JPS61197518A - Medicine for circulatory organ containing prostacycline compound as active component - Google Patents

Abstract

PURPOSE:To provide a medicine for circulatory organs, containing (17S)-17,20- dimethyl-9(O)-methano-DELTA<6(9alpha)>-PGI1 compound as an active component, having high chemical stability, and especially high selectivity to anti-platelet coagulation activity, and effective to stenocardia, arterioscrelosis, etc. CONSTITUTION:The objective agent contains the (17S)-17,20-dimethyl-9(O)- methano-DELTA<6(9alpha)>-prostaglandin I1 of formula (R is H, 1-10C alkyl, or 1 equivalent cation), as an active component. The group R is especially preferably H. Concrete examples of the compound are (17S)-17,20-dimethyl-9(O)-methano-DELTA<6(9alpha)>-PGI1 and its methyl ester. The compound of formula has stronger anti-platelet coagulation activity than other hypotensive activities, and has high selectivity of the action. It is administered preferably orally or by intravenous injection. It is used as an antistenocardia, vasodilator, antithrombotic agent, hypotensive agent, anticerebral apoplexy agent, etc., and for the suppression of malignant tumor and of metastasis.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention provides (178)-17,20-nemethyl-9+0
The present invention relates to a cardiovascular agent containing 1-methano-Δ6(9'')-prostaglandin I as an active ingredient.

<Prior art> Natural prostacyclin is a local hormone produced mainly in the inner wall of arteries in the living body, and has strong physiological activities such as platelet aggregation inhibiting activity and vasodilatory activity, which affect the cells of the living body. It is an important factor that regulates function, and attempts have been made to directly provide it as a medicine (P, J, Lawis, J, O, Gra
dy et al.

” C11nical Pharmacology o
f Prostacyclin'.

Riven Press, N.Y., 1981).

However, natural prostacyclin is highly susceptible to hydrolysis within the molecule (because it has an enol ether bond, it is easily deactivated under neutral or hostile conditions, and although it is a preferred compound as a pharmaceutical because of its chemical instability). For this reason, a chemically stable synthetic prostacyclin conductor that has the same reproductive activity as natural prostacyclin has been eagerly sought both domestically and internationally.

Among these, derivatives in which the oxygen atoms at the 6,9-positions of brostazyclin are substituted with methylene groups, i.e., 6.9 (01-methanoprostacyclin) (carbacyclin), which is a prostacyclin with sufficient chemical stability, are known (J, R, Vane et al. + 'Pros
tacyclin”.

Raven Press, N.Y., 1979
, pp. 31-41) is expected to be used as a pharmaceutical. However, this 6.9 (01-methanoprostacyclin) had a weaker biological activity than natural prostacyclin, and could not be said to be completely different in its action selectivity, so it could not necessarily be said to be a preferable compound (・.On the other hand, it was stable As a prostacyclin, the oxygen atom at the 6,9-position is replaced with -N
= group-substituted derivatives, namely iminoprostacyclin, are known, and their biological activity is known to be comparable to natural prostacyclins (G).

I,, Bundy et al. + Tetruhedron Le
tter5 + 1371 (1978) and W, Bir
tmann et al., Tetrah-edr*n, Le
ter5+ 23, 3647 (1982)).

As a stable prostacyclin, Sunari9(0)-meta/-Δ6(9")-prostaglandin 11, a derivative in which the oxygen atoms at the 6-9 positions are substituted with a methylene group and two -CH groups, is known. Its biological activity is stronger than that of carbacycline (terrestrial + Tetrahed).
ronLetters, Volume 24, 3493M, 19
1983 reference Il1!4).

<Object of the Invention> The object of the present invention is to have a chemically stable and well-developed pharmacological action. (17S)-17,20-') methyl-9(0
)-Methano-Δ6(9'')-prostaglandin I as an active ingredient.

<Configuration and Effects of the Invention> The present inventors evaluated the biological activity of 9(0)-methano-Δ6(9(t)-prostaglandin I), and found that 9(0)-methano-△6(9(t)-prostaglandin I) specifically showed Methyl groups were introduced one by one, and the configuration at position 17 was (Sl-configuration (178)-
17,20-dimethyl-9Fol-methanol-6 (9
a)-Prostaglandin I was found, and the present invention was achieved.That is, the present invention is directed to (17S)-17,20-dimethyl- expressed by the following formula.
It is a cardiovascular agent containing 9(0)methano-Δ6(9(')-prostaglandin II as an active ingredient).

In the above formula (1), R is a hydrogen atom 1 c, -ct
.

represents an alkyl group or 1 equivalent of a cation. C1~
Examples of the alkyl group of CIO include methyl, ethyl, n-)cy leech+1 so-furovir In-gutyl, 5ec-butyl, tart-butyltn-pentylTn-hexyl+n-heptyl-n-octyl, n-
Straight chain or branched ones such as nonyl + fl 7 syl can be mentioned. One equivalent of cation is, for example, an alkali metal cation such as Na+, K+; 1/2
Ca", 1/2Mg", 1/3A1"7'z Which 2
Valent or trivalent metal cation; ammonium ion.

Examples include ammonium cations such as tetramethylammonium ion.

As R, hydrogen atom, methyl group! Sodium is preferred, and hydrogen atoms are particularly preferred.

Preferred specific examples of prostacyclins provided by the present invention are as follows.

+11 (17S)-17,20-dimethyl-9(0
)-Meta/-△6(9″)-Prostagra/Jin 11t
21 (+73) -17,20-jime 1000/re 9 to+-meta, -8 6 (9α),,, □Tagranoji 71. Methyl ester +31 (17S) -17,20-tmethyl-9
(O)-Methanone-△6(9″)-Prostagra 7-7ethyl ester+41 (17S)-17,20-one methyl-9(0
)-methano-Δ6(9a)-prostaglandin I, isopropyl ester 15) (178) -17,20-)methyl-9(
0)-Methano-△6(9')-P Stagra/Zin I-
゛Tyl ester +61 (178) -17,20-dimethyl-9(
0)-Methano-△6(9“)-Prostagra/Zinl,
5ec-butyl ester +71 (17S) -17,20-dimethyl-9
(0)-Methano-Δ6(9″)-Prostaglandin 1
．． t-butyl ester +81 (17S) -17,20-dimethyl-9
(O)-Methano-△6(9″)-Prostaglandin 1
1 hexyl ester +91 (+78)-17,20-dimethyl-9(0
1-Methano-△6(9“)-prostaglandin 1.oc'tyl ester Ql (17S)-17,20-dimethyl-9(0)
- Meta 7 no △ 6 ('tct) - Broth Grandin I
, Danel ester α'l (17S)-17,20-dimethyl-9(O
)-methano-△6(9(t)-prostaglan2in I,
Sodium illusion Q'a (17S) 17 + 20-claw +
9 (01-methano-6(9")-prostaglanodin 1 Potassium salt 3 (178)-17,20-dimethyl-9(0)
-Methano-Δ6(9")-Prostaglandin 11 Calcium Salt @@ (178)-17,20-2 Methyl-9(0)
-Methano-Δ6(9")-Prostaglandin 11 Calcium Salt C'fQ (17S)-17,20-C)Til-9t
Ol-) tano Δ6(9")-prostaglan 2in I,
Aluminum salt ae (17S)-17,20-dimethyl-9(0)
-Meta/-86(9'')-prostaglandin ■, ammonium salts and the like.

Formula C1l (17S) 17 +
20) Methyl-9 (ω-methano-muro(9ct)
)-Prostagra/Zin I, etc., for example, according to the following Sche.
mel, using a known method (M, 5hibasa
lci et al.

Chemistry Letters, 1984, 579-58271: M, 5hlbasaki et al. 9 104th Annual Meeting of Japanese Society of American Studies.

30H-1-3, 1984; T. Mase et al.
rahedrnn Latters, 25, 50
87-5090 (1984))'.

Scheme I CM) HOCH.

[1-23 In the above formula, R1 and R2 are the same or different, and T!
I (C, ~C?) A group that forms a 7-cetal bond with the oxygen atom of a silyl group or hydroxyl group.

Examples of the tri(CI-C,I) hydrocarbon silyl group include trimethylsilyl and triethylsilyl.

tri(C1~ra)alkylsilyldimethylphenylsilyl group such as t-butyldimethylsilyl group f)
Preferred examples include xyphenyl(C,-C,)7-rukylsilyl, triphenylsilyl, tribenzylsilyl, and the like, such as Q-C,)alkylphenylsilyl, t-butyldiphenylsilyl, and the like.

# of hydroxyl group! An example of a group that forms a 7-cetal bond with an elementary atom is methoxymethyl.

1-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-propyl, (2-methoxyethoxy)
Mention may be made of the methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-okimbisicR (3.1.0) hex-4-yl group. . Among these, 2-tetrahydropyranyl + 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl, (2-methoxyethoxy)methyl or 6,6-cymethyl-3-oxa-2-oxybicyclol: 3.1.0)
Particularly preferred is the hex-4-yl group.

Among these, t-butyldimethylsilyl group and 2-tetrahydropyranyl group are particularly preferred as R1 or W.

Step 1 of the above Schemes is a methylenation reaction, and by using a reagent prepared from zinc-dibromomethane-titanium tetrachloride, L. Lombardo
Follow the method of '''C (TetrahedronL
etters, vol. 23, p. 4293, 1982
) can be easily carried out and the starting material is the above formula (
Allylmethylenecyclopentanones represented by the above formula (2) can be obtained from allylcyclohephtanones represented by 3).

Step 2 is a normal hydroporation reaction,
After reacting 7lylcyclobentanone represented by the above formula (2) with a holane rust conductor such as 9-polabicyclo[3.3.1]nonane or dicyamylborane, oxidation with hydrogen peroxide aqueous-alkali is performed. As a result, the diode represented by the above formula [■] can be obtained. (Reference; )(, O.H.
ouae.

Modern Synthetic Reacti
ons 2nd Edition+Stop3 is alcohol oxidation followed by cyclization fuldol condensation reaction. The alcohol reaction of the diols represented by the above formula [■] is Sworn oxidation (oxalyl chloride-dimethylsulfoxide-triethyl 7mine; D. Swern et al. 9 J. Org. Ch@m., vol. 43, p. 2480, 1978). etc. (Reference: New Experimental Chemistry Course, Volume 15 [1], Chemical Society of Japan, Maruzen @) K- is achieved. The cyclization fludol condensation reaction following the oxidation reaction is achieved by using dibenzyl ammonium triple olacetate, and the above formula
Unsaturated aldehydes represented by can be obtained.

Step 4 is a Wittig condensation reaction and a methyl esterification reaction of carboxylic acid. The Wittig condensation reaction is carried out by the usual method (reference; A. Maerker + O
rganic Reactions, vol. 14, 27
0-49074, Ed. by R. Adams e
tal. , John Wllley and Sons,
New York, 1965). For example, this can be achieved by reacting 3-carpoxybrobyl triphenyl-phosphonium bromide with bottadium t-butoxide in tetrahydrofuran to form a ylide, and reacting it with an unsaturated aldehyde represented by the above formula. By subjecting the carboxylic acid product obtained by K in this manner to a normal methyl esterification reaction such as diazomethane, (17S)-17,20-dimethyl-
9(0)-methano-Δ4·6(9″)-prostaglandin II (M) can be obtained.(17S)-17,2 represented by the above formula [W] obtained here
0-dimethyl-9(O-methanol-△4.6(9″)-
The chamber configuration of the double bond at the 4-position of prostaglandin I, class [■] is generally a mixture of the E-form and the 2-form.

5tep 5 is a hydrogenation reaction, which is the usual catalytic reduction method (New Experimental Chemistry Course, Volume 15 (6), 3rd Army).

333-448 M1 Edited by the Chemical Society of Japan, Maruzen ■)). The catalyst used is
homogeneous catalysts such as tris(triphenylphosphine)rhodium(I), chlorohydridotris(triphenylphosphine)ruthenium(Ill), and heterogeneous catalysts such as activated R with palladium and platinum with ffl/J'' -1 is better than chlortris(triphenylphosphine)rhodium (I+.The solvent is benzene.

Hydrocarbon solvents such as toluene and hexane; alcohol solvents such as methanol and ethanol; and ester solvents such as ethyl acetate are used (although benzene is preferred). It is expressed as (
178) -17,20-di) chill-9(01-methanol△6(9″)-frostaglandin 1° class is a
Rich column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC), etc., or column chromatography with silver nitrate - 9 thin layer p
M jtJ can be done by Madography.

5tep6 is (178)-1 expressed by the above formula [resistance]
7,20-Jime 1,000 Roux 9(0)-Methano-Δ6(9″)
- Deprotection reaction of the 11th and 15th positions of prostaglandin I. When the anchoring group is a group that forms an acecool bond with the acid # and M of the hydroxyl group, 1, for example, acetic acid, P-
) Using a pyridinium salt of luenesulfonic acid or a cation exchange resin as a catalyst, for example, water, tetrahydrofuran, ethyl ether, dioxane, acetone.

This reaction is preferably carried out using acetonitrile or the like as a reaction solvent. The reaction is normally carried out at a temperature range of -78°C to +30°C for about 10 minutes to 3 days. Also, Kenki Yasu)!
j (Ct-Cr)hydrocarbon-silyl group, 1, e.g. acetic acid.

in the presence of tetrabutylammonium fluoride, cesium fluoride, preferably either of the latter two,
Reaction solvent as described above (preferably a reaction solvent outside the water plate)
It is carried out at a similar time and for a similar amount of time.

The reaction solution thus obtained may be treated in accordance with a commonly used method or may be post-treated. For example, by adding JllIW organic solvent to hexane, pentane, petroleum ether, ethyl alcohol, ethyl acetate, and sodium water, or by directly condensing the reaction mixture under reduced pressure, the resulting organic mixture is washed with brine. After drying anhydrous magnesium sulfate, anhydrous sulfuric acid, anhydrous potassium carbonate, etc., the organic medium is removed under reduced pressure to obtain a crude product. The crude product is
If desired, purification can be carried out by means of purification such as column chromatography, thin-layer pomadography, liquid pomadography, or the like.

In this way, the debinding and recycle reaction is achieved, and the above formula [1-1
] (178) -17゜20-dimethyl-
9(0)-methano-Δ6(9a)-prostaglandin 11 ethyl ester is obtained.

5tsp 7 is an ester hydrolysis reaction and can be achieved by conventional methods. For example, caustic soda, potassium, an aqueous solution or water-alcohol mixture of calcium hydroxide, or an alcohol containing sodium methoxide, potassium methoxide, or sodium ethoxide.
This can be carried out by hydrolysis in a mixed solution of water. In addition, for example, using a 1-11 element such as lipase, the hydrolysis reaction is carried out in water or a solvent containing water at a temperature of -10°C to +60°C for about 10 minutes to 24 hours. The subsequent transfer treatment and processing can be carried out using the same method as described above, using bales neutralized with acids such as dilute hydrochloric acid and oxalic acid.
and is represented by the following formula Cl-21 ( ] 7S)
-17,20-dimethyl-9(0)-meta/-△6(9
″)-Prostaglandin ■1 can be obtained.

The carboxyl group-containing compound produced by the above-mentioned hydrolysis reaction is then further subjected to a salt-forming reaction, if necessary, to yield the corresponding carboxylate. The salt-forming reaction is known per se, and a basic compound such as thorium hydroxide, potassium hydroxide, or sodium carbonate, or ammonia, trimethylamine,
This is carried out by neutralizing monoethanolamine, morpholine, etc. using a conventional method. In this way, prostacyclins h'-of the present invention are obtained.

The aryruncoupentanones represented by the formula CXJ, which are the raw material compounds used in the production method of the present invention, can be produced by a method known per se (t￥f
-44336).

That is, the following formula [V-] R'0 [wherein R1 is the same as defined above]. ] The cyclobentenones represented by the following formula [■] [wherein,
R2 is the same as the above constant @. ] Organolithium compound represented by the following formula ■] CuQ
......Sen 1 type, Q bar R'y'7U child 1 Sea f/N, 7
R20CI of the following formula [x] obtained by carrying out a conjugate addition reaction with a copper compound represented by 1 and reacting the obtained enolate with a chloroform allyl.

[In the formula, the definitions of lent and W are the same as the above definitions. ] Allyloxycarbonylcyclopentanones represented by can be obtained by subjecting them to a decarboxylation allylation reaction using tetrakis(triphenylphosphine)palladium(0).

The optically active cyclobentenones represented by the above formulas [~1] can be obtained by methods known per se (Japanese Patent Application Laid-open No. 57-1979-1).
159777).

Further, the organolithium compound represented by the above formula [X] can be prepared by a method known per se, that is, by the following formula [Kari] [wherein, the definition of R1 is the same as the above definition. ] and t-
It can be easily obtained by reacting an organic lithium compound such as butyllithium. The iodononene represented by the formula [Kari] can be obtained by a method known per se (Japanese Patent Application Laid-Open No. 58-32834).
It can be obtained from K.

(17g)-17,20-cysimethyl-9 of the present invention
(01-methano-Δ6(9d)-prostaglandin 1
Category 1 has surprisingly strong biological activity.
・Ru. For example, (178) -17,20-dimethyl-
9(0)-methano-Δ6(9″)-prostaglandin tt (compound [l-2)) can not only suppress ADP-induced rabbit platelet aggregation with IC5o=0.0024μjl/=t, but also Oral administration (to9/K
Platelet aggregation was measured 1 hour and 2 hours after s+) (ox vivo).

Aggregation was inhibited by 100%.

In addition, the compound of the present invention has a particularly strong antiplatelet aggregation effect compared to other pharmacological effects such as antihypertensive action, and has high selectivity of action (・
It is also a compound.

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 vascular system control.

The active compounds of the invention may be used in patients for example anti-anginal, vasodilating, hypotensive, anti-thrombotic, anti-arteriosclerosis, anti-myocardial infarction, anti-endotoxic shock, anti-pulmonary hypertension, anti-stroke,
Anti-transier/toincier attack (trans
i-ent Ischemic Attack),
It can be administered for anti-thrombocytopenic purpura, anti-deep vein thrombosis or anti-peripheral vasculopathy disease. The active compounds of the present invention may also be used to inhibit malignant SRS or to inhibit malignant m.
It can also be administered to inhibit tumor metastasis. The compounds of the invention can also be used during organ transplantation, vascular surgery or extracorporeal circulation. For example, blood, blood products, blood substitutes, and other isolated body parts (e.g., limbs or organs; attached to the original body) may also be stored separately or used for transplantation. It can be used as an additive in fluids used for artificial extracorporeal circulation and perfusion, including when prepared or newly attached to the body.During such circulation and perfusion, condensed platelets enter the blood vessels and This has a tendency to block the circulatory organs. The presence of the active compounds according to the invention prevents this blockage. For this purpose, the active compounds according to the invention are administered gradually or in batches to the circulating blood. , the blood of a blood donor animal,
The part of the body to be perfused (attached to or separated from the recipient)
or two or all of these K, e.g. 0.001 μg to 10 μm, continuously injected at 17 m/min.

These compounds can be administered orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, etc., for the above purpose, but oral or intravenous administration is preferable.

For oral administration, solid or liquid preparations can be provided. Examples of solid preparations include tablets, gunpowder,
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 bicarbonate, calcium carbonate.

Potato starch, cane sugar, mannitol.

Mixed with carboxymethyl cell sheath, etc. Preparation operations are carried out according to conventional methods, but additives for formulation other than those mentioned above may be included, such as lubricants such as calcium stearate, magnesium stearate, and glycerin.

Liquid preparations for oral administration include 1, e.g. emulsions, solutions,
Including suspensions, syrups or xyls. These formulations contain commonly used pharmaceutically acceptable carriers such as water or liquid paraffin.

Coconut oil 1 fraction coconut oil, soybean oil.

An oily base such as corn oil can also be used as a carrier.

Enteric-coated preparations for oral administration include, for example, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer, or methacrylic acid, methyl methacrylate copolymer in the solid preparation as described above. It is manufactured by spraying a solution of an enteric substance in an organic solvent or in water to form an enteric coating. IL! such as powders and granules! 1-Soluble solid preparations can also be encapsulated.

The pharmaceutically acceptable carrier herein includes other adjuvants, fragrances, stabilizers, or preservatives that are normally used as necessary.

The liquid preparation may also be administered in capsules made of absorbable materials such as gelatin.

In addition, the prostacyclin of the present invention is hydroxyprotamine as a nasal solution for intranasal administration.

Preferably used are those in which a base such as cellulose or lactose and prostacyclin are dissolved or pore-formed in saline or isotonic glucose solution.

Solid preparations for rectal administration include herbal medicines containing one or more active substances and prepared by methods known per se.

Preparations for parenteral administration may be presented as sterile, aqueous (non-aqueous solutions, suspensions, or emulsions).

11. Vegetable oils such as purpyl glycol, polyethylene glycol or olive oil.

Injectable organic esters such as ethyl oleate are pharmaceutically acceptable carriers. Such formulations also
Preservatives, 0! Auxiliary agents such as wetting agents, emulsifiers, dispersants, and stabilizers may be included. These bath solutions, clouding agent products, and emulsifying agents can be made sterilized, for example, by passing them through a bacteria-retaining filter, adding a sterilizing agent, or irradiating them as appropriate. 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 d, β or r-cyclodextrin or methylated cyclodextrin.

The dosage of the compounds of the present invention will depend on the condition of the subject receiving the administration. l
Although it varies depending on age, sex, body weight, route of administration, etc., it can be administered in a usual amount of 0.01μ9 to xoomp/xoomp/body weight/day.

Such a dose may be administered once or several times a day, for example, in divided doses of 2 to 6 times.

The present invention will be explained in more detail below with reference to Examples.

(Example 1) 1 ul (2R, 3R, 4R) -2-7lylu-4-t-gthyrunmethylsilyloxy-3-((tE, 3S.

5S)-3-t-7'Tyldimethylsilyloxy-5-
Methyl-1-nonenyl)cyclopentanone (compound (n
)) Dissolve 1.75 g in 40 d of methylene chloride and cool with water to form a zinc-methylene bromide-titanium tetrachloride reagent (zinc 92 g,
From methylene bromide 32-9 titanium tetrachloride 37d, tetrahydrofuran 800d, L, Lomb a rd
o et al.'s method (TetrahsdronLette
rs, vol. 23, p. 4293, 1982) K therefore 81in! ') 35k was added and stirred at room temperature for 1.5 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution 20011/20011 with stirring, and then 200 at of n-hexane was added and passed through Celite.

Oral separation - After shaking at one plate, the aqueous layer was diluted with n-hex/20
Extract again with 0- and combine the organic layers with 250 ml of saturated saline solution.
It was washed with 11+7 and dry refined with magnesium sulfate. By distilling off the solvent, 1.62 g (crude rate 93%) of (
IR,211,3R)-3-7lylu-1-t-7'Tyldimethylsilyloxy-2-((tg,3s,5s)-
3-t-butyldimethyl-silyloxy-5-methyl-
1-nonenyl)-4-methylene-cyclopentane (compound (10)) was obtained.

, NMr! (CDCl3.δppm) 0.85
(24B, bs), 3.5-4.3 (2H, br),
4.7-5.2 (4H, m), 5.42 (2H, m)
, 5.3-6.1 (1) I, m );・IR(
liquid Ill, cIR-') 1460, 1254, 11
10,965,835,772;-Mass 520
(n+), 505,463,421,323,2
89,257° (Example 2) [■] 9-polavisic Gl [3,3,1]nonane (dimer) 1.89 # was dissolved in 20 mK of tetrahydrofuran and cooled on ice under a nitrogen atmosphere. (IR, 2R, 3R)-3
-Allyl-1-t-7'Tyldimethylsilyloxy-2
-((Ig, 38.58)-3-t-gtylddimethylsilyloxy-5-methyl-1-nonenyl)-4-methylenecyclopentane (compound ()IQl, 61.P solution Ikd in tetrahydrofuran (7d) and stirred for 2 hours under water cooling. 4.9 m of 5N aqueous sodium hydroxide solution
After adding 3.3 d of hydrogen peroxide solution, add 50 ml of hydrogen peroxide solution.
The mixture was stirred at -60°C for 1 hour. Add 6 liters of saturated saline to the reaction mixture.
After extraction by adding 0ml and 100ml of ethyl acetate, the aqueous layer was extracted again with 100ml of ethyl acetate, and the organic compound was washed successively with a saturated aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, and then dried over magnesium sulfate. When the solvent was distilled off, a crude product of 2.4,! i+ was obtained. When this was purified using a silica gel column, (IR, 2R, 38
,4S)-1-t-butyldimethylsilyloxy-2-
1(IE, 38.58)-3-t-butyrunmethylsilyloxy-5-methyl-1-nonenyl)-4-hydroxymethyl-3-(3-hydroxypropyl)cyclopentane (compound [■] ) h” -1,36# (yield 7
9ch) Obtained.

・ direction), +4.17°(CO,58,(JI(
J, ) ;, NFillR(CD(J, , δp
pm) 0.84 (24H, bs), 3.3-3
．． 8(4H,br), 3.8-4.2(2H,b
r), 5.38 (2H.

m); ・IRC liquid, steel-") 3360, 1460, 12
52,1055゜967.836.775; ・M ass (m/e) 499 (M-t
B u ), 424 + 406-367 *325
．． 275; (Example 3) HO.

(IV) Oxalyl chloride 612 μl methylene chloride (10M/
) A solution of dimethyl sulfoxide 1.191/methylene chloride (2d) was added dropwise under cooling at −60° C. under a nitrogen atmosphere. After stirring at -60°C for 30 minutes, (IR, 2R, 38
,48)-1-t-butyldimethylsilyloxy-2-
((Ig, 3S, 58)-3-t-butyldimethylsilyl-oxy-5-methyl-1-nonenyl)-4-hydroxymethyl-3-(3-hydroxypropyl)-cyclopentane (compound [tv:) ) 1.30 g of methylene chloride (5d) solution was added and stirred at -60°C for 30 minutes. Triethylamine 4.89 m ft Dropping chamber Stirred at room temperature for 30 minutes, dibenzylamine trifluoroacetate
) After adding 728 mg, the solvent was distilled off and benzene 15
Added m. The mixture was stirred at 70° C. for 7 hours, added with 50 l of hexane, filtered through Celite, added with 5 Qm of water, and shaken in a liquid-free separatory funnel.

After extracting the aqueous layer again with n-hexane, the organic layer was extracted with a saturated aqueous potassium hydrogen sulfate solution and a saturated aqueous sodium hydrogen carbonate solution.
l N Hj%! It was washed successively with Japanese brine, dried over magnesium sulfate, and the solvent was distilled off. Obtained roughness 1; paraboloid (
When purified by silica gel column chromatography (1,fi 2 g), 1.041 (yield: 83%) of (17S
) -17,20-dimethyl-6-formyl-1,2,
3,4,5-pentanol-9 +01-methanol-△6(
9d)-Prostaglandin ■, methyl ester 11.
15-bis-t-7' methyldimethylsilyl ether (compound (vl)) was obtained.

, @)','-52,1' (CO,55,CHCl
5'')-NMR (CDCA!3, Jppm) 0.
85 (24H), 2.9-3.4 (IH, br),
3.5-4.2 (2H, rn), 5.42 (2H.

m) + 6-67 (IH+ s)・fR (liquid film, equipment-') 1684, 1460, 1260, 1120° 1005.972, 838.778; ・Masa (m/e) 477 (M-tBu), 43
5,387゜〔■〕 3-carpoxypyltriphenylphosphoniump
2.45 g of amide was suspended in tetrahydrofuran 751117, 23 su of 0.5 M potassium t-butoxide tetrahydrofuran solution was added dropwise at room temperature, and 40 g of
The mixture was stirred for a minute. (178)-17,20-dimethyl-6-
Formyl-1,2,3,4,5-pentanol-9(0)
-methano-Δ6(9d)-p.

Staglandin I, methyl ester 11.15-bis-
t-7Tyldimethylsilyl ether (compound ~)) 1.
One solution of 0 g of tetrahydrofuran (15 m) was added dropwise, and after stirring at room temperature for 30 minutes, 100 dIk of ice-water was added. After adding 80ml of ethyl acetate, stir vigorously and add oxalic acid (2ml).
720 m9 of hydrate) was added to adjust the pH of the aqueous layer to 3-4.

Ethyl acetate 70111 was added for extraction, water 1-1 was re-extracted with ethyl acetate 150-1, and the combined organic layers were washed with saturated brine. Dry with magnesium sulfate, evaporate the solvent, dissolve the entire amount of the obtained crude product (1,041) in 201 L of methylene chloride, and apply the ether solution of diazomethane to thin layer chromatography until the spot of the raw material disappears. After adding with stirring, the mixture was stirred for 10 minutes. When the solvent was distilled off and the resulting residue was purified by silica gel column chromatography, 954 g (81 g) of (178) 17+ was found in the eluate of ethyl 4-thiacetate-n-hexane.
20-dimethyl-9(0)-methano-Δ4.6(9″)
-Pstagranne I, methyl ester 11.15-
-His-t-phthyldimethylsilyl ether (compound [
M]) was obtained.

, NMR (CDCA!, , δppm) 0.85
(24H), 3.67 (3H.

s) + 3.6 4.2 (2H9m) + 5
-0 5-6 (4H+m), 5.97 (2/3
H, d, J=11Hz), 6.22(1/
3H, d, J=16Hz)・IR(liquid film, (X
-') 1740, 1255, 1115, 968°83
8.775 Example 5) (W)' [■] The reaction is carried out using a normal atmospheric pressure hydrogenation reactor. (Reference: New Experimental Chemistry Course, Volume 15 (■).

335 pages 2 Edited by the Chemical Society of Japan, Maruzen ■). Chlorotris (triphenylphosphine) rhodium (Il) was placed in the reaction vessel.
120119 was added and the gas in the first reaction vessel was replaced with hydrogen. (17S)-17,20-dimethyl9(O)-
Methanol-Δ4.6(9″)-Prostaglandin I, Methyl Ester 11.15-Bis-t-butyldimethyl-
Silyl ether (compound [:M) ) (s o o m
A solution of benzene (4Rt) of
7S) -17,20-di, t, -9(01-i 1
/-Δ6(9α)-p, 3 taglandin 11 methyl ester 11.15-bis-t-butyldimethylsilyl ether (compound [■]) was further analyzed by high performance liquid chromatography = (Waters, Pre
pLC/System 500, PrepPAK
-500/5ILCa) to separate and purify (ethyl acetate-n-hexane (0:100 to 10:90) +1
23 g (15% yield) of pure (178)-17,2
0-dimethyl-9(01-methano-Δ6(9a)-prostaglan I, methyl ester dimethylsilyl ether (compound [■]) Ik was obtained.

- NMR (CD (J3, spm) 0.8 -
0.9 (24H), 2.6-3.2 (IH,
br), 3.66(3H,S), 3.5-4.3(
2H, rn), 5.18 (IH, bs), 5.4
3 (2H, m).

・IR (liquid film, α-') 1740, 1255.11+
0.1002.

968, 835,772 (Example 6) (r-1:) (17S) -17.20-dimethyl-9(O)
-Methano-Δ6(Ld)-Prostaglandin E1 Methyl Ester 11.15-Bis-t-7'Tyldimethylsilyl Ether (Compound [■)) 100 q is dissolved in 3 d of tetrahydrofuran, and tetrabutylammonium fluoride ( 530 (1 g of trihydrate) was added thereto, and the mixture was stirred at room temperature for 16 hours. Water (25 sd) was added, extracted twice with ethyl acetate (25 iu x 2), and the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. When the obtained crude product was purified by silica gel column chromatography, 54 mq (yield 85%) of (
17S)-17.20-dimethyl-9(0)-methano-Δ6(9″)-p-staglandin I, methyl ester (compound CI-1) was obtained.

, NMR (CDCI, δppm) 0.88
(6H,m), 2.6-3-2 (
IH + br), 3-66 (3H, S
), 3, 71(1)1.

bq, J=8Hz), 3.8-4.3 (
IH,br), 5.20(IH,bs),
5.42 (2H, m)・IR (liquid film, C11
-1) 1740.1086,995,965 (Example 7
) HO HO MuH.

CI-2:] (178)-17.20-dimethyl-9f
ol-methanoΔlsa), rostaglandin 11 methyl esul (compound CI-1'l) 50 to 9 was dissolved in 0.5 m of ethanol, and 2 N aqueous sodium hydroxide solution was added.
, 13- were added thereto, and the mixture was stirred at room temperature for 5 hours. While stirring after adding water (10d) and ethyl acetate (10m/)! Normalized hydrochloric acid was added dropwise to make the water layer weakly acidic. After extraction twice with ethyl acetate (10d, 20II), the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off.

The resulting residue was purified by silica gel column chromatography. n-hexane-ethyl acetate-acetic acid (3
: 7 : 0.0 2 5~2 : 8 : 0.0
2 5 ) 43119 (yield 90φ) (1
7S)-17.20-dimethyl-9(O)-methane-Δ6(9a)-pustabrandinl, (compound Cl-21) was obtained.

, NMR (CDCl3.δpf'') O-88 (6H
+m), 2-98 (IH, bd, J=7Hz)
, 3.75 (IH, bq, J=8Hz) + 4
．． 13 (IH, b p + J =71(z) +
5-29 (IH.

bs), 5.47 (IH, dd, J=15Hz
, 8Hz).

5.50 (IH, dd, J=15Hz, JHz),
5.95 (3H.

b r, D! Disappears at 0) ・IR (liquid film, equipment) 3350.3400-240
0,1712°1085.995,968, Mass (m/e) 360 (M-H2O),
342,316 (Example 8) The in vitro platelet aggregation inhibitory effect of the test system was assayed using rabbits. .8 Trisodium citrate solution 11I! Blood was collected at a ratio of 90 to 1,
Upper layer IkPRP after centrifugation at 1000 rpm for 10 minutes
(platelet-rich plasma). The lower part is Sara K
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 6×10 5 /μl by dilution with PPP.

Add 25 μl of the test system to 250 μl of adjusted PRP and incubate for 2 minutes at 37°C.
10 μM (final) of P was added and changes in transmittance were recorded using an acribometer. The test drug was dissolved in ethanol at a concentration of 10 y/d, and then diluted sequentially with phosphate buffer (pH 7, 4) before use.

The aggregation inhibition rate was determined using the following formula.

Inhibition rate (a) = (1--) x to.

T.

Permeability T of To' (!J acid buffer addition system): Permeability inhibition rate of test drug addition system 50% Ik: Minimum drug concentration t I Cs
.

Shown as a value.

(17S)-, 17,20 of Example 7 as a test system
IC using -dimethyl-9(O)-methano-Δ6(M)-prostaglandin I, (compound (1-2))
I found 5°. The results are shown in Table 1.

9( obtained in Example 3 by intravenous injection under anesthesia)
The effect of O)-methano-Δ6(9)-prostaglandin I on blood pressure and heart rate in rats was investigated.

That is, a male Wistar rat weighing 250 g was used, and this rat was treated with urethane 500II9/I'4 and α-chloralose (ct-chloralome).
Too month 9/Kf was administered intraperitoneally, anesthetized and fixed.

The test compound was dissolved in a small amount of ethanol, diluted with physiological saline, and finally injected into the vein of a rat via a catheter inserted into the femoral vein at a level where the amount of ethanol was 5% or less. Injected.

Blood pressure was measured using a pressure transducer through a catheter inserted into the carotid artery of the rat.

The effect of the test compound on blood pressure was expressed as the dose of the test compound that lowered the mean blood pressure by 20% (ED, .mu.I/Kg) with respect to the mean blood pressure value before administration of the test compound.

As a test system, Example 7 (1783-17°20-dimethyl-9(0)-methano-Δ6(9″)-prostaglandin II (compound Cl-2)) was used.

The results are shown in Table 1.

611) Platelet aggregation effect (IC5o) obtained with the above (1+, tiil) *Hypertensive lowering effect (EDyo
) from the value of ED,. /IC,. This was used as an index of desired action selectivity.

The results are shown in Table 1.

(Example 9) Extra vivo platelet #collection inhibiting effect Extra
The platelet aggregation inhibition rate in vivo was determined using guinea pigs (6111).
After ethanol rms, Hartley guinea pigs 5o to 4509 were orally administered with a 30% alcohol solution in physiological saline and only a 30% alcohol solution as a control at a dose of 1 m/KIi.

3. By cardiac puncture at 1 hour and 2 hours after administration.
The sample was collected at a ratio of 9 parts blood to 1 part 8% trisodium citrate, and centrifuged at 700 rpm for 10 minutes. The upper layer was separated as PRP (platelet-rich plasma), and the lower layer was further centrifuged at 2800 rpm for 10 minutes, and the upper layer divided into two layers was separated as PPP (platelet-poor plasma).

250 μl of the obtained PRP was placed in an alibometer cuvette, incubated at 37° C. for 2 minutes at 1 ncubatton, and then incubated at 37° C. for 2 minutes. IM) 25 μl of a 10 μM ADP 2 sodium solution dissolved and adjusted in Lissu Shiojo Gogogi solution (pH 8,0) was added, and an agglutination curve was recorded for 3 minutes. The maximum degree of platelet aggregation within that time was read and the platelet aggregation inhibition rate was calculated using the following formula.

Tc: Transmittance of the control (administration of only 30% furfur solution) group TD: Transmittance results of the test drug administered group are shown in Table 2. Compound Cl-2 of Example 7 was used as the test drug.

÷F ξyg total: 4J
vo Ic oh (・very strong and durable pla
telet aggregation inhibit
It has inaction.

(Example 10) Tablets were manufactured, each having the following composition.

? There are 20 μg of old components (・ means 100 μg of lactose 2
80 genus 9 ginger starch
8011+9 polyvinylbipridone
11-9 Magnesium stearate
519576 M9 Active ingredients, lactose and potato starch/are mixed and evenly wetted with a 20% ethanol solution of polyvinylhyrrolidone, 20. Men 7'Yu's full passage, 45
It was dried at 10°C and passed through a 15-piece mesh again. The solid magnesium stearate thus obtained was mixed and compressed into tablets.

As active ingredient, typically the compound of Example 7 [I-2
] was used.

(Example 11) One hard gelatin capsule was prepared containing the following composition.

Active ingredient: 20 μg (・ means 100 μg Microcrystalline cellulose 195 Calyx amorphous silicon J
51 g 400 ■ The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into hard gelatin capsules.

As active ingredient, typically the compound Cl-2 of Example 7:
) was used.

(Example 12) The compound (1-2) of Example 7 was dissolved in fractionated coconut oil. Also, the shell component of the following formulation was dissolved by heating, and 1
Soft capsules were manufactured by a conventional method using a soft capsule manufacturing machine so that each capsule contained 50μ9 of the compound [1-2) of Example 7.

Shell formulation Piratine 10 parts by weight Glycerin 5 Sorbic acid 0.08 n Purified water 14 (Example 13) (Ampoule punishment) One ampoule (5'''8 amount) contains the following composition An ampoule was produced.

Active ingredient 200μI polyethylene glycol 600 20011g distilled water
The total amount of 59al polyethylene glycol and active ingredient were dissolved in water under nitrogen, boiled, cooled under nitrogen, and distilled. Pretreated water was added to this bath liquid, and the mixture was filtered under a sterile filter. This production is carried out under diffused light.

Filling was carried out in a nitrogen stream and sterilization was carried out at 121°C for 20
I did it for a minute.

In addition, as the above-mentioned active ingredient, the compound [I-
2'J was used.

Claims (1)

[Claims] 1. The following formula ▲ Numerical formula, chemical formula, table, etc.▼... (I) In the formula, R represents a hydrogen atom, an alkyl group of C_1 to C_1_0, or a cation of 1 equivalent. (17S)-17,20-dimethyl-9 (
A circulatory agent containing O)-methano-△^6^(^9^α^)-prostaglandin I_1 class as an active ingredient. 2. The circulatory system agent according to claim 1, wherein in the above formula [I], R is a hydrogen atom.