JPH0681728B2 - Laxative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a laxative containing a prostaglandin derivative.

2. Description of the Related Art Prostaglandins (hereinafter referred to as PGs) are names given to a group of fatty acids having various physiological actions contained in human and animal tissues and organs. PGs are prostanoic acid represented by the following formula Is used as the basic skeleton, but synthetic products include those obtained by modifying the above skeleton. PGs have a five-membered ring structure, Etc. In addition, the 5-6 position PG ₁ such carbon bond is a single bond: And PG ₂ 's in which the carbon at the 5-6 position is a double bond: Further, PG ₃ 's in which the carbons at positions 5-6 and 17-18 are double bonds: Classified as and.

PGs have various pharmacological effects such as vasodilation, inflammation,
Platelet aggregation, uterine muscle stimulating action, intestinal muscle stimulating action, antiulcer action and the like are recognized.

On the other hand, in human or animal metabolites, the carbon bond at the 13-14 position is saturated and the carbon at the 15 position is the carbon of the carbonyl group.
The existence of PGs and PGs in which the carbon bond at the 13-14th position is a double bond and the carbon at the 15th position is the carbon of the carbonyl group has been confirmed. These 13,14-dihydro-15-keto-prostaglandins and 15-keto-prostaglandins (hereinafter, simply referred to as 15-keto-PGs) are the corresponding PGs.
It is known that substances are naturally metabolized and produced by metabolic reactions by enzymes in the main body. These 15-
Keto-PGs hardly show various physiological activities possessed by PGs, and have been reported as pharmacologically and physiologically inactive metabolites (Acta Physiologica Scandinavica) Vol. 66, Pp. 509-, 1966).

The present inventor has conducted pharmacological studies on derivatives of 15-keto-PGs, and as a result, derivatives in which at least one halogen atom, particularly at least one fluorine atom, has been substituted at the 16-position are found from the results of enteropooling tests and the like. They have found that they exert a strong cathartic action, and have completed the present invention.

Means for Solving the Problems The present invention is a laxative characterized by containing 15-keto-16-halogen-prostaglandins (hereinafter referred to as 15-keto-16-halogen-PGs) as an active ingredient. Regarding

In the present specification, 15-keto-PGs are represented by the following nomenclature system. That is, 15-keto-PGs have the following basic skeleton: Based on the above, the carbon numbers constituting the α chain, ω chain and 5-membered ring of this basic skeleton are used as they are. That is, the number of carbons constituting the basic skeleton is 1 for the carboxyl carbon, and 2 to 7 are sequentially assigned to carbons on the α chain toward the 5-membered ring,
Up to 12 are attached to the carbon of the 5-membered ring, and up to 13 to 20 are attached to the ω chain, but when the number of carbons decreases on the α chain, the numbers are deleted sequentially from the 2nd position, and on the α chain. When the number is increased, it is designated as having a substituent in place of the carboxyl group (position 1) at the 2-position. When the carbon number decreases on the ω chain, the carbon number is sequentially decreased from the 20th position, and when the carbon number increases on the ω chain, the 21st and subsequent carbon atoms are designated as substituents. Regarding the stereoscopic configuration, the stereoscopic configuration of the basic skeleton is used unless otherwise specified.

Further, for example, PGD, PGE, and PGF have 9th position and / or 11th position.
A compound having a hydroxyl group at position 9 is used herein.
Compounds having other groups in place of the hydroxyl groups at the 11- and / or 11-positions are collectively referred to as PGs, in which case they are in the form of 9-dehydroxy-9-substituted or 11-dehydroxy-11-substituted To name.

The 15-keto-PGs used in the present invention include 15-keto-PGs
It suffices that the carbon at the position form a carbonyl group, 5-6
15-keto-PG ₁ in which the carbon bond at the position is a single bond, 15-keto-PG ₂ in which it is a double bond, carbon bond at the 5-6 position and 1
15-keto-wherein the carbon bond at the 7-18 position is a double bond
It may be any of PG ₃ .

That is, the 15-keto-16-halogen-PGs used in the present invention are irrespective of their five-membered ring structure or the presence or absence of a double bond or other substituents, a halogen atom at the 16-position, especially a fluorine atom. It is sufficient that at least one atom is substituted.

Generally, laxatives are roughly classified into laxatives that excrete soft but shaped feces and sharp laxatives that excrete watery feces, depending on the difference in efficacy.

Laxatives act by increasing the water content of stool and accelerating the movement of intestinal contents by one or a combination of two or more of the following three mechanisms.

(I) Water and electrolytes are retained in the intestinal lumen due to the drug's hydrophilicity or osmotic pressure, which increases intestinal volume and indirectly speeds migration.

(Ii) The drug acts on the intestinal mucosa to reduce the normal total absorption of electrolytes and water, and indirectly increases the movement of intestinal contents due to the increase in water content.

(Iii) The drug first acts on the intestinal motility to accelerate its movement, and the total absorption of water and electrolytes indirectly decreases due to the decrease in absorption time.

The enteropooling test used in the present invention is
The effect of (ii) is mainly examined, and the effect of the drug on the water retention in the intestinal tract is determined by measuring the amount of intestinal contents. Invention 15-keto-16-halogen-PG
The family very strongly express this enteropooling effect. However, in judging the effect of (iii)
Shows little intestinal contractile action, which is one of the indicators, or
It is very slight. Therefore, the present invention 15-keto-16-
The diarrhea-inducing action of halogen-PGs mainly acts directly or indirectly on the intestinal mucosa and affects the ability to transport electrolytes and water from the intestinal wall to the vascular system, resulting in absorption of water from the intestinal tract. It is considered that this is because the decrease in water content, the increase in water retention in the intestinal tract, and the promotion of migration of intestinal contents.

The 15-keto-16-halogen-PGs used in the present invention may be a salt or an esterified carboxyl group. Examples of the salt include physiologically acceptable salts, for example, salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and magnesium, or physiologically acceptable ammonium salts such as ammonia, methylamine and dimethyl. It may be amine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, tetraalkylammonium salt and the like. Examples of the ester include an alkyl ester having a straight chain or a side chain which may have an unsaturated bond such as methyl, ethyl, propyl, butyl, isopropyl, t-butyl, and 2-ethyl-hexyl;
Esters having an alicyclic group such as cyclopropyl, sirocpentyl, cyclohexyl and the like; for example, benzyl,
Esters having an aromatic group such as phenyl (the aromatic group may have a substituent); for example, hydroxyethyl, hydroxyisopropyl, hydroxypropyl, polyhydroxyethyl, polyhydroxyisopropyl, methoxyethyl, ethoxyethyl, Examples are hydroxyalkyl or alkoxyalkyl esters such as methoxyisopropyl; alkylsilyl esters such as trimethylsilyl and triethylsilyl; and tetrahydropyranyl esters.

Preferred esters are eg methyl, ethyl, propyl,
A lower alkyl ester having a straight chain or a side chain such as butyl, isopropyl and t-butyl; a benzyl ester; and a hydroxyalkyl ester such as hydroxyethyl and hydroxyisopropyl.

The 16th position halogen atom includes a fluorine atom, a chlorine atom,
A bromine atom is contained, and a fluorine atom is particularly preferable.

The 15-keto-16-halogen-PGs of the present invention may have an unsaturated bond on the basic skeleton. It may also be substituted with an atom or group. Examples of the unsaturated bond include a double bond at the 2-3 position, the 5-6 position or the 17-18 position or a triple bond at the 5-6 position. Examples of the atom or group to be substituted include a halogen atom such as fluorine and chlorine; an alkyl group such as methyl, ethyl, isopropyl and isopropenyl; an alkoxy group such as methoxy and ethoxy; a carbonyl group; a hydroxyl group; a phenyl group; a phenoxy group and the like. To be The position to be substituted is not limited, but is represented by the number of the basic skeleton, and is represented by the 3-position, 6-position, 17-position, 19-position and /
Or the 20th place is exemplified. In particular, an alkyl group at the 3-, 17- or 19-position; a carbonyl group at the 6-position; an alkyl group or an alkoxy group at the 20-position are typical.

PGs include compounds having a hydroxyl group at the 9- and / or 11-position carbon such as PGD, PGE, and PGF, but in the present specification,
Compounds having a hydroxyalkyl group or an alkyl group in place of the 9th and / or 11th hydroxyl groups are also treated as being included in PGs. Therefore, 15-keto-16 of the present invention
-Halogen-PGs include compounds in which 9-position and / or 11-position is a hydroxyl group, a hydroxyalkyl group or an alkyl group. The hydroxyalkyl group is preferably a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group or a 1-methyl-1-hydroxyethyl group, and the alkyl group is preferably a lower alkyl group, particularly a methyl group or an ethyl group. .

The configuration at the 9- and / or 11-position carbon is α,
It may be β or a mixture thereof.

The 15-keto-16-halogen-PGEs of the present invention include isomers of the compounds described above. Examples of these isomers include tautomers between the 11-position hydroxyl group and the 15-position carbonyl group, or optical isomers and geometric isomers. For example, The tautomerism between the hydroxyl group at 11-position and the carbonyl group at 15-position shown above is particularly remarkable in the case of a compound having a saturated 13-14 position and a fluorine atom at 16 position, and these are keto- It is suggested to exist as a hemiacetal equilibrium mixture.

A mixture of isomers, for example, an equilibrium mixture of a racemic or tautomeric hydroxy compound and hemiacetal also exhibits the same effect as when used alone.

The above-mentioned 15-keto-16-halogen-PGs of the present invention can be produced according to the method described in, for example, Japanese Patent Application Nos. 63-18326, 63-18327 and 63-108329. it can.
These descriptions are made a part of this specification.

As a method for producing a 15-keto-16-halogen compound, for example, as shown in the synthesis chart, commercially available (-) corey lactone is used as a starting material, and this is Collins-oxidized to obtain an aldehyde. (Halogen-2-oxoalkyl) phosphonate anion is reacted to obtain an α, β-unsaturated ketone, a double bond thereof is reduced to obtain a ketone, and the carbonyl group of the ketone is reduced to an alcohol, followed by silyl ether. Protect as. The alcohol is then obtained by de-p-phenylbenzoylation and the newly generated hydroxyl group is protected with dihydropyran to give tetrahydropyranyl ether. This gives a precursor for PGs in which the ω chain is a 13,14-dihydro-15-keto-16-halogen-alkyl group. Also, the ω chain is 15-keto-16-halogen-
The PGs that are alkyl groups can be synthesized by advancing the reaction while leaving the double bond of the above α, β-unsaturated ketone.

Using the tetrahydropyranyl ether as a raw material, 6-keto-PG ₁ is a tetrahydropyranyl ether reduced with diisobutylaluminum hydride to obtain lactol, which is (4-carboxybutyl)
After reacting the ylide obtained from triphenylphosphonium bromide and then esterifying, the double bond at the 5-6 position and the hydroxyl group at the 9 position are cyclized with NBS or iodine,
A halide is obtained, which is dehydrohalogenated with DBU or the like to obtain a 6-keto compound, the 15-position silyl ether protecting group is removed, and the tetrahydropyranyl protecting group is removed after Jones oxidation. Can be obtained by

Furthermore, PG ₂ is a reduction of the above tetrahydropyranyl ether to obtain lactol, which is reacted with an ylide obtained from (4-carboxybutyl) triphenylsulfonium bromide to obtain a carboxylic acid, and then esterified, It can be obtained by removing the silyl ether protecting group at the 15-position, oxidizing with Jones, and removing the tetrahydropyranyl ether protecting group.

Using the tetrahydropyranyl ether as a raw material, To obtain PG ₁ It can be obtained by catalytically reducing the double bond at the 5-6 position of the obtained compound and then removing the protecting group in the same manner as for PG ₂ . The hydrocarbon chains at positions 5, 6 and 7 are Synthesis of 5,6-dehydro-PG ₂ is a monoalkyl copper complex or dialkyl copper complex as shown below. Capture of copper enolate formed by 1,4-addition of 4 (R) -t-butyldimethylsiloxy-2-cyclopenten-1-one with 6-carboalkoxy-1-iodo-2-hexyne or its derivative Can be synthesized by

PGs having a methyl group instead of the 11-position hydroxyl group are 11-
The 11-dehydroxy-11-methyl-PGE type is obtained by reacting a PGA type obtained by Jones-oxidizing the 9-position hydroxyl group of a tosylate with a dimethyl copper complex. Alternatively, the p-phenylbenzoyl group is removed,
The resulting alcohol is tosylate, the unsaturated lactone obtained by treating it with DBU is lactol, the α-chain is introduced using the Wittig reaction, and the resulting alcohol (9-position) is oxidized to PGA type, By reacting it with a dimethyl copper complex, 11-dehydroxy-11
-Methyl-PGE type is obtained. The 11-dehydroxy-11-methyl-PGF type can be synthesized by reducing this with, for example, sodium borohydride.

PG having a hydroxymethyl group instead of the 11th hydroxyl group
As a class, 11-dehydroxy-11-hydroxymethyl-PGE type can be synthesized by photoadding methanol with benzophenone as a sensitizer to the PGA type obtained above. The 11-dehydroxy-1-hydroxymethyl-PGF type can be synthesized by reducing this with, for example, sodium borohydride.

The 15-keto-16,16-difluoro-PGs are dimethyl- (3,3'-difluoro-PG) in obtaining α, β-unsaturated ketones.
A 2-oxoalkyl) phosphonate anion may be used.

Also, for example, SYNTHESIS OF DIASTEREOMERIC BIS-UNSATU
RATED PROSTAGLANDINS (Prostaglandins Vol.14,61〜10
1,1977).

In the present invention, the synthetic method is not limited to this, and a suitable method such as a protection method and a redox method may be adopted.

15-keto-16-halogen-PG used in the present invention
The genus is the enteropooling action by substituting at least one halogen atom, especially at least one fluorine atom at the 16-position, regardless of the structure of its five-membered ring, or the presence or absence of a double bond or other substituents. , But the expression of 15-keto-16-halogen-is particularly preferable.
Examples of PGs are those in which the carbon bond at the 5-6 position is a double bond or 15-keto-16-halogen-containing 20 to 22 carbon atoms.
It is a PG. Another preferred group is so-called PGE type 15-keto-16-halogen-PGs having a ketone at the 9-position and a hydroxyl group at the 11-position on a 5-membered ring.

PG is generally recognized to have various pharmacological actions, but for example, PGE and PGF have a strong intestinal contraction action associated with the intestinal stimulatory action, but have a mild enteropooling action.
It is not possible to use E or PGF as a laxative because of side effects such as abdominal pain associated with intestinal contraction.

On the other hand, the 15-keto-16-halogen-PGs of the present invention exhibit extremely strong enteropooling action and inhibit absorption of water from the intestinal tract. On the other hand, this substance does not have the intestinal-constricting action of PGE or PGF, or even if it has such an action, it is extremely slight, and therefore causes diarrhea without causing abdominal discomfort such as abdominal pain associated with intestinal contraction. Furthermore, since it has a remarkable promoting effect on the intestinal transport ability and promptly recovers from diarrhea, it is extremely useful as a laxative.

The 15-keto-16-halogen-PGs of the present invention may be used as a drug for animals and humans, and is generally used systemically or locally by oral, suppository, enema and the like methods.
The dose varies depending on the animal, human, age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is preferably 0.001
~ 1000 μg / kg.

Solid compositions for oral administration according to the present invention include tablets, powders, granules and the like. In such solid compositions the one or more active substances is at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polypinylpyrrolidone, Mixed with magnesium aluminometasilicate. According to a conventional method, the composition may be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin gluconate, α, β or γ-cyclodextrin, dimethyl-α. -, Dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin and other etherified cyclodextrins, glucosyl-, maltosyl-cyclodextrin and other branched cyclodextrins, formylated cyclodextrins, sulfur-containing cyclodextrins, Stabilizers such as misoprotol and phospholipids may be included. When the above cyclodextrins are used, the stability may be increased by forming an inclusion compound with the cyclodextrins. In addition, stability may be increased by forming liposomes using phospholipids. If necessary, tablets or pills should be sucrose, gelatin, hydroxypropyl cellulose,
It may be coated with a gastric or enteric film such as hydroxypropylmethyl cellulose phthalate. Further, it may be a capsule of an absorbable substance such as gelatin.

Liquid compositions for oral administration may contain pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. , For example, purified water, vegetable oil such as ethanol, olive oil, coconut oil, etc. may be contained. This composition includes auxiliary agents such as lubricants, suspending agents, in addition to inert diluents,
It may contain a sweetening agent, a flavoring agent, an aromatic agent, a preservative and the like. Further, this liquid composition can be used by enclosing it in a soft capsule as it is.

The suppository according to the present invention, aseptic aqueous or non-aqueous solution, suspension, emulsion, detergent and the like as a liquid for parenteral administration such as enema may be included. Examples of the aqueous solution and suspension include distilled water, physiological saline and Ringer's solution.

Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate and the like. Such a composition further comprises a preservative,
Auxiliary agents such as wetting agents, emulsifying agents and dispersing agents may be included.

Hereinafter, the present invention will be described with reference to examples.

Synthesis Example I. Synthesis of 15-keto-16R, S-fluoro-PGE ₂ methyl ester (1) Methyl (5E) -7R- [2R-formyl-3R- (tetrahydropyranyl) oxy-5S-acetoxy-cyclopentyl] Synthesis of -5-heptenate: Collins oxidation of methyl (5E) -7R- [2R-hydroxymethyl-3R- (tetrahydropyranyl) oxy-5S-acetoxy-cyclopentyl] -5-heptenate (0.56g) in methylene chloride at 0 ° C according to a conventional method. (10 equivalents). Sodium hydrogen sulfate (15 g) was added to the reaction solution, and the mixture was filtered.

The filtrate was concentrated and methyl (5E) -7R- [2R-formyl-3R
-(Tetrahydropyranyl) oxy-5S-acetoxy-
Cyclopentyl] -5-heptenate was obtained.

Yield: 0.52 g (93%) (2) 9-acetoxy-16R, S-fluoro-15-keto-1
Synthesis of 1- (tetrahydropyranyl) oxy-PGF ₂ α methyl ester: Sodium hydride (60
%, 0.20 g) and phosphonate (1.36 g) were mixed for 10 minutes to obtain a clear solution. A tetrahydrofuran solution of (5E) -7R- [2R-formyl-3R- (tetrahydropyranyl) oxy-5S-acetoxy-cyclopentyl] -5-heptenate was added to this solution and stirred at 50 ° C for 3 hours. Acetic acid (0.30 ml) was added to the reaction solution, and the crude product obtained by post-treatment according to a conventional method was chromatographed (hexane-ethyl acetate =
3: 1) to obtain 9-acetoxy-16R, S-fluoro-15-keto-11- (tetrahydropyranyl) oxy-PGF ₂ α methyl ester.

Yield: 0.54 g (81%) (3) 9-acetoxy-16R, S-fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) oxy-PGF ₂ α
Synthesis of methyl ester: and PG _{2 in} which carbon at the 5-6 position is a double bond: 9-acetoxy-16R, S-fluoro-15-keto-11-
(Tetrahydropyranyl) oxy-PGF ₂ α methyl ester (0.54 g) was dissolved in methanol, sodium borohydride (37 mg) was added at −15 ° C., and the mixture was stirred for 30 minutes. The crude product obtained by the conventional method was chromatographed (hexane-ethyl acetate = 2: 1) to give 9-acetoxy-16R, S-fluoro-15R, S-hydroxy-11- (tetrahydropyranyl).
Oxy-PGF ₂ α methyl ester was obtained.

Yield: 0.55 g (100%) (4) Synthesis of 16R, S-Fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) oxy-PGF ₂ α methyl ester: 9-acetoxy-16R, S-fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) -PGF ₂ α methyl ester (0.180 g) was dissolved in methanol, potassium carbonate (0.25 g) was added, and Stir for hours. Acetic acid (0.2
1 ml) was added and the crude product obtained by the conventional method was chromatographed (hexane-ethyl acetate = 3: 2) to give 16R, S-fluoro-15R, S-hydroxy-11- (tetrahydropyranyloxy). -PGF ₂ α methyl ester was obtained.

Yield: 0.139 g (84%) (5) Synthesis of 16R, S-Fluoro-15-keto-11- (tetrahydropyranyl) oxy-PGE ₂ methyl ester: 16R, S-Fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) oxy-PGF ₂ α in methylene chloride at 0 ° C
The methyl ester (0.139 g) was Collins-oxidized (35 equivalents) according to a conventional method. Sodium hydrogen sulfate (6 g) was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated and chromatographed (hexane-ethyl acetate = 2: 1) to give 16R, S-fluoro-
15-keto-11- (tetrahydropyranyl) oxy-PGE ₂
The methyl ester was obtained.

Yield: 0.125 g (91%) (6) Synthesis of 15-keto-16R, S-fluoro-PGE ₂ methyl ester: 16R, S-Fluoro-15-keto-11- (tetrahydropyranyl) oxy-PGE ₂ methyl ester (0.125 g) was added to acetic acid-
The product was dissolved in a THF-water (4: 1: 2) mixed solvent and kept at 45 ° C. for 3 hours, and then the crude product obtained by a conventional method was chromatographed (benzene-acetic acid ester = 1: 1). 15-keto-16R, S
- to obtain a fluoro -PGE ₂ methyl ester.

Yield: 0.076 g (74%) II. Synthesis of 15-keto-16R, S-fluoro-PGE ₂ : (1) 16R, S-Fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) oxy-PGF Synthesis of ₂ α: A mixed solvent of 9-acetoxy-16R, S-fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) oxy-PGF ₂ α methyl ester (0.55 g) in methanol-1N sodium hydroxide aqueous solution (2: 1). , And kept at room temperature for 3 hours.

1N Hydrochloric acid was added and treated according to a conventional method to give 16R, S-fluoro-15R, S-hydroxy-11- (tetrahydropyranyl).
Oxy-PGF ₂ α was obtained.

Yield: 0.48 g (98%) (2) Synthesis of 16R, S-fluoro-15-keto-11- (tetrahydropyranyl) oxy-PGE ₂ : 16R, S-Fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) oxy-PGF _{2 in} methylene chloride at room temperature
α (0.48 g) was Collins-oxidized (10 equivalents) according to a conventional method. Sodium hydrogen sulfate (15 g) was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated and the silica gel (Mallinckrodt, CC
-4) was used for chromatography (hexane-ethyl acetate = 3: 1) to obtain 16R, S-fluoro-15-keto-11- (tetrahydropyranyl) oxy-PGE ₂ .

Yield: 0.25 g (53%) (3) Synthesis of 15-keto-16R, S-fluoro-PGE ₂ : 16R, S-Fluoro-15-keto-11- (tetrahydropyranyl) oxy-PGE ₂ (0.25 g) was added to acetic acid-THF-water (4: 1:
2) It was dissolved in a mixed solvent and kept at 45 ° C for 3 hours. The crude product obtained by the conventional method was treated with silica gel (Mallinckrodt, CC-
Chromatography (hexane-ethyl acetate = 3.5: 1) using 4) gave 15-keto-16R, S-fluoro-PGE ₂ .

Yield: 0.166 g (82%) III.Synthesis of 15-keto-16R, S-fluoro-PGF ₂ α methyl ester: (1) 9-acetoxy-15R, S- (t-butyldimethylsiloxy) -16R, S - fluoro-11-synthesis of (tetrahydropyranyl) oxy-PGF ₂ alpha methyl ester: 9-acetoxy-16R, S-fluoro-15R, S-hydroxy-11- (tetrahydropyranyl) oxy-PGF ₂ α methyl ester (0.356 g) was dissolved in dimethylformamide,
T-Butyldimethylsilyl chloride (0.31 g) and imidazole (0.28 g) were added, and the mixture was stirred overnight. The crude product obtained by the conventional method was chromatographed (hexane-ethyl acetate = 4: 1) to give 9-acetoxy-15R, S- (t-butyldimethylsiloxy) -16R, S-fluoro-11- ( Tetrahydropyranyl) oxy-PGF ₂ α methyl ester was obtained.

Yield: 0.363 g (83.4%) (2) 15R, S- (t-butyldimethylsiloxy) -16R, S
-Fluoro-11- (tetrahydropyranyl) oxy-PG
Synthesis of F ₂ α methyl ester: 9-acetoxy-15R, S- (t-butyldimethylsiloxy) -16R, S-fluoro-11- (tetrahydropyranyl) oxy-PGF ₂ α methyl ester (0.363 g) was dissolved in methanol and potassium carbonate (0.32 g g) was added and stirred for 7 hours. The crude product obtained by the conventional method was chromatographed (hexane-ethyl acetate = 3: 1) to give 15R, S- (t-butyldimethylsiloxy) -16R, S-fluoro-11- (tetrahydropyranyl). Oxy-PGF ₂ α methyl ester was obtained.

Yield: 0.298 g (88.0%) (3) 9,11-bis (tetrahydropyranyl) oxy-15
Synthesis of R, S- (t-butyldimethylsiloxy) -16R, S-fluoro-PGF ₂ α methyl ester: 15R, S- (t-butyldimethylsiloxy) -16R, S-fluoro-11- (tetrahydropyranyl) oxy-PGF ₂ α methyl ester (0.298 g) was dissolved in methylene chloride, and the mixture was dissolved at 0 ° C.
Then, dihydropyran (1.0 ml) and p-toluenesulfonic acid were added, and the mixture was stirred for 1 hour. The crude product obtained by the conventional method was chromatographed (hexane-ethyl acetate = 4:
1) and 9,11-bis (tetrahydropyranyl) oxy-1
5R, S- (t-butyldimethylsiloxy) -16R, S-fluoro-PGF ₂ α methyl ester was obtained.

Yield: 0.341 g (100%) (4) 9,11-bis (tetrahydropyranyl) oxy-16
Synthesis of R, S-fluoro-15R, S-hydroxy-PGF ₂ α methyl ester: 9,11-Bis (tetrahydropyranyl) oxy-15R, S-
(T-Butyldimethylsiloxy) -16R, S-fluoro-P
GF ₂ α methyl ester (0.341 g) was dissolved in tetrahydrofuran, 1.0 M tetrahydrofuran solution of tetrabutylammonium fluoride (0.75 ml) was added, and the mixture was stirred at 0 ° C. overnight. The crude product obtained by conventional treatment was chromatographed (hexane-ethyl acetate 2: 1) to give 9,11-bis (tetrahydropyranyl) oxy-16R, S-fluoro-15R, S-hydroxy-PGF ₂ α-methyl ester was obtained.

Yield: 0.260 g (92.0%) (5) 9,11-bis (tetrahydropyranyl) oxy-16
Synthesis of R, S-Fluoro-15-keto-PGF ₂ α methyl ester: 9,11-bis (tetrahydropyranyl) oxy-16R, S-fluoro-15R, S-hydroxy-in methylene chloride at 0 ° C
Collage PGF ₂ α methyl ester (0.260g) according to standard method
s Oxidized (25 eq). Sodium hydrogen sulfate was added to the reaction solution, and the mixture was filtered. The crude product obtained by concentrating the filtrate was chromatographed (hexane-ethyl acetate 4: 1) to give 9,1
1-Bis (tetrahydropyranyl) oxy-16R, S-fluoro-15-keto-PGF ₂ α methyl ester was obtained.

Yield: 0.245g (94.6%) (6 ) 15- keto -16R, the S- fluoro-PGF ₂ alpha methyl ester synthesis: 9,11-Bis (tetrahydropyranyl) oxy-16R, S-
Fluoro-15-keto-PGF ₂ α methyl ester (0.245g)
Was dissolved in acetic acid-THF-water (3: 1: 1) mixed solvent, and the solution was added to 45 ° C for 4
I kept it for hours. The crude product obtained by the conventional method was chromatographed ((hexane-ethyl acetate 1: 2) to give 15-keto-1.
6R, S-Fluoro-PGF ₂ α methyl ester was obtained.

Yield: 0.148g (86.8%) Synthesis Chart I Composite Chart II Synthesis Chart III Synthesis Chart IV Example 1 (Enteropooling action) Male rats (Crj Wister Rat, body weight 180 g to 240 g) were used in groups of 5 animals. After giving water only and fasting for 24 hours, 5 ml / kg of distilled water in which the test drug was suspended was administered, and 30 minutes later, the animals were killed by cervical dislocation. After laparotomy, the average value of the amount of intestinal contents per animal was calculated, and the increase / decrease when the control group was 100% was expressed as the ratio, and the dose that increased the amount of intestinal contents by 50% was defined as ED ₅₀ . The results are shown in Table-1.

Example 2 (Intestinal tract contracting action) The ileum was removed from a male rat (body weight: 300 to 400 g) and Tyrod was isolated.
e Suspended in liquid. After resting for 15 to 20 minutes until the ileum became stable, it was contracted several times with 1 × 10 ⁻⁶ g / ml of acetylcholine. After the same degree of contraction was obtained twice, the test drug was cumulatively administered every minute. Acetylcholine 1 is the contraction of the test drug
The ED ₅₀ value was defined as the ratio at which the contraction of × 10 ^-6 g / ml was defined as 100%, and the concentration showing the contraction of 5%. The results are shown in Table-1.

Example 3 (Intestinal Transportability) Rats (Crj: W male 5 weeks old, body weight 120 to 140 g) were used.
After fasting the animals overnight, the test drug was orally administered, and 30 minutes later, 5% activated carbon (suspended in 5% acacia) was orally administered. Twenty minutes later, the small intestine was excised, the total length of the small intestine (from the pylorus to the ileocecal region) and the length of the end of the charcoal powder were measured to determine the transport rate (%).

It was tested whether the delivery rate of the control group was significantly promoted as compared with that of the control group. The results are shown in Table-1.

Example 4 (cathartic action; rat) A rat (Slc; W male 6-week-old, weight: 135 to 155 g) was used without fasting. Animals were placed one by one in an isolated box lined with bedding paper and observed for about 1 hour without treatment for the first time, excluding diarrhea-feces-excreting animals and using only normal solid-type feces-excreting animals.

The effect of the test drug was evaluated every 1 to 2 hours after oral administration for 6 hours. For feces, those that are solid and do not adhere to the floor paper are considered normal stools, and those that adhere are considered diarrhea stools. If even one diarrhea stool is recognized, it is judged to have a cathartic effect (+). did.

The results were expressed as the ratio of the number of diarrhea / fecal excretion animals to the total animals used. By this method, ED ₅₀ was calculated from the final rate of cathartic effect. The results are shown in Table-1.

Example 5 (Physiological action; human) Using 10 healthy male volunteers, 1 group consisting of 5 volunteers and 2 volunteers
Divided into groups. One group was orally administered with 200 μl of coconut oil containing 20 μg of the test drug 2 as a test group, and another group was orally administered with 200 μl of coconut oil as a control group.

In the test group, 4 out of 5 patients experienced a feeling of fullness in the abdomen 2 to 5 hours after the administration, and exhibited watery diarrhea due to loose stool. At this time, no side effects were noted during abdominal pain, and other clinical findings were not particularly abnormal. In addition, at 8 hours after administration, there was no abdominal discomfort including the above 4 persons, and no particular abnormality was observed.

In the control group, all 5 persons did not have any particular abnormality even after 8 hours from the administration.

Example 6 Enteropooling action (similar to Example 1) and intestinal contraction action (similar to Example 2) were determined for the following test drugs. The results are shown in Table-2, Table-3 and Table-4.

The nmr and Mass of the test drug used in the examples are shown. ¹ NMR is Hitachi nmr spectrometer R-90H
It was measured using (solvent: deuterated chloroform).

Mass is a Hitachi mass spectrometer M-80B (EI
Method: Ionization voltage 70 eV; SIMS method: Silver plate-glycerin matrix).

(2) δ: 0.73 to 1.06 (3H, m), 1.06 to 2.89 (23H, m), 3.63 (3
H, s), 3.80 to 4.27 (1H, m), 4.44 (0.5H, m), 4.99 (0.5
H, m), 5.36 (2H, m) Mass (EI) m / z 384,366,346,335 (3) δ: 0.73 to 1.05 (3H, m), 1.09 to 2.97 (22H, m), 4.08 (1
H, m), 4.45 (0.5H, m), 5.00 (0.5H, m), 5.38 (2H, m),
4.88 to 6.88 (2H, brs) Mass (EI) m / z 352 (M ⁺ -H ₂ O) 282,281,226 (4) δ: 0.73 to 1.05 (3H, m), 1.23 (3H, t, J = 7Hz), 1.08 ~ 2.
91 (23H, m), 4.08 (2H, q, J = 7Hz), 3.83 ~ 4.25 (1H,
m), 4.44 (0.5H, m), 4.98 (0.5H, m), 5.35 (2H, m) Mass (EI) m / z398 (M ⁺ ), 380 (M ⁺ -H ₂ O), 226,109,95 , 81 (5) δ: 0.89 (3H, t, J = 6Hz), 1.10 to 2.88 (25H, m), 3.63 (3
H, s), 3.81 to 4.26 (1H, m), 4.26 to 4.63 (0.5H, m), 4.99
(0.5H, m), 5.35 (2H, m) Mass (EI) m / z398 (M ⁺ ), 380 (M ⁺ -H ₂ O) (6) δ: 0.73 ~ 1.08 (3H, m), 1.14 ~ 3.21 (18H, m), 4.26 (1
H, m), 4.58 (0.5H, m), 5.13 (0.5H, m), 5.35 (2H, m),
4.88 to 6.36 (2H, brs), 6.64 (1H, dd, J = 16Hz, J = 3Hz),
6.99 (1H, dd, J = 16Hz, J = 8Hz) Mass (EI) m / z368 (M +), 350 (M + -H 2 O), 330 (M + -H 2 OH
F) (7) δ: 0.74 to 1.04 (3H, m), 1.13 to 2.95 (19H, m), 3.62 (3
H, s), 4.23 (1H, m), 4.55 (0.5H, m), 5.10 (0.5H, m),
5.31 (2H, m), 6.60 (1H, ddd, J = 15Hz, J = 3Hz, J = 1Hz),
6.94 (1H, dd, J = 15Hz, J = 8Hz) Mass (EI) m / z382 (M +), 351 (M + -CH 3 O), 364 (M + -H
₂ O), 344 (M ⁺ -H ₂ O-HF) (8) δ: 0.93 (3H, t, J = 6Hz), 1.08 to 2.75 (22H, m), 2.88 (1
H, m), 3.63 (3H, s), 381 to 4.33 (1H, m), 5.35 (2H, m) Mass (EI) m / z 402 (M ⁺ ), 384 (M ⁺ -H ₂ O), 364 (M ⁺ -H ₂ OH
F), 353 (M ⁺ -H ₂ O-CH ₃ O) (9) δ: 0.75 to 1.05 (3H, m), 1.05 to 2.85 (24H, m), 4.43 (0.
5H, m), 4.98 (0.5H, m), 5.77 (1H, d, J = 16Hz), 7.01 (1
H, dt, J = 16Hz, J = 7.5Hz), 7.50 ~ 9.30 (1H, brs) Mass (EI) m / z 354 (M ⁺ ), 336 (M ⁺ -H ₂ O) (10) δ: 0.73 ~ 1.05 (3H, m), 1.05 to 2.82 (24H, m), 3.67 (3
H, s), 4.43 (0.5H, m), 498 (0.5H, m), 5.76 (1H, d, J = 1
6Hz), 6.91 (1H, dt, J = 16Hz, J = 7Hz) Mass (EI) m / z 368 (M ⁺ ), 348 (M ⁺ -HF), 337 (M ⁺ -CH
₃ O), 309 (M ⁺ -COOH ₃ ), 269 (M ⁺ -CH ₂ -CH = CH-COOCH ₃ ) (12) δ: 0.73 to 1.05 (3H, m), 1.10 to 2.90 (22H, m) , 3.87 (1
H, m), 4.13 (1H, m), 4.43 (0.5H, m), 4.30 ~ 4.80 (3H,
m), 4.98 (0.5H, m), 5.37 (2H, m) Mass (EI) m / z 372 (M ⁺ ), 354 (M ⁺ -H ₂ O), 336,284,256 (13) δ: 0.74 to 1.04 (3H , m), 1.07 to 2.86 (24H, m), 3.63 (3
H, s), 3.85 (1H, m), 4.13 (1H, m), 4.43 (0.5H, m), 4.9
9 (0.5H, m), 5.39 (2H, m) Mass (SIMS) m / z 387 (M ⁺ +1), 349 (M ⁺ + 1-H ₂ O) (14) δ: 0.92 (3H, t, J = 6Hz), 1.15 to 2.92 (24H, m), 3.63 (3
H, s), 3.50 to 3.95 (1H, m), 4.17 (1H, m), 5.39 (2H, m) Mass (EI) m / z 404,386,368,355 (15) δ: 0.88 (3H, t, J = 6Hz ), 1.15 ~ 2.90 (26H, m), 3.63 (3
H, s), 3.87 (1H, m), 4.14 (1H, m), 4.43 (0.5H, m), 4.9
8 (0.5H, m), 5.39 (2H, m) Mass (EI) m / z 400,382,364,362 (16) δ: 0.87 (3H, t, J = 6Hz), 1.10 to 2.90 (26H, m), 3.87 ( 1
H, m), 4.12 (1H, m), 443 (0.5H, m), 4.50 to 5.10 (3H, br
s) 499 (0.5H, m), 5.38 (2H, m) Mass (EI) m / z 400 (M ⁺ ), 382 (M ⁺ -H ₂ O), 362,344 (17) δ: 0.86 to 1.05 (3H, m), 1.15 to 2.75 (20H, m), 3.63 (3
H, s), 3.90 to 4.33 (2H, m), 4.54 (0.5H, m), 5.11 (0.5
H, m), 5.34 (2H, m), 6.52 (1H, dd, J = 16Hz, J = 3.5Hz),
6.91 (1H, dd, J = 16Hz, J = 9Hz) Mass (EI) m / z384 (M +), 366 (M + -H 2 O), 346 (M + -H 2 OH
F), 303,292 (18) δ: 0.87 (3H, t, J = 6Hz), 1.15 to 2.90 (28H, m), 3.63 (3
H, s), 3.86 (1H, m), 4.15 (1H, m), 4.45 (0.5H, m), 5.0
0 (0.5H, m), 5.40 (2H, m) Mass (EI) m / z 414 (M ⁺ ), 396 (M ⁺ -H ₂ O) 378,358 Effect of the invention 15-keto-16- used in the present invention Halogen-PGs are
It has a remarkable enteropooling effect and does not show side effects such as abdominal pain associated with intestinal contraction. Further, it also has a remarkable promoting effect on the intestinal transport ability, and actually has a remarkable cathartic effect also in animals and humans. Furthermore, since it is quick to recover from diarrhea, it is useful as a laxative such as a laxative or a laxative.

Therefore, the 15-keto-16-halogen-PGs of the present invention not only treat or prevent constipation, but also because patients with hernias and cardiovascular diseases do not breathe during defecation, or have rectal anal disease. It can also be used to soften a patient's stool. It can also be used to empty the intestine before examination or surgery or to wash out harmful substances from the intestine during drug or food poisoning.

Claims (7)

[Claims] 1. A laxative containing 15-keto-16-halogen-prostaglandins as an active ingredient. 2. The 15-keto-16-halogen-prostaglandins are 13,14-dihydro-15-keto-16-halogen-.
The laxative according to claim 1, which is a prostaglandin. 3. The laxative according to claim 1, wherein the 15-keto-16-halogen-prostaglandins are 15-keto-16-fluoro-prostaglandins. 4. The laxative according to claim 1, wherein the 15-keto-16-halogen-prostaglandins are 15-keto-16,16-difluoro-prostaglandins. 5. The 15-keto-16-halogen-prostaglandins are 13,14-dihydro-15-keto-16-fluoro-.
The laxative according to claim 1, which is a prostaglandin. 6. The laxative according to claim 1, wherein the 15-keto-16-halogen-prostaglandins are 13,14-dihydro-15-keto-16,16-difluoro-prostaglandins. . 7. The laxative according to claim 1, wherein the prostaglandins are prostaglandins E.