JPH0210150B2 - - Google Patents

Description

[Detailed Description of the Invention] <Industrial Application Field> The present invention provides novel 7-thiaprostaglandin E ₁
This field relates to alkenyl esters, their production methods, and drugs containing them as active ingredients. More specifically, novel 7-thiaprostaglandin E ₁ alkenyl esters and 7-thiaprostaglandin E ₁ carboxylic acids useful as pharmaceuticals are condensed with alkenyl alcohols in the presence of a condensing agent, and then deprotected as necessary. At least it relates to a method for producing the 7-thiaprostaglandin E ₁ alkenyl esters, and a drug containing the same as an active ingredient. <Prior Art> 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 effects, vasodilatory effects, etc., and its clinical application has begun. The biggest drawback of natural prostaglandins, especially PGE ₁ , is that they cannot be used orally because they are rapidly metabolized upon oral administration, and they usually have to be administered intravenously. Conventionally, various studies have been conducted on artificial prostaglandins in which one or two carbon atoms forming the skeleton of natural prostaglandins are replaced with sulfur atoms. For example, it has a skeleton in which the carbon atom at the 1st position is replaced with a sulfur atom (therefore, there is a sulfur atom at the 1st position, so it is displayed with the prefix 1S. Below, we will also refer to structures in which other positions are substituted with sulfur). Similarly, the number corresponding to the sulfur substitution position is prefixed with S) 1S
- Prostaglandin E ₂ or F ₂ α (J.Org.Chem.),
40, 521 (1975) and Japanese Patent Publication No. 53-34747), 3S-
11-deoxyprostaglandin E ₁ (Tetrahedron Letters, 1975 ,
765 and Journal of Medicinal Chemistry (J.Med.Chem.), 20 , 1662 (1977)), 7S―
Prostaglandin F ₁ α (J.Amer.Chem.
Soc.), 96 , 6757 (1974)), 9S-Prostaglandin E class ₁ (Tetrahedron Letters, 1974 , 4267 and
4459; Tetrahedron Letters
Lettera, 1976 , 4793 and Heterocycles, 6, 1097 (1977)), 11S-prostaglandin E ₁ or F ₁ α (Tetrahedron Letters, 1975 , 1165),
13S-Prostaglandin E or F (USP,
4080, 458 (1978)), and 15S-prostaglandin F ₂ (Tetrahedron Letters, 1977 , 1629). In addition, the present inventors previously succeeded in synthesizing 7-thiaprostaglandin E ₁ and reported it separately (Japanese Patent Application Laid-open No. 110562/1983, etc.). <Purpose of the invention> As a result of intensive research on the conversion of the ester moiety of 7-thiaprostaglandin E ₁ , which was previously reported, we have synthesized novel 7-thiaprostaglandin E ₁ alkenyl esters. The present invention was successfully achieved. <Structure and effects of the invention> In the present invention, the following formula [] In the formula, R ¹ represents a straight chain or branched C ₂ to C ₂₀ alkenyl group, R ² and R ³ are the same or different,
Hydrogen atom, tri(C ₁ - C ₇ ) hydrocarbon silyl group,
or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, or a group that forms an ester bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom, a methyl group, or a vinyl group, and R ⁵ represents a linear or branched chain. Branched _C3 - _C8 alkyl group; _C3 - _C8
straight or branched C1 _{- C5} substituted with an alkenyl group; a _C3 - _C8 alkynyl group; a _C3 - _C10 cycloalkyl group; or a _{C3 -} C10 cycloalkyl group
It represents an alkyl group, and n represents 0 or 1. A novel 7- compound represented by
Thiaprostaglandin E ₁ alkenyl esters are provided. R ¹ represents a straight chain or branched C ₂ -C ₂₀ alkenyl group. Examples include vinyl group, allyl group, 3-butenyl group, 2-butenyl group, 4-
pentenyl group, 2-petenyl group, prenyl group (3
-methyl-2-putenyl group), 2,4-hexadienyl group, 2,6-octadienyl group, neryl group, geranyl group, citronellyl group, farnesyl group, arachidyl group, and the like. Among these, allyl group, prenyl group, and geranyl group are particularly preferable as R ¹ . R ² and R ³ are the same or different, a hydrogen atom,
a group that forms an acetal bond with the oxygen atom of a tri(C ₁ to _{C 7} ) hydrocarbon silyl group or hydroxyl group;
Alternatively, it is a group that forms an ester bond with the oxygen atom of a hydroxyl group. As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, trimethylsilyl, triethylsilyl, t
- Tri(C ₁ to _{C 4} ) such as butyldimethylsilyl group
alkylsilyl, di(C ₁ -C ₄ )alkylphenylsilyl such as dimethylphenylsilyl, t-
Preferred examples include diphenyl( _C1 - _C4 )alkylsilyl such as butyldiphenylsilyl, triphenylsilyl, and tribenzylsilyl. Particularly preferred is t-butyldimethylsilyl group. Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2
-Ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex -4-yl group may be mentioned. Among these, 2-tetrahydropyranyl group is particularly preferred. Groups that form an ester bond with the oxygen atom of a hydroxyl group include, for example, formyl group, acetyl group,
( _C1 - _C5 ) alkanoyl groups such as propionyl group, butanoyl group, pentanoyl group; benzoyl group,
Substituted or unsubstituted benzoyl groups such as tolyl groups can be mentioned. Acetyl group and benzoyl group are particularly preferred. Among these, a hydrogen atom is particularly preferred as R ² or R ³ . In the above formula [], R ⁴ represents a hydrogen atom, a methyl group or a vinyl group. In the above formula [], R ⁵ is a linear or branched C ₃ -C ₈ alkyl group that may contain an oxygen atom; a C ₃ -C ₈ alkenyl group; a C ₃ -C ₈ alkynyl group; a phenyl group, a phenoxy group or a _C3 - _C10 cycloalkyl group; or
Straight chain or branched chain substituted with C ₁ - C ₆ alkoxy group, optionally substituted phenyl group, phenoxy group or C ₃ - C ₁₀ cycloalkyl group
Represents a _C1 - _C5 alkyl group. Straight-chain or branched _C3 - _C8 alkyl groups which may contain an oxygen atom include 2-methoxyethyl, 2-ethoxyethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 2-methyl-1 -butyl, 2-methylhexyl, 2-methyl-2-hexyl, 2-hexyl, 1,1-dimethylpentyl group, preferably 2-methoxyethyl, butyl, pentyl, hexyl, (R)- or (S)- 2-methylhexyl, 2-hexyl, 2-methyl-2-hexyl group, particularly preferably butyl, pentyl, hexyl, 2-hexyl,
(R)- or (S)-2-methylhexyl group can be mentioned. As the C ₃ to C ₈ alkenyl group, 2-putenyl group,
2-pentenyl group, 3-pentenyl group, 2-hexenyl group, 4-hexenyl group, 2-methyl-4-
Examples include hexenyl group and 2-octenyl group. As the C ₃ to C ₈ alkenyl group, 2-butynyl group,
2-pentynyl group, 3-pentynyl group, 2-hexynyl group, 4-hexynyl group, 2-methyl-4-
hexynyl group, 4-hexyn-2-yl group, 4-
Examples include heptyn-2-yl group. Examples of substituents for phenyl groups and phenoxy groups that may be substituted include halogen atoms, hydroxy groups, _C2 - _C7 acyloxy groups, _C1 - _C4 alkyl groups that may be substituted with halogen atoms, and halogen atoms. C ₁ -C ₄ alkoxy group, nitrile group, carboxyl group or (C _1
-C6 ) alkoxycarbonyl group and the like are preferred.
Examples of halogen atoms include fluorine, chlorine, bromine, etc.
In particular, fluorine or chlorine is preferred. Examples of _C2 - _C7 acyloxy groups include acetoxy, propionyloxy, n-butyryloxy, iso-butyryloxy, n-valeryloxy, caproyloxy, enantyloxy or benzoyloxy. Examples of C ₁ to C ₄ alkyl groups optionally substituted with halogen include methyl, ethyl, n-propyl, iso-propyl, n-butyl, chloromethyl,
Preferred examples include dichloromethyl and trifluoromethyl. Preferred examples of the _C1 - _C4 alkoxy group which may be substituted with halogen include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, trifluoromethoxy, etc. be able to.
Examples of the ( _C1 - _C6 ) alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl,
Examples include butoxycarbonyl, hexyloxycarbonyl, and the like. The substituted phenyl group has 1 to 3 substituents as described above.
, preferably one. Substituted or unsubstituted _C3 - _C10 cycloalkyl groups include saturated or unsaturated _C3 substituted or unsubstituted with the same substituents as mentioned above;
_-C10 , preferably _C5 - _C6 , such as cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. Straight chain or branched chain C 1 substituted with C ₁ - C ₆ alkoxy group, optionally substituted phenyl group _, phenoxy group, C ₃ - C ₁₀ cycloalkyl group
Among _C5 alkyl groups, _C1 to _C6 alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,
Examples include hexyl and oxy groups, and as the optionally substituted phenyl and phenoxy groups, the above-mentioned groups can be preferably used as they are.
The above-mentioned _C3 - _C10 cycloalkyl groups can be preferably mentioned as they are, and the straight-chain or branched _C1 - _C5 alkyl groups include methyl, ethyl, propyl, iso-propyl, butyl, and iso-propyl. -butyl, sec-butyl, t-butyl, pentyl, etc., and the substituent may be bonded to any position thereof. In the compound represented by the above formula [], n
represents 0 or 1. The configuration at position 8 of the compound represented by the above formula [] is the following formula [-1] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are the same as defined above. ] (8R) integral and the following formula [1-2] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are the same as defined above. ] (8S) represents either one of them or a mixture of them in any proportion. If n=0 in the above formula [], use the following formula [-3] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are the same as defined above. ] The natural configuration at position 15 represented by the following formula [-4] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are the same as defined above. ] represents either one of the non-natural configurations at position 15 or a mixture thereof in any proportion. The natural configuration at position 15 represented by the above formula [-3] is preferred. When n=1, it also includes (R), (S) at the 16th position, and a mixture thereof in any proportion. The configuration at the 11th and 12th positions of the compound represented by the above formula [] is a particularly useful stereoisomer because it is a natural prostaglandin E type ₁ . It also includes mixtures of proportions. Preferred specific examples of the novel 7-thiaprostaglandin E ₁ alkenyl esters represented by the above formula [] provided by the present invention include the compounds shown below. (1) 7-thiaprostaglandin E ₁ allyl ester (2) 7-thiaprostaglandin E _{1 2-} butenyl ester (3) 7-thiaprostaglandin E ₁ 2-pentenyl ester (4) 7-thia Prostaglandin E ₁ 4-pentenyl ester (5) 7-Thiaprostaglandin E ₁ prenyl ester (6) 7-Thiaprostaglandin E ₁ geranyl ester (7) 7-Thiaprostaglandin E ₁ citronellyl ester ( 8) 7-thiaprostaglandin E ₁ phalnesyl ester (9) 7-thiaprostaglandin E ₁ arachidyl ester (10) 7-thiaprostaglandin E ₁ 5-methyl-
3-henten-2-yl ester (11) 16-methyl-7-thiaprostaglandin
E ₁ allyl ester (12) 16,16-dimethyl-7-thiaprostaglandin E ₁ 2-butenyl ester (13) (17RS)-17,20-dimethyl-7-thiaprostaglandin E ₁ prenyl ester ( 14) (17R) -17,20-dimethyl-7-thiaprostaglandin E ₁ geranyl ester (15) (17S) -17,20-dimethyl-7-thiaprostaglandin E ₁ geranyl ester (16)17, 18-dehydro-7-thiaprostaglandin E ₁ 2,4-hexadienyl ester (17) 16-methyl-18,18,19,19-tetradehydro-7-thia-prostaglandin E ₁ citronellyl ester (18) 16,17,18,19,20-pentanol-16-phenyl-7-thia-prostaglandin E ₁ pharnesyl ester (19) 16,17,18,19,20-pentanol-16-phenoxy -7-Thia-prostaglandin E ₁
Arachidyl ester (20) 16,17,18,19,20-pentanol-16-cyclopentyl-7-thia-prostaglandin
E ₁ neryl ester (21) 16,17,18,19,20-pentanol-16-cyclohexyl-7-thiaprostaglandin
E ₁ allyl ester (22) 17,18,19,20-tetranol-16-propyloxy-7-thiaprostaglandin E ₁ butenyl ester (23) 17,18,19,20-tetranol-16-phenoxy- 7-Thiaprostaglandin E ₁ pentenyl ester (24) 15-deoxy-16-hydroxy-7-thiaprostaglandin E ₁ prenyl ester (25) 15-deoxy-16-hydroxy-16-vinyl-7-thiaprosta Grandin E ₁ citronellyl ester (26) 15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E ₁ geranyl ester (27) Hydroxyl group (11-position and 15
derivatives (28) in which the hydroxyl groups (11th and 15th positions) of the compounds of (1) to (26) are protected with t-butyldimethylsilyl groups (11th and 16th positions).
Derivatives (29) in which the hydroxyl groups (11th and 15th positions) of the compounds of (1) to (26) are protected with 2-tetrahydropyranyl groups (11th and 16th positions))
(or positions 11 and 16) are protected with an acetyl group. (30) Enantiomer of the compounds of (1) to (29) (31) Stereoisomer of the 8-position of the compounds of (1) to (30) (32) Stereoisomer of the 8-position of the compounds of (1) to (30) A mixture of stereoisomers in any proportion. Examples include, but are not limited to, the following. Also included are optical isomers at the 15th or 16th position of the compounds (1) to (32) and enantiomers of all of these. The novel 7-thiaprostaglandin E ₁ alkenyl esters of the present invention represented by the above formula [] and their enantiomers or mixtures thereof in arbitrary proportions are represented by the following formula (] In the formula, R ²¹ and R ³¹ are the same or different, and are a hydrogen atom, a tri(C ₁ - C ₇ ) hydrocarbon silyl group, a group that forms an acetal bond together with the oxygen atom of a hydroxyl group, or an ester bond together with the oxygen atom of a hydroxyl group. represents a group forming, R ⁴ is a hydrogen atom,
Represents a methyl group or a vinyl group, and R ⁵ is a straight or branched chain C ₃ that may contain an oxygen atom.
~ _C8 alkyl group; _C3 ~ _C8 alkenyl group; _C3 ~ _C8
Alkynyl group; optionally substituted phenyl group, phenoxy group or _C3 - _C10 cycloalkyl group; or _C1 - _C8 alkoxy group, optionally substituted phenyl group, phenoxy or _C3
- represents a linear or branched _C1 - _C5 alkyl group substituted with a _C10 cycloalkyl group, and n represents 0 or 1. Produced by condensing 7-thiaprostaglandin E ₁ carboxylic acids represented by the formula, its enantiomer, or a mixture thereof in any proportion with an alkenyl alcohol in the presence of a condensing agent, and then deprotecting as necessary. Can be done. Preferred values for R ²¹ and R ³¹ in the above formula [] are the same as those for R ² and R ³ above. Further, preferable values of R ³ , R ⁴ , R ⁵ , and n in the above formula [] are also the same as those described above. The condensing agent used in this reaction may be any agent that causes a condensation reaction between carboxylic acid and alcohol, such as dicyclohexylcarbodiimide, ethyl chloroformate, isobutyl chloroformate, trifluoroacetic anhydride, and the like. Preferred is dicyclohexylcarbodiimide. In this reaction, the condensing agent is 0.5 to 0 equivalents of 7-thiaprostaglandin E ₁ carboxylic acids represented by the above formula [],
Particularly preferably, 1 to 5 equivalents are used.
In this reaction, in order to proceed smoothly, a base such as 4-dimethylaminopyridine, pyridine, or triethylamine is added in an amount of 0.001 to 50 equivalents, preferably 0.01 to 50 equivalents.
Use 1 equivalent. Alkenyl alcohols are 0.5~
50 equivalents are used, preferably 1 to 3 equivalents. The reaction temperature is -78°C to 100°C, particularly preferably 0
A temperature range of about ℃ to 50℃ is adopted. The reaction time varies depending on conditions such as reaction temperature and is from 10 minutes to one week, but generally from about 30 minutes to several hours. 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, heptane, cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, tetrahydrofuran, dioxane,
Ether solvents such as dimethoxyethane and diethylene glycol dimethyl ether; halogen solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; other hexamethylphosphoric triamide (HMPA),
N,N-dimethylformamide (DMF), N,N
Examples include so-called aprotic polar solvents such as -dimethylacetamide, dimethylsulfoxide, sulfolane, and N-methylpyrrolidone, and it is also possible to use them as a mixed solvent of two or more solvents. Among these, halogen-based solvents such as methylene chloride are preferred as the solvent. The amount of organic medium used should be sufficient to allow the reaction to proceed smoothly, and is usually 1 to 100 times the amount of the raw materials, preferably 2 times the amount of the raw materials.
~20 times the amount is used. After the reaction, the resulting product is separated from the reaction solution and purified by conventional means. For example, extraction and washing, chromatography, or a combination thereof may be used. Furthermore, the compound with a protected hydroxyl group obtained here can then be subjected to a deprotection reaction if necessary. 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, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin is used as a catalyst, and water, tetrahydrofuran, etc. , ethyl ether, dioxane, acetone, acetonitrile, etc. as the reaction solvent.
The reaction usually takes place in the temperature range of -78°C to +50°C for 10 minutes to 3
It is held for about a day. In addition, the protecting group is tri(C ₁
~ _C7 ) In the case of a hydrocarbon silyl group, for example, acetic acid, tetrabutylammonium fluorite, cesium fluoride, hydrofluoric acid, hydrogen fluoride-pyridine, etc. are used, and the same temperature is used in the above reaction solvent. It will be carried out for about the same amount of time. 7 expressed by the above formula [] obtained in this way
-Thiaprostaglandin E ₁ alkenyl esters are useful compounds that have high pharmacological activity and are expected to improve selectivity of action and change pharmacokinetics (improved duration, etc.). Furthermore, among the thus obtained 7-thiaprostaglandin E ₁ alkenyl esters represented by the above formula [], derivatives in which R ² and R ³ are free hydroxyl groups have platelet aggregation inhibiting effects, vasodilatory effects, blood pressure It has prostaglandin-like effects such as depressing effect, and these physiological effects make it useful as a cardiovascular agent, such as a therapeutic or prophylactic agent for thrombosis, a platelet aggregation inhibitor, and an antihypertensive agent. In addition, gastrointestinal diseases such as duodenal ulcer, hepatitis,
Liver diseases such as fulminant hepatitis, hepatic coma, liver hypertrophy, and cirrhosis, pancreatic diseases such as pancreatitis, urinary diseases such as diabetic nephropathy, acute renal failure, cystitis, and urethritis, and respiratory diseases such as pneumonia and tracheitis. It can be used for the prevention and/or treatment of various diseases such as endocrine diseases, immune diseases, alcoholism, toxic symptoms such as carbon tetrachloride poisoning, and hypotension, and also for the prevention of cancer metastasis. For these purposes, the 7-thiaprostaglandin E ₁ alkenyl esters of the present invention can be administered orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, etc., but preferably Administration may be by oral or intracutaneous administration, and such routes of administration are convenient for the patient. 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 calcium carbonate, potato starch, alginic acid or lactose. The formulation is carried out according to conventional methods, but may contain additives other than diluents, such as lubricants such as magnesium stearate. Liquid preparations for oral administration include emulsions,
It can take the form of a bath solution, suspension, syrup or elixir. These can include commonly used inert diluents such as water or liquid paraffin. In addition to inert diluents, the preparations may also contain auxiliary agents, such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or preservatives. The liquid preparation may also be in the form of capsules of easily absorbed material such as gelatin. Liquid formulations may also be those in which the active ingredient is dissolved in fractionated coconut oil, coconut oil, soybean oil, corn oil, or the like. 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 nonaqueous solutions, suspensions, or emulsions. Non-aqueous solvents or suspending agents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation with a disinfectant, or by irradiation. Also,
A sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injectable solvent immediately before use. By using the 7-thiaprostaglandin E ₁ alkenyl esters of the present invention as a cyclodextrin inclusion compound, its stability increases and it becomes suitable for oral administration. It can also be formulated into a formulation. The clathrate compound can be prepared by, for example, dissolving cyclodextrin in water and/or a water-miscible organic solvent;
- Thiaprostaglandin E ₁ Produced by adding to alkenyl esters and heating the resulting mixture. The desired cyclodextrin clathrate compound is isolated by concentration under reduced pressure, by filtration with cooling, or by decantation. Cyclotextrin is α
-, β-, or γ-cyclodextrin, or a mixture thereof. The dosage of the 7-thiaprostaglandin E ₁ alkenyl ester of the present invention is 0.01 μg to 100 mg per kg body weight per day, preferably 1 μg to 10 mg. These dosages depend on the patient's medical condition, weight, age, or route of administration. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 (17R)-17,20-dimethyl-7-thia-
Dissolve 48 mg (0.12 mmol) of PGE ₁ in dry methylene chloride (1 ml) and add 62 μl of geraniol.
(0.36 mmol) was added. Under ice cooling, 4.5 mg (0.036 mmol) of 4-dimethylaminopyridine and then 37 mg (0.18 mmol) of dicyclohexylcarbodiimide were added, and the mixture was stirred for 30 minutes and then stirred at room temperature for 45 minutes. After adding ethyl acetate (15 ml) and filtering through Celite, water was added and the mixture was shaken using a separating funnel. After re-extracting the aqueous layer with ethyl acetate (15 ml), the combined organic layers were washed with an aqueous potassium hydrogen sulfate solution, an aqueous sodium hydrogen carbonate solution, and saturated brine, then dried over magnesium sulfate, and the solvent was distilled off. The resulting residue was separated and purified using silica gel column chromatography.
24 mg (yield 38%) of (17R)-17,20-dimethyl-7-thia-PGE ₁ geranyl ester was obtained in the hexane-ethyl acetate (1:1 to 3:7) eluate. NMR (CDCl ₃ , δ (ppm)); 0.89 (6H), 1.56 (3H, s), 1.67 (6H, s),
3.8~4.4 (2H, br), 4.51 (2H, d, J=7
Hz), 4.8 to 5.4 (2H, br), 5.61 (2H, m) IR (liquid film, cm ^-1 ); 3400, 2960, 2940, 2860, 1738, 1450,
1375, 1162, 965 Mass (FP-MS); 537 (M ⁺ +1) Example 2 (16RS)-15-deoxy-16-hydroxy-
16-Methyl-7-thiaprostaglandin E ₁ 100
mg (0.25 mmol) of dry methylene chloride (1.2
124 μl (0.72 mmol) of geraniol dissolved in
added. Under ice cooling, 9 mg (0.072 mmol) of 4-dimethylaminopyridine and then 74 mg (0.36 mmol) of dicyclohexylcarbodiimide were added, and the mixture was stirred for 30 minutes and then at room temperature for 1 hour. Ethyl acetate (20ml)
was added and filtered through Celite, water was added to the solution, and the mixture was shaken in a separatory funnel. After re-extracting the aqueous layer with ethyl acetate (20 ml), the combined organic layers were washed with an aqueous potassium hydrogen sulfate solution, an aqueous sodium hydrogen carbonate solution, and saturated brine, then dried over magnesium sulfate, and the solvent was distilled off. When the obtained residue was separated and purified by silica gel column chromatography, 70 mg (yield 52%) of (16RS)-15-deoxy-16-hydroxy-16- was found in the hexane-ethyl acetate (1:1) eluate.
Methyl-7-thiaprostaglandin E ₁ geranyl ester was obtained. NMR (CDCl ₃ , δ (ppm); 0.88 (3H, t), 1.14 (3H, s), 1.57 (3H,
s), 1.67 (6H, s), 3.9~4.3 (1H, br),
4.52 (2H, d, J=7Hz), 4.8~5.4 (2H,
br), 5.61 (2H, m) IR (liquid film, cm ^-1 ); 3400, 3960, 2940, 2860, 1740, 1450,
1160,965 Example 3 100 mg of 7-thiaprostaglandin E ₁ was dissolved in dry methylene chloride (1.5 ml), and 70 μl of allyl alcohol was added. Under ice-cooling, 5 mg of 4-dimethylaminopyridine and then 75 mg of dicyclohexylcarbodiimide were added, and the mixture was stirred for 15 minutes under ice-cooling and then at room temperature for 1 hour. Add ethyl acetate (20 ml) and add water (20 ml).
ml), the aqueous layer was re-extracted with 20 ml of ethyl acetate. The combined organic layers were washed successively with an aqueous potassium hydrogen sulfate solution, an aqueous sodium bicarbonate solution, and a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was separated and purified by silica gel column chromatography to obtain 52 mg (yield 47%) of 7-thiaprostaglandin E ₁ allyl ester in the hexane-ethyl acetate (2:3) eluate. NMR (CDCl ₃ , δ (ppm)); 0.88 (3H, t, J = 5Hz), 1.58 (3H, s),
1.67 (6H, s), 3.8~4.4 (2H, br), 4.55
(2H, bd, J=6Hz), 4.8~5.4 (2H, m),
5.4-6.0 (3H, m) Example 4 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 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 adjusted to 6-7×10 ⁵ /μl by dilution with PPP.
After adding 25 μl of the test drug to 250 μl of the adjusted PRP and preincubating at 37° C. for 2 minutes, 10 μM (final) of ADP was added, and changes in permeability were recorded using an acrigometer. The test drug was dissolved in ethanol to a concentration of 10 mg/ml, and then added to phosphate buffer (PH7.4).
It was used after being diluted sequentially. The aggregation inhibition rate was determined using the following formula. Inhibition rate (%) = (1-T/T ₀ ) × 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 _lC50 values. The results are shown in Table 1. [Table] Reference Example 1 Manufacture of Tablets Tablets each having the following composition were manufactured. Active ingredient 200μg Lactose 300mg Gym starch 80mg Polyvinylpyrrolidone 10mg Magnesium stearate 5mg 400mg Mix the active ingredient, lactose and Gyote starch, moisten it evenly with a 20% ethanol solution of polyvinylpyrrolidone, and pass through a 20 mesh sieve. , dried at 45°C, and passed through a 20-mesh sieve again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets. The compound obtained in Example 1 was typically used as the active ingredient. Reference Example 2 Production of Capsules Hard gelatin capsules were produced, each capsule containing the following composition. Active ingredient 200 μg Microcrystalline cellulose 300 mg Amorphous silicic acid 5 mg 315 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 compound obtained in Example 2 was typically used as the active ingredient. Reference Example 3 Production of Powder A powder having the following composition was produced. Active ingredient 200 μg Lactose 100 mg Corn starch 100 mg Hydroxypropyl cellulose 10 mg 220 mg The active ingredient (compound obtained in Example 1), lactose and corn starch are mixed, then an aqueous solution of hydroxypropyl cellulose is added and mixed, and dried to form a preparation. The drug was manufactured. Reference Example 4 Manufacture of soft capsules (17R)-17,20-dimethyl-7-thiaprostaglandin E ₁ geranyl ester is dissolved in fractionated coconut oil, and then the shell components of the following composition are dissolved by heating, (17R) in 1 capsule - 17,20
-Dimethyl-7-thiabbrostaglandin E ₁
Soft capsules containing 200 μg of geranyl ester were prepared using a soft capsule manufacturing machine in a conventional manner. Gelatin 10 parts by weight Glycerin 2 〃 Titanium White 0.2 〃 Water 0.2 parts by weight

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ represents a straight chain or branched C ₂ to C ₂₀ alkenyl group, R ² and R ³ are the same or different,
Hydrogen atom, tri(C ₁ - C ₇ ) hydrocarbon silyl group,
or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, or a group that forms an ester bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom, a methyl group, or a vinyl group, and R ⁵ represents a linear or branched chain. Branched _C3 - _C8 alkyl group; _C3 - _C8
Alkenyl group; _C3 - _C8 alkynyl group; _{C3 - C10} cycloalkyl group; or straight or branched C1- _{C5 substituted with a C3-C10 cycloalkyl} group _.
It represents an alkyl group, and n represents 0 or 1. ] Novel 7- which is a compound represented by and their enantiomers or mixtures thereof in arbitrary proportions.
Thiaprostaglandin E ₁ alkenyl esters. 2 Claim 1 in which R ¹ is a geranyl group
Novel 7-thiaprostaglandin E ₁ alkenyl esters described in . 3. The novel 7-thiaprostaglandin E ₁ alkenyl esters according to claim 1, wherein R ¹ is an allyl group. 4. A novel 7-thiaprostaglandin E ₁ alkenyl ester according to any one of claims 1 to 3, wherein n is 0. 5. A novel 7-thiaprostaglandin E ₁ alkenyl ester according to any one of claims 1 to 3, wherein n is 1. 6. Novel 7- according to any one of claims 1 to 5, wherein R ² and R ³ are both hydrogen atoms.
Thiaprostaglandin E ₁ alkenyl esters. 7 R ⁵ is n-butyl group, n-pentyl group or 2
- methylhexyl group, the novel 7-thiaprostaglandin E ₁ alkenyl esters according to any one of claims 1 to 6. 8 The following formula [] [In the formula, R ²¹ and R ³¹ are the same or different and are a hydrogen atom, a tri(C ₁ - _{C 7} ) hydrocarbon silyl group, a group that forms an acetal bond with the oxygen atom of a hydroxyl group, or an ester bond with the oxygen atom of a hydroxyl group. Represents a group that forms a bond, R ⁴ is a hydrogen atom,
Represents a methyl group or a vinyl group, ^R5 is a linear or branched _C3 - _C8 alkyl group; a _C3 - _C8 alkenyl group; a _C3 - _C8 alkynyl group; a _C3 - _C10 cycloalkyl group; or a straight chain or branched C1 _{- C5} alkyl group substituted with a _C3 - _C10 cycloalkyl group, and n represents 0 or 1. ] The following formula [] is characterized by condensing 7-thiaprostaglandin E ₁ carboxylic acids represented by the formula with an alkenyl alcohol in the presence of a condensing agent, and then deprotecting as necessary. [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are the same as defined above. ] A novel 7-thiaprostaglandin represented by
E ₁ Method for producing alkenyl esters. 9. The method for producing novel 7-thiaprostaglandin E ₁ alkenyl esters according to claim 8, wherein the condensing agent is dicyclohexylcarbodiimide.