operations, and an anion is added to the 2-position. It is assumed that the ions are in the form of so-called conjugated addition enolates. In the method of the present invention, for this conjugated addition enolate, the formula [] [In the formula, R ¹¹ is a C ₁ to C ₁₀ alkyl group, 5 to 6
represents a member alicyclic group or phenyl group. ] This is achieved by reacting with a nitroolefin represented by the following. R ¹¹ represents a C ₁ to C ₁₀ alkyl group, a 5 to 6-membered alicyclic group, or a phenyl group, and specific examples include the same groups as those exemplified for R ¹ , but methyl group, ethyl group, etc. Particularly preferred are groups. The nitroolefins are synthesized according to general nitroolefin synthesis methods and are relatively easily available compounds, for example, Yoshigoshi et al., Journal of
the American Chemical Society, 98 , 4679
(1976) and its cited documents are used as reference, and the process is illustrated as follows. [In the formula, R represents a hydrogen atom or a C ₁ to C ₁₀ hydrocarbon group. ] The reaction is a 4-substituted-2-
In the reaction system conjugated to cyclopentenones,
This is carried out by adding the nitroolefin represented by the above formula [], which may be diluted with the above aprotic organic medium. The nitroolefin reacts stoichiometrically equimolarly with the enolate produced by conjugate addition, but usually 0.5 to 2.0 mol per mol of the 4-substituted-2-cyclopentenone used initially. This is carried out using twice the molar amount, particularly preferably 0.8 to 1.2 times the molar amount. Reaction temperature is -120℃~0℃, preferably -90℃
A temperature range of about -30°C is adopted. Reaction time varies depending on reaction temperature, but usually -78℃ to -40℃
It is sufficient to allow the reaction to proceed for about 1 hour, and it is efficient to follow and determine the end point of the reaction using thin layer chromatography or the like. After the reaction, the resulting product is separated from the reaction solution and purified by conventional means. For example, extraction, washing,
It is carried out by chromatography or a combination of these methods. In this way, the hydroxyl group of the compound represented by the above formula [] is protected, and an ester of the carboxylic acid at the 1-position is obtained. Then, if necessary, the protecting group of the hydroxyl group is converted into a free hydroxyl group by a conventional method, and/or the ester is hydrolyzed and/or salt-formed by a conventional method to obtain the present invention. 6
- Nitroprostaglandin E class ₁ is produced. To give one example, removal of the hydroxyl protecting group is
When the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, p-toluenesulfonic acid, its pyridinium salt, or a cation exchange resin is used as a catalyst, and water, tetrahydrofuran, ethyl ether, dioxane, etc. are used as a catalyst. , methanol, ethanol, acetone, acetonitrile, etc. as the reaction solvent.
The reaction usually takes 10 minutes or more at a temperature range of -78°C to +100°C.
It will be held for about 3 days. In addition, when the protecting group is a tri(C ₁ -C ₆ ) hydrocarbon silyl group, for example, acetic acid, hydrofluoric acid, tetrabutylammonium fluoride, cesium fluoride, etc. are used as catalysts, and the protective group is reacted in the reaction solvent as described above. at similar temperatures and for similar times. In the case of an ester, the protective group for the carboxyl group is removed by using an enzyme such as lipase in the reaction solvent described above at a temperature of -10°C to +100°C for about 10 minutes to 24 hours. According to the present invention, the carboxyl group-containing compound produced by the above-mentioned protecting group removal reaction is then, if necessary, further subjected to a salt-forming reaction to give a carboxylic acid salt. The salt-forming reaction is known per se, and involves neutralizing a carboxylic acid with approximately the same amount of a basic compound, such as sodium hydroxide, potassium hydroxide, sodium carbonate, or ammonia, trimethylamine, monoethanolamine, morpholine, in a conventional manner. This is done by causing a reaction. 6-nitroprostaglandin E type ₁ represented by the above formula [] (including []', []ent and []'ent) produced by the above method, in which R ² and R ³ are hydrogen The following formula []′ which is an atom [In the formula, R ¹ and R ⁴ are the same as defined above. ] 6-nitroprostaglandin E class ₁ , which is the compound represented by the formula and its stereoisomers or mixtures thereof in arbitrary proportions, has platelet aggregation inhibiting activity, and therefore has antianginal, vasodilatory, and antihypertensive effects. ,
It can be used as a drug that controls vascular activity, such as anti-myocardial infarction, anti-thrombosis, anti-arteriosclerosis, and inhibition of malignant tumor metastasis. To give an example of physiological activity, 6-nitroprostaglandin E ₁ which is the compound obtained in Example 3
Methyl ester is rabbit PRP (platelet count 60×10 ⁴ /
As a result of evaluation using ADP (20 μM) as a coagulant, the IC ₅₀ was 4.5 to 0.5 μg/ml. These compounds can be administered orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, etc., for the above purpose, but oral or intravenous administration is preferred. For oral administration, it is formulated into solid or liquid preparations. Solid preparations include tablets, pills, powders, and granules. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as the commonly used sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethyl cellulose, etc. be done. The formulation is made according to conventional methods, but additives other than diluents,
For example, lubricants such as calcium stearate, magnesium stearate, and glycerin may be included. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, clouding agents, syrups or xyls, and commonly used inert diluents such as water or liquid paraffin. including. In addition to inert diluents, the formulations may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, stabilizers, or preservatives. Alternatively, the liquid preparation may be administered in a capsule made of an absorbable material such as gelatin. Solid preparations for rectal administration include suppositories containing one or more active substances and prepared by methods known per se. Preparations for parenteral administration are sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solutions or suspensions include, for example, propyl glycol, polyethylene glycol or vegetable oils such as olive oil, injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, and stabilizing agents. These can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of a disinfectant, or by irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use. The dosage of 6-nitroprostaglandin E ₁ , which is the active compound of the present invention, is 0.001 to 200 mg per kg of body weight per day, preferably 0.01 to 50 mg.
These dosages depend on the patient's medical condition, weight, age, or route of administration. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 (E)-dl-3-t-butyldimethylsilyloxy-1-iodo-1-octene (478 mg, 1.3 mmol)
A 2.2M solution of t-butyllithium in pentane (1.2ml, 2.6mmol) was added to an ether solution (10ml) of
It was added at 78°C and stirred for 2 hours. Add to this solution an ether solution (3 ml) of cuprous iodide (248 mg, 1.3 mmol) and tributylphosphine (578 mg, 2.9 mmol).
was added and stirred at -78°C for 1 hour. dl to this solution
A solution of -4-t-butyldimethylsilyloxy-2-cyclopentenone (212 mg, 1.0 mmol) in ether (6 ml) was added, and the mixture was stirred at -78°C for 15 minutes and at -40°C for 1 hour. After cooling to -78℃, 1-(4-methoxycarbonylbutyl)-1-nitroethylene (187
Add a solution of 1.0 mg, 1.0 mmol) in ether (5 ml).
The mixture was stirred for 1 hour at -40°C and for 30 minutes at -20°C. Ether was added, washed with an ammoniacal ammonium chloride aqueous solution, then an ammonium chloride aqueous solution, dried over magnesium sulfate, and concentrated to 1.74
g of crude product was obtained. This product was subjected to silica gel column chromatography (hexane: ethyl acetate =
A mixture of dl-11,15-bis(t-butyldimethylsilyl)-6-nitroprostaglandin E ₁ methyl esters and their 15-epimers (232 mg, 0.362 mmol, 36%) I got it. NMR ( _CDCl3 , δ (ppm)); 0.06 (12H, s), 0.84-0.86 (21H), 1.1-2.6
(22H, m), 3.61 (3H, s), 3.8~4.3 (2H,
m), 4.5-5.2 (1H, m), 5.35-5.55 (2H,
m). IR (liquid film, cm ^-1 ); 1740, 1555, 1460, 1440, 1360, 1255,
1160, 1100, 1005, 970, 875, 860, 840,
810,775. Mass (20eV; m/e, %); 626 (1, M-Me), 610 (4, M-OMe),
584 (29, M- ^t Bu), 570 (38), 553 (23), 498
(17), 493 (20), 464 (22), 438 (26), 421
(28), 405 (20), 330 (40), 299 (36), 277
(100), 245 (20), 215 (20), 175 (25), 75
(94). Example 2 (E)-3 was prepared in exactly the same manner as in Example 1.
(S)-t-Butyldimethylsilyloxy-1-iodo-1-octene (1.21 g, 3.3 mmol; [α] ²¹ _D
30.6°) and 4(R)-t-butyldimethyloxy-
2-cyclopentenone (636 mg, 3.0 mmol) and 11,15-bis(t-butyldimethylsilyl)-
6-nitroprostaglandin E ₁ methyl ester (656 mg, 1.023 mmol, 34%) was obtained. The NMR, IR, and Mass of this product matched those of the compound obtained in Example 1. [α] ²¹ _D −22.3° (MeOH, C0.71) Example 3 11,15-bis(t-butyldimethylsilyl)-6-nitroprostaglandin E ₁ methyl ester obtained in Example 2 (494 mg , 0.77 mmol) was dissolved in acetonitrile (10 ml), 1 ml of 47% hydrofluoric acid was added, and the mixture was stirred at room temperature for 1.5 hours. The mixture was neutralized with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to obtain 290 mg of crude product. Separated by silica gel column chromatography (hexane: ethyl acetate = 1:4), 6-nitroprostaglandin E ₁ methyl ester (256 mg, 0.62 mmol, 81
%) was obtained. NMR ( _CDCl3 , δ (ppm)); 0.87 (3H, m), 1.0-3.1 (24H, m), 3.57
(3H, s), 3.8~4.2 (2H, m), 4.5~5.1
(1H, m), 5.3-5.6 (2H, m). IR (liquid film, cm ^-1 ); 1740, 1550, 1435, 1360, 1245, 1200,
1160, 1075, 1015, 975. Mass (20eV; m/e, %); 395 (3, M- _H2O ), 377(3), 364(3), 347(8),
342(9), 324(27), 315(15), 299(13), 298
(12), 277 (38), 245 (40), 227 (22), 217
(42), 199 (27), 99 (100), 71 (38). [α] ²² _D −24.5° (MeOH, C0.20) Examples 4 to 7 The following compounds were synthesized in exactly the same manner as in Examples 2 and 3. Spectra are displayed together. The compound is 16,17,18,19,20-pentanol-16-cyclohexyl-6-nitroprostaglandin
E ₁ methyl ester (Example 4), 16, 17, 18,
19,20-pentanol-15-cyclopentyl-6-
Nitroprostaglandin E ₁ methyl ester (Example 5), 17(R),20-dimethyl-6-nitroprostaglandin E ₁ methyl ester (Example 6), and 17(S),20-dimethyl-6 - Nitroprostaglandin E ₁ methyl ester (Example 7).

[Table] Example 8 In vitro platelet aggregation inhibitory effect The in vitro platelet aggregation inhibitory effect of the test drug was assayed using rabbits. That is, blood was collected from the ear vein of a Japanese white male domestic rabbit weighing 2.5 to 3.5 kg at a ratio of 9 parts blood to 1 part 3.8% trisodium citrate solution.
After centrifugation at 1000 rpm for 10 minutes, the upper layer was separated as PRP (platelet rich plasma). The lower part is further
The mixture was centrifuged at 2800 rpm for 10 minutes, and the upper layer separated into two layers was separated as PPP (platelet poor plasma). The platelet count was diluted and adjusted to 6×10 ⁵ /μl with PPP. Add 25 μl of the test drug to 250 μl of adjusted PRP and pre-incubate at 37°C for 2 minutes, then add 20 μM ADP.
(final) was added and the change in transmittance was recorded using an acrigometer. The test drug is ethanol.
After dissolving the solution to a concentration of 10 mg/ml, it was diluted sequentially with phosphate buffer (PH7.4) and used. The aggregation inhibition rate was determined using the following formula. Inhibition rate (%) = (1-T/T ₀ ) x 100 T ₀ : Permeability of (phosphate buffer added system) T : Permeability of test drug added system Minimum of drugs with inhibition rate exceeding 50% Concentrations were expressed as IC ₅₀ values. The IC ₅₀ was determined using 6-nitroprostaglandin E ₁ methyl ester of Example 3 as a test drug and was found to be 4.5 to 0.5 μg/ml. Example 9 (Preparation of tablets) 1 tablet was manufactured having the following composition. Active Ingredients 200mg Lactose 280mg Gym Starch 80mg Polyvinylhyrolidone 11mg Magnesium Stearate 5mg 576mg The active ingredients, lactose and Gyote starch were mixed, evenly moistened with a 20% ethanol solution of polyvinylhyrolidone, and passed through a 20mm mesh sieve. , dried at 45°C, and passed through a 15 mm mesh sieve again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets. As active ingredients, typically Examples 3 and 4
The compound was used. Example 10 (Formulation of Capsules) Hard gelatin capsules were prepared, each capsule containing the following composition: Active Ingredients 200 mg Microcrystalline Cellulose 195 mg Amorphous Silicic Acid 5 mg 400 mg The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into hard gelatin capsules. The compounds of Examples 3 and 4 were typically used as active ingredients. Example 11 (Preparation of ampoule) An ampoule containing the following composition in one ampoule (5 ml volume) was manufactured. Active ingredient 200 mg Polyethylene glycol 600 200 mg Distilled water Total volume 50 ml Polyethylene glycol and active ingredient were dissolved in water under steam, which was boiled, cooled under steam and distilled. The pretreated water was added to this solution and the volume given was filtered under sterile conditions. This production is carried out under diffused light. Filling is done in a nitrogen stream and sterilization is at 121℃
It lasted for 20 minutes. Note that the compounds of Examples 3 and 4 were used as the above active ingredients. Example 12 Dissolve 10 mg of the compound of Example 3 in 5 ml of ethanol, sterilize it through a bacteria retention filter, add 0.1 ml per 1 ml ampoule, and seal the ampoule. The contents of the ampoule are diluted to the appropriate volume. For example, dilute to 1 ml with Tris-HCl buffer of pH 8.6 for injection administration. Example 13 (Toxicity test) Compound of Example 6 (TEI8091) and Example 7
An acute toxicity test was performed on ICR male mice (5 weeks old) using the compound (TEI8040). TEI8091 has an LD ₅₀ of 500 to 700 mg/Kg,
TEI8090 had an LD ₅₀ of >800 mg/Kg.

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group, or a pharmaceutically acceptable cation, R ² and R ³ are the same or different, and represent a hydrogen atom, a tri(C ₁ -C ₆ ) Represents a hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ is a C ₄ to _{C 8} linear or branched alkyl group, or a 5 to 6-membered alicyclic group , or a (C ₁ -C ₂ ) alkyl group substituted with a 5- to 6-membered alicyclic group. ] 6-nitroprostaglandin E type ₁ , which is a compound represented by the following, its stereoisomer, or a mixture thereof in any proportion. 2. 6-nitroprostaglandin E ₁ type according to claim 1, which is a compound represented by the above formula []. 3. 6-nitroprostaglandin E ₁ class according to claim 1 or 2, wherein in the above formula [], R ¹ is a hydrogen atom, a methyl group, or a sodium ion. 4. 6-nitroprostaglandin E ₁ class according to any one of claims 1 to 3, wherein in the above formula [], R ² and R ³ are hydrogen atoms. 5 In the above formula [], R ⁴ is a pentyl group, hexyl group, 2-hexyl group, 2-methylhexyl group, 2-ethoxyethyl group, cyclopentyl group,
Claim 1, which is a cyclohexyl group, a cyclopentylmethyl group, or a cyclohexylmethyl group
6-nitroprostaglandin E type ₁ according to any one of items 4 to 4. 6 The following formula [] [In the formula, R ²¹ represents a tri(C ₁ -C ₆ ) hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] 4-Substituted-2-cyclopentenones or their enantiomers represented by the following formula [] [In the formula, R ³¹ represents a tri(C ₁ to _{C 6} ) hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and Y is an iodine atom, a phenylthio group, or a (C ₁ to C ₅ ) It represents an alkyl-substituted ethynyl group or a cyano group, and R ⁴ is as defined above. ] Organocopper lithium compound or its enantiomer, or a mixture thereof in any proportion;
Conjugate addition reaction in an aprotic organic solvent,
Then, the following formula [] [In the formula, R ¹¹ is a C ₁ to C ₁₀ alkyl group, 5 to 6
represents a member alicyclic group or phenyl group. ] Reacted with nitroolefins represented by
The following formula [], which is subjected to deprotection and/or hydrolysis and/or salt-forming reaction as necessary. [In the formula, R ¹ , R ² , R ³ , and R ⁴ are the same as defined above. ] A method for producing 6-nitroprostaglandin E ₁ , which is a compound represented by the following and its stereoisomers, or a mixture thereof in arbitrary proportions. 7 The following formula [′] [In the formula, R ¹ and R ⁴ are the same as defined above. ] A compound for controlling vasoactivity containing 6-nitroprostaglandin E class ₁ , which is the compound represented by the above, its stereoisomer, or a mixture thereof in any proportion, as an active ingredient together with a pharmaceutically acceptable carrier. drug. 8 Claim No. 7 for inhibiting platelet aggregation
Drugs listed in section.