JPH03163022A - Pharmacological composition containing prostacyclins as active ingredient - Google Patents

Abstract

NEW MATERIAL:Compounds expressed by formula I (R<5> is H, 1-10C alkyl or phenyl, alicyclic group, etc., which can be substituted; R<1> is H or methyl; R<2> is unsubstituted 5-8C alkyl, phenyl, etc.; R<3> and R<4> are H, 2-7C acyl, etc.). EXAMPLE:9(O)-Methano- <6(9)>prostaglandin I1. USE:Useful as a vasodilator, antistenocardiac, hypotensive, antithrombotic, antiarteriosclerotic and antimyocardial infarction agents, etc. PREPARATION:New hydroxyprostacyclins expressed by formula II (R<3>' and R<4>' are 2-7C acyl, etc,; R<5>' is 1-10C alkyl, phenyl, etc.; R<8>, R<8>' and R<8>'' are 1-7C alkyl, aryl or arylalkyl) are treated with sulfonic acid anhydride in the presence of a base and the resultant compound, as necessary, is subjected to deprotection, hydrolysis and salt-forming reaction to afford the compounds expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a pharmaceutical combination that has prostacyclin as an effective agent. Furthermore, in detail 611I, the present invention provides a pharmaceutical compound containing as an active ingredient a novel prostacyclin in which the oxygen atom at the 6.9-1 position of prostaglandin 1 is replaced with methine, that is, -1-{C=. relating to things.

Prior Art> Prostacyclin is a local hormone that is mainly produced in the inner walls of arteries in living organisms, and is an important factor that regulates cellular functions in living organisms through its powerful bioactivation activities, such as platelet aggregation inhibitory activity and vasodilatory activity. Attempts are being made to provide this product directly as a medicine (P.J.
．． Lewis & J. 0. Grady'Clin
ical Pharmacology of Pros
ta-cyclin' Raven Press, N
．． Y. ．． 1981).

However, because the natural 11":1 stacycline!.th molecule has a non-7:9 IJI + enol ether bond that is easily decomposed by water, it is easily deactivated under neutral or acidic conditions, and it is not recommended as a medical collection product. ) It is not a desirable compound due to its chemical instability.For this reason, chemically stable synthetic prostacyclin derivatives that have the same biodegradation activity as natural prostacyclin have been intensively investigated at home and abroad.

Among them, 9(0)-methanoprostacyclin (carbacycline), which is a conductor in which the oxygen atom r-1 at the 6.9-1 position of prostacyclin is replaced with a methylene group, is a prostacyclin-depleted material that satisfies chemical stability. D.R. Mortons' Pro
stacyclin' J. R. Vane and
S. Bergstom, Eds, Raven Pr.
ess, N. Y. , l979, pp31-41
9) It is expected to be used as a medicine. But this 6.
9 (01-Methanobacterium stacycline) has a biological activity weaker than natural σ) 1-stacycline, and its action selectivity cannot be said to be specific, so it cannot necessarily be said to be a preferable 1-hybrid binding. On the other hand, as a stable prostacycnon, fSd4 conductor, nitriloprostacyclin, is known in which the oxygen atom at the 6,9-1 position is replaced with a 1N= group, and its biological activity is known to be comparable to that of natural prostacytalins. <G. LBundy et al., Tetrahe
Dron Letter, 1371 (1978) and W. Bartmann et al., Tetrahedron
Letter, 23. 3467 (19821
reference).

OBJECT OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition containing, as an effective ingredient, a novel single-portion stacycline that is chemically stable and has an excellent drug-embedding effect.

The present inventors focused on the scientific findings of the stabilized prostacyclin described above, and newly substituted the oxygen atom at the 6.9-1 position with a methine group, that is, a -CH= group. Discover derivatives,
This is the result of the present invention. That is, the present invention is a pharmaceutical composition containing a novel prostacyclin represented by the following formula [I] as an effective ingredient.

Here, R is a C0-C1o alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alicyclic group, a substituted or unsubstituted phenyl (C1-C2) alkyl group, a tri(C.-C7> It is a hydrocarbon monosilyl group, or a monoequivalent cation.

Examples of the 01 to C/10 alkyl group include methyl, ethyl, n-propyl, iso-propyl, n-butyl, see-butyl, tert-butyl, 0-pentyl, [1-hexyl, n-hebutyl, n-hexyl, -octyl,
Linear or branched ones such as n-/nyl and 11-decyl can be mentioned.

Substituents for substituted or unsubstituted phenyl groups include, for example, halogen atoms, hydroxy groups, C2--C7 acyloxy groups. C1-C which may be substituted with a halogen atom
4 C optionally substituted with alkyl group or halogen atom
Preferred are l-C4 alkoxy group, nitrile group, carboxyl group, (C1-C6) alkoxy group and carbonyl group. Here, as the halogen collector, fluorine, chlorine, bromine, etc., and particularly fluorine or chlorine are preferable. Examples of the C2-C7 acyloxy group include acetoxy, propionyloxy, 11-butyryloxy, iso-butyryloxy, n-valeryloxy, iso-valeryloxy, turnipinoleoxy, enantinoleoxy, and penzoyloxy.

Examples of the C1-C4 alkyl group optionally substituted with halogen include methyl, ethyl, n-probyl, iso-
Preferred examples include proyl, -butyl, chloromethyl, dichloromethyl, and trifluoromethyl. C1-C optionally substituted with halogen
Preferred examples of the 4-alkoxy include methoxy, polyoxy, n-proboxy, iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, and trifluoromethoxy.

Examples of the (Cs''C6)alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like.

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

Substituted or unsubstituted alicyclic groups include saturated or unsaturated 05-CB, preferably C5-C8, particularly preferably C6 groups, substituted with the same substituents as mentioned above or unsubstituted; Examples include cyclobetinole, cyclohexynole, cyclohexenyl, cycloheptyl, and cyclooctyl.

Examples of the substituted or unsubstituted phenyl (Ct-C2) alkyl group include benzyl, α-phenethyl, β-phenethyl, etc., in which the phenyl group is substituted with the same substituent as mentioned above or unsubstituted.

Examples of the tri(C1-C7)hydrocarbon monosilyl group include tri(Ct--C4)alkylsilyl such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and diphenyl(Ct) such as t-butyldiphenylsilyl. -Ca) Alkylsilyl.Tribenzylsilyl group or dimethyl(2,4.6-}-butylphenoxy>silyl group, etc. can be mentioned as preferred Q).

One equivalent cation includes Na+, K+, etc. σ) Alkali metal cation; 1/2 Ca2+, 1
/2 Mg2+1/3 Divalent or trivalent such as AI'”
Valid metal cations; examples include ammonium cations such as ammonium ions and tetramethylammonium ions.

As an example, Cl-CtO alkyl group, especially methyl group.
Or a hydrogen atom is preferable.

Rl 4i is a hydrogen atom or a methyl group. A hydrogen atom is preferred.

R2 is an unsubstituted C5-C8 alkyl group; a substituted C1-C5 alkyl group substituted with an optionally substituted phenyl group, phenoxy group, CI.108 alkoxy group, or C5-C8 cycloalkyl group; or a substituted or unsubstituted alicyclic group.

The unsubstituted alkyl group (j,...~Cs&) may be linear or branched, for example, "1-bentyl, 0-hexyl, 2-methyl-1-hexyl, 2
-methyl-2-hexyl, rt-heptyl, 0-octyl, etc., preferably n-pe〉.thyl, H-hexyl, 2
-Methyl-1-hexyl, 2methyl-2-hexyl and the like.

The alkyl group of the substituted C, . . . -C5 alkyl group may be linear or (branched), for example, methyl, ethyl, n-propyl, :SO-propyl, n
-butyl, see-butyl, t-butyl, n-bentyl and the like. These alkyl groups include phenyl group; phenoxy group; methoxy, ethoxy, 0-broboxy, iso-broboxy, n-butoxy, i
so-butoxy, shi-butoxy, rl-bentoxy,
Substituted with a C1-C6 alkoxy group such as n-hexoxy; a C5-C6 cycloalkyl group such as cyclopentyl or cyclohexyl. These substituents are further R5
may be substituted with the substituents listed as substituents for the substituted phenyl group.

Among these substituted C1-C5 alkyl groups, BI
J, for example, a fluorine atom, a chlorine atom, a phenoxy group which may be substituted with a methyl, ethyl or trifluoromethyl group, or a phenyl group, ~C2
Alkyl black, or proboxymethyl, ethoxyethyl,
[1] Boxyethyl, butoxymethyl, methoxyp1 cobyl, 2-dimethylethyl, dimethylethyl, dimethyl methyl, hexylmethyl, hexylenal 1cyclohexyldimethyl Methyl. 2-cyclohexyl-1,1-dimethylethyl (&Y preferred).

Substituted and unsubstituted alicyclic compounds (the same as those listed for R5 can be listed.As R2, ζ
Yo, II-bentyl,2-methyl-1-hexyl. Cyclobentyl or cyclohexyl groups are preferred.

Same or different from R3 and R44, hydrogen atom, C
2.~C7 acyl group, tri<ct~c,) hydrocarbon group - A group that forms an acetal bond with the oxygen atom of a silyl group or hydroxyl group.

Examples of the C2-C7 acyl group include acetyl,
? Examples include bionyl, dibutyryl, iso-butyryl, iso-valeryl, and enanthyl benzoyl.

Among these, C2-Cb fatty acyl groups such as "acetyl, n- or iso-butyryl, cabroyl, or c
h-benzoyl is preferred.

Examples of tri(Cl"C7) hydrocarbon-silyl compounds include those similar to those listed above. In the world where an acetal bond is expressed with the oxygen atom of hydroxyl, for example, methoxymenal, 1 -Ethoxyethyl, 2-methoxy-2-propyl.2ethoxy-2-propyl, (
2-methoxyethoxy)methyl, penzyloxymethyl, 2-tetrahydropyranyl, 2-detrahydrofuranyl, 4-(4-methoxytetrahydropyranyl) group or 6,6-dimethyl-3-oxo-2-oxo Mention may be made of the bicyclo[3.1.0]hex-4-yl group. Among these, 2-tetrahydride I1 pyranyl, 2-
Tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl, (2-methoxyethoxy)methyl, 4-(4-methoxydetrahydropyranyl) group, 6.
6-dimethyl-3-oxycer 2-oxobicic acid [3
．． 1.0] hex-4-yl group or dimethyl (2.4.
A silyl group (6-1 to 1-butylphenyloxy) is particularly preferred.

Examples of R3 or R4 include a butyldimethylsilyl group, 2-tetrahydrobilanyl group, acetyl group, 1-methoxy-1-methylethyl group, 4-(4-methoxytetrahydrobilanyl) group, 6 .6-dimethyl-3
-oxer2-oxobicyc[3.1.0]hex-4-yl group and dimethyl(2,4.6-}-L-butylphenyloxy>silyl group are preferred.

Specific examples of prostacytalins provided by the present invention include the following.

(11 9 (01 Methanol-Δ6 (92 Prostaglandin (21 16. 17. 18, 19. 20-Pentanol-15-Cic I1 Bentyl-9 (0) Methanol Δ6 (9》Prostaglandin ■1 +3) 16 .17, 18, 19. 20-pentanol-15-cyclohexyl-9(0) methanol Δ6
<9> Prostaglandin D1 <4+ 17. 20-dimethyl-9(0)methanolΔ
6 (9' prostaglandin I1 <51 15-methyl-9(O) methanol Δ619' prostaglandin ■l <61 <11 - Methyl ester of (5) +7+ +1
)--(5) ethyl ester {be} (6) 11.
15-bis-butyldimethylsilyl ether (9) The 11th position of <61 is a methoxyisopropyl group.
A compound in which the 15th position is protected with an L-butyldimethylsilyl group (101 <6) has a t-butyldiphenylsilyl group at the 11th position. Compound (11) in which the 15th position was protected with a butyldimethylsilyl group (the 11th position of 61 was protected with 4-(4-methyl-xidetrahydride-pyranyl) and the 15th position was protected with an L-butyldimethylsilyl group) The 11th position of the compound +12> +6) is dimenal (2,4.6 −
tri-L=butylphenyloxy〉silyl group, compound with 15th position protected by t-butyldimethylsilyl group+1
3+ +11~(5) Sodium salt of carboxylic acid. Ammonium l1 salt, potassium salt The prostacyclin of the invention is obtained by treating the hydroxyl prostacyclin represented by the formula -F [IIJ with sulfonic acid anhydride in the presence of salt, deprotecting it if necessary, and carrying out a deprotection reaction. By subjecting it to hydrolysis reaction and salt formation reaction, y! be left behind.

Hydroxypstacyclines of the above formula [I[], which are original compounds, are new compounds and are produced by the production method described below.

In the above formula [nl, R3' . R4' is the same or different and is a C2-C7 acyl group, or a group having an acetal bond together with the oxygen atom of a hydroxyl group, and specific examples of such groups are as described above. Rs, Ra', R8
# represents the same or different C1-C7 alkyl group, aryl group, or arylalkyl group. C1~C
As the alkyl group of 7, for example, methyl, ethyl, "1
-provil, iso-provil, n-butyl, se
e-butyl, te'rt-butyl, n-pentyl, n
-hexyl, n-heptyl and the like. Examples of the aryl group include a phenyl group, and examples of the arylalkyl group include a benzyl group. Examples include phenethyl group.

Hydroxypstacyclines are first dissolved in excess base in a medium and then treated with the sulfonic anhydride. Methylene chloride is used as the reaction solvent. Preferred are halogenated hydrocarbons such as ethane, chloroform, and carbon tetrachloride;
Methylene chloride is particularly preferably used. The base used is pyridine. Pyridine bases such as vicolin, collidine, lutisine, and 4-dimethylaminopyridine are preferred;
In particular, pyridine is preferably used, and 4-dimethylaminopyridine is preferably used in combination with pyridine.

The amount of Shio no Kei used is preferably 2 to 100 equivalents, preferably 10 to 30 equivalents, based on the raw material compound, and when 4-dimethylaminopyridine is used with pyridine, a catalytic amount is sufficient relative to the raw material compound. 0.1~? 6 equivalents are used.

The sulfonic acid anhydride is preferably trifluoromethanesulfonic acid or methanesulfonic acid. The anhydride of p-toluenesulfonic acid or the mixed acid anhydride of C1-C3 alkylsulfonic acid and trifluoromethanesulfonic acid is preferred, especially p-toluenesulfonic acid.
~ Refluoromethanesulfonic anhydride is good. The sulfonic anhydride used is preferably 2 to 100 equivalents, preferably 5 to 30 equivalents, based on the raw material. The reaction temperature is -30
'C50°C, preferably -10°C to 20°C.

The reaction time is confirmed by the disappearance of the raw material by TLC.

Treatment C of the thus obtained tailing liquid: First, a sufficient amount of saturated NaHCO3 water is added to the reaction liquid, and then post-treatment is carried out according to a conventional method. Regarding hexane, pentane,
Either add a pheasant-soluble organic solvent to water such as petroleum ether or ethyl ether, or directly coagulate the reaction mixture through pressure coagulation, and then wash the resulting organic mixture with brine and add anhydrous magnesium sulfate ly. After drying with anhydrous sodium sulfate, anhydrous potassium carbonate, etc., the organic medium is removed under reduced pressure to obtain a crude product. (2) The product can be processed by casino, chromatography, thin layer chromatography, etc., as desired. It can be purified by purification means such as support chromatography and chromatography. The raw material thus obtained can be further subjected to a deprotection reaction, a hydrolysis reaction, and a salt formation reaction, if necessary.

In some cases where the protective group forms an acetal bond with the oxygen atom of the hydroxyl group, the protective removal of the hydroxyl group can be carried out using catalysts such as acetic acid, a viridinium salt of P-}luenesulfonic acid, or a cation exchange resin. , e.g. water, tetrahydride
rFuran, ethyl ether, dioxane. Acetone, acetonitrile, etc. are anti-J. This is preferably carried out by using 6 solvents. The reaction is usually carried out at a temperature range of -78°C to +30°C for about 10 minutes to 3 days. In addition, when the protecting group is an acyl group, for example, an aqueous solution or a water-alcohol mixed solution of caustic soda, caustic potassium, calcium hydroxide, or sodium methoxide, potassium methoxide. Using a methanol or ethanol solution ψ containing sodium ethoxide, it is possible to completely eliminate the force of 11 water decomposition.

The hydrolysis reaction of the esdel group of the carboxyl group can be carried out using an enzyme such as lipase in water or a solvent containing water.
It is carried out for about 1 minute to 24 hours at a temperature range of ℃ to +60℃.

The product after the deprotection reaction or hydrolysis reaction can be purified by the same purification means as described above.

The carboxyl group-containing compound purified by the protecting group σ) removal reaction as described above is then further subjected to a salt purification reaction, if necessary, to give the corresponding carboxylate. The salt-forming reaction is known per se, and a basic compound such as sodium hydroxide, potassium hydroxide, or sodium carbonate, or ammonia. Trimethylamine, monoethanolamine. This is carried out by neutralizing morpholine using a conventional method.

The starting material compound [II] used in the production method of Mokumaki can be obtained by the reaction shown in f below.

[III] [IV] RJI' [V] R8' The compound of the above formula [III] is a known compound and can be produced by the method described in Proceedings of the 102nd Annual Meeting of the Pharmaceutical Society of Japan, P409 (1982). .

Compound [rV] can be obtained by isomerizing the exonic double bond of compound [I[[] and optionally converting the protecting group. Isomerization of exonic double bonds in methanol
This is achieved by heating ruthenium chloride trihydrate and anhydrous potassium carbonate. Conversion of the protecting group is carried out by the method described above.

Next, silylation is introduced into this product [IV] to form compound T.
This leads to h[V]. For the introduction of the silyl group, a silylating agent such as hexamethyldisilane is used, and while using preferably 0.05 to 0.50 equivalents of tetrabutylammonium fluoride as an auxiliary agent, the raw material compound Achieved by confirming disappearance.

The carbonyl group of the obtained ketone body [V] is reduced to form the compound '! which is the starting material of the present invention! IJ[II]. As a reducing agent, sodium borohydride,
Common carbonyl reducing agents such as lithium hydride, aluminum, etc. are preferably used, and the reaction conditions are selected to be mild. In this way, the desired hydroxystacyclines represented by formula [II] are obtained.

The novel prostacyclins represented by formula [I] provided by the present invention surprisingly have very strong biological activity. For example, 9(O}methanolΔ6(9》prostaglandin I1) can not only inhibit ADP-induced rabbit platelet aggregation at IC, 00.034/ml, but also inhibit cell killing of rabbit bone epithelial cells at pH 3 by 10. -'M has a cytoprotective effect.On the other hand, L1210 has a leukemia cell proliferation inhibitory effect, which was observed at an ICso of approximately 2-4 μg/ml.

The active compounds of the invention can be administered to warm-blooded animals, such as humans or non-human animals, in need of controlling vascular system activity. The active compounds of the invention can be administered prophylactically or therapeutically to warm-blooded animals in need of controlling vascular system movements.

The active compounds of the invention can be used in patients, for example, for antianginal, vasodilating, antihypertensive, antithrombotic, antiarteriosclerotic, antianginal, antimyocardial infarction, antiendotoxic shock, antipulmonary arterial hypertension.
Anti-stroke, anti-transient isochemical attack (
Transient Ischemic Attack)
It can be administered for patients with anti-thrombocytopenic purpura, anti-deep vein thrombosis or anti-peripheral vasculopathy. The active compounds of the present invention can also be administered to children to suppress malignant ulcers or metastasis of malignant tumors. The compounds of the invention can also be used during Mli organ transplantation, vascular surgery or extracorporeal circulation. For example, blood and blood products. Blood substitutes and other isolated body parts, such as limbs and organs, whether attached to the original body or when separated and stored or prepared for transplantation or attached to a new body. It can be used as an additive in fluids used for artificial extracorporeal circulation and perfusion (including in some cases). During such circulation and perfusion, condensed platelets tend to occlude blood vessels and ofi ring organs. This occlusion is avoided by the presence of the active compounds according to the invention. For this purpose, the active compounds according to the invention are administered gradually or in one or more doses to the circulating blood. Blood of blood donor animals. 0 to the part of the body to be perfused (attached to or separate from the recipient), or to two or all of these.
．． Continuous infusion at 1-1 not g/kg body weight/min.

These compounds can be administered orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, etc., for the above purpose, but it is preferable to administer them orally or intravenously. good.

For oral administration, solid or liquid formulations can be provided. Examples of solid preparations include tablets, pills,
Available in powder or granule form. In such solid formulations, one or more active substances are present in at least one pharmaceutically acceptable carrier, such as the commonly used sodium carbonate, calcium carbonate, potato starch.
Sucrose, mannitol. Mixed with carboxymethyl cellulose, etc. Preparation manipulation is carried out according to conventional methods, but
It may also contain additives for formulation other than those mentioned above, such as lubricants such as lesium stearate, magnesium stearate, and glycerin.

Liquid preparations for oral administration include emulsions, solutions,
Contains suspensions, syrups or xyls. These formulations contain commonly used pharmaceutically acceptable carriers such as water or liquid paraffin.

Enteric-coated preparations for oral administration include, for example, cellulose acetate phthalate, hydroxybutylated methylcellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer, or methacrylic acid. It is manufactured by applying an enteric coating by spraying an enteric-restricted organic solvent such as methyl methacrylate copolymer or an aqueous solution. Enteric-coated solid preparations such as powders and granules can also be wrapped in capsules.

The pharmaceutically acceptable carrier referred to in J3 herein includes other adjuvants, fragrance stabilizers, and preservatives that are commonly used as needed.

The liquid preparation may also be administered in a capsule made of an absorbable material such as gelatin.

In addition, the prostacyclin of the present invention (i) can be administered intranasally, and as a nasal solution for intranasal administration, for example, a base such as human oral pill cellulose or lactose and prostacyclin are mixed in saline or the like. Preferably used is one dissolved in a tense glucose solution or made WL cloudy.

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 presented as sterile aqueous or non-aqueous solutions, suspensions, or emulsions. The non-aqueous solutions or suspensions are based on pharmaceutically acceptable carriers, for example, probyl glycol, polyethylene glycol, or vegetable oils such as olive oil, or 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 solutions, suspensions, and emulsions can be made sterilized by appropriate treatments such as filtration through a bacteria-retaining filter, addition of a sterilizing agent, or 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 compound of the present invention can also be used by forming an inclusion compound with α, β or γ-cyclodextrin or methylated cyclodextrin.

The dosage of the compounds of the present invention will vary depending on the condition of the subject receiving administration.
, varies depending on age, gender, body weight, route of administration, etc., but is usually about 0. It can be administered in amounts of 0.2tt g to too mg/kg body weight/eye. The dosage may be administered once or in six or more times a day, for example in 2 to 6 divided doses.

·(Example> The present invention will be explained in more detail below with reference to Examples.

Reference example] (Nol t1 1' T I-1 1) 0 0 'I'' I-I P Al:7-l <66mg, 0.11mM> in methylene chloride (2ml) was cooled to 0°C. To this is added pyridine (20 equivalents), 4-DMAP (4-dimethylaminopyridine, catalytic amount) and trifluoromethanesulfonic anhydride (10 equivalents) in this order. TLC (ether: rl-hexane = 1:1) When the disappearance of the raw material is observed, a saturated NaCl{CO3 aqueous solution is added to it and extracted with ether.The ether layer is further extracted with saturated NaCl
After washing with water and drying with anhydrous MgSOa, the solvent is distilled off. The residue was subjected to silica gel chromatography (
Ether: When separated and purified using l-hexane-1:3, 18 mg (24%) of LI-like olefin was produced as a by-product.

Product: T R (neat) L/: 2925, 2850. 1735. 1440■-1
N! 'l (δ, CDCI3): 5.45 (m,
2}1). 5.25 (br.s.IH), 4.6H
m, 2H), 4.20-3.70 (m, 4tll, 3
．． 68 (s, 3H) 3.65-3.25 (m, 2H).
2.95 (m, IH) 0. 90 (m, 3HI Mass (m/e): 501 (M=OCHa), 345m/e 5
01j538 (calcd for C31H490%
, 501.3567M-OCH3) Reference Example 2 Olefin 2 (20+nr, 0.038mM) is heated at 65°C in a mixed solvent (1.5ml) of AcOH:H20:THF=3:1:1. TLC after 4 hours
(Acetone:methylene chloride-1:2) After confirming the disappearance of the raw materials, add saturated NaH to this reaction solution at 0°C.
A CO3 aqueous solution was added and further extracted with ether <10m+x4>. The ether layer was washed with a saturated NaCI aqueous solution, dried over anhydrous MgSO4, and then the solvent was distilled off. The residue was separated and purified by silica gel chromatography (acetone:methyl chloride = 1:2) to obtain 13 mg (95%) of 11 diol 4.

4: ppm 5.55 (m, 2H), 5jO (br.s, IH)
．． 4.15 (m, 2tl), 3.68 (93H),
3.00 (m, 2H). Reference Example 3 dial4 (13mg, 0.036mM) was added to a mixed solvent of HF-H20=3:1 at room temperature (
1 ml) and add 5M-NaOH (0.
2 ml) and continue stirring overnight.

Furthermore, when the temperature was gradually raised to 40'C and the reaction was carried out under these conditions for 20 hours, TL. Disappearance of the raw material was confirmed in C (Edel). After returning the reaction solution to room temperature, ether (20 ml
), and then deeply neutralized with 10% HCI water and pH 4.0 Sakuragai solution, and finally the pl was set to 3 to 4. This was extracted with ethyl acetate (20ml x 3), the organic layers were combined and washed with saturated Nail water (3ml x 2). After drying this with anhydrous MgSOa, the solvent was distilled off, and the resulting residue was further purified by silica gel column chromatography (ethyl acetate: meth/l=15:1).
When llIM was prepared, the desired 5 was obtained in 12 times (96%).

3350 2910 2850. 1700
1450 1250ppm 5.55(m,2}1t, 5jO(br.s.1}
1), 4.55 (m, 3H) 4.10 (m, IH)
．． 3.75 (m, IH), 3.00 (m, 1}
1), 2.75-2.20 (m.4Hl. 2.20
-1.90(m.2H)Mass (CI, NH3)
m/e: 368 (M+10NH4) m. p. 73-79' [al D: 16.0' (C, 0
．． 25, MeO}{>Example 1 In vitro platelet aggregation inhibitory effect The in vitro platelet aggregation inhibitory effect of the experimental 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 kf at a ratio of 9 parts blood to 1 part 3.8% trisodium citrate solution.
After centrifugation for 10 minutes, the upper layer was separated as PRP (platelet rich plasma). The lower part has an additional 2800 rpm.
Centrifuge for 10 minutes and separate the upper layer into two layers P1)
p (platelet-poor plasma). Platelet count was 6.
X 105/it! J was diluted with PPP. After adding 25 μl of the test drug to 250 μg of adjusted P R P and pre-incubating at 37°C for 2 minutes, ADP2
0 μfVl (final) was added and the change in transmittance was recorded using an acrigometer. The test drug was dissolved in ethanol to a concentration of 10/ml, and then diluted sequentially with phosphoric acid Sakuragai solution (pH 7.41) before use. The aggregation resistance was determined by the following formula.

'I”o: Transmittance T of (phosphate buffer addition system):
The lowest concentration of the drug at which the permeability inhibition rate of the test drug-added system exceeded 50% was indicated as the ICso value.

Icso was determined using 9(0) methanol Δb(9) prostaglandin It of Reference Example 3 as the test drug and found to be 40 ng/ml.

Example 2 n vivo blood pressure lowering effect A mixed anesthetic solution of urethane and α-chloralose (urethane 50 g) was administered to male Wistar rats weighing approximately 250 g (71
0 g/kg, α-chloralose 100 mt/lq
r) was administered intraperitoneally to anesthetize the mice. After anesthesia, the rat was fixed in a supine position, blood pressure was measured from the common carotid artery using a pressure transducer, and heart rate was calculated from the pulse wave. After the test compound of Reference Example 3 was dissolved in ethanol, it was diluted with 0.9% physiological saline, and the ethanol concentration was adjusted to be 10% or less even at the highest concentration. For administration, a force nerve inserted into the femoral vein was used, and the test solution of Reference Example 3 was rapidly intravenously injected at a volume of 1 ml/kg. A decrease in blood pressure was observed, and the dose required to decrease blood pressure by 20 mm}Ig was approximately 0.5 to 0.8 μg/kg. 1μg/
A slight increase in heart rate was observed above kg.

Example 3 Tablets were manufactured, each having the following composition.

Active ingredient 200μg lactose
280■ Potato starch 80■ Polyvinylvirolidone 11mg Magnesium stearate 5■ 576mg Mix the active ingredient, lactose and potato starch, evenly moisten it with a 20% ethanol solution of polyvinylpyrrolidone, and make a 20nwn mesh. Pass through the sieve of 4
It was dried at 5° C. and passed through a 15 mm mesh 21 sieve again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

The compound of Reference Example 3 was typically used as the active ingredient.

Tip Example 4 Hard gelatin capsules were prepared, one capsule containing the following combinations:

Active ingredients 200μg microcrystalline cellulose 195mg amorphous silicic acid
5 mg400■ Active portion in finely powdered form. Microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into hard gelatin capsules.

The compound of Reference Example 3 was typically used as an active component.

Example 5 <Preparation of ampoule> An ampoule containing the following combination in one ampoule (5 ml volume) was manufactured.

Talking component 200μg polyethylene glycol 600 200■ Distilled water
A total of 50 ml of polyethylene glycol and the active ingredient were dissolved in water under nitrogen, which was boiled, cooled under nitrogen and distilled. The pretreated 7k was added to this solution and the resulting volume was filtered under dry conditions. It is performed during the wooden shoyu diffuser.

Filling was carried out in a nitrogen stream and sterilization was carried out at 121'C for 2 hours.
It lasted 0 minutes.

J3, the compound of Reference Example 3 was used as the above active component.

Example 6 Compound 1 (1) of Reference Example 3 was dissolved in 5 ml of ethanol, passed through a bacteria retention filter to kill it, and 1 ml
Pour 0.1 ml into each ampoule and seal the ampoule. The contents of the ampoule are diluted to the appropriate volume.

For example, pH8. The solution is diluted to 1 ml with 6 Tris-HCl buffer and used for injection.

Reference example 4 Exoenone 6 was synthesized from cyclooctadiene, l5
It was used as a mixture of α and β. 6 (435■,0.
Dissolve 72mM) in methanol lm+) and add Rh
CI3.3H20 (0.13 mol equivalent) and anhydrous K2C03 (0.72 mol equivalent) are added and stirred under reflux for 2 hours. ]' After confirming disappearance of the raw materials by LC (ether 201 hexane-1=2), the solvent was distilled off under reduced pressure. The residue was subjected to alumina force ram chromatography (ether) to remove rhodium, and then purified by silica gel force ram chromatography (ether: n hexane - 1:2) to obtain endoenone 7, 335 mg (77 %>Obtained.

7; 2940. 1740. 1704ppm 7.20 (m, IH). 5.50 (m, 2H),
4.00 (m, 2H), 3.68 (S.3). 3
．． 20 (m, H), 2.60 (m, 2H) I7
Toe/77 (303 mg. 0.50 mM) was dissolved in HF (3 ml), and tetrabutylammonium fluoride (2.0 equivalents) was added to it at room temperature.
After 12 hours of P, J J'l', on T''LC (ether: methanol = 95:5), the original family disappears and the l5α, 15β monoisomers of the diol are observed as two spots. Add NaCl water and perform extraction with ether. The ether layer is dried over anhydrous MgSO4, and the solvent is distilled off. The resulting residue is separated and purified by silica gel force column chromatography (ether:methanol-95:5). When done, the 15α monoisomer of diol 8 and the 15
The β monoisomer has a total of 180 +w (95%) f!
It was done.

3450 2950, 1740. 1690p
pm'/. 30 (m, IH) 3. 69 (s, 3H). 5. 65 (m, 2}1) 4.05 (m 2H) Reference example 5 8 <l5α isomer) 15ζX-diol 8 (180 mg. 0.46m
Dihydrobilane is added to a solution of M> in methylene chloride (3 ml) at room temperature. Furthermore, when balatoluenesulfonic acid, which is a catalyst, is added, anti-J. U progresses instantly and becomes 'F''LC (
Ether:■-hexane-2:1), the disappearance of the raw material w
1 can be guessed. Add 14 ml of saturated N} water to the reaction solution, and extract with ether. The Edel layer is washed with saturated NaCl water and then dried with anhydrous MgSO4. The solvent was distilled off, and the residue was purified using silica gel chromatography (ether 201 hexane = 1 + 1) to obtain 241 mg of enone 9 (96%).

Reference Example 6 HMP of Ri111Bienone9 (229 mg. 0.42mM)
Add hexamethyldisilazane (1 ml) to solution A (2 ml) at room temperature.
.
Add L and C (edel:n-hexane=2:1) while observing the progress of the reaction. 1 hour after the disappearance of the raw materials was confirmed〉The reaction solution was diluted with ether (5 ml)
: Dilute with water and cool in a water bath. Add water (1 ml) to this
Terminate the reaction by adding little by little. After removing the aqueous layer,
The organic layer is washed several more times with small amounts of water to remove HMPA. This was dried over anhydrous MgSOa, and the residue obtained by distilling off the solvent was subjected to silica gel column chromatography (ether-rimmed n-hexane = 1:]) for 4 hours.
Ketone 1o is 214 mg (82
%〉obtained.

ppm 5 40 (m 2Hl 4. 60 (m, 2}1) 3 61 (s 3H}, 0. 03i, 9H)

Claims (1)

[Claims] 1. The following formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ [I] [In the formula, R^5 is a hydrogen atom, an alkyl group of C_1 to C_1_0, substituted or unsubstituted phenyl group, substituted or unsubstituted alicyclic group, substituted or unsubstituted phenyl (
C_1-C_2) alkyl group, tri(C_1-C_7)
Hydrocarbon-silyl group or monoequivalent cation; R^
1 is a hydrogen atom or a methyl group; R^2 is an unsubstituted C_5 to C_8 alkyl group, a substituted or unsubstituted alicyclic group, or an optionally substituted phenyl group, phenoxy group, C_1 to C_6 alkoxy group or C_5~
Substituted C_1 substituted with a cycloalkyl group of C_8
~C_5 is an alkyl group, and R^3 and R^4 are the same or different and form an acetal bond with a hydrogen atom, an acyl group of C_2 to C_7, a tri(C_1 to C_7) hydrocarbon-silyl group, or an oxygen atom of a hydroxyl group. It is the basis. ] Prostacyclin represented by is used as an active ingredient,
A pharmaceutical composition for controlling vascular system movement, comprising a pharmaceutically acceptable carrier. 2. The pharmaceutical composition according to claim 1 for vasodilation, hypotension, or antithrombosis. 3. Anti-arteriosclerosis, anti-angina pectoris, anti-myocardial infarction, anti-endotoxic shock, anti-pulmonary arterial hypertension, anti-stroke, anti-transient isochemical attack (Transient
The pharmaceutical composition according to claim 1 or 2 for anti-thrombocytopenia purpura, anti-deep vein thrombosis or anti-peripheral vasculopathy disease. 4. The pharmaceutical composition according to claim 1 for suppressing malignant tumors or suppressing metastasis of malignant tumors. 5. The pharmaceutical composition according to claim 1 for use in organ transplantation, vascular surgery, or extracorporeal circulation.