JPH0761944B2 - Brain function improving agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel use of a 15-keto-prostaglandin compound for improving brain function.

PRIOR ART Prostaglandins (hereinafter prostaglandins are designated as PG) are a group of organic carboxylic acids contained in human or other mammalian tissues or organs and exhibit a wide range of physiological activities. Naturally occurring PGs have a prostanoic acid backbone as a general structural feature.

Furthermore, PGs have PGAs and PGBs depending on the structural characteristics of the 5-membered ring.
, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs and
Although classified as PGJs, PGIs have the following skeleton closed between the α chain and the 5-membered ring.

On the other hand, some synthetic analogs have modified backbones. In addition, depending on the number of double bonds, these are subscript 1 ... 1 (13-14 position) -15-OH Subscript 2 ... 2 (13-14 position, 5-6 position) -15 -OH Subscript 3 ... 3 (13-14th, 5-6th and 17-18th)
Rank) −15−OH.

Further, PGFs are classified into α (hydroxyl group has alpha configuration) and β (hydroxyl group has beta configuration) depending on the configuration of the 9th hydroxyl group.

JP-A-58-164512 discloses 15-cycloalkyl-6-oxo-PGE ₁ , 15-cycloalkyl-PGI ₁ and I ₂ , 15-cycloalkyl-6,9α-nitrilo-PGI ₁ , and 15-cyclo. Alkyl-6,9α-thio-PGI ₁ and I ₂ describes that it has a protective effect against cell damage including cerebrovascular accident, JP-A-58-203911 discloses certain 15, 16, 17, 20
6-oxo-PG having a methyl group at one or two positions
E ₁ compound and PGI ₁ class and certain 15-cyclopentyl -PG
Described that I ₁ class has a protective effect against cell damage, JP-A-59-73522 describes that a certain PGD ₂ or PGE ₁ derivative can be a therapeutic agent for anoxic diseases of cerebral nerve cells. ing. In addition, carbacycline (also known as 9 (O) -methanoprostacyclin or 9) which is a synthetic PG derivative in which oxygen at the 6a position (9α position) of PGI ₂ is changed to methylene
(O) -methano PGI ₂ ) has a platelet aggregation inhibitory action. In addition, a compound (9-deoxy-9α, 6-nitrilo-5-thia PGF ₁ α) in which oxygen at the 6a position (9α position) of PGI ₂ is changed to nitrogen and methylene at the 5th position is changed to sulfur is also known. . However, none of these correspond to 15-keto-PG or its derivative.

It is described in EP-A-0310305 that 15-keto-PGs can be used as laxatives.

There are various possible causes for reducing brain function, but one is an abnormality in cerebral hemodynamics due to ischemic lesions, hemorrhagic lesions or local or diffuse pressure lesions due to edema / hydrocephalus, etc., The other is a secondary disorder of brain metabolism.

In these treatments, two factors, improvement of cerebral circulation and improvement of basic activity of brain cells, must be taken into consideration, and development of a drug having both of these improving actions is desired.

[Structure of the Invention] As a result of research on the biological activity of 15-keto-PG compounds, the present inventor has found that they have cerebral metabolism activating action, cerebral function protecting action and cerebral circulation improving action. The present invention has been completed by finding that it can be used as a therapeutic agent.

That is, the present invention provides a therapeutic agent for improving brain function, which contains a 15-keto-prostaglandin compound selected from the group consisting of 15-keto-prostaglandins D, E and F as an active ingredient. .

In the present invention, "improvement of brain function" means ischemic lesion,
Includes improvement of all symptoms based on or with cerebral hemodynamics due to local or diffuse pressure lesions due to hemorrhagic lesions, edema / hydrocephalus, or physical factors, etc. Amelioration of any condition that is based on or associated with a disorder of cerebral metabolism secondary to Specific examples of such symptoms include transient cerebral ischemic attack syndrome (TIA syndrome), ischemic cerebrovascular disease, thrombosis due to itch arteriosclerosis, and itch thrombosis of internal carotid artery (including branches). Lesion, cerebral infarction, cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, cerebral hypovascular abnormal vascular network, cerebral venous / sinus occlusive disease, systemic hypotension, anoxic ischemic encephalopathy, traumatic brain Vascular blockage, concussion, cerebral contusion, epidural hematoma, subdural hematoma, cerebral vasospasm, etc., and further cerebrovascular disorder (cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, hypertensive encephalopathy, etc.), encephalitis, brain tumor, Head injury (cerebral vascular occlusion, concussion, cerebral contusion, epidural hematoma, subdural hematoma, etc.), psychosis, metabolic disorders, drug poisoning (alcohol, drugs, narcotics, etc.), poison poisoning (heavy metals, organic solvents, yes) Toxic gas, biological poison, etc.), consciousness disorder due to physical disorders, etc. Nokosho (memory impairment, lowering of attention, hyperactivity,
Language disorder, mental retardation, etc.), amnesia, senile dementia,
This includes Alzheimer's disease and the like.

In the present invention, the term "treatment" includes the management of any disease, including prevention, treatment, alleviation, prevention of deterioration or alleviation of deterioration.

“15-Keto-prostaglandin compound” means the following 15-
It is abbreviated as keto-PG compound, but it has a
It includes any prostaglandin derivative having an oxo group instead of a hydroxyl group at the 15-position. Further, in the present invention, the term "prostaglandin I compound" means that one of the 6-position and the 9-position of prostanoic acid is 1 irrespective of the number of double bonds, the presence or absence of other substituents and the modification of the chain portion. It is intended to include any substitution product or derivative of the compound formed by ring closure via the atom (for example, C, O, S, N, etc.).

In naming the 15-keto-PG compounds of the present invention, the prostanoic acid numbers shown in formulas (A) and (B) are used.

The above formulas (A) and (B) have a basic skeleton of C-20, but the number of carbon atoms is not limited thereto in the present invention. That is, the number of carbon constituting the basic skeleton is 1 for carboxylic acid, and 2 to 7 are sequentially assigned to carbons on the α chain toward the 5-membered ring common to formulas (A) and (B) (6, 6a ( Or 9α), 7 to the ring formed in formula (B)), 8 to 12 to the carbon of the 5-membered ring common to formulas (A) and (B), and 13 to 20 on the ω chain. However, when the number of carbon atoms decreases on the α chain, the number is deleted from the 2-position sequentially, and when it increases on the α chain, it is assumed that the 2-position has a substituent in place of the carboxyl group (1-position). Name it. Similarly, 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.

Therefore, 15-keto-PG compounds having 10 carbon atoms in the ω chain are designated as 15-keto-20-ethyl-PGs. Also,
The 13-14 position is saturated, the 15-position has an oxo group instead of a hydroxyl group, and the 6a position (9α position) has a carbon atom (CH
_The PGI ₂ compound having ₂ ) is named 13,14-dihydro-15-keto-6a-carba-PGI ₂ [or 13,14-dihydro-15-keto-9 (O) -methano-PGI ₂ ]. .

Although the above formulas show the particular configuration, which is the most typical coordination, throughout this specification, compounds are assumed to have the above configuration unless otherwise indicated.

PGD, PGE, PGF or PGI generally refers to a compound having a hydroxyl group at the 9-position and / or 11-position of prostanoic acid, but the 15-keto-prostaglandin compound of the present invention has the 9-position and / or 11-position. To include compounds having other groups. The above compounds are 9-dehydroxy-
It is called 9-substituted or 11-dehydroxy-11-substituted compounds.

As mentioned above, the nomenclature of 15-keto-PG compounds herein is based on the prostanoic acid backbone. When this is named based on IUPAC, for example, 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂ is (Z) -7-{(1R, 2R, 3
R) -3-Hydroxy-2-[(4R, S) -fluoro-3
-Oxo-octyl] -5-oxo-cyclopentyl}
-Hept-5-enoic acid; 13,14-dihydro-15-keto-1
6,16-Difluoro-PGE ₂ is (Z) -7-[(1R, 2R, 3R)
-2- (4,4-difluoro-3-oxo-octyl)-
3-Hydroxy-5-oxo-cyclopentyl] -hept-5-enoic acid; 13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE ₂ methyl ester is methyl 7- { (1R, 2S, 3S) -3-Methyl-2-
[3-oxo-decyl] -5-oxocyclopentyl}
-Hept-5-enoate; 13,14-dihydro-6,15-diketo-19-methyl-PGE ₁ ethyl ester is ethyl 7-
{(1R, 2S, 3S) -3-Hydroxy-2- (7-methyl-
3-oxo-octyl) -5-oxo-cyclopentyl} -6-oxoheptanoate.

The 15-keto-PG compound used in the present invention may be a derivative of any PG having an oxo group in place of the hydroxyl group at the 15-position, which may be a saturated form, or a double bond (15- Keto-PG type 1 compound), double bonds at 13-14 and 5-6 positions (15-keto-PG type 2 compound),
Or it may have a double bond (15-keto-PG type 3 compound) at the 5-6, 13-14 and 17-18 positions. Also, 1
Also included are 3,14-dihydro forms.

An example of a representative compound that can be used in the present invention is 15-keto-
PGX (PGX is any PG selected from PGD to PGF), 13,14-
And dihydro-15-keto-PGX and the like, their substitution products and their derivatives.

Examples of the substitution product or derivative are compounds in which the carboxyl group at the α chain end of the above 15-keto-PG compound is esterified,
Physiologically acceptable salt, compound in which carbon bond at 2-3 position has double bond or carbon bond at 5-6 position has triple bond, 3-position, 5-position, 6-position, 16-position, 17-position, A compound having a substituent at the 19th and / or 20th carbons, a compound having a lower alkyl group or a hydroxy (lower) alkyl group in place of the 9th and / or 11th hydroxyl group, and the like.

In the present invention, examples of the substituent bonded to the carbon atom at the 3-position, 17-position and / or 19-position include an alkyl group having 1 to 4 carbon atoms, particularly a methyl group and an ethyl group. Examples of the substituent bonded to the 16th carbon atom include a lower alkyl group such as a methyl group and an ethyl group, a hydroxyl group, a halogen atom such as chlorine and fluorine, and an aryloxy group such as trifluoromethylphenoxy. Examples of the substituent on the carbon atom at the 17-position include halogen such as chlorine and fluorine. Examples of the substituent bonded to 20 position carbon atoms, C _1-4 lower alkyl group, saturated or unsaturated, such as alkyl, C _1-4 lower alkoxy groups such as alkyl, C _1-4 alkoxy -C _{1 -4} lower alkoxyalkyl such as -4alkyl. Substituents on the 5-position carbon atom include halogens such as chlorine and fluorine. Substituents on the 6th carbon atom include oxo groups that form carbonyl groups. When the 9-position also has a hydroxy group, a lower alkyl or a lower (hydroxy) alkyl substituent at the 11th carbon atom, the configuration of these groups may be α, β or a mixture thereof.

Further, the above derivative may be one having a substituent such as an alkoxy group, a phenoxy group or a phenyl group at the ω chain end of a compound having a ω chain shorter than that of natural PGs.

Particularly preferred compounds are, for example, a methyl group at the 16th carbon,
Compounds having a lower alkyl group such as an ethyl group, chlorine,
Compounds having a halogen atom such as fluorine, compounds having a lower alkyl group such as a methyl group and an ethyl group at the 19th carbon, compounds having a halogen such as chlorine and fluorine at the 5th carbon, oxo at the 6th carbon A compound having a group, a compound having a lower alkyl group such as a methyl group or an ethyl group at the 20th carbon, and a substituent such as a halogen atom or a halogenated alkyl group in place of the alkyl chain after the 16th carbon. It is a compound in which a phenyl group or a phenoxy group, which may have a group, is bonded to the 16th carbon atom.

Preferred compounds used in this invention have the formula [Wherein, X and Y are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, or oxo (provided that at least one of the groups X and Y is a group other than hydrogen, and the 5-membered ring is Optionally having at least one double bond), Z is hydrogen or halogen, A is —CH ₂ OH, —COCH ₂ OH, —COOH or a functional derivative thereof, and B is —CH ₂ —CH ₂ —. , -CH = CH-, -C≡C-, W is an oxygen atom or a carbon atom, R ₁ is unsubstituted or substituted with halogen, oxo or aryl, and is a divalent saturated or unsaturated, low to intermediate aliphatic. hydrocarbon residue, R ₂ is unsubstituted or halogen, hydroxy, oxo, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, substituted aryl or aryloxy, saturated or unsaturated, lower or medium aliphatic carbon Having a a] hydrogen residue.

Of the above compounds, one group of preferred compounds has the general formula [Wherein, Q ₁ is halogen, Q ₂ is hydrogen or halogen, E is —CH ₂ —CH ₂ — or —CH═CH—, Ra is hydrogen or a lower alkyl group, Rb is a single bond or a lower alkylene group, Rc Is an unsubstituted or halogen-substituted lower alkyl group, an unsubstituted or lower alkyl-substituted lower cycloalkyl group, an unsubstituted or halogen- or halo-lower alkyl-substituted monocyclic aryl group, an unsubstituted or halogen- or halo-lower alkyl-substituted A monocyclic aryloxy group] or a salt thereof when Ra is hydrogen.

In the above formula, the term “unsaturated” in R ₁ and R ₂ means that at least one or more double bonds and / or triple bonds are isolated as a bond between carbon atoms of a main chain or a side chain, Means to include separate or consecutive.Unsaturation between two consecutive positions is indicated by displaying the younger position number, and unsaturation between two non-consecutive positions is The preferred unsaturation is the double bond at the 2-position and the double or triple bond at the 5-position.

The term "low to middle aliphatic hydrocarbon" means a hydrocarbon having a straight or branched chain having 1 to 14 carbon atoms (however, the side chain preferably has 1 to 3 carbon atoms), and Is a hydrocarbon having 2 to 8 carbon atoms in the case of R ₁ and 6 carbon atoms in the case of R _2.
~ 12 hydrocarbons.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

Unless otherwise specified, the term "lower" has 1 carbon atom.
It is intended to include groups having ~ 6.

The term "lower alkyl" includes straight or branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Includes t-butyl, pentyl and hexyl.

The term "lower alkoxy" means lower alkyl-O-, wherein lower alkyl is as defined above.

The term "lower alkylene group" is a group obtained by removing one hydrogen from the above lower alkyl group, and includes, for example, methylene, ethylene, propylene, tetramethylene, 2-
Includes methyltetramethylene, pentamethylene, hexamethylene and the like.

The term "halo lower alkyl group" includes lower alkyl groups as defined above having at least 1, preferably 1-3 halogens as defined above, for example chloromethyl,
Bromomethyl, fluoromethyl, trifluoromethyl,
Including 1,2-dichloroethyl, 1,2,2-trichloroethyl, chloropropyl, chlorobutyl, chloropentyl, chlorohexyl and the like.

The term "hydroxy (lower) alkyl" means at least 1
It means alkyl as above substituted with one hydroxy group, for example hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.

The term "lower alkanoyloxy" means a group of the formula RCO-O-, where RCO- is an acyl resulting from the oxidation of a lower alkyl as described above, eg acetyl.

The term "cyclo (lower) alkyl" means a group resulting from ring closure of a lower alkyl group as defined above.

The term "aryl" embraces optionally substituted aromatic carbocyclic or heterocyclic groups, preferably monocyclic groups,
Examples include phenyl, tolyl, xylyl and thienyl. The substituent includes halogen and a halogen-substituted lower alkyl group (wherein the halogen atom and the lower alkyl group have the same meanings as described above).

The term "aryloxy" means a radical of the formula ArO-, where Ar is an aryl radical as described above.

The term "monocyclic aryl group" includes phenyl groups with or without lower alkyl substituents, such as phenyl,
Includes trilyl, xylyl, cumenyl and the like.

The term "monocyclic aryloxy group" is a group formed by the above monocyclic aryl group bonded to an oxygen atom (-O-), and includes, for example, phenoxy, tolyloxy, xylyloxy, cumenyloxy and the like.

The term "functional derivative" of the carboxyl group represented by A includes salts (preferably pharmaceutically acceptable salts), esters and amides.

Suitable "pharmaceutically acceptable salts" include commonly used non-toxic salts, salts with inorganic bases such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, Magnesium salt, etc.), ammonium salt, salt with organic base, for example, amine salt (eg, methylamine, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt,
Ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethyl-monoethanolamine salt, lysine salt, procaine salt, caffeine salt, etc., basic amino acid salt (eg, arginine salt, lysine) Salt etc.) Tetraalkylammonium salt and the like. These salts may be prepared, for example, from the corresponding acids and bases by conventional methods or by salt exchange.

Examples of the ester include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester,
Lower alkyl ester such as pentyl ester and 1-cyclopropylethyl ester, lower alkenyl ester such as vinyl ester and allyl ester, lower alkynyl ester such as ethynyl ester and propynyl ester,
Hydroxy (lower) such as hydroxyethyl ester
Aliphatic esters such as lower alkoxy (lower) alkyl esters such as alkyl ester, methoxymethyl ester, 1-methoxyethyl ester and the like and phenyl ester, tosyl ester, t-butylphenyl ester, salicyl ester, 3,4-dimethoxyphenyl Examples include optionally substituted aryl esters such as esters and benzamidophenyl esters, and aryl (lower) alkyl esters such as benzyl esters, trityl esters and benzhydryl esters.

Examples of the amide include mono- or di-lower alkylamides such as methylamide, ethylamide and dimethylamide, arylamides such as anilide and toluidide, and alkyl or arylsulfonylamides such as methylsulfonylamide, ethylsulfonylamide and trisulfonylamide.

Examples of preferred A _{groups, -COOH, -COOCH 3, -COOCH 2} C
_{H 3, -COOCH (CH 3)} 2, a -CONHSO ₂ CH _3.

Examples of preferred groups for R ₁ are — (CH ₂ ) ₂ —, — (CH ₂ )
_{6 -, - CH 2 CO (} CH 2) 2 -, - CH 2 CH = CH (CH 2) 3 -,
_{-CH 2 CO (CH 2) 4} -, - (CH 2) 2 CH = CH (CH 2) 2 -,
_{- (CH 2) 4 CH =} CH -, - CH 2 CH = C = CH (CH 2) 2 - , and the like.

Examples of preferred groups of B-CO-R _{2 is, - (CH 2) 2 CO} (CH 2) 4 -CH 3 - (CH 2) 2 CO (CH 2) 4 -COOH - (CH 2) 2 COC ( _{CH 3) 2 (CH 2)} 3 -CH 3 - (CH 2) 2 COCH 2 O- phenyl _{- (CH 2) 2 COCH 2} O- meta-chlorophenyl _{- (CH 2) 2 COCH 2} O- meth trifluorophenyl - _{(CH 2) 2 COCH 2 O} -3- thienyl _{- (CH 2) 2 CO (} CH 2) 2 - phenyl _{- (CH 2) 2 COCH 2} CH (CH 3) (CH 2 CH 3 - (CH 2) 2 _{COC (CH 3) 2 CH 2} OCH 2 CH 3 - (CH 2) 2 COCH (CH = CH) (CH 2) 3 CH 3 - (CH 2) 2 CO- cyclopentyl - (CH _{2) 2} CO- cyclohexyl - _{(CH 2) 2 CO (CH} 2) 2 cyclohexyl _{- (CH 2) 2 COCH 2} CH (CH 3) (CH 2) 2 -CH = C (CH 3) 2 - (CH 2) 2 COCH (CH 3) _{CH 2 CC≡CH -CH = CHCO (CH} 2) 4 -CH 3 -CH = CHCOC (CH 3) 2 (CH 2) 3 -CH 3 -CH = CHCOCH 2 O- phenyl -C H = CHCOCH ₂ O- meth chlorophenyl -CH = CHCOCH ₂ O- meth trifluorophenyl -CH = CHCOCH ₂ O-3- thienyl _{-CH = CHCO (CH 2) 2} - phenyl _{-CH = CHCOCH 2 CH (CH 3} ) _{(CH 2) 3 -CH 3 -CH} = CHCOC (CH 3) 2 CH 2 OCH 2 CH 3 -CH = CHCOCH (CH = CH) (CH 2) 3 CH 3 -CH = CHCO- cyclopentyl -CH = CHCO- cyclohexyl -C≡C-CO (CH _{2) 2} cyclohexyl _{-CH = CHCOCH 2 CH (CH 3} ) (CH 2) 2 CH = C (CH 3) 2 -CH = CHCOCH (CH 3) CH 2 CC≡CH - CH = CHCH ₂ COCH (CH ₃ ) (CH ₂ ) ₄ CH ₃ .

In the above formula (I), the arrangement of the ring, α and / or ω chain is
The arrangement of natural PGs may be similar or different.
However, the invention also includes mixtures of compounds having a natural configuration and compounds having a non-natural configuration.

Examples of typical compounds of this invention are 15-keto-PGD, E and F, 13,14-dihydro-15-
Keto-PGD, E and F and their 6-oxo derivatives, Δ ² -derivatives, 3R, S-methyl derivatives, 5R, S-fluoro derivatives, 5,5-difluoro derivatives, 16R, S-methyl derivatives, 16 , 16-dimethyl derivative, 16R, S-fluoro derivative, 16,16-difluoro derivative, 17S-methyl derivative, 17
R, S-fluoro derivative, 17,17-difluoro derivative, 20-
These are methyl derivatives, 20-ethyl derivatives, 19-desmethyl derivatives and 16-desbutyl-16-phenoxy derivatives.

In the compound used in the present invention, when the 13- and 14-positions are saturated, hemiacetal formation between hydroxy at the 11-position and keto at the 15-position may cause keto-hemiacetal equilibrium. When such tautomers exist, the abundance ratios of both isomers vary depending on the structures of other moieties or the types of substituents, and in some cases, one isomer may predominantly exist. In the present invention, both of them are included, and a compound may be represented by a keto-type structural formula or a nomenclature regardless of the presence or absence of such isomers, but this is for convenience and hemiacetal It does not seek to exclude types of compounds.

In the present invention, isomers such as individual tautomers, mixtures thereof or optical isomers, mixtures thereof, racemates and other stereoisomers can be used for the same purpose.

Some of the compounds used in this invention are disclosed in JP-A-64-52
It can be produced by the method described in JP-A No. 753, JP-A-1-104040, JP-A No. 1-151519, JP-A No. 2-131446, and the like.
Alternatively, these compounds may be prepared by methods similar to those described herein or known.

The 15-keto-PG compound has a cerebral metabolism activating action, a cerebral function protecting action and a cerebral circulation improving action, and thus is useful as a cerebral function improving therapeutic agent. Such activity can be measured using a standard method such as a complete ischemia model (cerebral function protecting action) by decapitation, a hypoxia load model (cerebral circulation improving action) and the like.

The compound used in the present invention can be used as a drug for animals and humans, and is usually used systemically or locally by a method such as oral, intravenous injection (including drip), subcutaneous injection, and rectal administration. . The dose depends on the type of subject, such as animal or human, age, weight, condition to be treated,
Although it varies depending on the desired therapeutic effect, administration method, treatment period, etc., usually when administered in 2 to 4 divided doses per day or in a continuous form, a dose of 0.001 to 500 mg / kg usually gives a sufficient effect.

The solid composition for oral administration according to the present invention includes:
Tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like are included. In such solid compositions, the one or more active substances comprises at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Acid mixed with magnesium aluminate. According to a conventional method, the composition comprises 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- etherified cyclodextrins such as α-, dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin, branched cyclodextrins such as glycosyl-, maltosyl-cyclodextrin,
Stabilizers such as formylated cyclodextrins, sulfur-containing cyclodextrins, misoprotols, phospholipids may be included. When the above cyclodextrins are used, they may form an inclusion compound with the cyclodextrins to increase the stability. In addition, stability may be increased by forming liposomes using phospholipids.
If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Further, it may be a capsule of a disintegratable substance such as gelatin. When fast-acting is required, sublingual tablets may be used. As the base, glycerin, lactose, etc. may be used.

Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs. It may contain an inert diluent generally used, for example, purified water, ethanol and the like. In addition to the inert diluent, this composition may contain an auxiliary agent such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, and a preservative.

Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
Aqueous solutions and suspension media include, for example, distilled water for injection, physiological saline and Ringer's solution.

Examples of non-aqueous liquids and suspension media include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbates and the like. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. These are sterilized by filtration through a bacteria-retaining filter, gas sterilization or radiation sterilization in the case of a bactericide. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

Another form is a suppository or vaginal suppository. These suppositories can be prepared by mixing an active ingredient with a base that softens at body temperature, such as cocoa butter, and may improve absorbability by using a nonionic surfactant having an appropriate softening temperature.

The present invention also provides a treatment method for improving brain function, which comprises administering the therapeutic agent of the present invention to a subject to be treated.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Synthesis Examples, Formulation Examples and Test Examples, but these do not limit the present invention.

Synthesis Example 1 16,16-Difluoro-13,14-dihydro-15-keto-PGE ₁
Method for synthesizing methyl ester (12) 1-1) (1S, 5R, 6R, 7R) -6-hydroxymethyl-7
-Synthesis of tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octane-3-one (2) Commercially available (-) corey lactone (1) (THP protected form) (3
Tetrabutylammonium fluoride in tetrahydrofuran solution (1.0M, 300m)
l) was added, and the mixture was stirred at room temperature for 3 hours.

The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography to give the title compound (2).

Yield: 21.70 g (82.8%) 1-2) (1S, 5R, 6R, 7R) -6-{(E) -4,4-difluoro-5-oxo-2-octenyl} -7-tetrahydropyranyloxy Synthesis of 2-oxabicyclo [3.3.0] octane-3-one (4) Dissolve a methylene chloride solution of oxalyl chloride (2.0M, 45.5 ml) in methylene chloride at -78 ° C under an argon atmosphere,
Dimethyl sulfoxide (12.9 ml) was added dropwise, and the mixture was stirred for 10 minutes. (1S, 5R, 6R, 7R) -6-hydroxymethyl-
A solution of 7-tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octane-3-one (2) (11.65 g) in methylene chloride was added dropwise, stirred for 30 minutes, and triethylamine (56 ml) was added dropwise. Stir for hours. The reaction solution was treated according to a conventional method to obtain an aldehyde derivative (3) as a crude product.

Under an argon atmosphere, dimethyl 3,3-difluoro-2-oxoheptylphosphonate (11.9 g) was added to a solution of thallium ethoxide (3.26 ml) in methylene chloride, and the mixture was stirred for 1 hour. The mixture was cooled to 0 ° C, the methylene chloride solution of aldehyde (3) prepared above was added, and the mixture was stirred at room temperature for 14 hours. Acetic acid, Celite, and saturated aqueous potassium iodide were added to the reaction solution, and the mixture was filtered. The filtrate was treated by a conventional method, and the obtained crude product was subjected to column chromatography to give the title compound (4).

Yield: 7.787 g (44.3%) 1-2) (1S, 5R, 6R, 7R) -6- (4,4-difluoro-5)
-Oxooctyl) -7-tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octane-3-one (5) Synthesis (1S, 5R, 6R, 7R) -6-{(E) -4, 4-difluoro-5
-Oxo-2-octenyl} -7-tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octane-3
5% palladium-carbon (catalytic amount) was added to an ethyl acetate solution of -one (4) (5.57 g), and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (5) as a crude product.

Yield: 5.48 g (97.8%) 1-3) (1S, 5R, 6R, 7R) -6- {4,4-difluoro-5.
(RS) -Hydroxyoctyl} -7-tetrahydroplanyloxy-2-oxabicyclo [3.3.0] octane-
Synthesis of 3-one (6) (1S, 5R, 6R, 7R) -6- (4,4-Difluoro-5-oxooctyl) -7-tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octane -3-ON (5) (5.4
Sodium borohydride (0.800 g) was added to a methanol solution of 8 g) at 0 ° C., and the mixture was stirred for 10 minutes. The reaction product was treated by a conventional method, and the obtained crude product was subjected to column chromatography to give the title compound (6).

Yield 5.46 g (99.5%) 1-4) Synthesis of 16,16-difluoro-13,14-dihydro-11-tetrahydropyranyloxy-PGF ₂ α methyl ester (9) Under argon atmosphere, (1S, 5R, 6R , 7R) -6- {4,4-Dihydro-5 (RS) -hydroxyoctyl} -7-tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octane-3-one (6) (2.579g) Of toluene solution of
The mixture was cooled to 78 ° C., a toluene solution of diisobutylaluminum hydride (1.5M, 9.6 ml) was added dropwise, and the mixture was stirred for 30 minutes.
Methanol and saturated Rochelle salt aqueous solution were added to the reaction solution,
It processed by the conventional method. A lactol body (7) was obtained as a crude product.

Under an argon atmosphere, a tetrahydrofuran solution of potassium t-butoxide (1.0 M, 52.84 ml) was added dropwise to a tetrahydrofuran suspension of 4-carboxybutyltriphenylphosphine bromide (11.72 g), and the mixture was stirred for 20 minutes. 0 this liquid
The mixture was cooled to ℃, the tetrahydrofuran solution of the lactol body (7) prepared above was added, and the mixture was stirred at room temperature for 15 hours.

The reaction solution was treated by a conventional method to obtain a carboxylic acid compound (8) as a crude product.

Under an argon atmosphere, 1,8-diazabicyclo [5.4.0] undec-7 was added to a solution of the carboxylic acid compound (8) in acetonitrile.
-Ene (DBU) (4.0 ml) and methyl iodide (1.7 ml)
Was added and stirred at 60 ° C. for 3 hours. The crude product obtained by the conventional method was subjected to column chromatography to give the title compound (9).

Yield: 2.737 g (84.5%) 1-5) Synthesis of 16,16-difluoro-13,14-dihydro-15-keto-11-tetrahydropyranyloxy-PGE ₂ methyl ester (10) Anhydrous chromium under argon atmosphere A solution of Collins reagent prepared by a conventional method from acid (16.18 g) and pyridine (26.2 ml) in methylene chloride was added to 16,16-difluoro-13,14 at -20 ° C.
- dihydro-11-tetrahydropyranyloxy-PGF ₂ alpha
A methylene chloride solution of methyl ester (9) (2.646 g) was added, and the mixture was stirred for 2 hours. The temperature was raised to −5 ° C., and the mixture was further stirred for 9 hours. Ether and sodium hydrogen sulfate were added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure and subjected to column chromatography to give the title compound (10).

Yield: 1.890 g (64.4%) 1-6) Synthesis of 16,16-difluoro-13,14-dihydro-15-keto-PGE ₂ methyl ester (11) 16,16-difluoro-13,14-dihydro-15 -Keto-11-
Tetrahydropyranyloxy-PGE ₂ methyl ester (1
0) (2.809g) in acetic acid, water, tetrahydrofuran 3: 1: 1
It was dissolved in a mixed solvent and stirred at 60 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and subjected to column chromatography to give the title compound (11).

Yield: 1.755 g (75.5%) 1-7) Synthesis of 16,16-difluoro-13,14-dihydro-15-keto-PGE ₁ methyl ester (11) 16,16-difluoro-13,14-dihydro-15 -Keto-PGE ₂
Methyl ester (11) (1.755g) in ethyl acetate solution 5
% Palladium-carbon (catalytic amount) was added, and under a hydrogen atmosphere,
Stir at room temperature for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to give the title compound (11).

Yield: 1.655 g (93.8%) ¹ HNMR (CDCl ₃ ) δ0.87 (3H, t, J = 7Hz), 1.15 to 2.05 (2
3H, m), 2.11 to 2.30 (3H, m), 2.50 (1H, dd, J = 7.5 and 17Hz), 3.10 to 3.20 (1H, br), 3.71 (3H, s), 4.05
~ 4.20 (1H, m).

Mass (D1-E1) m / z404 (M), 355 (M -H 2 O-CH
_{3 O), 297 (M-} C 5 H 9 F 2).

Synthesis Example 2 16,16-Difluoro-13,14-dihydro-15-keto-PGE ₁
Synthesis of (16) 2-1) (15RS) -16,16-Difluoro-13,14-dihydro-11-tetrapyranyloxy-PGF ₂ α Carboxylic acid derivative (8) (2.33 g) in dichloromethane (3
DBu (2.1 ml) and benzyl bromide (2.2 ml) were added to (00 ml) and the mixture was stirred at room temperature for 1.5 hours. The crude product obtained by the conventional treatment was purified by silica gel column to obtain benzyl ester (13).

Yield: 2.522 g (96.1%) 2-2) 16,16-difluoro-13,14-dihydro-15-
Keto-11-tetrapyranyloxy-PGE ₂ benzyl ester (14) The Collins reagent was prepared using chromic anhydride (13.5 g) and pyridine (21.8 ml) in dichloromethane (300 ml). Celite (40 g) was added thereto, and the benzyl ester (13) (2.550 g) was oxidized at -20 ° C. The crude product obtained after the conventional treatment was purified by silica gel to obtain the title compound (14).

Yield: 1.911 g (78.6%) 2-3) 16,16-difluoro-13,14-dihydro-15-
Keto-PGE ₂ benzyl ester (15) PGE ₂ benzyl ester (14) (1.550 g) was added to acetic acid-THF.
-Dissolved in water (3-1-1, 50 ml) and kept at 50 ° C for 4 hours. The crude product obtained by the conventional treatment was purified by silica gel column to obtain PGE ₂ benzyl ester (15).

Yield: 1.255 g (92.9%) 2-4) 16,16-difluoro-13,14-dihydro-15-
Keto-PGE ₁ (16) PGE ₂ benzyl ester (15) (0.844 g) was catalytically reduced using 5% palladium on carbon in ethyl acetate (30 ml). Column purification was performed to obtain 16,16-difluoro-13,14-dihydro-15-keto-PGE ₁ (16).

Yield: 0.404g ¹ HNMR (CDCl ₃ ) δ 0.94 (3H, t, J = 7.5Hz), 1.20 to 2.70
(26H, m), 4.19 (1H, m), 4.80 (2H, br).

Mass (DI-EI) m / z 390 (M ⁺ ), 372 (M ⁺ -H ₂ O), 354 (M
⁺ −2H ₂ O).

The route is shown in the following reaction formula.

Reference Example 1 Production of 6-benzoyloxy-2 (RS) -methyl fluorohexanoate (f) 1) Production of benzyl 6-hydroxyhexanoate (b) ε-caprolactone (a) (40 g), benzyl alcohol (100 ml) , And p-toluenesulfonic acid.H ₂ O (0.
The mixture of 7 g) was stirred at 100 ° C. for 16 hours. After conventional treatment, distillation under reduced pressure (1 mmHg, 140-154 ° C) was performed to obtain the title compound (b) (27.37 g).

Yield: 35% 2) Benzyl 6-benzoyloxyhexanoate (c)
Preparation of benzyl 6-hydroxyhexanoate (b) (27.37 g) in methylene chloride, 4-dimethylaminopyridine (1
9.53 g) and benzoyl chloride (19.02 g) were added, and the mixture was stirred for 2 hours. After conventional treatment, vacuum distillation (1 mmHg, 190-21
Then, the title compound (c) (38.09 g) was obtained.

Yield: 95% 3) Production of 6-benzoyloxyhexanoic acid (d) Benzyl 6-benzoyloxyhexanoate (c) (38.0
To a solution of 9 g) in ethyl acetate was added 5% palladium carbon (3 g), and the mixture was stirred under a hydrogen atmosphere for 24 hours. The crude product obtained by the conventional treatment was distilled under reduced pressure (1 mmHg, 182-192 ° C.) to obtain the title compound (d) (24.92 g).

Yield: 90% 4) Production of methyl 6-benzoyloxy-2 (RS) -bromohexanoate (e) Thionyl chloride (22 ml) was added dropwise to 6-benzoyloxyhexanoic acid (d) (14.92 g), and 65 The mixture was stirred at 0 ° C for 1 hour.
Carbon tetrachloride (50 ml), N-bromosuccinimide (22.5 g) and 48% hydrobromic acid (5 drops) were added to the reaction mixture, and the mixture was stirred at 85 ° C for 2
It was stirred for 0 hours. The reaction solution was allowed to cool and the solid was filtered off.
The filtrate was concentrated under reduced pressure, the obtained residue was dissolved in methanol, and the mixture was stirred at room temperature for 2 hours. The crude product obtained by the conventional method was subjected to silica gel column chromatography to obtain the title compound (e) (14.02 g).

Yield: 67% 5) Production of methyl 6-benzoyloxy-2 (RS) -fluorohexanoate (f) Methyl 6-benzoyloxy-2 (RS) -bromohexanoate (e) (14.02g), fluorinated A mixture of potassium (12.59g) and acetamide (12.3g) was stirred at 105 ° C for 6 hours. The crude product obtained by the conventional treatment was dissolved in ethyl acetate, 5% palladium carbon (0.4 g) was added, and the mixture was added under hydrogen atmosphere.
Stir at room temperature. The crude product obtained by a conventional method was subjected to silica gel chromatography to give the title compound (f) (5.28
g) and methyl 6-benzoyloxyhexanoate (g) (3.11 g, yield: 29%) were obtained. Title compound (f) Yield: 46% ¹ HNMR (CDCl ₃ ) δ: 1.55-2.18 (6H, m), 3.79 (3H,
s), 4.33 (2H, t, J = 7Hz), 4.77-4.86 (0.5H, m), 5.
05-5.12 (0.5H, m), 7.40-7.62 (3H, m), 8.00-8.10
(2H, m) Synthesis Example 3 5 (RS) -Fluoro-13,14-dihydro-6,15-diketo-PGE ₁ methyl ester [IUPAC nomenclature: 5 (RS) -fluoro-7-{(1R, 2S , 3S) -3-Hydroxy-2- (3-
Oxooctyl-5-oxo-cyclopentyl} -6-
Methyl oxoheptanoate] 3-1) (1S, 5R, 6R, 7R) -6-[(E) -3-Oxo-1-octenyl] -7- (4-phenyl) benzoyloxy-2-oxa Bicyclo [3.3.0] octane-3
Production of -one Commercially available (-)-corey lactone (10.0 g) was Collins-oxidized in dichloromethane to obtain an aldehyde. This was reacted with an anion prepared from dimethyl- (2-oxoheptyl) phosphonate (6.21g). The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (7.45 g).

Yield: 60% 3-2) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS)
-Hydroxy-1-octenyl] -7- (4-phenyl) benzoyloxy-2-oxabicyclo [3.3.0]
Preparation of octan-3-one (1S, 5R, 6R, 7R) -6-[(E) -3-oxo-1-octenyl] -7- (4-phenyl) benzoyloxy-
2-Oxabicyclo [3.3.0] octane-3-one (7.4
5g) in methanol solution at -20 ℃
・ 7H ₂ O (6.84 g), and sodium borohydride (0.6
9 g) was added and stirred for 1 hour.

The combined product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (7.64 g) as a mixture of diastereomers.

Yield: quantitative 3-3) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS)
-T-Butyldimethylsiloxy-1-octenyl] -7
Preparation of-(4-phenyl) benzoyloxy-2-oxabicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -hydroxy-1 -Octenyl] -7- (4-phenyl) benzoyloxy-2-oxabicyclo [3.3.0] octane-3
Imidazole (2.27 g) and t-butyldimethylsilyl chloride (3.78 g) were added to a dimethylformamide solution of -one (7.64 g), and the mixture was stirred at room temperature for 1 hour. The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (7.49 g) as a mixture of diastereomers.

Yield: 80% 3-4) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS)
-T-Butyldimethylsiloxy-1-octenyl] -7
-Hydroxy-2-oxabicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyldimethylsiloxy-1-octenyl ] -7- (4-Phenyl) benzoyloxy-2-oxabicyclo [3.3.
0] octane-3-one (7.49g), potassium carbonate (1.10
A mixture of g) and methanol was stirred at room temperature for 16 hours.
The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (4.69 g) as a mixture of diastereomers.

Yield: 92% 3-5) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS)
-T-Butyldimethylsiloxy-1-octenyl] -7
-Preparation of tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octan-3-one (1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyldimethylsiloxy- To a solution of 1-octenyl] -7-hydroxy-2-oxabicyclo [3.3.0] octane-3-one (4.69 g) in methylene chloride, dihydropyran (5.1
7 g) and pyridinium P-toluenesulfonate (0.77 g) were added, and the mixture was stirred at room temperature for 16 hours. The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (6) (5.37 g) as a mixture of diastereomers.

Yield: 94% 3-6) 2-{(1R, 2R, 3R, 5S) -2-[(E) -3
Preparation of methyl (RS) -t-butyldimethylsiloxy-1-octenyl] -5-hydroxy-3-tetrahydropyranyloxycyclopentyl} acetate (1S, 5R, 6R, 7R) -6-[(E) -3 ( RS) -t-Butyldimethylsiloxy-1-octenyl] -7-tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octane-3-one (1.85 g) in a 4: 1 mixture of methanol and water. After dissolution, lithium hydroxide (0.33 g) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was neutralized and extracted with ethyl acetate. The organic layer was separated, an ether solution of diazomethane was added, and the mixture was stirred at room temperature for 1 hour. The crude product obtained by a conventional method was subjected to silica gel column chromatography,
The title compound (1.82g) was obtained as a mixture of diastereomers.

Yield: 92% 3-7) 2-{(1R, 2R, 3R, 5S) -2-[(E) -3
Preparation of methyl (RS) -t-butyldimethylsiloxy-1-octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl} acetate 2-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t
-Butyldimethylsiloxy-1-octenyl] -5-hydroxy-3-tetrahydropyranyloxycyclopentyl} methyl acetate (4.45 g) in methylene chloride solution with dihydropyran (3.75 g) and pyridinium p-toluenesulfonate (0.56 g) Was added, and the mixture was stirred at room temperature for 16 hours. The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (4.24 g) as a mixture of diastereomers.

Yield: 74% 3-8) 6-benzoyloxy-2 (RS)-{2-
[(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-Butyldimethylsiloxy-1-octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl] -1
Preparation of methyl (RS) -hydroxyethyl} -2 (SR) -fluorohexaneacetate 2-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t
-Butyldimethylsiloxy-1-octenyl] -3,5-
To a toluene solution of methyl bis-tetrahydropyranyloxycyclopentyl} acetate (0.5g) was added DIBAL- at -78 ° C.
A toluene solution of H (1.5M.1.43 ml) was added, and the mixture was stirred for 1 hour. A crude aldehyde compound was obtained by a conventional method.

A tetrahydrofuran solution of LDA (0.9
4 mmol) was cooled to −78 ° C. and methyl 6-benzoyloxy-2 (RS) -fluorohexanoate (f) (0.23
A tetrahydrofuran solution of g) was added, and the mixture was stirred for 10 minutes.
To this was added the previously prepared solution of the crude aldehyde derivative in tetrahyfuran, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The crude product obtained by the conventional method was subjected to silica gel column chromatography to obtain the title compound (0.51 g) as a mixture of diastereomers.

Yield: 74% 3-9) 2 (RS)-{2-[(1R, 2R, 3R, 5S) -2-
[(E) -3 (RS) -t-butyldimethylsiloxy-1
-Octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl] -1 (RS) -hydroxyethyl}
Preparation of methyl-2 (SR) -fluoro-6-hydroxyhexanoate 6-benzoyloxy-2 (RS)-{2- [1R, 2R, 3R, 5
S) -2-[(E) -3 (RS) -t-butyldimethylsiloxy-1-octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl] -1 (RS) -hydroxyethyl} -2 ( SR) -methyl fluorohexanoate (2.
Potassium carbonate (0.47 g) was added to a methanol solution of 48 g), and the mixture was stirred at room temperature for 24 hours. The crude product obtained by the usual treatment was subjected to silica gel column chromatography to obtain the title compound (1.50 g).

Yield: 69% 3-10) 7-{(1R, 2R, 3R, 5S) -2-[(E) -3
(RS) -t-Butyldimethylsiloxy-1-octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl} -5 (RS) -methoxycarbonyl-5 (SR)
Preparation of methyl-fluoro-6-oxo-heptanoate 2 (RS)-{2-[(1R, 2R, 3R, 5S) -2-[(E)-
3 (RS) -t-butyldimethylsiloxy-1-octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl] -1 (RS) -hydroxyethyl} -2 (SR)
-Methyl fluoro-6-hydroxyhexanoate (1.23
g) was subjected to Collins oxidation (4.5 hours) at 50 ° C. under an argon atmosphere. The crude product obtained by the conventional method was dissolved in ether, and an ether solution of diazomethane was added, and the mixture was stirred at room temperature for 1 hour.
Stir for hours. The reaction solution was treated according to a conventional method, and the obtained crude product was subjected to silica gel column chromatography. The title compound (0.60 as a mixture of diastereomers
g) was obtained, and part of the raw material (0.41 g, recovery rate: 33%) was recovered.

Yield of the title compound: 47% 3-11) 7-{(1R, 2R, 3R, 5S) -2-[(E) -3
Preparation of methyl (RS) -t-butyldimethylsiloxy-1-octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl} -5 (RS) -fluoro-6-oxoheptanoate 7-{(1R, 2R , 3R, 5S) -2-[(E) -3 (RS) -t
-Butyldimethylsiloxy-1-octenyl] -3,5-
Bis-tetrahydropyranyloxycyclopentyl}-
5 (RS) -methoxycarbonyl-5 (SR) -fluoro-
Methyl 6-oxoheptanoate (0.80 g) was dissolved in a 50: 2.8: 1 mixture of dimethyl sulfoxide, sodium chloride and water, and the mixture was stirred at 135-140 ° C for 1.5 hours under an argon atmosphere. The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (0.55 g) as a mixture of diastereomers.

Yield: 75% 3-12) 5 (RS) -fluoro-7-{(1R, 2R, 3R, 5
Preparation of methyl S) -2-[(E) -3 (RS) -hydroxy-1-octenyl] -3,5-bis-tetrahydropyranyloxycyclopentyl} -6-oxoheptanoate 7-{(1R, 2R , 3R, 5S) -2-[(E) -3 (RS) -t
-Butyldimethylsiloxy-1-octenyl] -3,5-
Bis-tetrahydropyranyloxycyclopentyl}-
Methyl 5 (RS) -fluoro-6-oxoheptanoate (0.
52 g) in tetrahydrofuran solution tetra-n-fluoride
Butyl ammonium in tetrahydrofuran (1M, 2.3
ml) was added and the mixture was stirred at room temperature for 40 hours. The crude product obtained by a conventional method was subjected to silica gel column chromatography to give the title compound (0.34 as a mixture of diastereomers).
g) was obtained.

Yield: 67% 3-13) 5 (RS) -fluoro-7-{(1R, 2R, 3R, 5
S) -2- [3 (RS) -Hydroxyoctyl] -3,5-bis-tetrahydropyranyloxycyclopentyl} -6
-Preparation of methyl oxoheptanoate 5 (RS) -fluoro-7-{(1R, 2R, 3R, 5S) -2-
[(E) -3 (RS) -Hydroxy-1-octenyl]-
5% Palladium on carbon (0.06 g) was added to an ethyl acetate solution of methyl 3,5-bis-tetrahydropyranyloxycyclopentyl} -6-oxoheptanoate (0.34 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After conventional treatment, silica gel column chromatography was carried out to give the title compound (0.
30g) was obtained.

Yield: 88% 3-14) 5 (RS) -fluoro-6-oxo-7-
{(1R, 2R, 3R, 5S) -2- [3-oxooctyl] -3,5
-Bis-tetrahydropyranyloxycyclopentyl}
Preparation of methyl heptanoate 5 (RS) -fluoro-7-{(1R, 2R, 3R, 5S) -2-
A solution of methyl [3 (RS) -hydroxyoctyl] -3,5-bis-tetrahydropyranyloxycyclopentyl} -6-oxoheptanoate (0.30 g) in acetone was added at -30 ° C.
Then, Jones reagent (2.6M, 0.6 ml) was added, and the mixture was stirred for 1.5 hours. The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (0.24 g) as a mixture of diastereomers.

Yield: 80% 3-15) 5 (RS) -fluoro-7-[(1R, 2R, 3R)-
3-t-butyldimethylsiloxy-5-oxo-2-
Preparation of methyl (3-oxooctyl) cyclopentyl] -6-oxoheptanoate 5 (RS) -Fluoro-6-oxo-7-{(1R, 2R, 3R, 5
S) -2- [3-Oxooctyl] -3,5-bis-tetrahydropyranyloxycyclopentyl} heptanoate (0.24 g) was dissolved in a 3: 1: 1 mixed solvent of acetic acid, tetrahydrofuran and water, and 45 The mixture was stirred at ° C for 4.5 hours. The crude product obtained by the conventional treatment was subjected to silica gel column chromatography to obtain a diol (0.15 g).

Dimethylformamide solution of diol (0.15g),
Imidazole (0.35 g) and t-butyldimethylsilyl chloride (0.38 g) were added, and the mixture was stirred at room temperature for 5 hours. The crude product obtained by the conventional treatment was subjected to silica gel column chromatography to obtain a monosilyl compound (0.135 g).

The monosilyl compound (0.135 g) was subjected to Collins oxidation (15 minutes) in methylene chloride at room temperature. The crude product obtained by a conventional method was subjected to silica gel column chromatography to obtain the title compound (0.10 g).

Yield: 49% 3-16) 5 (RS) -fluoro-13,14-dihydro-6,1
Preparation of 5-Diketo-PGE ₁ Methyl Ester 5 (RS) -Fluoro-7-[(1R, 2R, 3R) -3-t-butyldimethylsiloxy-5-oxo-2- (3-oxooctyl) cyclopentyl] A hydrogen fluoride-pyridine solution (70:30, 0.04 ml) was added to an acetonitrile solution of methyl-6-oxoheptanoate (0.05 g), and the mixture was stirred at room temperature for 7 hours. The crude product obtained by the conventional method was subjected to silica gel column chromatography to give the title compound (0.38
g) was obtained.

Yield: 98% ¹ HNMR (CDCl ₃ ): δ0.87 (3H, t, J = 6.8Hz), 1.16-2.0
5 (14H, m), 2.23-3.15 (11H, m), 3.66 (3H, s), 3.9
8-4.12 (1H, m), 4.62-4.70 (0.5H, m), 4.85-4.95
(0.5H, m) Synthesis Example 4 5,5-difluoro-13,14-dihydro-6,15-diketo-PG
Synthesis of E ₁ methyl ester (1S, 5R, 6R, 7R) -6-[(E) -3-oxo-1-octenyl] -7- (4-phenylbenzoyloxy)-
Synthesis of 2-oxabicyclo [3.3.0] octane-3-one Corey lactone (10.0 g) in dichloromethane (160 m
l), Moffat oxidation (DMSO79.2g, dicyclohexylcarbodiimide 24.0g, pyridine 2.3ml and trifluoroacetic acid)
1.1 ml) to obtain corey lactone aldehyde.

Separately, the anion of dimethyl (2-oxoheptyl) phosphonate obtained from dimethyl (2-oxoheptyl) phosphonate (6.31 g) and sodium hydride (60%, 0.13 g) in dichloromethane (160 ml) was prepared. The dichloromethane solution (160 ml) of the aldehyde obtained above was added dropwise thereto, and the mixture was stirred at room temperature for 11/2 hours. The crude product obtained by the conventional treatment was purified by a silica gel column to obtain an unsaturated ketone.
Yield: 10.8 (85.3%) (1S, 5R, 6R, 7R) -6- (3-oxooctyl) -7-
Synthesis of (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octane-3-one Unsaturated ketone (10.8g) in ethyl acetate (150ml) 5%-
The mixture was stirred under hydrogen atmosphere using C (1.02 g) for 3 hours. This was treated in a conventional manner to obtain a saturated ketone. Yield: 8.20 g (1S, 5R, 6R, 7R) -6- (3,3-Ethylenedioxyoctyl) -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octane-3- Synthesis of ON To a toluene solution (100 ml) of saturated ketone (8.20 g), ethylene glycol (23.0 g) and p-toluenesulfonic acid (0.41 g) were added, and the mixture was refluxed for 4 hours, and the produced water was azeotropically removed. The crude product obtained by the conventional treatment was subjected to silica gel column chromatography to obtain a ketal. Yield: 8.23g
(91.3%) (1S, 5R, 6R, 7R) -6- (3,3-Ethylenedioxyoctyl) -7-hydroxy-2-oxabicyclo [3.3.0]
Synthesis of octan-3-one To a methanol solution (200 ml) of ketal (8.23 g) was added potassium carbonate (1.15 g), and the mixture was stirred overnight. After adding acetic acid (1 ml), the crude product obtained by a conventional method was purified by silica gel column to obtain alcohol. Yield: 4.70 g (90.0%) methyl 2-[(1R, 2R, 3R, 5S] -2- (3,3-ethylenedioxyoctyl) -5- (t-butyldimethylsilyloxy) -3- (tetra Synthesis of pyranyloxy) cyclopentyl] acetate A solution of alcohol (4.70 g) in dichloromethane (200 ml) was ice-cooled, dihydropyran (2.41 g) and p-toluenesulfonic acid (0.23 g) were added thereto, and the mixture was stirred for 1.5 hours. The crude product obtained by the usual method is purified by silica gel column and THP.
Got the body (5.54 g, 93%) A THP body (5.54 g) was dissolved in methanol (61 ml), a 5% sodium hydroxide solution (37 ml) was added, and the mixture was stirred at 50 ° C for 30 minutes. Obtained after neutralization with 0.5N hydrochloric acid under ice cooling and conventional treatment,
The crude product was treated with diazomethane to give the methyl ester (5.74g). Methyl ester DMF (80 ml) was added with t
-Butyldimethylsilane (2.11g) and imidazole (0.95g) were added and stirred. The crude product obtained after the conventional treatment was purified by a silica gel column to give the title compound. Yield 5.41
(71.2) 2-[(1R, 2R, 3R, 5S) -5- (t-butyldimethylsilyloxy) -2- (3,3-ethylenedioxyoctyl)
Synthesis of -3- (tetrapyranyloxy) cyclopentyl] ethyl alcohol t-butyldimethylsilyloxymethyl ester (5.41
g) was reduced with lithium aluminum hydride in ether (150 ml). The crude product obtained after the conventional treatment was purified by a silica gel column to obtain alcohol. Yield: 4.81 g (93.8%) (1R, 2R, 4S, 5R) -4- (3,3-ethylenedioxyoctyl) -1-dimethylsilyloxy) -2- (tetrapyranyloxy) -5-formyl Synthesis of Methyl Heclopentane Alcohol was swanned in dichloromethane (50 ml) (Oxalyl chloride 1.78 g, DMSO 2.19 g and triethylamine 4.
37 g) to give the aldehyde. Yield 4.60 g (96.0%) 1-[(1R, 2R, 4S, 5R) -5-{(7-t-butyldimethylsilyloxy-3,3-difluoro-2 (R, S) -hydroxy-4- Heptinyl} -4- (t-butyldimethylsilyloxy) -2- (tetrapyranyloxy)] 3,3-
Synthesis of ethylenedioxyoctane Activated zinc dust (2.54g) was added to a solution of aldehyde (1.00g) in THF (25ml) and cooled under ice-cooling to 5- (t-butyldimethylsilyloxy) -1-bromo-1,1. A solution of difluoro-2-pentyl (0.92 g) in THF (5 ml) was added dropwise. Mercuric chloride (0.11 g) was added, and the mixture was stirred under ultrasonic irradiation. After the usual treatment, silica gel column purification was performed to obtain the title compound. Yield 1.
40 g (45.9%) 1-[(1R, 2R, 4S, 5R) -5- {3,3-difluoro-2
Synthesis of (R, S) -7-dihydroxyheptyl} -4-hydroxy-2-tetrapyranyloxy] 3,3-ethylenedioxyoctane A solution of synthetic synthesis (0.96 g) in THF (15 ml) was ice-cooled, Tetrabutylammonium fluoride (1M, 2.57 ml) was added, and the crude product obtained by a conventional method of stirring for 1.2 hours was purified by a silica gel column to obtain triol (0.492 g).

This was catalytically reduced with 5% Pd-C (0.06g) in ethyl acetate (50ml). The crude product obtained by conventional treatment was purified by silica gel column to give the title compound. Yield 0.
487 g (48.6%) 5,5-difluoro-13,14-dihydro-13,13-ethylenedioxy-6-keto-11-tetrapyranyloxy-PGE ₁
Synthesis of methyl ester Triol (0.487g) was subjected to swan oxidation (oxalyl chloride 1.17g, DMSO1.51g, and triethylamine 3.17g) in dichloromethane (18ml) to give diketo-aldehyde (0.321g).
g, 67.3%). The resulting aldehyde (0.212g) was Jones oxidized (Jones reagent 2.67M153.6μ-50N4
The resulting carboxylic acid was converted to a methyl ester with diazomethane. The obtained crude product was purified by a silica gel column to give the title compound. Yield 0.152 g (67.8%) 5,5-difluoro-13,14-dihydro-6,15-diketo-PG
Synthesis of E1 Methyl Ester Ketal (0.152 g) was dissolved in acetic acid / THF / water (2/1/1) mixed solvent (6 ml) and kept at 45-50 ° C. for 2.5 hours. The crude product obtained after conventional treatment was purified by silica gel column to obtain the title compound. Yield 0.101 g (87.0%) 5- (t-butyldimethylsilyloxy) -1-bromo-
Synthesis of 1,1-difluoro-2-pentyne To a solution of 3-butyn-1-ol (10.0 g) in DMF (80 ml) was added imidazole (10.6 g) and t-butyldimethylsilane chloride (21.5 g) at 35 ° C. I kept it for 7 hours. After the usual treatment, it was distilled to give 5- (t-butyldimethylsilyloxy) -3.
-Given pentin. Yield 17.4 g (66%) Obtained 5- (t-butyldimethylsilyloxy) -3-
A solution of pentin (8.00g) in THF (100ml) was adjusted to -20 ° C.
-Butyl lithium (1,6M, 27.1 ml) was added dropwise and the temperature was raised to 0 ° C. A solution of dibromodifluoromethane in THF (5 ml) was added dropwise and stirred for 2 hours. After the usual treatment, the obtained crude product was purified with a silica gel column to obtain 5- (t-butyldimethylsilyloxy) -1-bromo-1,1-difluoro-2-pentyne. Yield: 3.67 g (27%) Formulation Example 1 (powder for injection) (parts by weight) 13,14-dihydro-15-keto-16,16-difluoro-PGE ₂ 1 mannitol 5 sterile water 0.4 The above ingredients were mixed, stirred Then, it was sterilized, filtered, and lyophilized to obtain a powder for injection.

Formulation Example 2 (solution for injection) (parts by weight) 13,14-dihydro-15-keto-16,16-difluoro PGE ₁ methyl ester 0.2 nonionic surfactant 2 sterile water for injection 98 Mix the above components The solution was sterilized to give an injectable solution.

Formulation Example 3 13,14-dihydro-15-keto-16 in methanol (10 ml),
16-difluoro-20-methyl-PGE ₂ (50 mg) was dissolved,
The resulting solution was further mixed with mannitol (18.5g).
The mixture was screened (pore size: 30 mm), dried at 30 ° C. for 90 minutes and then screened again. The resulting powder was mixed with particulate silica gel (Aerosil, 200 g) and the mixture was filled into a # 3 hard gelatin capsule (100). Capsules
0.5 mg of 13,14-dihydro-15-keto-per capsule
An enteric-coated capsule containing 16,16-difluoro-20-methyl-PGE ₂ .

Formulation Example 4 (powder for oral administration) (parts by weight) 13,14-dihydro-6,15-diketo-16,16-difluoro-
PGE ₁ methyl ester 5 lightweight silicic acid anhydride 5 Avicel 20 lactose 70 The above ingredients were mixed to obtain a powder for oral administration.

Formulation Example 5 (gelatin soft capsule) (parts by weight) 13,14-dihydro-6,15-diketo-5,5-difluoro-PG
E ₁ methyl ester 1 Panasate 899 The above ingredients were mixed and filled into a gelatin soft capsule.

In the above formulation examples, the active ingredient may be replaced with any other compound within the range used in this invention.

Test Example 1 Male Slc-ddY mice (5 weeks old, weight 27
~ 30g) 10-12 / group was used.

10 ml of test compound for subcutaneous or intravenous administration
Dissolved in Ringer's solution so that it could be dosed to the body weight per kg.

The mice were divided into layers by body weight, and each group was divided into 12 mice so that the average of each group was the same.

The test compound solution prepared with Ringer's solution was dosed so that it could be dosed to 10 ml / kg body weight.

(A) 30 minutes after the administration, the head was decapitated with guillotine, the heads were arranged in a stainless steel bat, and the duration of gasping (gasping, gasping movement of the mouth) that developed after decapitation was measured with a stopwatch.

(B) Further, 5 minutes after the administration, 4 mg / kg of KCN was intravenously administered, and the survival time was measured using the heartbeat as an index.

The results are shown in the table below.

As a test compound, 13,14-dihydro-15-keto-16R, S-
Subcutaneous administration was performed using fluoro-PGE ₂ methyl ester and 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂ ethyl ester. The result is that each dose is 0.5m
The gasping duration was extended at g / kg and 1 mg / kg.

Also, 13,14-dihydro-15-keto-1 was used as a test compound.
6R, S- fluoro -PGE _2, 13,14-dihydro-15-keto -1
Intravenous administration was performed using 6R, S-fluoro-PGE ₂ methyl ester and 13,14-dihydro-6,15-diketo-19-methyl-PGE ₁ ethyl ester. The results showed that the gasping duration was extended at doses of 1 mg / kg, 3 mg / kg and 10 mg / kg, respectively.

Test compound 1: 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂ 2: 13,14-dihydro-15-keto-16,16-difluoro-PGE _{2 From the} above results, 15-keto -Administration of prostaglandin compounds was found to extend gasping duration and survival.

Test Example 2 Male Crj-Wistar rats (body weight 250 to 350 g) were anesthetized by intraperitoneal administration of urethane (1.2 g / kg). The solution of test compound was administered at a dose of 0.5 ml / kg through a cannula previously inserted into the femoral vein. Tissue blood flow (ml / 100g / min) in the hippocampus of the brain was measured by hydrogen clearance using a tissue blood flow meter 10 minutes before administration, immediately after administration, 10 minutes and 20 minutes later (or even 40 minutes later). Measured.

The results are shown in the table below.

(The value in parentheses is 100 for the value 10 minutes before administration). DMCD (α-dimethylcyclodextrin) was tested as a control because compound 3 is a DMCD adduct. ) Test compound 2: See Test Example 1: 3: 13,14-dihydro-6,15-diketo-19-methyl-PGE ₁ ethyl ester / DMCD adduct (1:10) From the above results, test compound 2 or 3 Administration of
It was found that the hippocampal blood flow was increased. Compound 2
The data at the dose of 1.0 mg / kg indicate that the effect is more pronounced in animals with decreased blood flow (probably due to anesthesia and bleeding during surgery).

Test Example 3 A dog (body weight 8 to 10 kg) was exsanguinated and killed under ketamine anesthesia, the middle cerebral artery was excised, and a ring-shaped sample of about 4 mm was prepared using two L-shaped rods as a nutrient solution. It was hung in the Magnus tube containing. The blood vessel was loaded with 1 g of tension, and the tension change was recorded isometrically on a recorder via a transducer. After allowing the blood vessel to rest for about 90 minutes, it was contracted with serotonin (5-HT) 3 × 10 ⁻⁷ M, and after the contraction reached a peak, the test compound was cumulatively administered. Serotonin 3 × 10 ^-7
The shrinkage by M was defined as 100, and the shrinkage inhibition rate by the test compound was shown in percent.

The results are shown in the table below.

DMCD (α-dimethylcyclodextrin) is compound 3
Is a DMCD adduct and was tested as a control.

From the above results, it was found that the administration of Test Compounds 2 and 3 suppressed (relaxed) the contraction of cerebral blood vessels.

Test Example 4 A test was performed in the same manner as in Test Example 1 (a) except that the test compound was replaced.

The results are shown in the table below.

Test compound 4: 13,14-dihydro-15-keto-16,16-difluoro-PGE ₂ methyl ester Test compound 5: 13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE ₂ test compound 6: 13,14-dihydro-15-keto-16,16-difluoro-20-methyl -PGE ₂ - methyl ester test compound 7: 13,14-dihydro-15-keto-20-ethyl -16,16 - difluoro -PGE ₂ methyl ester test compound 8: 13,14-dihydro-15-keto-20-ethyl-16,16-difluoro -PGE ₂ test compound 9: 13,14-dihydro-6,15-diketo -5R , S-
Fluoro-PGE ₁ methyl ester test compound 10: 13,14-dihydro-15-keto-17R, S-fluoro-PGE ₂ methyl ester test compound 11: 13,14-dihydro-15-keto-16,16-difluoro- PGE ₂ isopropyl ester test compound 12: 13,14-dihydro-15-keto-16,16-difluoro-19-desmethyl-PGE ₂ methyl ester test compound 13: 13,14-dihydro-15-keto-16,16- Difluoro-19-desmethyl-PGE ₂ test compound 14: 13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ methyl ester test compound 15: 13,14-dihydro-6,15-diketo-5, 5-
Difluoro-PGE ₁ methyl ester test compound 16: 13,14-Dihydro-15-keto-11-dehydroxy-11-methyl-16R, S-Fluoro-PGE ₂ methyl ester test compound 17: 15-keto-16R, S -Fluoro-PGE ₂ test compound 18: 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₁ test compound 19: 13,14-dihydro-15-keto-20-ethyl-PGD ₂ isopropyl test compound 20: 13,14-Dihydro-15-keto-16R, S-fluoro-PGF ₂ α-methyl ester test compound 21: 13,14-Dihydro-15-keto-20-ethyl-PGF ₂ α-isopropyl ester test compound 24: 13,14-Dihydro-6,15-diketo-16,16
-Difluoro-PGE ₁ test compound 25: 13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ester test compound 26: 13,14-dihydro-15-keto-16,16-difluoro-PGD ₂ Methyl ester Test compound 27: 13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ Test example 5 (preparation of cerebral ischemic animal) Male ddY mice (5 weeks old) were anesthetized with sodium pentobarbital. The neck was incised along the midline, the common carotid arteries on both sides were exposed, and peeled off so as not to damage the vagus nerve running at the same time. A thread was applied to the common carotid artery, both ends of the thread were passed through a polyethylene tube (inner diameter: 0.5 mm, length: about 5 mm), and a thread knot was tied at the end of the tube so as not to come off. This operation was performed on both blood vessels.

The blood vessel was blocked by pulling the thread lightly into the tube and squeezing it without anesthesia, and fixing it with an arterial clamp so that the tube would not move. The common carotid artery on one side is blocked, and the blood flow on the other side is blocked 30 seconds later by the same operation, and after 10 minutes, the arterial clamp is removed to cut the thread knot and remove the tube to remove blood flow. I restarted it.

(One trial passive avoidance learning experiment) An avoidance learning device consisting of a floor grit made of acrylic resin measuring 25 cm in length and width and 4.5 cm in height and 3.0 cm in height and a wooden platform fixed in one corner was used. Twenty-four hours after surgery, the animals were placed on the platform as a learning acquisition trial, and the grid was energized (0.6 mA, 60 Hz) for 2 seconds immediately after landing on the floor.
The cerebral ischemia operation was performed 0 minutes later, and the time until returning to the cage, that is, the step-down latency was measured up to 300 seconds, which was used as an index for acquisition of passive avoidance learning behavior.

The test group was constructed as follows. Test compound is an acquisition trial
Subcutaneous administration was performed 10 minutes before.

The results are shown in the table below.

Claims (16)

[Claims] 1. A therapeutic agent for improving brain function comprising a 15-keto-prostaglandin compound selected from the group consisting of 15-keto-prostaglandin D, E and F compounds as an active ingredient. 2. A 15-keto-prostaglandin compound,
The agent according to claim 1, which is a 16-mono or dihalo-15-keto-prostaglandin compound. 3. A 15-keto-prostaglandin compound,
13,14-Dihydro-16-mono or dihalo-15-keto-
The agent according to claim 1, which is a prostaglandin compound. 4. A 15-keto-prostaglandin compound,
13,14-dihydro-16-mono or difluoro-15-keto-prostaglandin compounds. The agent according to claim 1. 5. A 15-keto-prostaglandin compound,
The agent according to claim 1, which is a 6,15-diketo-prostaglandin compound. 6. A 15-keto-prostaglandin compound,
The agent according to claim 1, which is a 13,14-dihydro-6,15-diketo-prostaglandin compound. 7. A 15-keto-prostaglandin compound,
The agent according to claim 1, which is a 15-keto-19-alkyl-prostaglandin compound. 8. A 15-keto-prostaglandin compound,
The agent according to claim 1, which is a 13,14-dihydro-15-keto-19-alkyl-prostaglandin compound. 9. A 15-keto-prostaglandin compound,
The agent according to claim 1, which is a 13,14-dihydro-15-keto-19-methyl-prostaglandin compound. 10. The agent according to claim 1, wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-6,15-diketo-5-mono or dihalo-prostaglandin compound. 11. The agent according to claim 1, wherein the 15-keto-prostaglandin compound is a 15-keto-prostaglandin D compound. 12. The agent according to claim 1, wherein the 15-keto-prostaglandin compound is a 15-keto-prostaglandin E compound. 13. The agent according to claim 1, wherein the 15-keto-prostaglandin compound is a 15-keto-prostaglandin F compound. 14. The agent according to claim 12, wherein the 15-keto-prostaglandin E compound is a 13,14-dihydro-15-keto-prostaglandin E compound. 15. The agent according to claim 1, wherein the 15-keto-prostaglandin E compound is a 15-keto-16-mono- or dihalo-prostaglandin E compound. 16. The agent according to claim 12, wherein the 15-keto-prostaglandin E compound is a 13,14-dihydro-15-keto-16-mono- or dihydro-prostaglandin E compound.