JPH0768129B2 - Organ protector - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to an organ protecting agent, and more particularly to an organ protecting agent containing prostacyclins as an active ingredient.

<Prior Art> Prostaglandins have various physiological actions such as strong platelet aggregation inhibitory action, blood pressure lowering action, gastric acid secretion production, smooth muscle contraction action, diuretic action, peripheral circulatory disorder, myocardial infarction. , A substance useful for the treatment or prevention of angina, arteriosclerosis, hypertension, gastric ulcer, duodenal ulcer, labor induction, abortion, etc.

Recently, it has been found that some of these prostaglandins have a so-called cytoprotective action, which protects cells of living tissues. This cytoprotective effect is present on all cells in the body, and for example, the therapeutic effect on gastric ulcer, the effect of reducing myocardial infarction, the effect of preventing lung damage due to endotoxin shock, etc. are derived from this cytoprotective effect. It is said to be present (Ayumi of Medicine, Vol. 125, 250
See page, 1983). It is also known that prostaglandins have a cytoprotective effect on hepatocytes. For example, 16,16-dimethyl-P which is a structural modification of PGE ₂
GE ₂ was reported to prevent carbon tetrachloride- and galactosamine-induced hepatocyte necrosis in rats [Foliar
Human chemica et cytochemica (Folia Histochemi
ca et Cytochemica), 18, 311 1980: and Gastroenterology, 81, 21
1 pages, see 1981] The PGE ₂ and its structural modifier (15-methyl PGE _2, 16,16-dimethyl -PGE _2, etc.) for hepatocyte protective effect of, also described in U.S. Patent 4,374,856 There is. Further, the cytoprotective effect of structurally modified 6-oxo-PGE ₁ has been reported in JP-A-58-164512 and JP-A-58-203911.

In addition, prostacyclin (PGI ₂ ) has been reported to have a protective effect on the hypoxic state of cat liver tissue [American Journal of Physiology (Amer.J.Physiol), 238, p. 176]. , 1980].
Further, it has been reported that there is 6,9α- nitrilo -PGI _1, and the like also liver cytoprotection a derivative of prostacyclin (JP 58-164512, see each Nos. 58-203911 Publication). Further, it has been reported that the carbacyclin derivative iloprost and the cyanoprostacyclin class nileprost also have a protective effect on the liver, pancreas and kidney (see Japanese Patent Publication No. 61-502819).

Recently, prostaglandins are also used in the field of organ transplantation due to their strong cytoprotective action (see Kazuo Ohta, "Modern Medicine", Vol. 18, 2693-2697, 1986). In other words, at the time of organ transplantation, prostaglandins are used for organ preservation in order to protect the organs excised by an organ donor, minimize the damage to organs until the time of transplant surgery, and preserve them in good condition. There is. For example, natural prostacyclin (PGI ₂ ) has been reported to be effective in preserving the liver and kidney (M. Monden, et al, Ann.Sur.
g., vol.196, p38,1982; JW Bradley, et al, Transplant.P
roc., vol.15, p424, 1983) and that OP-41483, a derivative of prostacyclin, is effective for renal preservation (M. Tob.
imatsu, et al, Transplant, Proc., vol.17, p1461,1985)
Moreover, it has been reported that prostaglandins are effective in suppressing rejection at the time of organ transplantation due to their strong cytoprotective action (Kazuo Ohta, “Modern Medicine” above).

By the way, natural prostacyclin is a local hormone produced mainly in the inner wall of blood vessels of arteries in the living body, and has strong physiological activity, for example, platelet aggregation inhibitory activity,
Taking advantage of the fact that it is an important factor that regulates the cell functions of the living body through vasodilatory activity, etc., an attempt has been made to directly use this as a drug "P.J.Lewis, J.O.Grady" (PJLewis). , JOGrad
y) et al., “Clinical Pharmacology of Prostacycl
in) ", Raven Press, NY, 1981) natural prostacyclin has an enol ether bond that is very easily hydrolyzed in the molecule, so it is easily inactivated under neutral or acidic conditions, and its chemical property as a drug. Because of its instability, it cannot be said to be a preferable compound, and thus chemically stable synthetic prostacyclin derivatives having physiological activities similar to those of natural prostacyclin have been intensively studied [Synthesis, 1984, p. 449. The present inventors have proposed the prostacyclins 9 (O), which have sufficient chemical stability by replacing the oxygen atom at the 6- and 9-positions of prostacyclin with a methine group (-CH =). -Methano-Δ6 ^(9α) -prostaglandin I ₁ (isocarbacyclines) was successfully synthesized (Japanese Patent Laid-Open No. 59-2100).
44). This derivative has a potent activity of inhibiting platelet aggregation, a blood pressure-lowering effect and the like comparable to natural prostacyclin, and was useful as a cardiovascular agent (JP-A-59-210044, 61-61). 197518 No.).

<Purpose of the invention> The present inventors have studied the organ protective action of various prostaglandins, and have found that a specific prostacyclin has a high protective action, and have reached the present invention.

<Structure and Effect of Invention> That is, the present invention provides the following formula [I]: It is an organ protective agent containing a prostacyclin represented by and / or its enantiomer as an active ingredient, particularly an organ protective agent effective for the liver.

In the above formula [I], R ¹ represents a hydrogen atom, a C _{1 to} C ₁₀ alkyl group, or 1 equivalent of a cation. Examples of the C _{1 to} C ₁₀ alkyl group include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n. Examples thereof include linear or branched ones such as -octyl, n-nonyl and n-decyl. One equivalent of cation is, for example, an alkali metal cation such as Na ⁺ , K ⁺ ; 1/2 Ca ²⁺ , 1/2 Mg
^Examples thereof include divalent or trivalent metal cations such as ²⁺ 1/3 Al ³⁺ ; ammonium cations such as ammonium ion and tetramethylammonium ion. R ¹ is particularly preferably a hydrogen atom or a methyl group.

In the above formula [I], R ² represents a hydrogen atom or a methyl group, and a methyl group is particularly preferable.

In the above formula [I], R ³ is a linear or branched chain C _{3 to} C ₁₀
Alkyl group; linear or branched C _{3 to} C ₁₀ alkenyl group; linear or branched C _{3 to} C ₁₀ alkynyl group; optionally substituted C _{3 to} C ₁₀ cycloalkyl group: optionally substituted phenyl; optionally substituted phenoxy group optionally; or optionally substituted phenyl group is substituted with optionally substituted C ₃ be also be phenoxy or substituted optionally -C ₁₀ cycloalkyl group Represents a straight or branched chain C ₁ -C ₅ alkyl group.

As the straight chain or branched chain C ₃ -C ₁₀ alkyl group, n-
Propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, 1-methylpentyl, 1-
Examples thereof include metrihexyl, 1,1-dimethylpentyl, 2-methylpentyl, 2-methylhexyl, 5-methylhexyl and 2,5-dimethylhexyl groups, preferably n-butyl, n.
Examples include -pentyl, n-hexyl, (R)-or (S)-or (RS) -1-methylpentyl, (R)-or (S)-or (RS) -2-methylhexyl groups.

The C ₃ -C ₁₀ alkenyl group 2-butynyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 4-hexenyl, 2-
Methyl-4-hexenyl, 2,6-dimethyl-5-heptenyl group and the like can be mentioned.

The C ₃ -C ₁₀ alkynyl group 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 4-hexynyl, 2-
Octynyl, 5-decynyl, 1-methyl-3-pentynyl, 1
Examples include -methyl-3-hexynyl and 2-methyl-4-hexynyl groups.

The C ₃ -C ₁₀ cycloalkyl group which may be substituted includes cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl,
(C ₁ -C ₆ ) alkylcyclopentyl, (C ₁ -C ₄ ) alkylcyclohexyl, dimethylcyclopentyl, dimethylcyclohexyl, chlorocyclopentyl, bromocyclohexyl, iodocyclopentyl, fluorocyclohexyl group and the like, but preferably cyclopentyl group , A cyclohexyl group.

Examples of the substituent of the optionally substituted phenyl group and the optionally substituted phenoxy group include a halogen atom,
Hydroxy groups, C ₂ -C ₇ acyloxy group, optionally C ₁ -C ₄ alkyl group optionally substituted by a halogen atom, a substituted C ₁ optionally -C ₄ alkoxy group with a halogen atom, a nitrile group, a carboxyl group Alternatively, a (C ₁ -C ₆ ) alkoxycarbonyl group and the like are preferable. The halogen atom is preferably fluorine, chlorine, bromine or the like, particularly fluorine or chlorine. C ₂ ~
Examples of the C ₇ acyloxy group include acetoxy, propionyloxy, n-butyryloxy, iso-butyryloxy, n
Mention may be made of -valeryloxy, iso-valeryloxy, caproyloxy, enanthyloxy or benzoyloxy. C ₁ -which may be substituted with halogen
Examples of the C ₄ alkyl group include methyl, ethyl, n-propyl, i
Preferred examples include so-propyl, n-butyl, chloromethyl, dichloromethyl, trifluoromethyl and the like. C ₁ -C ₄ optionally substituted with halogen
Examples of the alkoxy group include methoxy, ethoxy, n-
Preferred examples include propoxy, iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, trifluoromethoxy and the like. Examples of the (C ₁ -C ₆ ) alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl and the like.

The substituted phenyl group or the substituted phenoxy group can have 1 to 3, preferably 1 substituent as described above.
Optionally substituted phenyl group, optionally substituted phenoxy group, optionally substituted C ₃ -C ₁₀ straight or branched chain C ₁ -C ₅ substituted by a cycloalkyl group
A phenyl group which may be substituted in an alkyl group,
As the phenoxy group which may be substituted, the above-mentioned ones can be preferably cited as they are. As the C ₃ -C ₁₀ cycloalkyl group, the above-mentioned ones can be preferably used as they are, and the substituents also include the above-mentioned substituted phenyl and the substituents of the substituted phenoxy group. As the straight-chain or branched-chain C _{1 to} C ₅ alkyl group, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, s
ec-Butyl, t-butyl, pentyl group and the like can be mentioned, and the substituent may be bonded to any position thereof.

R ³ represents, among these, n-butyl, n-pentyl, 1-methylpentyl, 2-methylhexyl, cyclopentyl, cyclohexyl, 2,6-dimethyl-5-heptenyl, 1-methyl-3-pentenyl, 1 -Methyl-3-hexynyl is preferred.

The compound represented by the above formula [I] used in the present invention includes the (R) -configuration, the (S) -configuration at the 16-position and a mixture thereof in any ratio.

8 of the prostacyclins represented by the above formula [I]
The configurations of the 9-position, the 9-position, the 11-position, and the 12-position are the same as the natural prostaglandins, and thus are particularly useful stereoisomers. , Or a mixture thereof in any ratio.

Specific preferred examples of the prostacyclins used in the present invention are as follows.

(1) 15-deoxy-16-hydroxy-9 (O) -methano-Δ ^{6 (9α)} -prostaglandin I ₁ (2) 15-deoxy-16-hydroxy-16-methyl-9
(O) -methano- ^{6 (9α) -prostaglandin} I ₁ (3) (1), (2) (16S) -form (4) (1), (2) (16R) -form (1) ) To (4) methyl ester, ethyl ester, butyl ester, sodium salt, potassium salt, ammonium salt, and enantiomers of these compounds, but not limited thereto.

The physical property values of typical compounds among the above compounds are shown below. 15-deoxy-16-hydroxy-16-methyl-9
(O) -methano-Δ6 ^(9α) -prostaglandin I ₁ NMR (CDCl ₃ , δppm) 0.88 (3H, t, J = 6Hz), 1.10 (3H, s), 2.65-3.2 (1H, m) , 3.5−3.9 (1H, m), 4.6−5.2 (3H, br; disappeared at D ₂ O), 5.26 (1H, bs), 5.25−5.55 (2H, m). IR (liquid film, cm ^-1 ) 3350.3100-2400.1705.965. The prostacyclins represented by the above formula [I] are easily produced by a known method, and the production method thereof is, for example, JP-A-59-210044. And 61-197518 and the like. Alternatively, for example, it can be obtained by the method shown in the following Scheme I, which the present inventors separately applied.

Step 1 of the above Scheme I is an alkylation reaction, and according to the method of Murahashi et al. (J. Am. Chem. Soc., 99, 2361, 1977), allyl alcohol [II] was replaced with n-butyllithium,
Then, it is reacted with cuprous iodide, and then the following formula [VI] 1- [3-lithiopropyl] -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane and N, N represented by
-Methylphenylaminotriphenylphosphonium can be synthesized by reacting in the presence of iodide. 1- [3-lithiopropyl] -4-methyl-2,6,7-trioxabicyclo [2.2.2.] Octane represented by the above formula [VI] is 1- [3-bromopropyl]-
It can be obtained by reacting 4-methyl-2,6,7-trioxabicyclo [2.2.2.] Octane with t-butyllithium (EJ Corey et al., Tetrahedron Letters,
24, page 5571, 1983).

Step 2 is a hydrolysis reaction of an orthoester, which proceeds by using a normal hydrolysis reaction of an orthoester using an acid catalyst. For example, the ortho ester [II
The diol ester compound [IV] can be obtained by dissolving I] in a mixed solvent of methanol and water and adding a small amount of pyridine salt of p-toluenesulfonic acid.

Step 3 is a hydrolysis reaction of the ester, which can be achieved by a normal alkali hydrolysis reaction. For example, a carboxylic acid body [V] can be obtained by adding an aqueous solution of lithium hydroxide, sodium hydroxide or the like to a tetrahydrofuran solution of a diol ester body [IV] and reacting.

Step 4 is a desilylation reaction, which can be progressed by using a fluorine compound such as tetrabutylammonium fluoride hydrofluoric acid or an acid such as acetic acid or p-toluenesulfonic acid which is a usual desilylation reaction. For example, by reacting the disilyl compound [V] with tetrabutylammonium fluoride in tetrahydrofuran,
It can be led to isocarbacyclines [I-3].

Step 5 is an esterification reaction or a salt formation reaction, which can be achieved by using an ordinary esterification method or salt formation method. Methyl esters can be obtained, for example, by using diazomethane, and also alkyl iodides /
The alkyl ester can also be obtained by using diisopropyl ester amine. Further, for example, a carboxylic acid salt can be obtained by using an ordinary salt forming reaction using sodium hydroxide, potassium hydroxide and the like.

Enol [II], the raw material for the manufacturing method shown in Scheme I
Can be easily synthesized by using a method known in the literature (T. Mase et al., Tetra-hedron Letters, 25 volumes,
See page 5087, 1984, etc.).

The prostacyclins represented by the above formula [I] surprisingly have a very strong organ protecting effect. For example, when the liver excised from an organ-donating rat (donor) is stored refrigerated in a preservation solution at the time of liver transplantation in a rat, by adding the prostacyclin represented by the above formula [I], damage to the preserved liver is minimized. As a result, the survival rate of the transplanted rat after liver transplantation is significantly improved as compared with the control group preserved and transplanted without adding prostacyclin.

The above-mentioned active compound is added to a preservative solution or a perfusate as an organ protective agent for minimizing the damage of the organ in the preservation of the organ removed from the organ donor (donor) during the organ transplant surgery. Can be used.
The active compound can also be administered to transplant patients as an organ protective agent for suppressing or preventing rejection after organ transplant. This active compound includes all organs as a control organ when used as an organ protective agent for the purpose of organ preservation and / or suppression of rejection in organ transplantation. Among them, for example, liver, kidney, heart , Effective against organs such as pancreas, lung, bone marrow, etc., and particularly effective against liver.

When this active compound is used as a protective agent in the preservation of transplanted organs, the active compound may be added to the preservation solution or the perfusate as it is or in various solvents in which the active compound can be uniformly dissolved or dispersed. It can be added as a solution or suspension. As the solvent for the above purpose,
For example, alcohols such as ethanol, propylene glycol, glycerin, polyethylene glycol, water,
Saline, triacetin, etc., and mixtures thereof in any proportion are particularly preferred. These solutions and suspensions can be sterilized by appropriately performing treatments such as passing through a bacteria-retaining filter, heat sterilization, blending of a sterilizing agent, and irradiation. Alternatively, an aseptic drug substance or a solid preparation may be produced, and the aseptic solvent may be added just before use.

Further, when using this active compound as an organ protective agent for suppressing or preventing rejection after organ transplantation,
It is administered orally or parenterally, such as rectally, subcutaneously, intramuscularly, intravenously, intraarterially, and transdermally, preferably orally or intravenously.

For oral administration, a solid preparation or a liquid preparation can be prepared. Examples of solid formulations include tablets, pills,
There are powders and granules. In such solid dosage forms, one or more active substances are combined with at least one pharmaceutically acceptable carrier, such as the commonly used sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethylcellulose and the like. Mixed. The formulation operation is carried out according to a conventional method, but additives other than those described above for formulation, for example, lubricants such as calcium stearate, magnesium stearate and glycerin may be contained.

Liquid formulations for oral administration include, for example, emulsions, solutions,
Includes suspensions, syrups or xyls. These formulations contain a commonly used pharmaceutically acceptable carrier such as water or liquid paraffin.

An oily base such as coconut oil, fractionated coconut oil, soybean oil and corn oil can also be used as a carrier.

Preparations for oral administration include solid preparations such as those mentioned above, and enteric preparations such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer or methacrylic acid, methyl methacrylate copolymer. It is also possible to spray an organic solvent or water solution of a soluble substance and apply an enteric coating to prepare an enteric formulation. Enteric coated solid preparations such as powders and granules can be encapsulated.

Pharmaceutically acceptable carriers include other auxiliary agents, fragrances, stabilizers, or preservatives, which are usually used as needed.

Liquid powder formulations may also be administered in capsules made of an absorbable material such as gelatin.

Solid form preparations for rectal administration include suppositories which contain one or more active substances and are manufactured by a method known per se.

Formulations for parenteral administration are provided as sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solutions or suspensions include vegetable oils such as propyl glycol, polyethylene glycol or olive oil,
An injectable organic ester such as ethyl oleate is a pharmaceutically acceptable carrier. 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 sterilized by appropriate treatments such as passing through a bacteria-retaining filter, blending of a bactericide or irradiation. In addition, a sterile solid preparation can be produced and used by dissolving it in sterile water or a sterile injectable solution 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.

Examples of the dosage form for transdermal administration include ointments and the like. These are molded by a usual method.

Further, this active compound can be used as a therapeutic agent for various organ disorders, for example, for the treatment or prevention of liver injury due to its strong cytoprotective action and organ protective action. For example, in patients, toxic liver injury, fatty liver, hepatitis (especially alcoholic hepatitis, viral hepatitis), cirrhosis, fulminant hepatitis, hepatic coma,
It can be administered for the treatment or prevention of acute or chronic liver diseases such as hepatic hypertrophy, obstructive jaundice, parasitic liver disease, liver tumor, liver abscess, and liver tuberculosis. In addition, it can be administered for the treatment or prevention of organ diseases such as kidney, pancreas, stomach, heart and lung.

In order to use this active compound as a therapeutic agent for various organ disorders, it can be administered orally or rectally, subcutaneously, intramuscularly, intravenously,
Although it can be administered orally intradermally such as intraarterial or transdermal, it is preferably orally or intravenously. These preparations are the same as the preparations described for the case of using the present active compound as an organ protective agent for suppressing or preventing rejection after organ transplantation.

The amount of this prostacyclin used as a protective agent for preservation of transplanted organs varies depending on the type of organ, simple preservation or perfusion preservation, and the condition, weight, etc. of the transplanted organ. Has a concentration of 10
Used in the range of ^-12 to 10 ^-3 mg / ml, preferably 10 ^-10 to 1
Used in the range of 0 ^-5 mg / ml. When the prostacyclin is used as an organ protective agent for suppressing the rejection reaction after organ transplantation or as a therapeutic agent for various organ disorders, the dosage is the condition of the recipient, age, sex, Normally bake 0.01μ, depending on body weight, administration route, etc.
It can be administered in an amount of g-100 mg / Kg-body weight / day.
Such a dose may be once or several times a day, for example, 2 to 6
It can also be administered in divided doses.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 An organ preservation solution having the following composition was produced.

(1) Isotonic citric acid solution (control stock solution) The following compounds (compound group (A)) were dissolved in 1 distilled water.

After 0.1N hydrochloric acid was added to this solution to adjust the pH to 7.1, it was sterilized with a bacteria-retaining filter (0.22 μm).

(2) Isotonic citric acid solution containing prostacyclin (PG
Preservative Solution Containing (i) Preservative Solution Containing PG-a (17S) -17,20-Dimethyl-9 (O) -methano-Δ
^{6 (9α) -prostaglandin} I ₁ (compound a) 10μ of ethanol solution (10mg / ml) of 990μ of physiological saline
(PG stock solution). Compound group (A) as in (1)
Was dissolved in 1 of distilled water, and 1 ml of the above PG stock solution was added thereto. After 0.1N hydrochloric acid was added to this solution to adjust the pH to 7.1, it was sterilized with a bacteria-retaining filter (0.22 μm).

(Ii) PG-containing stock solution-b 15-deoxy-16-hydroxy-16-methyl-9-
(O) ^{-methano-Δ6 (9α) -prostaglandin} I ₁
(Compound b) 10μ of ethanol solution (10mg / ml) of 990μ of physiological saline
(PG stock solution). Compound group (A) as in (1)
Was dissolved in 1 of distilled water, and 1 ml of the above PG stock solution was added thereto. After 0.1N hydrochloric acid was added to this solution to adjust the pH to 7.1, it was sterilized with a bacteria-retaining filter (0.22 μm).

Example 2 Liver Transplantation Experiment A liver transplantation experiment was performed using inbred Lewis rats (body weight: 175 to 290 g). The technique of removing the liver from the donor rat (donor) and orthotopic liver transplantation was performed according to the method of Kamada et al. (Toru Tamaki, “Transplantation”, Vol. 21, 46-).
See page 53, 1986). Donor rat liver has 50
Hartmann's solusion added with unit heparin and cooled to 4 ° C, then cooled to 4 ° C
5 ml of each of the following preservation solutions was perfused through the portal vein. After removing the perfused liver, it was placed in a beaker containing Hartmann's solution, weighed, placed in a beaker containing each of the following preservation solutions, and stored at 0 ° C.
Stored for 16 hours. The preserved liver was weighed again, then perfused with 10 ml of plasma solution and orthotopically transplanted.

* Preservative solution-Control group ... Control preservative solution of Example 1, (1) -Prostacyclin group ... PG-containing preservative solution-a and PG-containing preservative solution-b of Example 1, (2).

Table 1 shows the results obtained by examining the survival rate of rats that survived for 2 weeks or more after transplantation and the presence or absence of liver excretion.

As is clear from Table 1, the above-mentioned prostacyclins have an organ-protecting action that minimizes damage to the preserved liver in organ transplantation. In particular, the PG-containing preservation liquid-b according to the present invention is compared with the PG-containing preservation liquid-a,
From the viewpoint of bile excretion and survival rate, the action is obviously strong.

Reference Example 1 (Preparation of Ampoule) An ampoule containing the following composition in one ampoule was produced.

That is, the active ingredient was dissolved in ethanol, distilled water was added, and the mixture was passed under a sterile condition through a bacteria-retaining filter to fill a sterile ampoule.

The active ingredient was (17S) -17,20-dimethyl-9.
(O) ^{-methano-Δ6 (9α) -prostaglandin} I ₁
And (17S) -17,20-dimethyl-9 (O) -methano-
^{Δ6 (9α) -prostaglandin} I ₁ sodium salt was used.

Reference Example 2 (Preparation of Ampoule) An ampoule containing the following composition in one ampoule (5 ml capacity) was produced.

That is, polyethylene glycol and the active ingredient were dissolved in water under nitrogen, which was boiled, cooled under nitrogen and distilled. Pre-treated water was added to this solution to a given volume and passed under sterile conditions. This manufacturing is performed in the diffused light.

The filling was performed in a nitrogen stream, and the sterilization was performed at 121 ° C. for 20 minutes.

As the active ingredient, (17S) -17,20-dimethyl-9 (O) -methano-Δ6 ^(9α) -prostaglandin I ₁ was used.

Reference Example 3 One tablet having the following composition was produced.

That is, the active ingredient, lactose and potato starch are mixed and evenly moistened with a 20% ethanol solution of polyvinylpyrrolidone, passed through a 20 mm mesh sieve and kept at 45 ° C.
And dried again, and passed through a 15 mm mesh screen again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

As an active ingredient, typically (17S) -17,20-dimethyl-
9 (O) ^{-methano-Δ6 (9α) -prostaglandin}
I ₁ was used.

Reference Example 4 A hard gelatin capsule containing one capsule having the following composition was produced.

That is, the active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and filled into hard gelatin capsules.

As the active ingredient, 15-deoxy-16-hydroxy-16-methyl-9 (O) -methano-Δ6 ^(9α) -prostaglandin I ₁ was typically used.

Reference Example 5 (17S) -17,20-Dimethyl-9 (O) -methano-Δ
^{6 (9α) -prostaglandin} I ₁ was dissolved in fractionated coconut oil, and the skin component according to the following formulation was dissolved by heating to prepare (17S) -17,20-dimethyl-9 in one capsule.
(O) ^{-methano-Δ6 (9α) -prostaglandin} I ₁
Was produced by a conventional method using a soft capsule manufacturing machine so that the content of 50 μg was 50 μg.

Claims (8)

[Claims] 1. The following formula [I]: An organ-protecting agent containing a prostacyclin represented by and / or its enantiomer as an active ingredient. 2. The organ protecting agent according to claim 1, wherein R ¹ in the above formula [I] is a hydrogen atom or a methyl group. 3. The organ protecting agent according to claim 1, wherein R ² in the above formula [I] is a hydrogen atom. 4. The organ protecting agent according to claim 1, wherein R ³ in the above formula [I] is a 2-methylhexyl group. 5. The organ protecting agent according to claim 1, wherein R ² in the above formula [I] is a methyl group. 6. The organ protecting agent according to claim 1, wherein R ³ in the above formula [I] is an n-butyl group. 7. A prostacyclin represented by the above formula [I] is 15-deoxy-16-hydroxy-16-methyl-
9 (0) -methano-Δ ^{6 (9α) -prostaglandin}
The organ protective agent according to claim _1, which is I ₁ . 8. The organ protecting agent according to claim 1, wherein the organ is a liver.