JPS61204163A - 7-thiaprostaglandin e1 alkenyl ester compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is 2-20C alkenyl; R<2> and R<3> are H tri(1-7C hydrocartbon) silyl, a group forming acetal bond together with O of hydroxyl group, etc.; R<4> is H, methyl or vinyl; R<5> is 3-8C alkyl, 3-8C alkyl, 3-8C alkenyl, etc., which may contain O atom; n is 0 or 1], its enantiomer, or their arbitrary mixture. EXAMPLE:(17R)-17,20-dimethyl-7-thia-prostaglandin E1 geranyl ester. USE:A compound having high physiological activity and expected to be effective to improve the selectivity fo the action and to change the drug movement. For example, it useful as a remedy for thrombosis, a hypotensor, etc. PREPARATION:The compound of formula I can be produced by condensing 7-thiaprostagladin E1 carboxylic acid of formula II [R<21> and R<31> are tri(1-7C hydrocarbon)silyl, etc.] with an alkenyl alcohol in the presence of a condensation agent, and if necessary deprotecting the product.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to new fi-archiab a-staglandin alkenyl esters, a method for producing the same, and a drug containing the same as an active ingredient. More specifically, new archa-a staglandin E1 alkenyl esters and 7-17a staglandin E, carboxylic acids useful as pharmaceuticals are condensed with alkenyl alcohols in the presence of a condensing agent,
The present invention then relates to a method for producing the 7-17P staglandin fluorofluorkenyl ester by deprotection as necessary, and to a drug using the same as an effective fraction.

<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 the a-staglandins, puxtaglandin E has strong platelet aggregation inhibiting effects, vasodilatory effects, etc., and its clinical application has begun.

The biggest drawback of natural prostaglandins, especially KP(J), is that they cannot be used orally because they are rapidly metabolized upon oral administration, and they usually have to be administered intravenously.

Hitherto, various studies have been conducted on human nibrostaglandins in which one or two of the 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 IS.The same applies to structures in which other positions are substituted with sulfur). (indicated by the number corresponding to the sulfur substitution position and S)) IS-Pa taglandin E or F,
Alpha species (J, Org, Chem, L+ 4 0.5
2 1 (1975) and JP-A-53-34747
L 3S-11-deoxyprostaglandin E.

(TetrahsdronL
@tters ) * 1975.765 and Journal Ogmedicinal Chemistry (J, Mad.

Chem, ), 20+1662 (1977))t 7
S-Prostaglandin F, alphas (Journal of the American Chemical Society (J, Amer.

Chem, Soe, )t 96, 6757 (1974)
), 9 S-Prostaglandin E, etc. (Tetrahedron Letters (T@trah@dron Le
tters ) + 1974 +4267 and 445
9; Tetrahedron Letters
Lettera) w 1976.4793 and Heterocycles.

611097 (1977)), 11 S-Pa taglandin E, or F, α (Tetrahedron letters (T
etrahedron Lsters) + 19
75.

1165), ] 3 S-prostaglandin E or F
(USP, 40801458 (1978)).

and 158-buta staglandin F* (tetrahedron letters (T@trahadron L@tter)
s) *197711629) etc. are known.

In addition, the present inventors previously discovered that 7-thiaprostaglandin E
, were successfully synthesized and reported separately (Japanese Patent Application Laid-Open No. 110-1988)
562, etc.).

<Purpose of the invention> As a result of intensive research regarding the conversion of the ester moiety of 7-thiaprostaglandin Els as previously reported,
The present invention was achieved by successfully synthesizing novel 7-thi7puxtaglandin E and alkenyl esters.

<Structure and Effects of the Invention> The present invention provides novel 7-thi-7 prostaglandin E, flutenyl, which is a compound represented by the following formula (I), their enantiomers, or mixtures thereof in arbitrary proportions. Esters are provided.

R1 represents a straight chain or branched C1-C1° alkenyl group. Examples include vinyl group, 7lyl group,
3-butenyl group, 2-butenyl group + 4-pentenyl group, 2-pentenyl group.

Prenyl group (3-methyl-2-butenyl group).

Examples include a 2,4-hexagenyl group, a 2,6-octagenyl group, a neryl group, a geranyl group, a cytochneryl group, a 7-arnesyl group, and a 7-rachidyl group. Among these, particularly preferred as R1 are a 7lyl group, a prenyl group, and a geranyl group.

R2 and Rs are the same or different, hydrogen atom, )I
J(C, -Cy) A group that forms an acetal bond with a hydrocarbon silyl group or an oxygen atom of a hydroxyl group, or a group that forms an ester bond with an oxygen atom of a hydroxyl group.

) Examples of the (C, ~Ct) hydrocarbon silyl group include trimethylsilyl and trinitylsilyl.

Tri(C+~C4) such as t-butyldimethylsilyl group
Di( such as furkylsilyl, dimethylphenylsilyl group)
Preferred examples of diphenyl(C+-C,)ylkylsilyl groups such as C+-C4)alkylphenylsilyl and t-butyldiphenylsilyl groups include triphenylsilyl and tribenzylsilyl groups. t-
Butyldimethylsilyl group is particularly preferred.

Hydroxyl a! An example of a group that forms a cetal bond with a frozen atom is methoxymethyl.

1-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-propyl, (2-methoxyethoxy)
Methyl, benzyloxymethyl, 2-tetrahytomipyranyl, 2-tetrahytomio7ranyl or 6,6-dimethyl-3-oxa-2:1”xobicic a(3,1,0)hex-4-yl group are mentioned. be able to.

Among these, 2 to tetrahydrocupyranyl groups are particularly preferred.

Examples of groups that form an ester bond with the #atom of the hydroxyl group include (c,-Cs)alkanoyl groups such as formyl group, acetyl group, buta-pionyl group, buta/yl group, and pebtanyl group; benzoyl group, toluyl group, etc. Examples include substituted or unsubstituted benzoyl groups such as groups. Acetyl group and benzoyl group are particularly preferred.

As R1 or R1, 5% of water is preferably used.

In the above formula CI), R4 represents a hydrogen atom, a methyl group or a vinyl group.

In the above formula CI3, R1 is a straight chain or branched a that may contain an oxygen atom Cs~C, a furkyl group; C8
~C, alkenyl group; C, ~C8 furkynyl group; optionally substituted phenyl group, phenoxy group or C
8-CI6 cyclofurkyl group; or C1-C6 alkoxy group, optionally substituted phenyl group, phenoxy group, or C3-C. Represents a straight chain or branched @C1-C, furkyl group substituted with a cycloalkyl group.

Straight chain or branched chain C5~ which may contain an oxygen atom
C, alkyl groups include 2-methoxyethyl, 2-ethoxyethyl, and 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) −Z −
Methylhexyl, 2-hexyl, 2-methyl-2-hexyl group, particularly preferably butyl.

Pentyl, hexyl, 2-hexyl, (R)- or (S)-2-methylhexyl groups may be mentioned.

C1-C, as a fulkenyl group (2-guthynyl group, 2
-pentenyl group, 3-pentenyl group.

2-hexenyl group, 4-hexenyl group, 2-methyl-4
-hexenyl group, 2-octenyl group and the like.

03~C-alkynyl group or 2-zutinyl group, 2-
pentynyl group, 3-pentynyl group.

2-hexynyl group, 4-hexynyl group, 2-methyl-4
-hexynyl group, 4-hexyn-2-yl group, 4-heptyn-2-yl group, and the like.

Examples of substituents for the optionally substituted phenyl group and phenoxy group include a halogen atom.

Human axy group, c, ~c? 7 hydroxy group, C1-C alkyl group optionally substituted with a halogen atom, C7-C4 alkoxy group optionally substituted with a halogen atom, nitrile group, carboxyl group or (C1-Cs) alkoxycarbonyl Groups etc. are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. ct~c? Examples of the siloxy group include acetoxy, propionyloxy, n-butyryloxy, 1so-butyryloxy, n-valeryloxy, and 1so-valeryloxy.

Mention may be made of cabuquiloxy, enantyloxy or benzoyloxy.

/1c1 The C, ~ c4 furkyl group which may be substituted with methyl, ethyl, n-propyl, 1
so-propyl, n-methyl, lyaa-methyl, dicy
Preferred examples include o-methyl and trifluoromethyl. Examples of the CI-C4 flukoxy group which may be substituted with halogen include methoxy.

Ethoxy, n-a-poxy, 1so-a-boxy,
Preferred examples include n-butoxy, rioo methoxy, di-a-methoxy, and trifluoromethoxy. Examples of the (C+ to C6) alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl.

Can you name methoxycarbonyl, hexyloxycarbonyl, etc.?

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

Substituted or unsubstituted C9-C1° cyclofurkyl groups include saturated or unsaturated C1-C1°, preferably C, -C, for example cyclofurkyl groups substituted with the same substituents as mentioned above or unsubstituted. a pill, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohebutyl.

Examples include cyclooctyl and cyclodecyl.

C1-C6 alkoxy group, optionally substituted phenyl group, phenoxy group, linear or branched C1-Cs furkyl group substituted with C1-C1゜cyclofurkyl group, C, -C, alkoxy group For example, methoxy, ethoxy.

Examples include a-boxy, imp-a-boxy, methoxy, monobutoxy, hexyl, and oxy groups, and as the optionally substituted phenyl and phenoxy groups, the above-mentioned groups can be preferably used as they are. As the C5-C11l cycloalkyl group, the above-mentioned ones can be mentioned as they are, and as the straight or branched 'C2-C, furkyl group, methyl, ethyl, propyl, 1so
-Propyl, butyl, 1so-butyl, 5ec-7
Examples include 'tyl, t-7'tyl, pentyl, etc., and the substituent may be bonded to any position thereof.

In the compound represented by the above formula (1), n represents O or 1.

The configuration of the 8-position of the compound represented by the above formula CI) is:
It represents either (8R) monomer represented by the following formula Cl-1) and (8S) monomer represented by the following formula Cl-2), or a mixture thereof in any ratio.

In the above formula CD, if n = 00, the following formula Cl-3
) and the naturally occurring configuration at position 15 represented by the following formula Cl-
4) Represents either one of the non-natural configurations at position 15 represented by or a mixture thereof in any proportion. The above formula C
The naturally occurring configuration at position 15, represented by l-3), is preferred. When n = 1, it also includes (R), (S) at position 16, and a mixture thereof in any proportion.

11th position of the compound represented by the above formula CI).

The configuration at position 12 is a particularly useful stereoisomer because it is a natural prostaglandin E1 type, but the present invention also includes its mirror image or a mixture thereof in any proportion.

Preferred specific examples of the novel 7-thiaprostaglandin E represented by the above formula (I) and alkenyl esters provided by the present invention include the compounds shown below.

(1) 7-thiaprostaglandin E, 7lyl ester (2) 7-thiaprostaglandin E, 2-guthynyl ester (3) 7-thiaprostaglandin E, 2-pentenyl ester (4) 7- 1,700 7 a Staglandin E, 4-pentenyl ester (517-thiapux Taglandin E, /Renyl ester (6) Archia a Staglandin E, Geranyl ester (7) Archia a Staglandin E1 Citon a Neryl ester (8) Archia a Staglandin E, farnesyl ester (9) Archa-a Staglandin EI Araxyl Ester Ql 7-Thiaprostaglandin E, 5-Methyl-3-henten-2-yl ester αIJ 16-Methyl-7-Thia Prostaglandin E, Allyl ester α3 16,16-dimethyl-7-thiaprostaglandin E, 2-7'tenyl ester α3 (17R8
)-17,20-dimethyl-7-′thia7′-staglandin E, frenyl ester α9 (17RJ-17,20-dimethyl-7-′thia7′-staglandin E,
173) -17,20-dimethyl-archiab a staglandin E, geranyl ester Ql 17 , 18
-dehyde a -archabCl stablandin E+ 2
14-Hexagenyl ester αn 16-Methyl-IL18,19.19-tetradehydecou 7-thiaprostaglandin EII Cytochneryl ester αI IL17tlL19*20-Pentanol-16
- Phenyl Fuchsia staglandin E.

Farnesyl ester u! J 16, 17. IL19t20-pentanol-16-futxy7-thi7-buxtaglandin E,
7 rachidyl ester 121m 16.17+18.19.20-pentanol-16-cyclopentyl-7-thia-prostaglandin E, neryl ester C11) 16t17,18.19.20-h7ri/
Ru 16-cyc a hexyl 7-thiapx taglandin E, allyl ester @ 17t18.19.20-tetra true 16-p a biruo in sea archi ab a staglandin E, butenyl ester r2317+IL19t20-T) 5 / Ru 1
67 Enoxy-7-thiapa staglandin E, pentenyl ester (2415-deoxy-16-hydroxy-7-thiapa staglandin E, prenyl ester (to)) Staglandin E, cytoneryl ester (a) 15-deoxy-16-hydroxy-16-methyl-archiab a Staglandin E, geranyl ester @(l) ~ hydroxyl group (11-position and 16-position, or 11-position and The hydroxyl group (
Derivatives where positions 11 and 15 or positions 11 and 16 are protected with 2-tetrahytomipyranyl groups
A derivative in which the hydroxyl groups (11th and 15th positions, or 11th and 16th positions) of the compound are protected with a 7-cetyl group. The stereoisomer at position 8 of the compound (
Examples include, but are not limited to, mixtures of stereoisomers at the 8-position of the compounds shown in 11 to 3f in arbitrary proportions. Also included are optical isomers at position or 16, and enantiomers of all of these.

The novel 7-thiaprostaglandin FJ of the present invention represented by the above formula CI), fullkale esters and their enantiomers, or mixtures thereof in arbitrary proportions are 7-thiaprostaglandin FJ represented by the following formula [11]. a tag runn E.

This can be achieved by condensing a carboxyl compound, its enantiomer, or a mixture thereof in any proportion with an alkenyl alcohol in the presence of a condensing agent, and then, if necessary, removing it.

Preferred values for H*+ and R8I in the above formula (II) are the same as those for ul and as above.

In addition, the properties of R", R', R', and n in the above formula (n) are the same as those described above. The condensing agent used in this reaction is a combination reaction of carboxylic acid and alcohol. Any substance that gives r6 may be used, and examples thereof include dicyclohexylcarbodiimide, ethyl chloroformate, imptylacium formate, and trifluoroacetic anhydride.Preferably, dicyclohexylcarbodiimide is used.In this reaction, the condensing agent is represented by the above formula. The reaction is carried out using 0.5-50 times the equivalent of the 7-17-buta staglandin E represented by (II), particularly preferably 1-5 times the equivalent of the carboxylic acid.

In this reaction, in order to proceed smoothly with the reaction, a base such as 4-dimethylami7pyridine, pyridine, triethylamine, etc. is used in an amount of o, o o i to 50 equivalents, preferably 0.01 to 1 equivalent. Flutenyl alcohol is used in an amount of 0.5 to 50 equivalents, preferably 1 to 3 equivalents.

The reaction temperature is -78°C to 100°C, particularly preferably 0°C to
A temperature range of about 50°C 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, non-clining organic medium that is liquid at the reaction temperature and does not react with the reaction reagents should be used.

Such aprotic inert organic media include, for example,
Pentane, hexane, heptane.

Saturated hydrocarbons such as cyclohexane Riaaform,
Halogenated solvents such as carbon tetrachloride and 1,2-dicuclethane; and other hexamethylphosphoric tri7mide (H
MPAJ, N, N-dimethylformamide (DMF),
N,N-dimethyl 7cetamide, dimethyl sulfoxide.

Examples include so-called aprotic polar solvents such as sulfolane and N-methylvicrytone, and it is also possible to use them as a mixed solvent of two or more solvents. Among these, the preferred solvent is a rogen-based bath medium such as methylene chloride.

The amount of organic medium to be used is sufficient as long as the reaction proceeds smoothly, and is usually 1 to 100 times the amount of the raw materials, preferably 2 to 20 times the amount of the raw materials.

After the reaction, the resulting product is separated from the reaction solution and made into silk by conventional means. For example, extraction and washing, chromatography, or a combination thereof may be used.

Furthermore, the hydroxyl group-retained compound obtained here can then be subjected to a deprotection reaction 6 if necessary.

If the protecting group is a group that forms an acetal bond with the nitrogen atom of the hydroxyl group, for example, acetic acid.

p-Toluenesulfone (ILp-1) Suitable (not implemented) by using a pyridinium salt of toluenesulfonic acid or a cation exchange resin as a catalyst and using water, tetrahydrofuran, ethyl ether, dioxane, 7-cetone, acetonitrile, etc. as a reaction solvent. The reaction is usually carried out at -78°C to +5°C.
It is carried out at a temperature range of 0''C for about 10 minutes to 3 days. When the protecting group is a (C, - C?) hydrocarbon silyl group, for example, acetic acid.

Tetragutylammonium fluoride, cesium fluoride, fluoride water 11! , hydrogen fluoride-pyridine, etc., in the reaction bath medium described above at the same temperature and for a similar period of time.

The thus obtained archa-a staglandin E and alkenyl esters represented by the above formula CI) have high pharmacological activity, and are useful as they can be expected to have improved selectivity of action and changes in pharmacokinetics (improved duration, etc.) It is a compound.

Moreover, 7- represented by the above formula CI) obtained in this way
Among thiaprostaglandin EI alkenyl esters, derivatives in which R2 and R1 are free hydroxyl groups have prostaglandin-like effects such as platelet aggregation inhibiting effect, vasodilatory effect, and blood pressure lowering effect, and due to these physiological effects, It is expected to be 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,
Fulminant hepatitis, hepatic coma, liver enlargement.

Liver diseases such as cirrhosis, pancreatic diseases such as pancreatitis, diabetic nephropathy, acute renal failure, urinary diseases such as cystitis and urethritis, respiratory diseases such as pneumonia and tracheitis, endocrine diseases, immune diseases and alcoholism, It can be used for the prevention and/or treatment of various diseases such as poisoning symptoms such as carbon chloride poisoning and hypotension, and also for the prevention of cancer metastasis.

For these purposes, the 7-thiaprostaglandin E and flukenyl esters of the present invention can be administered orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, etc.5, but are preferably administered. The administration may be by oral or rectal administration (such routes of administration are convenient for the patient).

For oral administration, it is formulated into solid or liquid preparations. Tablets are solid preparations.

Available in pills, powders, or granules. In such solid formulations, one or more active substances are present in at least one inert diluent, such as the commonly used calcium carbonate.

Mixed with potato starch, alginic acid or lactose. The preparation 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, bath solutions,
It can take the form of a cloudy agent, syrup, or elixir. These can include commonly used inert diluents such as water or liquid paraffin.

In addition to the inert diluent, this formulation contains adjuvants such as wetting agents, clouding agents, sweeteners, and SL flavoring agents.

It may also contain fragrances or preservatives.

The liquid preparation may also be in the form of capsules of easily absorbed material such as gelatin.

Liquid formulations may also have the active ingredient dissolved in fractionated coconut oil, coconut oil, soybean oil, and sorghum oil. 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 preparations also contain preservatives, humectants.

Adjuvants such as emulsifiers and dispersants may be included. These can be applied, for example, through bacteria retention filters.
It can be sterilized by sterilization, mixing with a stimulant, or irradiation.

Alternatively, a sterile solid preparation can be used by dissolving it in sterile water or a sterile injection solvent immediately before use.

When the 7-thiaprostaglandin E and flutenyl esters of the present invention are used as a cyclodextrin clathrate, its stability increases and it becomes suitable for oral administration, so it can be formulated as a cyclodextrin clathrate. It can also be converted into

Inclusion compounds include, for example, cyclodextrin combined with water and/or
Alternatively, by dissolving it in a water-miscible organic solvent and adding it to 7-thiaprostaglandin E and flutenyl esters dissolved in a water-miscible organic solvent and heating the resulting mixture. Manufactured. The desired cyclodextrin clathrate compound is isolated by concentration under reduced pressure, by cooling, or by decantation. Cyclodextrin is α-1β
-1 or r-cyclodextrin or a mixture thereof can be used.

The dosage of the 7-thiaprostaglandin fulkenyl esters of the present invention is 0.00% per day per body weight. Ofμl～
100 μg, preferably 1 μg to 10 μg. These dosages are determined based on the patient's medical condition, weight, age, age, and route of administration (
more influenced.

Hereinafter, the present invention will be explained in more detail using examples.

Example 1 (17R)-17,20-dimethyl-7-thia-PGg
, 48# (0.12 mmol) was dissolved in dry methylene chloride (1117), and geraniol 62p
i (0.36 mmol) was added. Under water cooling, 4-tmethylaminopyridine 4.5 In9 (0,036 mm
ol), then dicyclohexylcarbodiimide 37~
(0.18 mmol) was added and stirred for 30 minutes.
Stir for 5 minutes. Ethyl acetate (15 ml) was added and mixed with celite, water was added to f51OL, and the mixture was shaken for 15 minutes. After re-extracting the aqueous layer with ethyl acetate (15ml, l), the combined organic layers were washed with an aqueous solution of potassium hydrogen sulfate, an aqueous solution of sodium hydrogencarbonate, and saturated brine, then dried over 51L of magnesium, and the solvent was distilled off. The resulting residue was separated and purified using silica gel column chromatography.
Hexane-ethyl acetate (1:1 to 3:7) @Yamabe yielded 24 dA (yield 38%) of (17R-17,20-dimethyl-7-thia PGE, geranyl ester).

NMR (CDC4, δ (P%)) sO, 89 (6H
) = 1.56 (3Hms).

1.67 (6H+s), 3.8-4.4 (2Htbr)
.

4.51 (2He d * J”=7Hz)-4,
8-5.4 (2H, br), 5.61 (2H, m) IR
C liquid film, 3-'), 3400.2960, 2940.2860°1738.
145θ, 1375, 1162.965Mass(F
D-MS); 537(M+1) Example 2 (16R8)-15-deoxy-16-hydroxy-1
6-methyl-7-thiaprostaglandin E, 10
0Q (0,25 mmol) was dissolved in dry methylene chloride (1,211177) and geraniol 124x
l (0.72 mmol) was added. Under water cooling, 4-dimethylamine/pyridine 919 (0,Q72 mmol)
, then dicyclohexylcarbodiimide 74jlP
After stirring for 30 minutes, 1
Stir for hours. Add ethyl acetate (2017)
After filtration, water was added to the solution F, and the solution was separated by liquid separation a-to. After re-extracting the aqueous layer with ethyl acetate (2017), the combined organic layers were extracted with an aqueous solution of potassium hydrogen sulfate [, *I! The mixture was washed with an aqueous solution of hydrogen and saturated brine, then dried over magnesium sulfate, and the solvent was distilled off. The resulting residue was separated using silica gel column chromatography to obtain hexane-ethyl acetate (1:1) II extracting portion 70■ (yield 5
452) (16R8)-15-deoxy-16-hydroxy-16-methyl-7-17Pa staglandin E, geranyl ester was obtained.

NMR (CD (J, , δ (1%)); 0.88 (
3) 1+t), 1.14(3H+s).

1.57 (3H=s), 1.67 (6H+a)-3,9
~4.3(1)1,br).

4.52 (2H, d, J = 7m8 to 4 8~5.4 (2H, br ), 5.61 (2H
, m) IR(a membrane, fi-') ;3
400 * 2960 + 2940 + 2860-
1740.145011160.965 Example 3 7-Thiaprostaglandin E, 1001M9' was dissolved in dry methylene chloride (1,51j)K, and 70μ of 7lyl alcohol was added. Under water cooling, 4-dimethyl 7 minobyridine 5~ and then dicyclohexylcarbodiimide 751r9 were added, and the mixture was stirred for 15 minutes under water cooling and at room temperature for 1 jlP. Add 1tPd ethyl (20m) and add water (201m).
After washing with j), the aqueous layer was re-extracted with 20 rsl of ethyl acetate. The combined organic layers were diluted with an aqueous solution of potassium hydrogen sulfate and aqueous sodium bicarbonate solution.

After washing successively with saturated brine, drying over magnesium sulfate, and evaporating the solvent. The resulting residue was separated and purified by silica gel column chromatography, and 52 das (yield range: 47) of 7-1,7 aa staglandin E, allyl ester was obtained in the hexane-ethyl acetate (2:3) eluate. Ta.

NMR(CD(J, , δ(p喀１鵬));
0.88 (3H, t, J=5 days z).

1.58 (3M, s), 1.67 (6H, s)
.

3.8-4.4 (2H, br).

4.55 (2H, bdl J=611z).

4.8~5.4 (2Hon), 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 U at a ratio of 90 parts of 3.8% trisodium citrate solution to 1000 fl.
After centrifugation for 0 minutes, the upper layer was separated as PRP (obedient platelet plasma). The lower layer was further centrifuged for 2800 flO minutes, and the upper layer, which was divided into two layers, was separated as ppp (platelet poor plasma). Platelet count is 6-7 x 10"/
Dilution II4 was made with PPP in μl. g4! ! PR after l
Add 25 μl of the test drug to 250 μl of P, preincubate at 37°C for 2 minutes, and then add 10 μl of ADP.
M (final) was added and the change in transmittance was recorded using an acribometer. The test drug was dissolved in ethanol to a concentration of 109/-, and then dissolved in phosphate buffer (p
) 17.4) and used. The aggregation inhibition rate was determined using the following formula.

Inhibition rate (chi) = (1-5) x 100 T, : Permeability T of (IJ acid buffer addition system): Permeability of test drug addition system The lowest concentration of drug at which the inhibition rate exceeds 50% is IC ,.

Shown as a value. The results are shown in Table 1.

Table 1 Example 5 manufacturing of tablets Tablets were manufactured, each having the following composition.

Active ingredient 200μ9 Milk II 300W
9 Potato Starch 80 Da Polyvinyl Bicridone 1019 Magnesium Stearate 5 Iv 400 Da Mix the active ingredients, lactose and potato starch, evenly moisten it with a 20 part ethanol solution of polyvinyl bicarbonate, pass through a sieve through 20 meshes, It was 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.

'Jl! Example 6 Preparation of Capsules Hard latin capsules were prepared, each capsule containing the following composition:

Active ingredient 200μI Microcrystalline SE/I, o-S 30059 Amorphous silicic acid 55P 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.

Example 7 Manufacture of powders A powder having the following composition was produced.

Active ingredient: 200 μl Lactose: 100 ~ Corn starch: 100 ■ Human cuxib a-pilcella-se: 10 da 220 da Mix the active ingredient (compound obtained in Example 1), lactose, and corn starch, and then add hydroxypropyl cellulose aqueous solution to this. A powder was prepared by mixing and drying.

Example 8 (17R)-17,20-dimethyl-archiab a staglandin E and geranyl ester were dissolved in fractionated coconut oil, and then a shell component having the following composition was dissolved by heating,
(17R)-17,20-dimethyl-7 in one capsule
-Thiaprostaglandin E, geranyl ester 200
Soft capsules containing μI were produced by a conventional method using a soft capsule making machine.

Gelatin 10 parts by weight Glycerin 2

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[I
] [In the formula, R^1 is a straight chain or branched chain C_2 to C_2_
0 represents an alkenyl group, R^2 and R^3 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 oxygen atom of a hydroxyl group. represents a group that forms an ester bond with R^4, where R^4 is a hydrogen atom,
Represents a methyl group or a vinyl group, R^5 is a straight chain or branched chain C_3 to C_8 alkyl group that may contain an oxygen atom; C_3 to C_6
Alkenyl group; C_3-C_8 alkynyl group; optionally substituted phenyl group, phenoxy group or C_3-C_1_0 cycloalkyl group; or C_1-C_6 alkoxy group, optionally substituted phenyl group, phenoxy group or C_3-C_1_0 It represents a straight chain or branched chain C_1 to C_3 alkyl group substituted with a cycloalkyl group, and n represents 0 or 1. Novel 7-thiaprostaglandin E_1 alkenyl esters which are compounds represented by the above, their enantiomers, or mixtures thereof in arbitrary proportions. 2. Novel 7-thiaprostaglandin E_1 alkenyl esters according to claim 1, wherein R^1 is a geranyl group. 3. Novel 7-thiaprostaglandin E_1 alkenyl esters according to claim 1, wherein R^1 is an allyl group. 4. Novel 7-thiaprostaglandin E_1 according to any one of claims 1 to 3, wherein n is 0.
Alkenyl esters. 5, the novel 7-thiaprostaglandin E_1 according to any one of claims 1 to 3, wherein n is 1;
Alkenyl esters. The novel 7-thiaprostaglandin E_1 alkenyl ester according to any one of claims 1 to 5, wherein 6, R^2, and R^3 are all hydrogen atoms. 7. Novel 7-thiaprostaglandin E according to any one of claims 1 to 6, wherein R^5 is an n-butyl group, n-pentyl group, or 2-methylhexyl group.
_1 Alkenyl esters. 8. The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[II] In the formula, R^2^1 and R^3^1 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 an oxygen atom. Straight chain or branched chain C_3-C_6 alkyl group that may contain; C_3-C_8 alkenyl group; C_3-C_8 alkynyl group; optionally substituted phenyl group, phenoxy group or C_3-C_1_0 cycloalkyl group; or C_1- Represents a linear or branched C_1-C_3 alkyl group substituted with a C_6 alkoxy group, an optionally substituted phenyl group, a phenoxy group, or a C_3-C_1_0 cycloalkyl group, and n represents 0 or 1. The following formula [I] is characterized in that 7-thiaprostaglandin E_1 carboxylic acids represented by are condensed with alkenyl alcohols in the presence of a condensing agent, and then deprotected as necessary. There is▼・・・・・・〔 I
] [In the formula, R^1, R^2, R^3, R^4, R^5 and n are the same as defined above. ] A method for producing a novel 7-thiaprostaglandin E_1 alkenyl ester represented by: 9. The method for producing novel 7-thiaprostaglandin E_1 alkenyl esters according to claim 8, wherein the condensing agent is dicyclohexylcarbodiimide. 10. A cardiovascular agent comprising an effective amount of the novel 7-thiaprostaglandin E_1 alkenyl ester represented by the above formula [I] and a pharmaceutically acceptable carrier.