JPH0848665A - Treating agent for disease in hepatic and biliary tract system - Google Patents

Abstract

PURPOSE:To obtain a PG-based treating agent for diseases in the hepatic and biliary tract system, containing 16,16-difluoro-15-keto-PGs as an active ingredient and having no or extremely rare side effects such as diarrhea. CONSTITUTION:This treating agent contains a compound of the formula [A is COOH, etc.; B is CH2-CH2 or CH=CH; X is H or OH; R1 is a bivalent 6C aliphatic hydrocarbon residue; R2 to R5 are each H, methyl, ethyl, etc.; Q is a single bond or a 1-6C aliphatic hydrocarbon; (m) is 0 or 1] as an active ingredient. 13,14-Dihydro-15-keto 16,16-difluoro-19-methyl-PGE is exemplified as the compound of the formula. The PG derivative is capable of manifesting improving actions on hepatopathy comparable to those of a conventional compound having a straight omega-chain. The treating agent is useful for treating fulminant hepatitis, fatty liver, hepatic coma, various acute and chronic hepatitises, hepatolenticular degeneration, hepatic hypertrophy, portal hypertension, obstructive jaundice, hepatic abscess, cirrhosis, hepatoma, cholecystitis, cholelithiasis, biliary colic, fat hypersensitivity, etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a prostaglandin E derivative which has not been specifically disclosed in conventional publications and its use. This invention provides a hepatic / biliary tract disease treatment agent which has no or extremely little side effects such as diarrhea.

[0002]

BACKGROUND OF THE INVENTION Prostaglandins (hereinafter prostaglandins are referred to as PG) are contained in human or other mammalian tissues or organs and exhibit a wide range of physiological activities. Acid 1
It is a group. Naturally occurring PGs generally have a prostanoic acid backbone.

[0003]

[Chemical 3]

On the other hand, some synthetic analogs have modified backbones. Natural PGs have P
GAs, PGBs, PGCs, PGDs, PGEs, P
It is classified into GFs, PGGs, PGHs, PGIs and PGJs, and further, depending on whether or not it has an unsaturated bond at positions 13-14, 5-6 and 17-18 of the chain portion, A, B. .. Named as follows with numbers 1 to 3 attached to the lower right of J. Subscript 1 ... 13,14-Unsaturated-15-OH Subscript 2 ... 5,6- and 13,14-Disaturated-15
-OH subscript 3 ... 5,6-, 13,14- and 17,18
-Classified as triunsaturated-15-OH. Further, PGFs are classified into α (hydroxyl group is α-configuration) and β (hydroxyl group is β-configuration) according to the configuration of the 9-position hydroxyl group.

Natural PGE ₁ , PGE ₂ and PGE ₃ are known to have vasodilatory, hypotensive, hypogastric secretion, intestinal motility, uterine contraction, diuretic, bronchodilator and antiulcer activity. Further, natural PGF _1α , PGF _2α and PGF _3α are known to have blood pressure elevation, vasoconstriction, intestinal motility enhancement, uterine contraction, luteal regression and tracheal constriction activity.

US Pat. No. 4,374,856 describes that 15-methyl-PGE ₂ and 16,16-dimethyl-PGE ₂ have a hepatocyte-protecting action, and JP-A-58-1
No. 64512 is 15-cycloalkyl-6-oxo-
PGE ₁ , 15-cycloalkyl-PGI ₁ and I ₂ ,
15-cycloalkyl-6,9α-nitrilo-PGI ₁ ,
And 15-cycloalkyl-6,9α-thio-PCI ₁
And I ₂ have a protective effect on cells including hepatocytes, and JP-A-58-203911 has a methyl group at one or two of positions 15, 16, 17, 20. 6-oxo -PGE ₁ acids and PGI ₁ class and certain 15-cyclopentyl -PGI ₁ compound is described to have a protective effect on cells, including hepatocytes,
JP-A-62-129218 discloses 4 or 7-thia-P.
It is described that GE ₁ can be a therapeutic agent for liver diseases. However, none of these correspond to 15-keto-PG or its derivative.

The fact that 15-keto-16halo-PGs have an enteropooling action and can be used as laxatives is disclosed in European Patent Application Publication No. 0310305 (JP-A-2-10305).
(Corresponding to No. 109).

European Patent Application Publication No. 0424
No. 156 (corresponding to JP-A-3-204816, hereinafter referred to as Publication A) describes that 15-keto-PGs can be used for the treatment of liver / biliary tract diseases, and the above-mentioned 15-keto. -PGs also conceptually include those in which the 16-position is substituted with fluorine and the ω chain has a specific side chain. However, there is no specific disclosure (examples) of these, nor is it suggested that their pharmacological properties differ from others.

European Patent Application Publication No. 0284180
JP-A No. 64-52753 (hereinafter abbreviated as Publication B) and JP-A-2-32055 (hereinafter abbreviated as Publication C) are (13,14-dihydro) 15-keto-16,
It is described that the 16-difluoro-PGE compound has an antiulcer action, and the compound conceptually includes those having a specific side chain on the ω chain. However, there is no specific disclosure (examples) of these, nor is it suggested that their pharmacological properties differ from others.

[0010]

The present invention has the general formula (I)

[Chemical 4] [Wherein A is —COOH, a pharmaceutically acceptable salt thereof or an ester hydrolyzable by esterase; B is —CH ₂ —CH ₂ — or —CH═CH—; X is a hydrogen atom or a hydroxyl group (provided that When a double bond is present on the five-membered ring, X is a hydrogen atom); R ₁ is a divalent saturated or unsaturated C 6
Aliphatic hydrocarbon residue; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen atoms, methyl groups or ethyl groups, provided that R ₂ , R ₃ , R ₄
And at least one of R ₅ is a methyl group or an ethyl group; Q is a single bond or a linear or branched C 1
~ C6 aliphatic hydrocarbon group, m means 0 or 1]
And a therapeutic agent for hepatic / biliary tract disease containing the above compound as an active ingredient.

The compounds of the above formula (I) are conceptually included in the compounds described in Publication A, the compounds described in Publication B and the compounds described in Publication C, but any publications have hitherto been published. It is a compound that has not been specifically disclosed. In addition, the compound of formula (I) has a better therapeutic effect on hepatic and biliary tract diseases than the compounds specifically disclosed in publications A, B, and C, and has no side effects, or It has the characteristic of being attenuated.

In the present invention, the "liver / biliary tract disease" includes all symptoms associated with or associated with hepatocellular disorders and all symptoms associated with biliary tract disorders, such as fulminant hepatitis and fatty liver. (Especially alcohol fatty liver),
Hepatic coma, various acute and chronic hepatitis (alcoholic hepatitis,
Toxic hepatitis, viral hepatitis A, viral hepatitis B, non-A non-B viral hepatitis, serum hepatitis, chronic active hepatitis, etc.),
Liver lens nuclear degeneration, hepatic hypertrophy, portal hypertension, obstructive jaundice, liver abscess, liver cirrhosis (particularly alcoholic liver cirrhosis, hepatic cirrhosis), parasitic liver disease, liver tumor, liver tuberculosis, cholecystitis, gallstones Illness, cholangitis, biliary colic, hypersensitivity, etc.

In the present invention, the term "treatment" refers to prevention,
Management of any disease, including treatment, alleviation, prevention of exacerbation or alleviation of exacerbation. The nomenclature of PGE derivatives of the present invention uses the number of prostanoic acid shown in formula (A). The above formula (A) has a basic skeleton of C-20, but also in the present invention, since the carbon numbers constituting the basic skeleton have the same number of carbons on the α chain, the carboxylic acid is defined as 1 To the carbon on the α chain in order from 2 to 7 in order of 8 to 12
Up to the carbon of the five-membered ring, 13 or less on the ω chain, when the carbon number increases on the ω chain, it is named as having a substituent at the carbon at the 20th position, and the carbon number of the ω chain The carbon numbers are named as decreasing carbon numbers as they decrease above. Regarding the three-dimensional arrangement, unless otherwise specified,
It should follow the configuration of the basic skeleton.

Although the formulas above show the most typical coordination of a particular configuration, throughout this specification, unless otherwise stated, compounds are assumed to have the configuration described above. As mentioned above, the PGE derivative is named based on the prostanoic acid skeleton in the present specification, but it can also be named based on IUPAC. An example based on this nomenclature will be specifically shown in Synthesis Examples.

The PG derivative used in the present invention may be a saturated compound, and further has a double bond at the 13-14 position (PG type 1 compound) and a double bond at the 13-14 position and the 5-6 position (P.
G type 2 compound). Also included are 13,14-dihydro forms.

In the above formula, the term "unsaturated" in R1 is
As a bond between carbon atoms of a main chain or a side chain, it is meant to include at least one or more double bond and / or triple bond in an isolated, separated or continuous manner. In accordance with normal nomenclature, the unsaturation between two consecutive positions is indicated by displaying the younger position number, and the unsaturation between two non-consecutive positions is indicated by displaying both position numbers. Preferred unsaturations are the double bond at the 2-position and the double or triple bond at the 5-position.

The term "C6 aliphatic hydrocarbon" means a hydrocarbon having a straight chain with a carbon number of 6 (hereinafter used in the same meaning), and may have a branched chain (however, a branched chain). The branched chain preferably has 1 to 3 carbon atoms). As a specific example of R1,
For example:

Embedded image Such.

Suitable "pharmaceutically acceptable salts" include:
Including 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, salts with organic base , For example, amine salt (for example, 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 and by salt exchange.

"Ester which can be hydrolyzed by esterase" is an ester which can be decomposed into a corresponding carboxyl compound and alcohol by the action of esterase of animal ester hydrolase, and is administered to mammals (eg humans). Sometimes it produces the corresponding carboxyl compounds in the body.

Examples of such ester include lower alkyl ester such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, 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) alkyl ester such as hydroxyethyl ester, lower alkoxy (lower such as methoxymethyl ester, 1-methoxyethyl ester, etc. ) Aliphatic esters such as alkyl esters and for example phenyl esters, tosyl esters, t-
Butyl phenyl ester, salicyl ester, 3,4-
Examples include optionally substituted aryl esters such as dimethoxyphenyl ester and benzamidophenyl ester, and aryl (lower) alkyl esters such as benzyl ester, trityl ester and benzhydryl ester.

In the above formula (I), the arrangement of rings, α and / or ω chains may be the same as or different from the arrangement of natural PGs. However, the invention also includes mixtures of compounds having a natural configuration and compounds having a non-natural configuration.

In the compound used in the present invention, 13,
When the 14th position is saturated, the 11th hydroxy and 15
The formation of a hemiacetal between the two ketos may result in a 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. It does not seek to exclude acetal-type compounds.

In the present invention, individual tautomers,
Its mixture or optical isomers, its mixture, racemate,
Isomers such as other stereoisomers can be used for the same purpose.

The above-mentioned PGE derivative has an action of preventing or treating disorders of hepatocytes and biliary tracts, and is therefore useful as a therapeutic agent for hepatic / biliary tract disorders. Such activity is
It can be measured using a standard method such as a galactosamine disorder model.

The compound used in the present invention can be used as a drug for animals and humans, and is usually systemically or locally administered orally, intravenously (including drip), subcutaneously,
It is used by methods such as intrarectal administration. The dose varies depending on the type of subject such as animal or human, age, weight, symptom to be treated, desired therapeutic effect, administration method, treatment period, etc., but usually 2 to 4 divided doses per day or When administered in a continuous form, a sufficient dose is usually obtained at a dose of 1 to 1000 μg / kg (po).

Solid compositions for oral administration according to the present invention include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like. In such solid compositions one or more of the active substances comprises at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, Mixed with magnesium aluminometasilicate. According to a conventional method, the composition may be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate or a disintegrant such as calcium fibrin gluconate, α, β or γ-cyclodextrin, dimethyl- Etherified cyclodextrins such as α-, dodimethyl-β, trimethyl-β- or hydroxypropyl-β-cyclodextrin, branched cyclodextrins such as glycosyl and maltosyl-cyclodextrin, formylated cyclodextrins, sulfur-containing cyclodextrins, misoprotol , May contain stabilizers such as phospholipids. When the above cyclodextrins are used, an inclusion compound may be formed with the cyclodextrins to increase the stability in some cases. In addition, stability may be increased by forming liposomes using phospholipids. Tablets or pills should be white sugar,
It may be coated with a film of a gastric or enteric substance such as gelatin, hydroxypropylcellulose, cedroxypropylmethylcellulose phthalate, etc.
It may be coated with two or more layers. Further, capsules made of a disintegrable substance such as gelatin may be used. When immediate action is required, a sublingual tablet may be used. Glycerin, lactose and the like may be used as a base.

Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs. It may contain a commonly used inert diluent, for example, purified water, ethanol and the like. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

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,
Includes saline and Ringer's solution.

Examples of non-aqueous liquid and suspension media include propylene glycol, polyethylene glycol,
There are vegetable oils such as olive oil, alcohols such as ethanol, and polysorbates. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide, gas sterilization or radiation sterilization. They can also be used to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.

Another form is a suppository or vaginal suppository. These suppositories can be prepared by mixing an active ingredient with a base softening at body temperature such as cacao butter, and the absorbency may be improved by using a nonionic surfactant having an appropriate softening temperature.
The present invention also provides a method for treating liver / biliary tract diseases, which comprises administering the therapeutic agent of the present invention to a subject to be treated.

The present invention will be specifically described below based on Examples (Synthesis Examples and Test Examples). The following abbreviations are used in the following description. THF: tetrahydrofuran, DMSO: dimethyl sulfoxide, DBU: 1,8
-Diazabicyclo [5.4.0] undec-7-ene

[0032]

EXAMPLES Synthesis Example 1 1 : Z-7-[(1R, 2R, 3R) -2- (4,4-difluoro-7-methyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] Heptanoic acid (1
3,14- dihydro-15-keto-16,16-difluoro-19-methyl -PGE ₂₎ Synthesis of (12):

[Chemical 6]

1-1 : (1S, 5R, 6R, 7R) -6-
(Z-4,4-difluoro-7-methyl-3-oxooct-1-enyl) -7- (tetrahydropyranyloxy)
-2-Oxabicyclo [3,3,0] octane-3-one
(4)

[Chemical 7] Corey lactone, (1S, 5R, 6R, 7R) -6- (hydroxymethyl) -7- (tetrahydropyranyloxy)-
2-Oxabicyclo [3,3,0] octane-3-one
A solution of (1) (6.800 g) in dichloromethane (40 ml) was added to oxalyl chloride (2M dichloromethane solution, 30 m).
l) in dichloromethane (100 ml), DMSO (8.
45 ml) and triethylamine (16.9 ml) were used for swern oxidation. Corey aldehyde,
(1S, 5R, 6R, 7R) -6-formyl-7- (tetrahydropyranyloxy) -2-oxabicyclo [3,3,
0] octane-3-one (2) was obtained. Sodium hydride
(60%, 1.273 g) in THF (50 ml) was added to a suspension of dimethyl (3,3-difluoro-6-methyl-2-oxoheptyl) phosphonate (3) (8.664 g) in THF (10 ml).
ml) solution and stirred for 1 hour, then zinc chloride (4.337 g)
Was added and stirred for 1 hour. TH of corey aldehyde (2)
The F (20 ml) solution was added, and the mixture was stirred at room temperature for 15 hours. The crude product obtained by conventional treatment was purified by silica gel column (n
-Hexane / ethyl acetate = 3/1) to give the title compound (4)
I got Yield: 6.144 g (57.8%)

1-2 : (1S, 5R, 6R, 7R) -6-
(4,4-Difluoro-7-methyl-3-oxooctyl) -7- (tetrahydropyranyloxy) -2-oxabicyclo [3,3,0] octan-3-one (5)

Embedded image To a solution of compound (4) (6.144 g) in THF (40 ml),
Dimethylphenylsilane (3.17 ml) and Wilkinson's catalyst (0.142 g) were added and kept at 50 ° C for 2 hours. The crude product obtained by the conventional method is purified by silica gel column.
(n-hexane / ethyl acetate = 2/1 to 3/2) to give the title compound (5). Yield: 3.386 g (54.8%)

1-3 : (1S, 5R, 6R, 7R) -6-
{4,4-Difluoro-3 (RS) -hydroxy-7-methyloctyl} -7- (tetrahydropyranyloxy)-
2-Oxabicyclo [3,3,0] octane-3-one
(6)

[Chemical 9] Sodium borohydride (0.138 g) was added to a solution of the compound (5) (3.386 g) in methanol (50 ml), and the mixture was added at 0 ° C.
And stirred for 10 minutes. The crude product obtained by the conventional method was purified by silica gel column (n-hexane / ethyl acetate = 1/1).
The title compound (6) was obtained. Yield: 3.183 g (93.5%)

1-4 : Z-7-[(1R, 2R, 3R, 5
S) -2- {4,4-Difluoro-3 (RS) -hydroxy-7-methyloctyl} -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] hept-5
-Enoic acid (8)

[Chemical 10] A solution of the compound (6) (2.883 g) in toluene (70 ml) was adjusted to -78 ° C, diisobutylaluminum hydride (1M toluene solution, 17.8 ml) was added thereto, and the mixture was stirred for 1 hour. Lactol, {1S, 3 (RS), 6
R, 7R} -6- {4,4-Difluoro-3 (RS) -hydroxy-7-methyloctyl} -7- (tetrahydropyranyloxy) -2-oxabicyclo [3,3,0] octane-3 -Ools (7) are obtained. (4-carboxybutyl)
A suspension of triphenylphosphonium bromide (12.64 g) in THF (50 ml) and potassium t-butoxide (1M
The corresponding ylide was prepared from a THF solution, 57.0 ml). The temperature was set to -30 ° C, and THF (3) of lactol (7) was added to this.
0 ml) solution was added and stirred for 15 hours. Carboxylic acid, Z-7-[(1R, 2R, 3R, 5S) -2-
{4,4-Difluoro-3 (RS) -hydroxy-7-methyloctyl} -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-enoic acid
(8) was obtained.

1-5 : Z-7-[(1R, 2R, 3R, 5
S) -2- {4,4-difluoro-3 (RS) -hydroxy-
7-Methyloctyl} -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-
Phenacyl enoate (9)

[Chemical 11] Diisopropylethylamine (4.73 ml) and phenacyl bromide (5.67 g) were added to a solution of carboxylic acid (8) in acetonitrile (50 ml), and the mixture was kept at 45 ° C for 2 hours.
The crude product obtained by conventional treatment was purified by silica gel column (n
-Hexane / ethyl acetate = 3/2) to give the title compound (9)
I got Yield: 3.618 g (83.4%, 3 reaction steps)

1-6 : Z-7-[(1R, 2R, 3R)-
Phenacyl 2- (4,4-difluoro-7-methyl-3-oxooctyl) -3- (tetrahydropyranyloxy) -5-oxocyclopentyl] hepto-5-enoate (1
0)

[Chemical 12] Ogizalyl chloride (2M dichloromethane solution, 17.8 ml)
Dichloromethane (50 ml) diluted with DMSO (5.1 m
l) and triethylamine (10 ml)
(9) was swernified. The crude product obtained by the conventional treatment was purified by silica gel column (n-hexane / ethyl acetate = 2.
/ 1) to give the title compound (10). Yield: 3.034 g (84.4%)

1-7 : Z-7-[(1R, 2R, 3R)-
2- (4,4-difluoro-7-methyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl]
Phenacyl hept-5-enoate (11)

[Chemical 13] Compound (10) (3.034 g) was added to acetic acid / THF / water (3/1
/ 1) It melt | dissolved in the mixed solvent and it hold | maintained at 50 degreeC for 3 hours. The crude product obtained by the conventional method was purified by silica gel column (n-hexane / ethyl acetate = 3/1) to obtain the title compound (11). Yield: 1.945g (74.4%)

1-8 : Z-7-[(1R, 2R, 3R)-
2- (4,4-difluoro-7-methyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl]
Hept-5-enoic acid (12)

Embedded image Zinc (0.72) was added to an acetic acid solution of compound (11) (0.362 g).
4 g) was added and stirred for several hours. The crude product obtained by the conventional treatment was purified by silica gel column (dichloromethane / methanol = 25/1) to obtain the title compound (12). Yield: 0.235 g (84%) nmr (CDCl ₃ ) δ: 0.92 (6H, d, J = 6.0)
Hz), 1.33 to 2.74 (19 H, m), 2.36 (2 H,
t, J = 7.0 Hz), 4.19 (1H, m), 5.40 (2H,
m) mass m / z: 402 (M ⁺ ), 384 (M ⁺ -H)
₂ O), 366 (M ⁺ -2H ₂ O),

[Chemical 15]

Synthesis Example 2 2 : 7-[(1R, 2R, 3R) -2- (4,4-difluoro-7-methyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] heptanoic acid ( 13,1
4-dihydro-15-keto-16,16-difluoro-
Synthesis of 19-methyl-PGE ₁ ) (2-16)

Embedded image

2-1 : {1S, 5R, 3 (RS), 6R, 7
R} -6- (t-butyldimethylsiloxymethyl) -7-
(Tetrahydropyranyloxy) -2-oxabicyclo [3,3,0] octane-3-ol (2-2)

[Chemical 17] Commercially available corey lactone, (1S, 5R, 6R, 7R) -6
-(T-Butyldimethylsiloxymethyl) -7- (tetrahydropyranyloxy) -2-oxabicyclo [3,3,
[0] Octane-3-one (2-1) (15.0 g) was reduced in toluene (75 ml) at -78 ° C with diisopropylaluminum hydride (1M solution in toluene, 61 ml). Lactol (2-2) was obtained by the conventional treatment. Crude yield: 15.32 g (104%)

2-2 : Z-7-[(1R, 2R, 3R, 5
S) -2- (t-Butyldimethylsiloxymethyl) -5-
Hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-enoic acid (2-3)

Embedded image A suspension of (4-carboxybutyl) triphenylphosphonium bromide (54.67 g) in THF (110 ml) was added to 0.
C, and potassium t-butoxide (1M THF solution, 24
7 ml) was added to give the corresponding ylide. To this was added a solution of lactol (2-2) in THF (50 ml) at room temperature to 1.
Stir for 5 hours. Carboxylic acid (2-3) was obtained by the conventional treatment. Crude yield: 36.62g

2-3 : Z-7-[(1R, 2R, 3R, 5
S) -2- (t-Butyldimethylsiloxymethyl) -5-
Hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-enoate isopropyl (2-4)

[Chemical 19] Carboxylic acid (2-3) in acetonitrile (150 ml),
Isopropyl iodide (24.0 ml) and DBU at room temperature
(3-4 ml) using isopropyl ester (2-4)
And The crude product obtained by the conventional method is subjected to silica gel column purification (n-hexane / ethyl acetate = 5/1 to 3/1),
The title compound (2-4) was obtained. Yield: 18.32 g (90.7%, 3 reaction steps)

2-4 : Z-7-[(1R, 2R, 3R, 5
S) -5-acetoxy-2- (t-butyldimethylsiloxymethyl) -3- (tetrahydropyranyloxy) cyclopentyl] hept-5-enoate isopropyl (2-5)

Embedded image Compound (2-4) (18.32 g) was added to dichloromethane (90 m
l) at 0 ° C. in pyridine (8.9 ml) and acetyl chloride
(7.8 ml) was added and the mixture was stirred for 30 minutes and at room temperature for 1.5 hours.
The title compound (2-5) was obtained by the conventional treatment. Yield: 20.09g

2-5 : Z-7-[(1R, 2R, 3R, 5
S) -5-acetoxy-2- (hydroxymethyl) -3-
(Tetrahydropyranyloxy) cyclopentyl] hept-5-enoate isopropyl (2-6)

[Chemical 21] A solution of compound (2-5) (20.09 g) in THF (50 ml) was charged with tetrabutylammonium fluoride (1 MTH).
F solution (74.3 ml) was added, the mixture was kept at room temperature overnight, and the crude product obtained by a conventional method was purified by silica gel column (n-hexane / ethyl acetate = 2/3) to give the title compound (2-6 )
I got Yield: 15.50 g (98.9% 2 reaction steps)

2-6 : 7-[(1R, 2R, 3R, 5S)-
5-Acetoxy-2- (hydroxymethyl) -3- (tetrahydropyranyloxy) cyclopentyl] isopropyl heptanoate (2-7)

[Chemical formula 22] Compound (2-6) (15.50 g) with ethyl acetate (20 ml)
Medium 5% palladium-carbon (catalytic amount) and hydrogen gas were used for reduction. Yield: 15.50g

2-7: 7-[(1R, 2R, 3R, 5S)-
5-Acetoxy-2-formyl-3- (tetrahydropyranyloxy) cyclopentyl] isopropyl heptanoate (2-8)

[Chemical formula 23] Compound (2-7) (15.50 g) dichloromethane (100 m
l) solution was added to oxalyl chloride (2M dichloromethane solution,
54.3 ml), DMSO (15.4 ml) and triethylamine (50.0 ml) were used for swern oxidation. Silica gel column purification (n-hexane / ethyl acetate = 7 /
Then, the title compound (2-8) was obtained. Yield: 15.21 g (98.1%)

2-8 : 7-[(1R, 2R, 3R, 5S)-
Isopropyl 5-acetoxy-2- (E-4,4-difluoro-7-methyl-3-oxooct-1-enyl) -3- (tetrahydropyranyloxy) cyclopentyl] heptanoate (2-10)

[Chemical formula 24] Potassium t-butoxide (1M THF solution, 14.9 ml)
And dimethyl (3,3-difluoro-6-methyl-2-oxoheptyl) phosphonate (2-9) (4.078 g) in TH
The F (20.4 ml) solution was added and the mixture was stirred at room temperature for 30 minutes, then zinc chloride (2.027 g) was added and the mixture was stirred at room temperature for 30 minutes.
Aldehyde (2-8) (2.883 g) in THF (14.4 m)
1) The solution was added and the mixture was heated under reflux for 62 hours. The crude product obtained by the conventional method was purified by silica gel column (n-hexane / ethyl acetate = 4/1) to obtain the title compound (2-10). Yield: 3.393 g (87.5%)

2-9 : 7-[(1R, 2R, 3R, 5S)-
Isopropyl 5- (5-acetoxy-2- (4,4-difluoro-7-methyl-3-oxooctyl) -3- (tetrahydropyranyloxy) cyclopentyl] heptanoate (2-
11)

[Chemical 25] Compound (2-10) (2,000 g) in acetic acid (20 ml),
Reduction was performed with 5% palladium-carbon (0.200 g) and hydrogen gas. Yield: 1.995g (99.4%)

2-10: 7-[(1R, 2R, 3R, 5S)
-2- (4,4-Difluoro-7-methyl-3-oxooctyl) -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] heptanoic acid (2-12)

[Chemical formula 26] Compound (2-11) (1.995 g) was added to methanol (20 m
l) 6-N sodium hydroxide solution (5.8 ml) was added to the solution and stirred for 15 hours. Crude product (2-12) after conventional treatment
I got Yield: 1.828g

2-11 : 7-[(1R, 2R, 3R, 5S)
Benzyl 2- (4,4-difluoro-7-methyl-3-oxooctyl) -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] heptanoate (2-1
3)

[Chemical 27] Compound (2-12) (1.828 g) was added to acetonitrile (18
ml) at room temperature, DBU (1.04 ml) and benzyl iodide (0.83 ml) were added, and the mixture was stirred for 2.5 hours. Yield: 1.717 g (84.7% 2 reaction steps)

2-12 : 7-[(1R, 2R, 3R, 5S)
Benzyl (2-14) -2- (4,4-difluoro-7-methyl-3-oxooctyl) -3- (tetrahydropyranyloxy) -5-oxocyclopentyl] heptanoate

[Chemical 28] Compound (2-13) (1.700 g) in dichloromethane
(17 ml) was swanified with oxalyl chloride (0.51 ml) in dichloromethane (5.1 ml), DMSO (0.83 ml) and triethylamine (3.27 ml). The crude product obtained by the conventional treatment was purified by silica gel column (n-hexane / ethyl acetate = 3/1) to obtain the title compound (2-14). Yield: 1.574 g (92.8%)

2-13 : 7-[(1R, 2R, 3R) -2
Benzyl (2-15)-(4,4-difluoro-7-methyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] heptanoate

[Chemical 29] Compound (2-14) (1.565 g) was added to acetic acid / water / THF (4
/ 2/1) In a mixed solvent (70 ml), the mixture was kept at 45 ° C for 3 hours. The crude product obtained by the conventional method is purified by silica gel column.
(n-hexane / ethyl acetate = 4/1) to give the title compound
(2-15) was obtained. Yield: 1.169g (87%)

2-14 : 7-[(1R, 2R, 3R) -2
-(4,4-Difluoro-7-methyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] heptanoic acid (2-16)

Embedded image Compound (2-15) (1.150 g) was added to ethanol (20 m
Debenzylated with 5% palladium-carbon (0.230 g) and hydrogen gas in 1). Silica gel column purification
(n-hexane / ethyl acetate = 100 / 0-40 / 60)
The title compound (2-16) was obtained. Yield: 0.731 g (78%) nmr (CDCl ₃ ) δ: 0.92 (6H, d, J = 6.0)
Hz), 1.20 to 2.13 (22H, m), 2.26 (1
H, dd, J = 17.5Hz, J = 11.5Hz), 2.60
(1H, dd, J = 17.5Hz, J = 7.0Hz) 4.1
9 (1H, m) mass m / z: 404 (M +), 386 (M + -H 2
O), 368 (M ⁺ -2H ₂ O),

[Chemical 31]

Synthesis Example 3 3 : 7-[(1R, 2R, 3R) -2- {4,4-difluoro-5 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] Heptanoic acid (1
3,14-Dihydro-15-keto-16,16-difluoro-17 (R) -methyl-PGE ₁ ) (3-10)

[Chemical 32]

3-1 : 7-[(1R, 2R, 3R, 5S)-
5-acetoxy-2- {E-4,4-difluoro-5
(R) -Methyl-3-oxooct-1-enyl} -3-
(Tetrahydropyranyloxy) cyclopentyl] methyl heptanoate (3-3)

[Chemical 33] Two types of amides obtained from (d.l) -2,2-difluoro-3-methylhexanoic acid and (R)-(+)-phenylethylamine were collected by normal-layer column chromatography to determine the retention time. Dimethyl (3,3-difluoro-4 (R) -methylheptyl) phosphonate (3-
2) To a solution of (0.796 g) in THF (5 ml) was added potassium t-butoxy (1M THF solution, 2.63 ml) and the mixture was stirred at room temperature for 30 minutes, and then zinc chloride (0.340 g) was added and stirred for 1 hour. The aldehyde, 7-[(1R, 2R, 3R, 5S) -5-acetoxy-2-formyl-3-, obtained in the same manner as in Example 2 except that methyl iodide was used instead of isopropyl iodide. (Tetrahydropyranyloxy)
Cyclopentyl] methyl heptanoate (3-1) (0.825
A solution of g) in THF (5 ml) was added and the mixture was heated under reflux for 3 days.
The crude product obtained by conventional treatment was purified by silica gel column (n
-Hexane / acetic acid = 3/1) to give the title compound (3-3). Yield: 0.664g (59%)

3-2 : 7-[(1R, 2R, 3R, 5S)
-5-acetoxy-2- {4,4-difluoro-5 (R)
Methyl-3-methyl-3-oxooctyl} -3- (tetrahydropyranyloxy) cyclopentyl] heptanoate (3
-4)

Embedded image Compound (3-3) (0.632 g) was added to ethyl acetate (10 ml)
Reduction with 5% palladium on carbon (0.065 g) and hydrogen gas in the middle gave the title compound (3-4). Yield: 0.631 g (100%)

3-3 : 7-[(1R, 2R, 3R, 5S)-
5-acetoxy-2- {4,4-difluoro-3 (RS)
Methyl-hydroxy-5 (R) -methyloctyl} -3- (tetrahydropyranyloxy) cyclopentyl] heptanoate (3-5)

Embedded image Compound (3-4) (0.630 g) in methanol (10 ml)
Sodium borohydride (0.044g) at -40 ° C in the medium
I reduced it with. The crude product obtained by the conventional treatment was purified by silica gel column (n-hexane / ethyl acetate = 2/1) to obtain the title compound (3-5). Yield: 0.619g (98%)

3-4 : 7-[(1R, 2R, 3R, 5S)
-2- {4,4-difluoro-3 (RS) -hydroxy-
5 (R) -methyloctyl} -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] heptanoic acid (3-6)

Embedded image Compound (3-5) (0.619 g) in ethanol (11 ml)
1-N sodium hydroxide solution (11.3 ml) was added to the solution, and the mixture was stirred at room temperature. Yield: 0.583g

3-5 : 7-[(1R, 2R, 3R, 5S)-
2- {4,4-difluoro-3 (RS) -hydroxy-5
(R) -Methyloctyl} -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] benzyl heptanoate (3-7)

Embedded image Compound (3-6) (0.583 g) was added to acetonitrile (10 m
The title compound (3-7) was obtained using diisopropylethylamine (0.79 ml) and benzyl bromide (0.54 ml) in 1). Silica gel column purification (n-hexane / ethyl acetate = 3/2) was performed. Yield: 0.633 g (96% 2 reaction steps)

3-6 : 7-[(1R, 2R, 3R) -2-
Benzyl (3-8) {4,4-difluoro-5 (R) -methyl-3-oxooctyl} -3- (tetrahydropyranyloxy) -5-oxocyclopentyl] heptanoate

[Chemical 38] Compound (3-7) (0.633 g) in dichloromethane (7 m
1) The solution was swernified with oxalyl chloride (0.47 ml) in dichloromethane (10 ml), DMSO (0.77 ml) and triethylamine (1.89 ml). The crude product obtained by conventional treatment was purified by silica gel column (n-hexane / ethyl acetate = 4/1) to give the title compound.
(3-8) was obtained. Yield: 0.593 g (94%)

3-7 : 7-[(1R, 2R, 3R) -2-
Benzyl (3-9) {4,4-difluoro-5 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] heptanoate

[Chemical Formula 39] Acetic acid (20 ml) and water (10 ml) were added to a solution of the compound (3-8) (0.590 g) in THF (5 ml), and the mixture was added at 45 ° C.
I kept it for 3.5 hours. The crude product obtained by the conventional treatment was purified by silica gel column (n-hexane / ethyl acetate = 7/3).
The title compound (3-9) was obtained. Yield: 0.407g (81%)

3-8 : 7-[(1R, 2R, 3R) -2-
{4,4-Difluoro-5 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] heptanoic acid (3-10)

[Chemical 40] Compound (3-8) (0.407 g) in ethanol (15 ml)
Medium 10% palladium-carbon (0.080 g) and hydrogen gas were used for reduction. Silica gel column purification (n-
Hexane / ethyl acetate = 100/0 to 30/70),
The title compound (3-10) was obtained. Yield: 0.153 g (46%) nmr (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.
0Hz), 1.00 (0.6H, d, J = 7.0Hz), 1.
10 (0.4H, d, J = 7.0Hz), 1.13-1.30
(21H, m), 2.34 (2H, t, J = 7.5Hz), 2.5
8 (1H, dd, J = 17.5Hz, J = 7.5Hz), 2.6
2 (1H, dd, J = 17.5Hz, J = 7.5Hz), 2.9
0 (1H, t, J = 7.5Hz), 4.02 to 4.28 (1H,
m) mass m / z: 404 (M ⁺ ), 386 (M ⁺ -H)
₂ O), 368 (M ⁺ -2H ₂ O),

Embedded image

Synthesis Example 4 4 : 7-[(1R, 2R, 3R) -2-{(4,4-difluoro-5 (S) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl ] Heptanoic acid
Synthesis of (13,14-dihydro-15-keto-16,16-difluoro-17 (S) -methyl-PGE ₁ ) (4-1)

Embedded image

Two kinds of amides obtained from (d, l) -2,2-difluoro-3-methylhexanoic acid and (R)-(+)-phenylethylamine were separated by normal layer column chromatography. , Dimethyl (3,3-difluoro-4 (S) -methylheptyl) phosphonate (4-2) obtained using the one with a long retention time

[Chemical 43] The title compound (4-
1) was obtained. nmr (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.
0 Hz), 0.98 (0.6 Hz, d, J = 7.0 Hz), 1.
09 (0.4H, d, J = 7.0Hz), 1.14 to 2.30
(21H, m), 2.34 (2H, t, J = 7.5Hz), 2.6
7 (1H, dd, J = 17.5Hz, J = 7.5Hz), 2.7
0 (1H, dd.J = 17.5Hz, J = 7.5Hz), 2.9
0 (1H, t, J = 7.5Hz), 4.04 to 4.26 (1H,
m) mass m / z: 404 (M ⁺ ), 386 (M ⁺ -H)
₂ O), 368 (M ⁺ -2H ₂ O)

[Chemical 44]

Synthesis Example 5 5 : 7-[(1R, 2R, 3R) -2- {4,4-difluoro-5 (R), 7-dimethyl-3-oxooctyl}-
3-Hydroxy-5-oxocyclopentyl] heptanoic acid (13,14-dihydro-15-keto-16,16-
Difluoro-17 (R), 19-dimethyl-PGE ₁ ) (5-
Synthesis of 1)

Embedded image

Two types of amides obtained from (dl) -2,2-difluoro-3.5-dimethylhexanoic acid and (R)-(+)-phenylethylamine were separated by normal layer column chromatography. Dimethyl (3,3-difluoro-4 (R), 6-dimethyl-
2-oxoheptyl) phosphonate (5-2)

Embedded image The title compound (5-
1) was obtained. nmr (CDCl ₃ ) δ: 0.86 (4H, d, J = 7.
0Hz), 0.94 (2H, d, J = 7.0Hz), 0.98
(0.7H, d, J = 7.0Hz), 1.08 (0.3H, d, J
= 7.0 Hz), 1.13-2.43 (20H, m), 2.34
(2H, t, J = 6.5Hz), 2.58 (1H, dd, J = 1
7.5 Hz, J = 7.5 Hz), 2.71 (1H, dd, J = 1)
7.5 Hz, J = 7.5 Hz), 3.91 (1 H, t, J = 7.
5 Hz), 4.03 to 4.30 (1 H, m) mass m / z: 418 (M ⁺ ), 400 (M ⁺ -H)
₂ O), 382 (M ⁺ -2H ₂ O),

[Chemical 47]

Synthesis Example 6 6 : 7-[(1R, 2R) -2- (4,4-difluoro-
7-Methyl-3-oxooctyl) -5-oxocyclopentyl] heptanoic acid (13,14-dihydro-15-
Keto-11-dehydroxy-16,16-difluoro-
19-methyl-PGE ₁ ) (6-3)

Embedded image

6-1 : 7-[(1R, 2R) -2-
{(4,4-Difluoro-7-methyl-3-oxooctyl} -5-oxocyclopent-3-enyl] heptanoic acid (6-2)

[Chemical 49] 7-[(1R, 2R, 3R) -obtained in the same manner as in Synthesis Example 2
3-Hydroxy-2- (4,4-difluoro-7-methyl-3-oxooctyl) -5-oxocyclopentyl]
Heptanoic acid (6-1) (0.533g) was dissolved in acetic acid (10ml) and kept at 70 ° C overnight. The crude product obtained by the conventional method was purified by silica gel column (dichloromethane / methanol = 20/1) to give the title compound (6-2). Yield: 0.36969 g (77.9%)

6-2 : 7-[(1R, 2R) -2- (4,
4-difluoro-7-methyl-3-oxooctyl]-
5-oxocyclopentyl] heptanoic acid (6-3)

Embedded image Compound (6-2) (0.533 g) was dissolved in methanol,
Reduction was performed with 10% palladium on carbon (0.0281 g) and hydrogen gas. Purify by silica gel column (dichloromethane / methanol = 20/1) to give the title compound (6-3).
I got Yield: 0.4576 g (81.0%) nmr (CDCl ₃ ) δ: 0.92 (6H, d, J = 6.
0 Hz), 1.17 to 2.23 (22H, m), 2.34 (3
H, t, J = 7.5 Hz), 2.77 (2H, m) mass m / z: 388 (M ⁺ )

Synthesis Example 7 7 : 7-[(1R, 2R) -2- {4,4-difluoro-5 (R), 7-dimethyl-3-oxooctyl} -5-
Oxocyclopentyl] heptanoic acid (7-7) (13,14
-Dihydro-15-keto-11-dehydroxy-16,
16-difluoro-17 (R), 19-dimethyl-PGE
₁ ) Synthesis:

[Chemical 51]

7-1 : (1S, 5R, 6R, 7R) -6-
(t-Butyldimethylsiloxymethyl) -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3,3,0]
Octane-3-on (7-2)

Embedded image Commercially available corey lactone, (1S, 5R, 6R, 7R)-
6- (hydroxymethyl) -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3,3,0] octane-3
-On (7-1), (5,000 g) in DMF (7 ml),
Compound (7-2) was prepared using imidazole (2.9 g) and t-butyldimethylsilane chloride (4.28 g).

7-2 : (1S, 5R, 6R, 7R) -6-
(t-Butyldimethylsiloxymethyl) -7-hydroxy-2-oxabicyclo [3,3,0] octane-3-one
(7-3)

Embedded image The compound (7-2) was converted to the compound (7-3) by using potassium carbonate (3.920 g) in methanol (40 ml). Silica gel column purification (ethyl acetate / n-hexane = 1/2)
did. Yield: 3.196g (78.6%)

7-3 : (1S, 5R, 6R, 7R) -6-
(t-Butyldimethylsiloxymethyl) -7- (1-imidazolethiocarbonyloxy) -2-oxabicyclo
[3,3,0] octane-3-one (7-4)

[Chemical 54] Compound (7-3) (2,500 g) was added to dichloroethane (20 m
In 1), thiocarbonyldiimidazole (2.273 g) was used to give compound (7-4). Silica gel column purification
(Ethyl acetate / n-hexane = 1/1). Yield: 3.451 g (99.7%)

7-4 : (1S, 5R, 6R) -6- (t-
Butyldimethylsiloxymethyl) -2-oxabicyclo
[3,3,0] octane-3-one (7-5)

[Chemical 55] Tributyltin hydride (5.06 g) in toluene (130
ml) solution with heating under reflux, compound (7-4) (3,450 g)
Was added to give compound (7-5).

7-5 : (1S, 5R, 6R) -6- (Hydroxymethyl) -2-oxabicyclo [3,3,0] octane-3-one (7-6)

[Chemical 56] Compound (7-5) was added to concentrated hydrochloric acid (3.50%) in THF (70 ml).
The compound (7-6) was prepared by using (ml). It was purified by silica gel column (ethyl acetate). Yield: 1.206g (88.8g)

7-6 (1S, 5R, 6R) -6-Formyl-2-oxabicyclo [3,3,0] octane-3-one
(7-7)

[Chemical 57] Compound (7-6) (1.200 g) was added to oxalyl chloride (2.9).
3 g) in dichloromethane (40 ml), DMSO (3.6
0 g) and triethylamine (6.22 g) were used for swern acidification to obtain the title compound (7-7). Yield: 0.9109g (76.9%)

7-7 (1S, 5R, 6R) -6- {E-4,
4-Difluoro-5 (R), 7-dimethyl-3-oxooct-1-enyl} -2-oxabicyclo [3.3.0] octane-3-one (7-8)

Embedded image 2 obtained from (dl) -2,2-difluoro-3,5-dimethylhexanoic acid and (R)-(+)-phenylethylamine
Dimethyl amide (3,3
-Difluoro-4 (R), 6-dimethyl-2-oxoheptyl) phosphonate (7-9) (phosphonate in Example 5
(Identical to (5-2)) (0.882g)

Embedded image In THF (2.4 ml) and sodium hydride (63.
It was treated with a suspension of 8%, 0.1103 g) in THF (1.5 ml), to which was added compound (7-7) (0.5202 g) in THF.
(4 ml) was added. The title compound (7-8) was obtained by the conventional treatment. Yield: 0.6651g (72.1%)

7-8 (1S, 5R, 6R) -6- {4,4-
Difluoro-5 (R), 7-dimethyl-3-oxooctyl} -2-oxabicyclo [3.3.0] octane-3-one (7-10)

Embedded image Compound (7-8) (0.6645 g) in ethanol at 5%
Hydrogenated with Pd-carbon. It was used in the next reaction without purification. 7-9 (1S, 5R, 6R) -6- {4,4-difluoro-
5 (R), 7-dimethyl-3 (RS) -hydroxyoctyl}
-2-Oxabicyclo [3.3.0] octane-3-one
(7-11)

[Chemical formula 61] Compound (7-10) in methanol (14 ml) at -40 ° C
Reduction with sodium borohydride (0.040 g) at. The crude product obtained by conventional treatment was purified by silica gel column (n-hexane / ethyl acetate = 3/2) to give the title compound.
(7-11) was obtained. Yield: 0.6499 g (96.6% 2 reaction steps)

7-10 {(1S, 3 (RS), 5R, 6R} −
6- {4,4-difluoro-5 (R), 7-dimethyl-3 (R
S) -Hydroxyoctyl} -2-oxabicyclo [3.
3.0] Octane-3-ol (7-12)

Embedded image Compound (7-11) (0.6495 g) in toluene (3 ml)
Diisobutylaluminum hydride (1.
It was reduced with a 5M toluene solution (2.86 ml). The title compound (7-12) was obtained by the conventional treatment.

7-11 Z-7-[(1R, 2R, 5S)-
2- {4,4-difluoro-3 (RS) -hydroxy-5
(R), 7-Dimethyloctyl} -5-hydroxycyclopentyl] hept-5-enoic acid (7-13)

[Chemical formula 63] The compound (7-12) was added to the ylide formed from a suspension of (4-carboxybutyl) triphenylphosphonium bromide (3.16 g) in THF (9 ml) and potassium t-butoxide (1M THF solution, 14.3 ml). A THF (9 ml) solution was added to obtain the title compound (7-13). 7-12 Z-7-[(1R, 2R, 5S) -2- {4,4-
Benzyl difluoro-3 (RS) -hydroxy-5 (R), 7-dimethyloctyl} -5-hydroxycyclopentyl] hept-5-enoate (7-14)

[Chemical 64] Compound (7-13) in acetonitrile (19 ml) was treated with benzyl bromide (1.57 g) and diisopropylamine (1.19).
The title compound (7-14) was obtained using g). The crude product obtained by the conventional method was purified by silica gel column. Yield: 0.9257g (91.7%)

7-13 Z-7-[(1R, 2R) -2-
{4,4-Difluoro-5 (R), 7-dimethyl-3-oxooctyl} -5-oxocyclopentyl] hept-5
Benzyl enoate (7-15)

Embedded image Compound (7-14) (0.9255g) in dichloromethane
It was swernified with a solution of oxalyl chloride (1.19 g) in dichloromethane (20 ml), (35 ml), DMSO (1.46 g) and triethylamine (2.37 g). The crude product obtained by the conventional treatment was purified by silica gel column (n-hexane / ethyl acetate = 8/1). Yield: 0.8701g (94.8%)

7-14 7 [(1R, 2R) -2- {4,4-
Difluoro-5 (R), 7-dimethyl-3-oxooctyl {-5-oxocyclopentyl] heptanoic acid (7-16)

[Chemical formula 66] Compound (7-15) (0.8695 g) in ethanol (9 ml)
Reduction with medium 10% Pd carbon and hydrogen gas gave the title compound (7-16). Yield: 0.5569 g (77.8%) nmr (CDCl ₃ ) δ: 0.86 (3H, d, J = 6.6).
Hz), 0.93 (3H, d, J = 6.6Hz), 0.98 (3
H, d, J = 7.1 Hz), 11.1-2.50 (22H,
m), 2.34 (2H, t, J = 7.6Hz), 2.74 (2H,
t, m), 7 to 9 (1H, br) mass m / z: 402 (M ⁺ ),

Embedded image

Synthesis Example 8 8 : 7-[(1R, 2R, 3R) -2- {4,4-difluoro-6 (S) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] Heptanoic acid (7-
8) (13,14-dihydro-15-keto-16,16-
Synthesis of difluoro-18 (S) -methyl PGE ₁ ):

[Chemical 68]

8-1 : Ethyl 4 (S) -methylhexanoate (8-2)

[Chemical 69] Commercially available 2 (S) -methyl-1-bromobutane (8-1) (1
A solution of 0.0 g) in ether (10 ml) and ether (20 ml)
2 (S) -methyl-1-butylmagnesium bromide was prepared from magnesium (1.61 g) in (ml). This was reacted with diethyl oxalate (7.74 g) to give the compound
(8-2) was obtained. Yield: 4.82g (53%)

8-2 : 2,2-difluoro-4 (S)
-Ethyl methylhexanoate (8-3)

Embedded image Compound (8-2) (4.82 g) was converted to compound (8-3) using dimethylaminosulfur trifluoride (4.1 ml).
And Yield: 4.13g (76%) bp 66-70 ° C / 10m
mHg

8-3 : Dimethyl {3,3-difluoro-5 (S) -methyl-2-oxoheptyl} phosphonate
(8-4)

Embedded image Dimethyl methylphosphonate (5.23 g) in THF (60
Compound (8-3) (4.09 g) was reacted with a phosphonate anion prepared at -78 ° C from a solution of n) -butyllithium (25.8 ml of 1.6 M hexane solution).
Silica gel column purification (ethyl acetate / hexane = 7/3)
did. Yield: 4.66 g (81%)

8-4 : 7-[(1R, 2R, 3R) -2-
{4,4-Difluoro-6 (S) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] heptanoic acid (8-6)

Embedded image An aldehyde, Z-7-[(1R, 2R, 3R, obtained in the same manner as in Example 3 except that the double bond was not hydrogenated.
5S) -5-acetoxy-2-formyl-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-
Compound similar to Example 3 using methyl enoate (8-5) and dimethyl [3,3-difluoro-5 (S) -methyl-2-oxoheptyl] phosphonate (8-4).
(8-6) was obtained. nmr (CDCl ₃ ) δ: 0.89 (3H, t, J = 7.
6Hz), 1.01 (3H, d, J = 5.6Hz), 1.12-
2.14 (21H, m), 2.26 (1H, dd, J = 17.7
Hz, J = 10.1 Hz), 2.35 (2H, t, J = 7.6H
z), 2.58 (1H, dd, J = 17.7Hz, J = 7.6H
z), 4.18 (1H, m) mass m / z; 404 (M ⁺ ), 386 (M ⁺ -H)
₂ O),

Embedded image

Synthesis Example 9 9 : 7-[(1R, 2R) -2- {4,4-difluoro-
6 (S) -Methyl-3-oxooctyl} -5-oxocyclopentyl] heptanoic acid (9-3) (13,14-dihydro-15-keto-11-dehydroxy-16,16-difluoro-18 (S ) -Methyl-PGE ₁ ) synthesis:

[Chemical 74]

9-1 : 7-[(1R, 2R) -2- {4,
Benzyl 4-difluoro-6 (S) -methyl-3-oxooctyl} -5-oxocyclopent-3-enyl] heptanoate (9-2)

[Chemical 75] The synthetic intermediate obtained in Example 8, 7-[(1R, 2R, 3
R) -2- {4,4-Difluoro-6 (S) -methyl-3-
Oxooctyl} -3-hydroxy-5-oxocyclopentyl] benzyl heptanoate (9-1) (0.466 g)
The acetic acid (15 ml) solution of was maintained at 70-80 ° C. for 20 hours to obtain the compound (9-2). Silica gel column purification (ethyl acetate / hexane = 1/4) was performed. Yield: 0.399g (79%)

9-2 : 7-[(1R, 2R) -2-
{4,4-Difluoro-6 (S) -methyl-3-oxooctyl} -5-oxocyclopentyl] heptanoic acid (9
-3)

[Chemical 76] Compound (3) (0.399 g) was added to ethanol (20 ml)
In, reduction was carried out using a catalytic amount of 5% palladium / carbon and hydrogen gas. Purify with a silica gel column to give the title compound (9
-3) was obtained. Yield: 0.260 g (80%) nmr (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.
6Hz), 0.98 (3H, d, J = 6.6Hz), 1.13-
2.50 (23H, m), 2.35 (2H, t, J = 7.6H
z), 2.73 (2H, m) mass m / z; 388 (M ⁺ ),

Embedded image

Synthesis Example 10 10 : 7-[(1R, 2R) -2- {4,4-difluoro-5 (R) -methyl-3-oxooctyl} -5-oxocyclopentyl] heptanoic acid (10-3 ) (13,14-Dihydro-15-keto-11-dehydroxy-16,16
- difluoro -17 (R) - Synthesis of methyl -PGE _1):

Embedded image

10-1 : 7-[(1R, 2R) -2-
{4,4-Difluoro-5 (R) -methyl-3-oxooctyl} -5-oxocyclopentyl] heptanoic acid (1
0-3)

Embedded image Compound obtained in the same manner as in Example 3 = Compound in Example 3
Same as (3-9) = 7-[(1R, 2R, 3R) -2-
Benzyl (10-1) {4,4-difluoro-5 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] heptanoate was prepared in the same manner as in Example 9 to give a colorless oily compound ( 10-3). nmr (CDCl ₃ ) δ: 0.92 (3H, t, J = 6.
6Hz), 1.00 (3H, d, J = 6.6Hz), 1.08-
2.50 (23H, m), 2.34 (2H, t, J = 7.6H
z), 2.74 (2H, m) mass m / z; 388 (M ⁺ ).

Synthesis Example 11 11-1 : 7-[(1R, 2R, 3R) -2- {4,4-
Difluoro-5 (S), 7-dimethyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] heptanoic acid (11-1) (13,14-dihydro-15-keto-16,16-difluoro- Synthesis of 17 (S), 19-Dimethyl-PGE ₁ ):

Embedded image

(D.l) -2,2-difluoro-3,5-
Two kinds of amides obtained from dimethylhexanoic acid and (R)-(+)-phenylethylamine were fractionated by normal-layer column chromatography, and dimethyl (3.3-) obtained using the one having a long retention time. Difluoro-4 (S), 6-dimethyl-2-oxoheptyl) phosphonate (11-2)

[Chemical 81] In the same manner as in Example 5 except that the title compound (11
-1) was obtained. nmr (CDCl ₃ ) δ: 0.86 (3H, d, J = 6.
6Hz), 0.94 (3H, d, J = 6.6Hz), 0.98
(2H, d, J = 7.1Hz), 1.08 (1H, d, J = 7.1)
Hz), 1.16 to 2.48 (21H, m), 2.35 (2H,
t, J = 7.6 Hz), 2.50 to 2.80 (1 H, m), 2.
92 (1H, br), 4.05 to 4.30 (1H, m), 5.5
~ 7.5 (1H, br) mass m / z; 418 (M ⁺ ), 400 (M ⁺ -H)
₂ O),

[Chemical formula 82]

Synthesis Example 12 12-1 : 7-[(1R, 2R) -2- {4,4-difluoro-5 (S), 7-dimethyl-3-oxooctyl}-
5-oxocyclopentyl] heptanoic acid (12-2) (1
3,14-Dihydro-15-keto-11-dehydroxy-16,16-difluoro-17 (S), 19-dimethyl-
Synthesis of PGE ₁ ):

[Chemical 83]

Using the compound (12-1) obtained in Example 11 in the same manner as in Examples 9 and 10, the title compound (12
-2) was obtained.

[Chemical 84] nmr (CDCl ₃ ) δ: 0.86 (3H, d, J = 6.6
Hz), 0.94 (3H, d, J = 6.6Hz), 0.98 (3
H, d, J = 7.1 Hz), 1.11-2.50 (22H,
m), 2, 34 (2H, t, J = 7.6Hz), 2.75 (2
H, m), 8-10 (1H, br) mass m / z; 402 (M ⁺ ),

Embedded image

Synthesis Example 13 13: 7-[(1R, 2R, 3R) -2- (4,4-difluoro-6,6-dimethyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] heptane Acid (13,
14-dihydro-15-keto-16,16-difluoro--18,18- dimethyl -PGE ₁₎ Synthesis of (13-2)

[Chemical 86] Dimethyl (3,3-difluoro-5,5-dimethyl-2-
Compound (13-2) was obtained in the same manner as in Example 3 except that oxoheptyl) phosphonate (13-1) was used.

[Chemical 87] n. m. r. (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.1H
z), 1.01 (6H, s), 1.13 to 2.12 (21H,
m), 2.25 (1H, dd, J = 17.7Hz, J = 116H
z), 2.34 (2H, t, J = 7.6Hz), 2.68 (1H,
dd, J = 11.6 Hz, J = 6.6 Hz), 4.17 (1 Hz,
m)

Synthesis Example 14 14: 7-[(1R, 2R, 3R) -2- (4,4-difluoro-6-ethyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] heptanoic acid ( 13,14
- dihydro - keto-16,16-difluoro-18-ethyl -PGE ₁₎ Synthesis of (14-2)

Embedded image Compound (14-2) was obtained in the same manner as in Example 3 except that dimethyl (3,3-difluoro-5-ethyl-2-oxoheptyl) phosphonate (14-1) was used.

[Chemical 89] n. m. r. (CDCl ₃ ) δ: 0.86 (3H, t, J = 7.1H
z), 1.2 to 2.1 (23H, m), 2.25 (1H, dd, J
= 17.7 Hz, J = 11.1 Hz), 2.33 (2 H, t, J
= 6.6 Hz), 2.58 (1 H, dd, J = 17.7 Hz, J
= 6.6Hz), 4.18 (1H, m) mass m / z: 418 (M), 400 (M -H 2 O), 382
(M -2H ₂ O),

[Chemical 90]

Synthesis Example 15 15: 7-[(1R, 2R, 3R) -2- (4,4-difluoro-6-methyl-3-oxoheptyl) -3-hydroxy-5-oxocyclopentyl] heptanoic acid ( 13,14
-Dihydro-15-keto-16,16-difluoro-1
8-Methyl-20-nor-PGE ₁ ) (15-9)

Embedded image

15-1 (1S, 5R, 6R, 7R) -6-
{E-4,4-difluoro-3 (RS) -hydroxy-6-
Methylhept-1-enyl {-7- (tetrahydropyranyloxy) -2-oxabicyclo [3.3.0] octane-
3-on (15-3)

Embedded image (1S, 5R, 6R, 7R) -6- (was obtained in the same manner as in Example 1 except that dimethyl (3,3-difluoro-5-methyl-2-oxohexyl) phosphonate (15-2) was used. E
-4,4-Difluoro-6-methyl-3-oxohept-1-enyl) -7- (tetrahydropyranyloxy)-
2-Oxabicyclo [3.3.0] octane-3-one (1
5-1) (2.285 g) in methanol (50 ml) in the presence of cesium chloride heptahydrate using sodium borohydride to give the title compound (15-3). Yield: 1.989 g (86.6%)

15-2 {1S, 3 (RS), 5R, 6R, 7
R} -6- {E-4,4-Difluoro-3 (RS) -hydroxy-6-methylhept-1-enyl} -7- (tetrahydropyranyloxy) -2-oxabicyclo [3.3.0]
Octane-3-ol (15-4)

Embedded image Compound (15-3) (1.989 g) was added to toluene (40 ml)
The title compound (15-4) was obtained using diisobutylaluminum hydride in the medium.

15-3 Z-7-[(1R, 2R, 3R, 5
S) -2- {E-4,4-Difluoro-3 (RS) -hydroxy-6-methylhept-1-enyl} -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-enoic acid (15-5)

Embedded image (4-Carboxybutyl) triphenylphosphonium bromide (7.490 g) in THF and t-butoxy potassium (1
MTH solution, 33.8 ml) and the THF solution of the compound (15-4) obtained above was added to the ylide prepared to give the title compound.
(15-5) was obtained.

15-4 Z-7 [(1R, 2R, 3R, 5S)
-2- {E-4,4-difluoro-3 (RS) -hydroxy-6-methylhept-1-enyl} -5-hydroxy-
Benzyl 3- (tetrahydropyranyloxy) cyclopentyl] hept-5-enoate (15-6)

Embedded image Compound (15-5) was added to diisopropylethylamine (2.68 ml) and benzyl bromide in acetonitrile (30 ml).
The title compound (15-6) was obtained using (1.83 ml). Yield: 1.613 g (55.8%, 2 reaction steps)

15-5 Z-7-[(1R, 2R, 3R, 5
S) -2- (E-4,4-difluoro-6-methyl-3-
Oxohepto-1-enyl) -5-oxo-3- (tetrahydropyranyloxy) cyclopentyl] hepto-5-enoate benzyl (15-7)

[Chemical 96] Compound (15-6) (1.613 g) was added to oxalyl chloride (2
M dichloromethane solution, 7.14 ml) of dichloromethane
(70 ml) solution, DMSO (2.47 ml) and triethylamine (4.2 ml) were swernified. Yield: 1.218g (76.1%)

15-6 Z-7-[(1R, 2R, 3R, 5
S) -2- (E-4,4-difluoro-6-methyl-3-
Oxohept-1-enyl) -3-hydroxy-5-oxocyclopentyl] hepto-5-enoate benzyl (15
-8)

Embedded image Compound (15-7) (1.150 g) was added to acetic acid, THF, water (3 /
It was dissolved in a mixed solvent of 1/1) and kept at 50 ° C. for 2 hours to give the title compound (15-8). Yield: 0.812g (83.1%)

15-7 7-[(1R, 2R, 3R, 5S)-
2- (4,4-difluoro-6-methyl-3-oxoheptanyl) -3-hydroxy-5-oxocyclopentyl]
Heptanoic acid (15-9)

Embedded image Compound (15-8) (0.739 g) was added to ethyl acetate (30 ml)
Hydrogenated with 5% Pd-carbon in to give the title compound (1
5-9) was obtained. Yield: 0.5053 g (83.4%) n. m. r. (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.1H
z), 1.2 to 2.15 (20H, m), 2.24 (1H, dd,
J = 17.7Hz, J = 11.6Hz), 2.33 (2H, t, J
= 7.1Hz), 2.56 (1H, dd, J = 17.7Hz, J
= 6.6 Hz, 4.17 (1 H, m) mass m / z: 390 (M ⁺ ), 354 (M ⁺ -2H ₂ O),

Embedded image

Synthesis Example 16 16: 7-[(1R, 2R, 3R) -2- {4,4-difluoro-6 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] Heptanoic acid (16-
2) (13,14-dihydro-15-keto-16,16-
Synthesis of difluoro-18 (R) -methyl-PGE ₁ )

[Chemical 100] Dimethyl prepared from (R) -2-methylbutanol {3,
The title compound (16-2) was obtained in the same manner as in Example 8 except that 3-difluoro-5 (R) -methyl-2-oxoheptyl} phosphonate (16-1) was used. n. m. r. (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.1H
z), 1.00 (3H, d, J = 6.6Hz), 1.15-2.
15 (22H, m), 2.25 (1H, dd, J = 17.7Hz,
J = 11.1Hz), 2.35 (2H, t, J = 6.6Hz),
2.58 (1H, dd, J = 17.7Hz, J = 6.6Hz),
4.18 (1H, m) mass m / z: 404 (M +), 386 (M + -H 2 O), 368
(M ⁺ -2H ₂ O),

[Chemical 101]

Synthesis Example 17 17: 7-[(1R, 2R, 3R) -2- (4,4-difluoro-8-methyl-3-oxononyl) -3-hydroxy-5-oxocyclopentyl] heptanoic acid (17 -2) (1
3,14- dihydro-15-keto-16,16-difluoro--20,20- dimethyl -PGE ₁₎ Synthesis of

Embedded image The title compound (17-2) was obtained in the same manner as in Example 3 except that dimethyl (3,3-difluoro-7-methyl-2-oxooctyl) phosphonate (17-1) was used.

Embedded image n. m. r. (CDCl ₃ ) δ: 0.90 (6H, d, J = 6.1H
z), 1.15 to 2.15 (23H, m), 2.24 (1H, d
d, J = 17.7 Hz, J = 11.1 Hz), 2.36 (2 Hz,
t, J = 6.6Hz), 2.59 (1H, dd, J = 17.7H)
z, J = 6.6Hz), 4.18 (1H, m) mass m / z: 502 (M +), 484 (M + -H 2 O),

[Chemical 104]

Synthesis Example 18 18: 7-[(1R, 2R) -2- (4,4-difluoro-8)
-Methyl-2-oxononyl) -5-oxocyclopentyl] heptanoic acid (18-1) (13,14-dihydro-
15-keto-11-dehydroxy-16,16-difluoro--20,20- dimethyl -PGE ₁₎ Synthesis of

Embedded image The title compound (18-1) was obtained in the same manner as in Example 6 using the compound (17-2) obtained in Example 17. n. m. r. (CDCl ₃ ) δ: 0.89 (6H, d, J = 6.6H
z), 1.15 to 2.25 (27H, m), 2.36 (2H, t,
J = 7.1Hz), 2.78 (1H, m)

Synthesis Example 19 19: 7-[(1R, 2R) -2- {4,4-difluoro-6
(R) -Methyl-3-oxooctyl} -5-oxocyclopentyl] heptanoic acid (19-2) (13,14-dihydro-15-keto-11-dehydroxy-16,16-
Synthesis of difluoro-18 (R) -methyl-PGE ₁ )

[Chemical formula 106] Synthetic intermediate obtained in Example 16, 7-[(1R, 2R, 3R)
Benzyl-2- {4,4-difluoro-6 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] heptanoate (19-1) was used in the same manner as in Example 6. The compound (19-2) was obtained.

[Chemical formula 107] n. m. r. (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.1H
z), 0.97 (3H, d, J = 6.1Hz), 1.1 to 2.2
5 (25H, m), 2.34 (2H, t, J = 6.6Hz), 2.
76 (1H, m) mass m / z: 404 (M +), 386 (M + -H 2 O), 368
(M ⁺ -2H ₂ O)

Test Example 1 Crj: Wister rat (7 weeks old, body weight 220-
250 g) was used. After fasting the rats for 16 hours, an acute liver injury model was prepared by intraperitoneally administering 800 mg / kg of hydrochloric acid-D-galactosamine. Twenty-four hours after the administration of galactosamine, blood was collected under ether anesthesia to separate serum. Serum was measured with an automatic analyzer (AU550, manufactured by Olympus Optical Co., Ltd.), and a serum biochemical liver function test was performed.

The test substance was dissolved in 0.5% ethanol physiological saline and was orally administered by gavage using an oral sonde for rats 30 minutes before, 2 hours and 6 hours after the administration of galactosamine. Serum biochemical liver function tests were performed on the following 4 items.・ Glutamate oxaloacetate transaminase (GO
T) -Glutamate pyruvate transaminase (GPT) -Lactate dehydrogenase (LDH) -Total bilirubin (T-Bil)

Based on the results of serum biochemical liver function tests,
To what extent the increase due to the administration of galactosamine was suppressed by the administration of the test substance was determined as the inhibition rate (%). The suppression rate was calculated by the following calculation formula.

[Equation 1] The occurrence of diarrhea and loose stool was observed up to 2 hours after the third administration of the test substance, and the number of individuals with diarrhea and loose stool observed was recorded. The results are shown in Table 1.

[0116]

[Table 1]

Test substance 1: 13,14-dihydro-15
- keto-16,16-difluoro -PGE ₂ (publication A compound according) test substance 2: 13,14-dihydro-15-keto -16,
16-Difluoro-19-methyl-PGE ₂ (Compound of Synthesis Example 1) From the above results, 30
Diarrhea was observed in 3/10 cases after administration of μg / kg, whereas the test substance 2 which is the compound of the present invention shows no diarrhea in all cases. Therefore, it can be seen that the test substance 2 clearly separates the diarrhea effect which is the side effect of the test substance 1.

Test Example 2 The procedure of Test Example 1 was repeated. However, the following substances were used as test substances. Table 2 shows the results.

[0119]

[Table 2]

Test substance 3: 13,14-dihydro-15
-Keto-16,16-difluoro-PGE ₁ (Compound described in Publication A) Test substance 4: 13,14-Dihydro-15-keto-16,
16-Difluoro-17 (R) -methyl-PGE ₁ (Compound of Synthesis Example 3) Test substance 5: 13,14-dihydro-15-keto-16,
16-Difluoro-19-methyl-PGE ₁ (Compound of Synthesis Example 2)

From the above results, the known compound, Test Substance 3, was administered to 100 μg / kg of diarrhea in 1/6 cases, and 2 /
While loose stools were observed in 6 cases, test substances 4 and 5 which are the compounds of the present invention do not show diarrhea at all. Therefore, it can be seen that the test substances 4 and 5 clearly separate the diarrhea effect which is the side effect of the test substance 3.

Test Example 3 The same procedure as in Test Example 1 was performed. However, the following substances were used as test substances. The results are shown in Table 3.

[0123]

[Table 3]

Test substance 6: 13,14-dihydro-15
- keto-16,16-difluoro -17 (R), 19-dimethyl -PGE ₁ (compound of Synthesis Example 5) Test substance 7: 13,14-dihydro-15-keto -11
- De-hydroxy-16,16-difluoro-19-methyl -PGE ₁ (compound of Synthesis Example 6) Test substance 8: 13,14-dihydro-15-keto -16,
16-Difluoro-17 (S) -methyl-PGE ₁ (Compound of Synthesis Example 4)

From the above results, the test substances 6, 7 and 8 which are the compounds of the present invention show no diarrhea at all even in the case of administration of 1000 μg / kg. Therefore, it can be seen that the test substances 6, 7 and 8 very well separate the diarrhea effect which is a side effect of the known substance.

Test Example 4 The procedure of Test Example 1 was repeated. However, the following substances were used as test substances. The results are shown in Table 4.

[0127]

[Table 4]

Test substance 9: 13,14-dihydro-15
-Keto-16,16-difluoro-18 (S) -methyl-
PGE ₁ (Compound of Synthesis Example 8) Test substance 10: 13,14-dihydro-15-keto-1
1-dehydroxy-16,16-difluoro-17 (R)
-Methyl-PGE ₁ (Compound of Synthesis Example 10)

Test Example 5 The same procedure as in Test Example 1 was carried out. However, the following substances were used as test substances. The results are shown in Table 5.

[Table 5] Test substance 11: 13,14-dihydro-15-keto-1
6,16-Difluoro-18 (R) -methyl-PGE1
(Compound of Synthesis Example 16) Test substance 12: 13,14-dihydro-15-keto-1
6,16-Difluoro-18-methyl-20-nor-P
GE1 (Compound of Synthesis Example 15) Test substance 13: 13,14-dihydro-15-keto-1
6,16-Difluoro-18-ethyl-PGE1 (Compound of Synthesis Example 14)

[0130]

EFFECTS OF THE INVENTION The PG derivative of the present invention shows a similar level of ameliorating action to liver damage as compared with the compounds having a linear ω chain known in the prior art, and has a clear side effect such as diarrhea. Is separated into. Such advantages cannot be deduced from the prior art.

Claims (28)

[Claims] 1. A compound represented by the general formula (I): [Wherein A is —COOH, a pharmaceutically acceptable salt thereof or an ester hydrolyzable by esterase; B is —CH ₂ —CH ₂ — or —CH═CH—; X is a hydrogen atom or a hydroxyl group (provided that When a double bond is present on the five-membered ring, X is a hydrogen atom); R ₁ is a divalent saturated or unsaturated C 6
Aliphatic hydrocarbon residue; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen atoms, methyl groups or ethyl groups, provided that R ₂ , R ₃ , R ₄
And at least one of R ₅ is a methyl group or a methyl group; Q is a single bond or a linear or branched C 1
~ C6 aliphatic hydrocarbon group, m means 0 or 1]
A therapeutic agent for hepatic and biliary tract diseases, which comprises a compound represented by 2. The active ingredient is 13,14-dihydro-15.
-Keto-16,16-difluoro-19-methyl-PG
The therapeutic agent for hepatic and biliary tract diseases according to claim 1, which is E, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by esterase. 3. The active ingredient is 13,14-dihydro-15.
-Keto-16,16-difluoro-17-methyl-PG
The therapeutic agent for hepatic and biliary tract diseases according to claim 1, which is E, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by esterase. 4. The active ingredient is 13,14-dihydro-15.
-The keto-16,16-difluoro-17,19-dimethyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by an esterase, for treating the hepatic / biliary tract disease according to claim 1. 5. The active ingredient is 13,14-dihydro-15.
-Keto-16,16-difluoro-18-methyl-PG
The therapeutic agent for hepatic and biliary tract diseases according to claim 1, which is E, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by esterase. 6. The active ingredient is 13,14-dihydro-15.
-Keto-16,16-difluoro-18,18-dimethyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by an esterase, The therapeutic agent for liver / biliary tract diseases according to claim 1. 7. The active ingredient is 13,14-dihydro-15.
-Keto-16,16-difluoro-18-ethyl-PG
The therapeutic agent for hepatic and biliary tract diseases according to claim 1, which is E, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by esterase. 8. The active ingredient is 13,14-dihydro-15.
-Keto-16,16-difluoro-18-methyl-20
-The drug for treating hepatic and biliary tract diseases according to claim 1, which is nor-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by esterase. 9. The active ingredient is 13,14-dihydro-15.
-Keto-16,16-difluoro-20,20-dimethyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by an esterase, The therapeutic agent for hepatic / biliary tract diseases according to claim 1. 10. The active ingredient is 13,14-dihydro-1.
The agent for treating liver / biliary tract diseases according to claim 1, which is 5-keto-11-dehydroxy-16,16-difluoro-19-methyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by esterase. . 11. The active ingredient is 13,14-dihydro-1.
The agent for treating hepatic and biliary tract diseases according to claim 1, which is 5-keto-11-dehydroxy-16,16-difluoro-17-methyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by esterase. . 12. The active ingredient is 13,14-dihydro-1.
The liver / biliary tract disease according to claim 1, which is 5-keto-11-dehydroxy-16,16-difluoro-17,19-dimethyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by esterase. Treatment agent. 13. The active ingredient is 13,14-dihydro-1.
The agent for treating liver / biliary tract diseases according to claim 1, which is 5-keto-11-dehydroxy-16,16-difluoro-18-methyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by esterase. . 14. The active ingredient is 13,14-dihydro-1.
The liver / biliary tract disease according to claim 1, which is 5-keto-11-dehydroxy-16,16-difluoro-20,20-dimethyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by esterase. Treatment agent. 15. A compound represented by the general formula (I): [Wherein A is —COOH, a pharmaceutically acceptable salt thereof or an ester hydrolyzable by esterase; B is —CH ₂ —CH ₂ — or —CH═CH—; X is a hydrogen atom or a hydroxyl group (provided that When a double bond is present on the five-membered ring, X is a hydrogen atom); R ₁ is a divalent saturated or unsaturated C 6
Aliphatic hydrocarbon residue; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen atoms, methyl groups or ethyl groups, provided that R ₂ , R ₃ , R ₄
And at least one of R ₅ is a methyl group or an ethyl group; Q is a single bond or a linear or branched C 1
To C6 aliphatic hydrocarbon group m means 0 or 1]. 16. 13,14-Dihydro-15-keto-
16. The compound according to claim 15, which is 16,16-difluoro-19-methyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 17. A 13,14-dihydro-15-keto-
The compound according to claim 15, which is 16,16-difluoro-17-methyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 18. 13,14-Dihydro-15-keto-
16,16-Difluoro-17,19-dimethyl-PG
The compound according to claim 15, which is E, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 19. 13,14-Dihydro-15-keto-
16. The compound according to claim 15, which is 16,16-difluoro-18-methyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 20. 13,14-Dihydro-15-keto-
16,16-Difluoro-18,18-dimethyl-PG
The compound according to claim 15, which is E, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 21. 14,14-Sihydro-15-keto-
The compound according to claim 15, which is 16,16-difluoro-18-ethyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 22. 13,14-Dihydro-15-keto-
16,16-Difluoro-18-methyl-20-nor-
16. The compound according to claim 15, which is PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 23. 14,14-Dihydro-15-keto-
16,16-Difluoro-20,20-dimethyl-PG
The compound according to claim 15, which is E, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 24. 13,14-Dihydro-15-keto-
11-dehydroxy-16,16-difluoro-19-
16. Methyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by esterase.
A compound as described. 25. 13,14-Dihydro-15-keto-
11-dehydroxy-16,16-difluoro-17-
16. Methyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by esterase.
A compound as described. 26. 14,14-Dihydro-15-keto-
11-dehydroxy-16,16-difluoro-17,
The compound according to claim 15, which is 19-dimethyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase. 27. 14,14-Dihydro-15-keto-
11-dehydroxy-16,16-difluoro-18-
16. Methyl-PGE, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by esterase.
A compound as described. 28. 13,14-Dihydro-15-keto-
11-dehydroxy-16,16-difluoro-20,
The compound according to claim 15, which is 20-dimethyl-PGE, a pharmaceutically acceptable salt thereof, or an ester hydrolyzed by an esterase.