JPH04187637A - Hypermnesic agent - Google Patents

Abstract

PURPOSE:To obtain a hypermnesic (memory-improving) agent effective for keeping the memory or preventing the loss of memory by using 15-keto- prostaglandin compound as an active component. CONSTITUTION:The objective hypermnesic (memory-improving) agent effective for the prevention, treatment, amelioration, prevention of aggravation or reduction of aggravation of dysmnesia contains a 15-keto-prostaglandin(PG) compound as an active component. The 15-keto-PG compound is e.g. 13,14-dihydro-16-mono or dihalo-15-keto-PG, 6,15-diketo-PG, 15-keto-19-alkyl-PG and 13,14-dihydro-6,15- diketo-5-mono or dihalo-PG.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application This invention relates to a new use of 15-keto-prostaglandin compounds in improving memory.

[Prior art] Prostaglandins (hereinafter prostaglandins are referred to as PG)
(denoted as ) are a group of organic carboxylic acids found in human and other mammalian tissues or organs that exhibit a wide range of physiological activities. Naturally occurring PGs have a brostanic acid skeleton as a general structural feature.

(α chain) Furthermore, PGs are classified into PGAs, PGEs, PGGs, PGDs, PGHs, PGFs, PGGs, PGHs, and PCls, depending on the structural characteristics of the five-membered ring.
PCls have the following skeleton in which the α chain and 5 are closed between the rings.

On the other hand, some synthetic analogs have modified backbones. Also, depending on the number of double bonds, subscript 1...
1 piece (13th-14th place)-15-OH subscript 2...2 pieces (
13-14th place, 5th-6th place) -15-OH subscript 3...3
pieces (13th-14th, 5th-6th and 17th-18th) -1
It is subclassified as 5-OH.

Furthermore, PGFs are classified into α (the hydroxyl group is in the alpha configuration) and β (the hydroxyl group is in the beta configuration) depending on the configuration of the hydroxyl group at the 9-position.

JP-A-58-164512 discloses 15-cycloalkyl-6-oxo-PGE, 15-7 chloroalkyl-PC
I, and ■2.15-7 chloroalkyl-6.9α-nitrilo-PCl, as well as 15-cycloalkyl-6,
9α-thio-PG1. JP-A No. 58-203911 describes that it has a protective effect against cell damage including cerebrovascular damage.
．． 6-oxo-PGE, and PCI, having a methyl group at one or two positions at position 20, and specific 15-7
JP-A No. 59-73522 describes that clopentyl-PC1 has a protective effect against cell damage.
Some types of PGD, or PGE.

It is described that the derivative can be used as a therapeutic agent for oxygen deficiency diseases of brain nerve cells. In addition, carbacycline (also known as 9(○)-methanoprostacyclin or 9(0)-methanoPG■), which is a synthetic PG derivative in which the oxygen at the 6α position (9th position) of PCl is changed to methylene, is Has aggregation inhibiting effect. It is a compound in which the oxygen at the 6α position (9th position) of PCI is changed to nitrogen and the methylene at the 5th position is changed to sulfur (9-deoxy/-9α, 6-nitrilo-5-thiaP
GF, α) is also known. However, these are all 1
It does not apply to 5-keto-PG or its derivatives.

It is described in European Patent Application No. 0310305 that 15-keto PGs can be used as laxatives.

There are various possible causes of memory loss, one of which is an abnormality in cerebral circulation due to head trauma, and the other is an organic abnormality (for example, dementia).

In these treatments, two factors must be taken into consideration: improvement of cerebral circulation and improvement of basic activity of brain cells, and the development of drugs that have both of these improving effects is desired.

[Structure of the Invention] As a result of research on the biological activity of 15-keto PG compounds, the inventor found that they can be used as memory improving agents because they have memory retention or memory loss prevention effects. He completed this invention.

That is, the present invention provides a memory improving agent containing a 15-keto-prostaglandin compound as an active ingredient.

In this invention, “memory improvement error” refers to
This includes improving or preventing or alleviating a decline in one or more of the following processes (memory, retention, recollection, recognition).

In this invention, the term "agent" includes medicines for the management of any disease, including prevention, treatment, alleviation, prevention of deterioration, or alleviation of deterioration of memory disorders.

"15-keto-prostaglandin compound" refers to the following 1
Abbreviated as 5-keh-pc compound, any prostaglandin derivative having an oxo group instead of a hydroxyl group at the 15th position of the brostanic acid skeleton, regardless of the presence or absence of an open double bond at the 13th and 14th positions. including. In addition, when referring to "prostaglandin I compound" in this invention,
Regardless of the number of double bonds, the presence or absence of other substituents, and the deformation of the chain moiety, the 6- and 9-positions of brostanoic acid are ring-closed via one atom (for example, C1○, S, X, etc.). It is intended to include any substitutions or derivatives of the compound that occur.

When naming the 15-ke+--pc compounds of this invention, the numbers of broscunic acid shown in formulas (A) and <B) are used.

Although formulas (A) and (B) have a basic skeleton of C-20, the present invention is not limited by the number of carbon atoms. That is, the carbon numbers constituting the basic skeleton are 1 for carbonic acid, and numbers 2 to 7 are numbered in order toward the 5-membered ring common to formulas (A) and (B) to the carbons on the α chain (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), 13
~20 are attached to the ω mirror, but when the number of carbon atoms decreases on the α chain, the numbers are deleted sequentially from the 2nd position, and when it increases on the α chain, a carboxyl group (1st position) is added to the 2nd position. ) is named with a substituent instead. Similarly, if the number of carbons decreases over the ω mirror, the carbon numbers are sequentially subtracted from the 20th position,
When increasing on the ω mirror, carbon atoms after the 21st are named as substituents. In addition, regarding the steric configuration, the steric configuration of the above-mentioned basic skeleton shall be followed, unless otherwise specified.

Therefore, 15-keto PG compounds having 10 carbon atoms in the ω chain are named 15-keto-20-ethyl-PGs. In addition, the PGT compound is saturated at positions +3-14, has an oxo group instead of a hydroxyl group at the 15th position, and has a carbon atom (CH) instead of an oxygen atom at the 63rd position (9a position).
13.14-dihyde el-15-keto 6a-carba-
pG+, [or 13, l4-dihydro-15-keto-9(O)-methano-PCI,].

The above formula shows a specific configuration, which is the most typical configuration, and in this specification, unless otherwise specified, compounds are assumed to have the above configuration.

PGD, PGE, PGF, or P(, Group I) generally refers to compounds having a hydroxyl group at the 9-position and/or 11-position of brostanic acid, but the 15-keto-prostaglandin compound of this invention has a hydroxyl group at the 9-position and/or the 11-position of brostanic acid. or compounds having another group at the 11th position.The above compounds are referred to as 9=tehytoroki/-9-substituted or 11-tehitoroki/-11-substituted compounds.

As mentioned above, the naming of 15-keto PG compounds herein is based on the brostanic acid backbone.

If this is named based on IUPAC, for example 13.
14-/HiFO-15-keto 16R,S-fluoro~
PGE, (Z)-7'-RIR, 2R, 3R) -3
-1 Nidooxy 2 E(4R,S) -Fluoro-
3-oxo-octyl]-5-oxo-/lylopentyl)-hept-5-enoic acid, +3.14-dihydro-15
-keto-16,16-difluoro-PGE, is (Z)-
7-[(IR,2R,3R)-2-(4,4-difluoro-3-oxo-octyl)-3-hydroquine-5-oxo-7-lylopentylcohebuto-5-enoic acid; 13.
14-dihydro-15-keto-20-ethyl=11-tehytroquine-11R-methyl-PGE, methyl ester is methyl 7-1(IR,2S,3S)-3-methyl-
2-33-oxode/ru:-5-oxo/lylobentyl)-hept-5-enoate: 13.14-dihydro-6,15-/keto 19-methyl-PGE, ethyl ester is ethyl 7 1 (JR, 2S , 3S)-3-hydroquine-2-(7-methyl-3-oxo-octyl)
-5-oxo-7lylobentyl)-6-oxhebutanoate.

The 15-keto PG compound used in this invention is any P compound having an oxo group instead of a hydroxyl group at the 15th position.
C derivatives, these may be saturated, and 1
Double bonds at positions 3-14 (15-keto PG type 1 compounds), double bonds at positions 1114 and 5-6 (15-keto PG type 2 compounds), or positions 5-6, 13-14 and It may have a double bond at position 17-18 (15-keto PG type 3 compounds). Also included is a 13.14-dihydro form.

Examples of typical compounds that can be used in this invention include 15-keto-PGX (PGX is any PG selected from PGA-PGJ), 13.14-dihydro-15-ke1-PGX, and substitutions thereof. bodies and their derivatives.

Examples of substituents or derivatives include compounds in which the carfoquinol group at the terminal of the α chain of the j5-keto PG compound is esterified, physiologically acceptable salts, carbon bonds at the 2-3 positions,
A compound having a double bond or a carbon bond at the 5-6 position or a triple bond, a compound having a substituent at the 3-position, 5-position, 6-position, 16-position, 17-position, 19-position and/or 20-position carbon, 9
These include compounds having a lower alkyl group or a hydroquine (lower) alkyl group in place of the hydroxyl group at the position and/or the 11th position.

In this invention, the substituents bonded to the carbon atoms at the 3rd, 17th, and/or 19th positions include, for example,
4 alkyl groups, particularly methyl and ethyl groups. Examples of the substituent bonded to the carbon atom at position 16 include lower alkyl groups such as methyl and ethyl groups;
Examples include hydroxyl groups, halogen atoms such as chlorine and fluorine, and aryloquine groups such as trifluoromethylphenylene and the like. Examples of the substituent for the carbon atom at position 17 include halogens such as chlorine and fluorine. Substituents bonded to the carbon atom at position 20 include saturated or unsaturated lower alkyl groups such as C3-4 alkyl, lower alkoxy groups such as Cl-4 alkyl, Cl-4 alkyl/C+-4
Contains lower alfky/alkyl such as alkyl. Substituents for the carbon atom at the 5-position include halogens such as chlorine and fluorine. The substituent for the carbon atom at the 6-position includes an oxo group that forms a carbonyl group. When the carbon atom at the 9th or 11th position has a hydroxy group, lower alkyl or lower (hydroxy)alkyl substituent, the configuration of these groups may be α, β or a mixture thereof.

Furthermore, the above derivatives may have a substituent such as an alkoxy group, a fenoquine group, or a phenyl group at the end of the ω chain of a compound whose ω chain is shorter than that of natural PGs.

Particularly preferred compounds include compounds having a lower alkyl group such as a methyl group or ethyl group at carbon position 16, compounds having a halokene atom such as chlorine or fluorine, and compounds having a halogen atom such as chlorine or fluorine at carbon position 19, such as a methyl group or ethyl group at carbon position 19. Compounds with lower alkyl groups, compounds with halogens such as chlorine and fluorine at the carbon position 5, compounds with an oxo group at the carbon position 6, and compounds with a methyl group, ethyl group, etc. at the carbon position 20. It is a compound that has a lower alkyl group, and may have a substituent such as a haloken atom or a halogenated alkyl group instead of the alkyl chain after the 16th carbon atom. It is a bonded compound.

Preferred compounds for use in this invention are of the formula a group other than hydrogen, and the 5-membered ring may have at least one double bond), Z is hydrogen or haloken, A is -CH, ○H, -cocH, ○H, -C○○ H or a functional derivative thereof, B is -CH, -CH, -1-CH=CH-1-C=C-
1 W is an oxygen atom or a carbon atom, R is a divalent saturated or unsaturated, low to intermediate aliphatic hydrocarbon residue, unsubstituted or substituted with halogen, oxo or aryl, R is unsubstituted or a halogen atom , hydroxy/, oxo, lower alkoxy/, lower alkali/yl/, /chloro(lower) alkyl, aryl or aryloyl, ・substituted, saturated or unsaturated, low to intermediate aliphatic hydrocarbon It has a residue.

In the above formula, the term 7-unsaturated Σ in R1 and R2 is
Bonds between carbon atoms in the main chain or side chains include one or more double and/or triple bonds, isolated, separated or in series. According to the usual nomenclature. , unsaturation between two consecutive positions is indicated by displaying the younger position number, and unsaturation between two non-consecutive positions is indicated by displaying both position numbers. and a double bond or triple bond at position 5.

The term "low to intermediate aliphatic hydrocarbon" means a hydrocarbon having a straight chain or branched chain having 1 to 14 carbon atoms, preferably a side chain having 1 to 3 carbon atoms. , preferably R
In the case of 1, it is a hydrocarbon having 2 to 8 carbon atoms, and in the case of R3, it is a hydrocarbon having 6 to 12 carbon atoms.

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

The term "lower" means one carbon atom unless otherwise specified.
-6 is included.

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

The term "lower alkokene" means lower alkyl-O-phenyl, where lower alkyl is as defined above.

The term "hydroxy (lower) alkyl" means at least one
It means an alkyl as defined above substituted with two hydroxy groups, such as hydroquinemethyl, 1-hydroxyethyl, 2-hydroquinethyl and 1-methyl-■-hydroxo/ethyl.

The term “lower alkanoyloxy/7.” refers to the formula RCO-○-
(Here, RC, 〇- means a group represented by lower alkyl as described above or aryl formed by oxidation, such as acetyl).

The term "[/chloro(lower)alkyl]" means a group formed by ring closure of the above-mentioned lower alkyl group.

The term "aryl" includes optionally substituted aromatic carbocyclic or heterocyclic groups (preferably monocyclic groups),
Examples include phenyl, tolyl, quinolyl and thienyl. Examples of the substituent include haloken, haloken im low a alkyl group (herein, the halokene atom and lower alkyl group have the above meanings).

“The term aryloquine J refers to the formula Ar○− (where Ar
means a group represented by the above-mentioned aryl group).

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, such as salts with inorganic bases, such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (cal/lamb salts, etc.). ammonium salts, salts with organic bases, e.g. ami/salts (e.g. methylamine, trimethylamine salts, /chlorhexylamine salts, hennruamine salts, piperinone salts, ethylene 7amine salts, ethanolamine salts) , noethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt, lysine salt, brocaine salt, caffeine salt, etc.), basic amino acid salts (e.g. alkynine salt, lysine salt) etc.) Tetraalkylammonium salts, etc. are removed. These salts may be prepared, for example, from the corresponding acids and bases by conventional methods or by salt exchange.

Examples of esters include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester,
Lower alkyl esters such as pentyl ester, 1-7 chlorobrobyl ethyl ester, lower alkenyl esters such as vinyl ester and allyl ester, lower alkynyl esters such as ethynyl ester and propynyl ester, aliphatic esters such as lower alkoxy/(lower) alkyl esters such as ) alkyl esters, metquin methyl esters, )-methoxyethyl esters and examples evaphenyl esters, toflu esters, t-butylphenyl esters, salicyl esters; 3. Aryl esters such as optionally substituted aryl esters such as 4-dimethoxy/phenyl ester and henzamidophenyl ester, benzyl ester, trityl ester, benzhydryl ester, etc.
lower) alkyl esters.

Amides include mono- or lower alkyl amides such as methylamide, ethylamide, dimethylamide, arylamides such as anilide and toluiside, alkyl or arylsulfonylamides such as methylsulfonylamide, ethylsulfonylamide, tolylsulfonylamide, etc. I get hurt.

Examples of preferred Z groups are -COCH2-coocH3, -
C○○CH, CH3, -C○○CH (C1+,), ...
CO\H3○, CH.

In the above formula (1), the arrangement of the ring, α and/or ω chain is as follows:
It may be similar or different from the arrangement of natural PCs. However, the invention also encompasses mixtures of compounds with natural and non-natural configurations.

Examples of typical compounds of this invention are: 15-keto PGs, 13. l 4-dihydro-15
- Keto PGs and their 6-oxo derivatives, △2
- derivative, 3R,S-methyl derivative, 5R.

S-fluoro derivative, 5. S-difluoro derivative, 16
R,s-methyl derivative, 16.16-dimethyl derivative,
16R,S-fluoro derivatives, 16.16-difluoro derivatives, 17S-methyl derivatives, 17R,S-fluoro derivatives, 17.17-difluoro derivatives, 20-methyl derivatives, 20-ethyl derivatives, 19-desmethyl derivatives and 16- This is 1 piece of Solanum butyl-16-phenol/derivative.

In the compound used in this invention, when the l3.14 position is saturated, a keto-hemiasecure equilibrium may occur due to the formation of hemiacetal between the hydroxyl at the 11th position and the keto at the 15th position. If such tautomers exist, the abundance ratio of both isomers varies depending on the structure of other parts or the type of substituents, and in some cases, one isomer may be overwhelmingly present. , in this invention, both of these are included, and compounds may be represented by keto-type structural formulas or nomenclature regardless of the presence or absence of such isomers, but this is for convenience and is not limited to hemiacetal. It is not intended to exclude type compounds.

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

Some of the compounds used in this invention are
No. 52753, JP-A No. 1-104040, JP-A No. 1-104040, JP-A No. 1-104040, JP-A No.
151519, JP-A-2-131446, and the like.

Alternatively, these compounds may be made by methods similar to those described herein or by known methods.

The above-mentioned 15-ke1-PG compound has a memory retention effect and is therefore useful as a memory improving agent. Such activity can be measured using standard methods such as ischemia models, head impact models, etc.

The compounds used in this invention can be used as drugs for animals and humans, and are usually administered systemically or locally by oral, intravenous injection (including infusion), subcutaneous injection, or rectal administration. Ru. The dosage depends on the type of subject, such as animal or human, its age, weight, the condition being treated,
Although it varies depending on the desired therapeutic effect, administration method, treatment period, etc., a sufficient effect can usually be achieved at a dosage of 0001 to 500 mg/kg when administered in two to four divided doses per day or in continuous form.

The solid composition for oral administration according to the present invention includes:
Includes tablets, draws, sublingual tablets, capsules, pills, powders, granules, etc. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, dextrose, hydroquinopropylcellulose, microcellulose, starch, Polyvinylpyrrolidone is mixed with magnesium metasilicate and luminate. The composition is prepared in a conventional manner with additives other than inert diluents, such as lubricants such as magnenium stearate, disintegrants such as calcium/umimum cellulose glufate, α-, β- or γ-cyclodextrin, Etherification of dimethyl-α-1/methyl-β-, trimethyl-β- or human loki7-broby-β-cyclodextrin/branched clodextrin, glycone-ru, malton-ru cyclotextrin, etc./clotextrin,
Stabilizers such as formylated 7-clodextrins, sulfur-containing/clodextrins, misoprodol, phospholipids may be included. When the above-mentioned fuculotextrins are used, they may form inclusion compounds with the fuculodextrins to increase stability. Furthermore, stability may be increased by forming into liposomes using phospholipids.

Tablets or pills may be coated with a film of gastric or enteric substances such as white sugar, ceratin, hydroquinopropylcellulose, hydroquinepropylmethylcellulose phthalate, or coated with two or more layers. You can. Additionally, the capsules may be made of a material that can be disintegrated, such as gelatin.

When immediate action is required, sublingual tablets may be used.

Glycerin, lactose, etc. may be used as the base.

Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups, and extracts. - May contain inert diluents used in boat fishing, such as purified water, ethanol, etc.

In addition to inert diluents, the compositions may also contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic agents, and preservatives.

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

Injections for parenteral administration according to the present invention include sterile aqueous or nonaqueous solutions, suspensions, and emulsions.

Aqueous solutions and suspension media include, for example, distilled water for injection, physiological saline, and linogel solution.

Examples of non-aqueous solutions and suspension media include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbates. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of disinfectants, by gas sterilization or by radiation sterilization. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

Another form is a suppository or pessary. These suppositories can be made by mixing the active ingredient with a base that softens at body temperature, such as cocoa butter, and absorption may be improved by using a nonionic surfactant with an appropriate softening temperature.

The invention also provides a method of improving memory comprising administering to the subject to be treated an agent of the invention.

EXAMPLE 2 This invention will be explained in more detail with reference to synthesis examples, formulation examples, and test examples, but these are not intended to limit the invention.

Synthesis example 1 16.16-7 full length low 13.14-7 high-quality = 15
- Keto PGE, , Synthesis method of methyl ester (12) 1-], ) (IS, 5R, 6R, 7R) -6-Hytroloki/methyl-7-thitrahydrobylanyl ox 7-2-
Oxabi/Chlo H33, o2 octan-3-one (2)
Synthesis of commercially available (-)Coley lactone (1) (THP protected form)
(37.9 g) in tetrahydrofuran solution.

A solution of tetrabutylammonium chloride in tetrahydrofuran (1.0M, 300ml) was added, and the mixture was stirred at room temperature for 3 hours.

The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain the title compound (2).

Yield 21.70g (82.8%) 1-2) (IS, 5R, 6R, 7R)-6-f (El-
4,4-difluoro-5-oxo-2-octenyl)-
Synthesis of 7-titrahydrobilanyloki7-2-oxabi/chloroH33oioctan-3-one (4) A solution of oxalyl chloride in methylene chloride (2.0 to 1.455 m was dissolved in methylene chloride, dimethylsulfoquinide (12.9mQ) was added dropwise and stirred for 10 minutes.To this, (IS, 5R, 6R,
7R) -6-hydroxyloki/methyl-7-thitrahydrobyranyloxy/-2-oxabi/riguchi 5330] octa/
A methylene chloride solution of -3-one (2811,65 g) was added dropwise, stirred for 30 minutes, and triethylamine (56 m) was added dropwise.
was added dropwise and further stirred for 1 hour. The reaction solution was treated according to a conventional method to obtain aldehyde compound (3) as a crude product.

Thallium Etkind (326mQ) under Archon atmosphere
Dimethyl 3,3-difluoro-2-oxoheptylphosphonate (11.9 g) was added to the methylene chloride solution of and stirred for 1 hour. After cooling to O'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 potassium iodide water were added to the reaction solution, and the mixture was filtered. The filtrate was treated in a conventional manner, and the resulting crude product was subjected to column chromatography to obtain the title compound (4).

Yield: 1 ton, 787 g (44,3%) 1-2) (Is, 5R, 6R, 7R) -6-(4,4
Synthesis of octan-3-one (5) (IS, 5R, 6R, 7
R)-6-i(E)-4,4-difluoro-5-oxo-2-octenyl)-7-titrahydrobilanyl quin-2-oxabi/chloro[3,3,0]octan-3-one (4M5.57g) in ethyl acetate solution with 5% para/
Add Umu carbon (catalytic amount) and heat at room temperature under hydrogen atmosphere.
Stir for hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure,
The title compound (5) was obtained as a crude product.

Yield 5.48g (97.8%) 1-3) (IS, 5R, 6R, 7R) -6-14,4-
difluoro-5(R3)-hydroquinooctyl)-7-
Chitrahydrobilaniluo beef/-2-oxabi/black I3
3. ol, synthesis of octan-3-one (6) (]S,
5R,6R,7R)-6-(4,4-difluoro-5-
oxooctyl)-7-thitrahythrobyranyloxine-2-oxabinclo: 3.3 or octan-3-one (5) (5, 4, 8 g) was added to a methanol solution at 0 °C.
Add sodium borohydride (0800g) and
The mixture was stirred for a minute. The reaction product was treated in a conventional manner, and the obtained crude product was subjected to column chromatography to obtain the title compound (6).

Yield: 5.46g (99.5%) 1-4) 16.16-difluoro-13,14-dihydro-11-tetrahydrobyranyl oxine-PGF,
Synthesis of α-methylesternodin9) In an alcon atmosphere, (I
S, 5R, 6R, 7R)-6-(4,4-dihydro-
5(RS)-Hydroquinooctyl)-7-tetrahydrobilanyloxy-2-oxyvinco[3,3,O]
A toluene solution of octan-3-one (6) (2,579 g) was cooled to -78°C, a toluene solution of /isobutylaluminum hydride (1,5\1.9.6 mC) was added dropwise, and the mixture was stirred for 30 minutes. Add methanol to the C reaction solution, saturate the reaction solution,
/El salt aqueous solution was added and treated in a conventional manner. Lactol compound (7) was obtained as a crude product.

In an alcohol/alcohol atmosphere, a tetrahydrofuran solution (1.0 M, 52.84 m) of potassium t-butyl, . The solution was cooled to O'C, the tetrahydrofuran solution of the lactol compound (7) prepared above was added, and the mixture was stirred at room temperature for 15 hours.

The reaction solution was treated in a conventional manner to obtain carbonic acid compound (8) as a crude product.

In an alkone atmosphere, 4.0 m of 1,8-noasapincroco540]untese-7-ene (DBU) and 1.7 m of methyl iodide were added to a solution of the carbonic acid (8) in acetonitrile. The mixture was stirred at 60° C. for 3 hours. The crude product obtained by conventional treatment was subjected to column chromatography to obtain the title compound (9).

Yield 2.737g (84.5%) 1-5) 16.16-/fluoro13.14-7
Synthesis of human o-15-keto-11-tetrahydropyranyloxy-PGE, methyl ester (10) Under an argon atmosphere, Collins reagent was prepared from chromic anhydride (16.18 g) and pyridine (26.2 m) by a conventional method. in methylene chloride solution at -20'C, 16,16
-difluoro-13,14-dihydro-11-tetrahydropyranyloxy-PGF, α-methyl ester (9)
A methylene chloride solution of (2,646 g) was added and 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 obtain the title compound (10).

Yield: 1.890 g (64,4%) 16) Synthesis of 16,16-difluoro-13,14-dihydro-15-keto-PGE2 methyl ester (11) 16,16-fluoro13.14-7hydro15
-keto-11-tetrahydropyranyloxy-PGE,
Methyl ester (1○) (2809 g) was dissolved in a 3:1:1 iFta solvent of acetic acid, water, and tetrahydrofurano;
The mixture was stirred at 60°C for 5 hours. When the reaction solution was concentrated under reduced pressure and subjected to column chromatography, the title compound (
11) was obtained.

Yield 1.755g (75,5%) 1-7) 16.16-difluoro-13,ll-dihydro-15-keto PGE, methyl ester (11)
Synthesis of 16,16-difluoro-13,14-onehydro 15
-Keto PGE, methyl ester (11) (1755g
) in ethyl acetate solution of 5% palladium-carbon (catalytic amount)
was added thereto, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered and i1! The liquid was concentrated under reduced pressure and subjected to column chromatography to obtain the title compound (11).

Yield: l 655g (93,8%) 'HNMI statement (CDCI, ) 60.87 (3H,t,
J=7Hz), 1. l 5-2.05 (23) (, m)
, 2.11-230 (3H, m), 250 (I H, d
d, J = 7.5 and 17Hz), 3. IC
1-3,20 (l H, br), 3°71 (3H, s)
, 4.05-4.20 (IH, m).

Mass (D l - E l ) m/z404 (M
), 355 (M-H, 〇-CH30), 297
(M-C5H9F,).

The route is shown in the reaction formula below.

D H O Formulation example 1 (powder for injection) (parts by weight) 13.14-dihydro-15-keto-16,16-difluoroPGE, 1 mannitol 5 sterile water
0.4 The above ingredients were mixed, stirred, sterilized, filtered and lyophilized to obtain a powder for injection.

Formulation example 2 (solution for injection) (parts by weight) 13.14-7 human low 15-keto- 16,16-difluoroPGE.

Methyl ester 02 Nonionic surfactant 2 Sterile water for injection
98 The above ingredients were mixed and then lyophilized to obtain an injectable solution.

Formulation Example 3 13.14-dihydro-15 in methanol (10 ml)
-keto-16,16-difluoro-20-methyl-PG
E = (50 mg) was dissolved and the resulting solution was further mixed with mannitol (18.5 g). The mixture was sieved (pore size: 30 mm), dried at 30'C for 90 minutes and sieved again. The generated powder is made into fine particle paste gel (
Aeroful, 200 g) and the mixture was filled into No. 3 hard gelatin capsules (100). Capsules contain 0.5 mg of 13.14-dihydro-15 per capsule.
-keto-16,16-difluoro-20-methyl-PG
E.

It is an enteric-coated capsule containing.

Formulation example 4 (powder for oral administration) (parts by weight) 13.14-Nytro 6.15-Noketo 16.16-/Fluoro PGE, methyl ester 5 Lightweight silicic anhydride 5 Avicel
20 lactose
70 The above components 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-PGE.

Methyl ester 1 Panasate 89
9 The above ingredients were mixed and filled into soft gelatin capsules.

In the above formulation examples, the active ingredient may be replaced by any other compound within the scope of use in this invention.

Test Example 1 (Preparation of cerebrovascular animals) A ddY strain male mouse (5 weeks old) was fixed in the dorsal position under anesthesia with bentoparbital sodium, and the neck was incised along the midline to expose the common arteries on both sides. At the same time, the vagus nerve was removed so as not to damage it. Thread the thread over the common artery, and connect both ends of the thread to polyethylene tubes (inner diameter 0.5zz,
A knot was made at the end of the tube to prevent the tube from slipping out. This operation was performed for blood vessels on both sides.

Blood flow was blocked without anesthesia by pulling the thread lightly to draw the blood vessel into the tube, constricting it, and fixing the tube by clamping the artery to prevent it from moving. The common artery on the − side is blocked, and after 30 seconds, the blood flow is blocked in the same way for the blood vessels on the other side. After 10 minutes, the arterial clamp is removed, the thread knot is cut, and the tube is removed to allow blood flow. was restarted.

(-Trial Passive Avoidance Learning Experiment) A grid made of acrylic resin, each measuring 25 cm in length and width, was fixed to the floor grid and one corner of it. 5cm, height 3. An avoidance learning device consisting of a 0 cm wooden platform was used. 24 hours after surgery, as a learning acquisition trial, the animals were placed on a platform, and immediately after coming down to the floor, electricity was applied to the grid (0.6 mA, 60 Hz) for 2 seconds, and 10 minutes later, a cerebral ischemia operation was performed. , the time required to return to K7, ie, Step Town Latin/-, was measured up to a maximum of 300 seconds, and was used as a bridge for acquiring passive avoidance learning behavior.

The test group was composed as follows. Test compounds were administered subcutaneously 10 minutes before the acquisition trial.

Group Administration route Number of animals 1 Normal group s, c, 222, Ischemic control group s, c, 213, Test compound 11tt9/9 s, c, 204,
〃10 μ97 to 9 s, c, 195,
〃10011 g/9 s, c, 206 test compound 21 tlf! / to 9 s, c, 217
〃 10 μ97 to 9 s, c, 208
, ” 9 s, c, in 100μfl/
2] The results are shown in the table below.

Group Ste, Butaran Latin/-(++)1
274, o=ts, 82 +・97
．． o:+5. 33 124, 6=23
．． 54 137, 8:27. 05'
! 4 183.2±258 6 130.6±227 7 135.1±249 8 **177.9±248 ++ pku○ 01 vs Group 1 *il p<0.01 vs Group 2 Compound 1:
13.14-dihydro-15-keto-16,16-difluoro-PGE.

Compound 2: 13.14-dihydro-15-keto-16,
16-difluoro-PGE.

Patent applicant: Ueno Pharmaceutical Applied Research Institute Co., Ltd. Representative: Patent attorney: Aohaku Haka (1 person)

Claims (11)

[Claims] (1) A memory improving agent containing a 15-keto-prostaglandin compound as an active ingredient. (2) The 15-keto-prostaglandin compound is 16
2. The agent according to claim 1, which is a -mono- or dihalo-15-keto-prostaglandin compound. (3) The 15-keto-prostaglandin compound is 13
, 14-dihydro-16-mono or dihalo-15-keto-prostaglandin compound. (4) The 15-keto-prostaglandin compound is 13
, 14-dihydro-16-mono or difluoro-15
The agent according to claim 1, which is a -keto-prostaglandin compound. (5) The 15-keto-prostaglandin compound is 6,
The agent according to claim 1, which is a 15-diketo-prostaglandin compound. (6) The 15-keto-prostaglandin compound is 13
, 14-dihydro-6,15-diketo-prostaglandin compound. (7) The 15-keto-prostaglandin compound is
The agent according to claim 1, which is a -keto-19-alkyl-prostaglandin compound. (8) The 15-keto-prostaglandin compound is 13
, 14-dihydro-15-keto-19-alkyl-prostaglandin compound. (9) The 15-keto-prostaglandin compound is 13
, 14-dihydro-15-keto-19-methyl-prostaglandin compound. (10) The 15-keto-prostaglandin compound is
Claim 1 which is a 3,14-dihydro-6,15-diketo-5-mono or dihalo-prostaglandin compound.
Agents listed. (11) The 15-keto-prostaglandin compound is
The agent according to claim 1, which is a 5-keto prostaglandin I compound.