JP3183650B2 - Prostaglandin compounds - Google Patents

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 a conventional publication. The compound of the present invention is useful as an agent for treating hepatic / biliary diseases without or with very few side effects such as diarrhea.

[0002]

BACKGROUND OF THE INVENTION Prostaglandins (hereinafter prostaglandins are referred to as PGs) are contained in tissues and organs of humans and other mammals and exhibit a wide range of physiological activities. Acid 1
Group. Naturally occurring PGs generally have a prostanoic acid skeleton.

[0003]

Embedded image

Some synthetic analogs, on the other hand, have modified backbones. Natural PGs have a 5-membered ring structure,
GAs, PGBs, PGCs, PGDs, PGEs, P
GFs, PGGs, PGHs, PGIs and PGJs, and A, B. and B. depending on whether or not they have unsaturated bonds at positions 13-14, 5-6 and 17-18 of the chain portion.・ ・ The numbers 1 to 3 are attached to the lower right of J and named as follows. 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 (the hydroxyl group has an α-configuration) and β (the hydroxyl group has a β-configuration) according to the arrangement of the hydroxyl group at the 9-position.

[0005] Native PGE ₁ , PGE ₂ and PGE ₃ are known to have vasodilation, hypotension, decreased gastric secretion, intestinal hyperactivity, uterine contraction, diuresis, bronchodilation and anti-ulcer activity. Also, natural PGF _{1 α,} PGF ₂ α and PGF _{3 alpha} is elevated blood pressure, vasoconstriction, intestinal tract movement enhancement, uterine contraction, are known to have a luteolysis and bronchoconstriction activities.

US Pat. No. 4,374,856 describes that 15-methyl-PGE ₂ and 16,16-dimethyl-PGE ₂ have hepatocyte protective action,
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 describes that I ₂ has a protective effect on cells, including hepatocytes, JP 58-203911 has one or two methyl groups of certain of 15,16,17,20 6-oxo -PGE ₁ class and PGI1 class and certain 15-cyclopentyl -PGI ₁ compound is described to have a protective effect on cells, including hepatocytes, JP 62-129218 is 4 or 7 thia -PGE ₁ class is described that could cause liver disease therapeutic agents. However, none of these correspond to 15-keto-PG or its derivatives.

[0007] It has been reported that 15-keto-16 halo-PGs have an enteropuling action and can be used as laxatives.
No. 109).

[0008] European Patent Application Publication No. 0424
No. 156 (corresponding to JP-A-3-204816, hereinafter abbreviated as Publication A) describes that 15-keto-PGs can be used for the treatment of hepatic and biliary tract diseases. -PGs conceptually include those in which the 16-position is substituted with fluorine and which has a specific side chain on the ω chain. However, there is no specific disclosure (Examples) of these, and it is not suggested that their pharmacological properties are different from others.

EP-A-0 284 180
(Corresponding to JP-A-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 describes that the 16-difluoro-PGE compound has an anti-ulcer effect, and the compounds conceptually include those having a specific side chain on the omega chain. However, there is no specific disclosure (Examples) of these, and it is not suggested that their pharmacological properties are different from others.

[0010]

According to the present invention, there is provided a compound represented by the general formula (I):

Embedded image Wherein A is —COOH, a pharmaceutically acceptable salt or an aliphatic ester, an aryl ester and an aryl thereof.
Esters selected from (lower) alkyl esters; B is-
CH ₂ —CH ₂ — or —CH ＝ CH—; X is a hydrogen atom or a hydroxyl group (however, when a 5-membered ring has a double bond, X is a hydrogen atom); R ₁ is —CH ₂ —CH ₂ — CH ₂ -CH ₂
-CH ₂ -CH ₂ - or _{-CH 2 -CH = CH-CH 2} -
CH ₂ —CH ₂ —; R ₂ , R ₃ , R ₄ and R ₅ represent a hydrogen atom,
A methyl group or an ethyl group, provided that at least one of R ₂ , R ₃ , R ₄ and R ₅ is a methyl group or an ethyl group; Q is a single bond, methylene or ethylene, and m is 0 or 1.] The present invention provides the compounds shown.

The compounds of the above formula (I) are conceptually encompassed by the compounds described in the aforementioned publication A, the compounds described in the publication B and the compounds described in the publication C. Are compounds that have not been specifically disclosed. Further, the compound of the formula (I) has a better onset and persistence of a therapeutic effect on hepatic and biliary diseases as compared with the compounds specifically disclosed in the publications A, B and C, and has no side effect or It has the characteristic of attenuating.

In the present invention, the term "hepatic / biliary disease" includes any symptom based on or accompanied by impairment of hepatocytes and any symptom based on impairment of the biliary tract, such as fulminant hepatitis, fatty liver disease and the like. (Especially alcoholic fatty liver),
Hepatic coma, various acute and chronic hepatitis (alcoholic hepatitis,
Toxic hepatitis, hepatitis A virus, hepatitis B virus, non-A non-B virus hepatitis, serum hepatitis, chronic active hepatitis, etc.),
Liver lens nuclear degeneration, liver hypertrophy, portal hypertension, obstructive jaundice, liver abscess, cirrhosis (especially alcoholic cirrhosis, hepatic cirrhosis), parasitic liver disease, liver tumor, liver tuberculosis, cholecystitis, gallstone Disease, cholangitis, biliary colic, hypersensitivity, etc.

In the context of the present invention, the term "treatment" encompasses the management of any disease, including prevention, treatment, alleviation, prevention of deterioration or reduction of deterioration. In naming the PGE derivative of the present invention, the number of prostanoic acid shown in the formula (A) is used. The above formula (A) has a basic skeleton of C-20. In the present invention, the number of carbon constituting the basic skeleton is α.
Since the number of carbon atoms on the chain is the same, carboxylic acid is set to 1 and 2 to 7 are sequentially assigned to carbon atoms on the α chain toward the five-membered ring, and 8 to 1
Up to 2 is attached to the carbon of the five-membered ring, and 13 or less is attached to the ω chain. When the number of carbons increases on the ω chain, the carbon at position 20 is named as having a substituent. They are named as sequentially decreasing carbon numbers as they decrease on the chain.
Unless otherwise specified, the configuration conforms to the configuration of the basic skeleton.

Although the above formulas indicate the specific configuration, which is the most typical configuration, in this specification, unless otherwise specified, compounds will have the above configuration. As described above, in the present specification, the PGE derivative is named based on the prostanoic acid skeleton, but may be named based on IUPAC. Examples according to this nomenclature are specifically shown in Synthesis Examples.

The PG derivative used in the present invention may be a saturated derivative, 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 type compound).
G type 2 compound). Further, a 13,14-dihydro form is also included. Examples of R ₁ include the following.

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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 salts, salts with organic bases For example, amine salts (e.g., 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 salts, procaine salts, caffeine salts, etc.), basic amino acid salts (eg, arginine salts, lysine salts, etc.), tetraalkylammonium salts and the like. These salts may be prepared, for example, from the corresponding acids and bases by conventional methods and by salt exchange.

The compound of the present invention may be an ester which can be hydrolyzed by an esterase, and such an ester is an ester which can be decomposed into a corresponding carboxyl compound and an alcohol under the action of an animal ester hydrolase esterase. Yes, it produces the corresponding carboxyl compound in the body when administered to a mammal (eg, a human).

Examples of such esters include lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and 1-cyclopropylethyl ester;
Vinyl esters, lower alkenyl esters such as allyl esters, ethynyl esters, lower alkynyl esters such as propynyl esters, hydroxy (lower) alkyl esters such as hydroxyethyl esters, methoxymethyl esters, and lower alkoxy (lower alkoxy) such as 1-methoxyethyl esters ) Aliphatic esters such as alkyl esters and e.g. phenyl esters, tosyl esters, t-
Butylphenyl 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 configuration of the ring, α and / or ω chain may be the same as or different from the configuration of natural PGs. However, the invention also encompasses mixtures of compounds having a natural configuration and compounds having a non-natural configuration.

In the compound used in the present invention,
When 14-position is saturated, hydroxy at 11-position and 15-position
The formation of a hemiacetal between the keto at the top position may result in a keto-hemiacetal equilibrium. When such a tautomer is present, the ratio of both isomers varies depending on the structure of the other portion or the type of the substituent, and in some cases, one isomer may be overwhelmingly present. In the present invention, both of these are included, and the compound may be represented by a keto-type structural formula or a nomenclature irrespective of the presence or absence of such an isomer. It is not intended to exclude acetal type compounds.

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

The above-mentioned PGE derivatives have an action of preventing or treating hepatocyte and biliary disorders, and are therefore useful as agents for treating hepatic and biliary disorders. Such activity is
It can be measured using a standard method such as a galactosamine disorder model.

The compounds used in the present invention can be used as drugs for animals and humans, and are usually used systemically or locally by oral, intravenous injection (including drip), subcutaneous injection,
Used by such methods as rectal administration. The dosage varies depending on the type of the subject such as an animal or a human, the age, the body weight, the condition to be treated, the desired therapeutic effect, the administration method, the treatment period, etc., and is usually 2 to 4 divided doses per day or When administered in a continuous form, a dose of 1 to 1000 μg / kg (po) usually gives a sufficient effect.

The 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, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with magnesium metasilicate aluminate. The composition may be prepared in a conventional manner using additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose 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-, maltosyl-cyclodextrin, formylated cyclodextrins, sulfur-containing cyclodextrins, misoprotols And 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 a liposome using a phospholipid. Tablets or pills as needed
Gelatin, hydroxypropylcellulose, may be coated with a film of a gastric or enteric substance such as sedroxypropylmethylcellulose phthalate,
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 the liquid composition for oral administration include emulsions, solutions, suspensions, syrups, elixirs and the like. 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,
Physiological saline and Ringer's solution are included.

As a medium for non-aqueous solutions and suspensions, for example, propylene glycol, polyethylene glycol,
Vegetable oils such as olive oil, alcohols such as ethanol, polysorbates and the like. 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.

Hereinafter, the present invention will be specifically described 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

[0030]

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):

Embedded image

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

Embedded image Corey lactone, (1S, 5R, 6R, 7R) -6- (hydroxymethyl) -7- (tetrahydropyranyloxy)-
2-oxabicyclo [3,3,0] octan-3-one
(1) A solution of 6.800 g of dichloromethane (40 ml) in oxalyl chloride (2M dichloromethane solution, 30 m
l) in dichloromethane (100 ml), DMSO (8.
45 ml), and Swern oxidation using triethylamine (16.9 ml). A conventional treatment was carried out to give a corehydehyde, (1S, 5R, 6R, 7R) -6-formyl-7- (tetrahydropyranyloxy) -2-oxabicyclo [3,
[3,0] Octane-3-one (2) was obtained. To a suspension of sodium hydride (60%, 1.273 g) in THF (50 ml) was added dimethyl (3,3-difluoro-6-methyl-2-oxoheptyl) phosphonate (3) (8.664 g) in THF.
(10 ml) solution and stirred for 1 hour, then zinc chloride (4.3)
37 g) and stirred for 1 hour. Corey aldehyde
A solution of (2) in THF (20 ml) was added, and the mixture was stirred at room temperature for 15 hours. The crude product obtained by a conventional method was purified by a silica gel column (n-hexane / ethyl acetate = 3/1) to obtain the title compound (4). 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 Compound (4) (6.144 g) in THF (40 ml) was added to a solution of
Dimethylphenylsilane (3.17 ml) and Wilkinson's catalyst (0.142 g) were added and kept at 50 ° C. for 2 hours. Crude product obtained by conventional treatment 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] octan-3-one
(6)

Embedded image To a solution of the compound (5) (3.386 g) in methanol (50 ml) was added sodium borohydride (0.138 g).
For 10 minutes. The crude product obtained by a conventional method was purified by a silica gel column (n-hexane / ethyl acetate = 1/1).
Then, 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)

Embedded image A solution of compound (6) (2.883 g) in toluene (70 ml) was cooled to −78 ° C., and diisobutylaluminum hydride (1M toluene solution, 17.8 ml) was added thereto, followed by stirring 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 -All (7) was obtained. (4-carboxybutyl)
A suspension of triphenylphosphonium bromide (12.64 g) in THF (50 ml) and potassium t-butoxide (1M)
THF solution, 57.0 ml) to give the corresponding ylide. -30 ° C and the lactol (7) in THF
(30 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)

Embedded image To a solution of the carboxylic acid (8) in acetonitrile (50 ml) were added diisopropylethylamine (4.73 ml) and phenacyl bromide (5.67 g), and the mixture was kept at 45 ° C for 2 hours.
The crude product obtained by the usual 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] hept-5-enoate (1
0)

Embedded image Ogizaryl chloride (2M dichloromethane solution, 17.8m
l) in dichloromethane (50 ml), DMSO (5.
Compound (9) was Swern-oxidized using 1 ml) and triethylamine (10 ml). The crude product obtained by a conventional treatment was purified by a 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)

Embedded image Compound (10) (3.034 g) was added to acetic acid / THF / water (3 /
1/1) It was dissolved in a mixed solvent and kept at 50 ° C. for 3 hours. The crude product obtained by the usual treatment was purified by silica gel column (n-
Hexane / ethyl acetate = 3/1) to give the title compound (11)
I got Yield: 1.945 g (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 To a solution of compound (11) (0.362 g) in acetic acid was added zinc (0.7
24g) and stirred for several hours. The crude product obtained by a conventional method was purified by a silica gel column (dichloromethane / methanol = 25/1) to obtain the title compound (12). Yield: 0.235 g (84%) n. m. r. (CDCl ₃ ) δ: 0.92 (6H, d, J =
6.0Hz), 1.33-2.74 (19H, m), 2.3
6 (2H, 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),

Embedded image

[0039] Synthesis Example 2 2: 7 - [(1R , 2R, 3R) -2- (4,4- difluoro-7-methyl-3-oxo-octyl) -3-hydroxy-5-oxocyclopentyl] heptanoic acid ( 13,14
-Dihydro-15-keto-16,16-difluoro-1
Synthesis of 9-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] octan-3-ol (2-2)

Embedded image 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 with diisopropylaluminum hydride (1 M in toluene, 61 ml) at -78 ° C in toluene (75 ml). Lactol (2-2) was obtained by a 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 (1 MTHF solution, 24
7 ml) was added to give the corresponding ylide. To this was added a lactol (2-2) solution in THF (50 ml), and the mixture was added at room temperature.
Stir for 5 hours. The carboxylic acid (2-3) was obtained by a conventional treatment. Crude yield: 36.62 g

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

Embedded image The carboxylic acid (2-3) was dissolved in acetonitrile (150 ml),
Isopropyl iodide (24.0 ml) and DBU at room temperature
(36.0 ml) using isopropyl ester (2-4).
And The crude product obtained by a conventional method was purified by a silica gel column (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
Pyridine (8.9 ml) and acetyl chloride (7.8 ml) were added thereto at 0 ° C., and the mixture was stirred for 30 minutes and at room temperature for 1.5 hours. The title compound (2-5) was obtained by a conventional treatment. Yield: 20.09 g

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

Embedded image To a solution of compound (2-5) (20.09 g) in THF (50 ml) was added tetrabutylammonium fluoride (1 MTH
F solution, 74.3 ml), and kept at room temperature overnight.
Hexane / ethyl acetate = 2/3) to give the title compound (2-
6) was obtained. Yield: 15.50 g (98.9% in 2 reaction steps)

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

Embedded image Compound (2-6) (15.50 g) was added to ethyl acetate (20 ml).
In 5% palladium-carbon (catalytic amount) and hydrogen gas. Yield: 15.50 g

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

Embedded image Compound (2-7) (15.50 g) dichloromethane (100
The solution was swane-oxidized using oxalyl chloride (2M solution in dichloromethane, 54.3 ml), DMSO (15.4 ml) and triethylamine (50.0 ml). Purification by a silica gel column (n-hexane / ethyl acetate = 7/3) gave the title compound (2-8). Yield: 15.21 g (98.1%)

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

Embedded image potassium tert-butoxide (1MTHF solution, 14.9 ml)
Of dimethyl (3,3-difluoro-6-methyl-2-oxoheptyl) phosphonate (2-9) (4.078 g)
After adding an HF (20.4 ml) solution and stirring at room temperature for 30 minutes,
Zinc chloride (2.027 g) was added and the mixture was stirred at room temperature for 30 minutes. The aldehyde (2-8) (2.883 g) in THF (1
(4.4 ml) and heated under reflux for 62 hours. The crude product obtained by a conventional method was purified by a silica gel column (n-hexane / ethyl acetate = 4/1) to give the title compound (2-10)
I got Yield: 3.393 g (87.5%)

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

Embedded image Compound (2-10) (2.000 g) in acetic acid (20 ml)
Reduction was carried out using 5% palladium-carbon (0.200 g) and hydrogen gas. Yield: 1.995 g (99.4%)

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

Embedded image Compound (2-11) (1.995 g) was added to methanol (20 m
1) 6-N sodium hydroxide solution (5.8 ml) was added to the solution, and the mixture was stirred for 15 hours. The crude product (2-1) was treated in a conventional manner.
2) was obtained. Yield: 1.828 g

2-11 : 7-[(1R, 2R, 3R, 5
S) -2- (4,4-Difluoro-7-methyl-3-oxooctyl) -5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] benzyl heptanate (2-
13)

Embedded image Compound (2-12) (1.828 g) was added to acetonitrile (1
In 8 ml), DBU (1.04 ml) and benzyl iodide (0.83 ml) were added at room temperature, and the mixture was stirred for 2.5 hours. Yield: 1.717 g (84.7% in two reaction steps)

2-12 : 7-[(1R, 2R, 3R, 5
S) -2- (4,4-Difluoro-7-methyl-3-oxooctyl) -3- (tetrahydropyranyloxy) -5
-Oxocyclopentyl] benzyl heptanate (2-1
4)

Embedded image Compound (2-13) (1.700 g) in dichloromethane
(17 ml) was swane-oxidized using a solution of oxalyl chloride (0.51 ml) in dichloromethane (5.1 ml), DMSO (0.83 ml) and triethylamine (3.27 ml). The crude product obtained by a conventional method 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
-(4,4-Difluoro-7-methyl-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] benzyl heptanate (2-15)

Embedded image Compound (2-14) (1.565 g) was treated with acetic acid / water / THF.
The mixture was kept at 45 ° C. for 3 hours in a mixed solvent (4/2/1) (70 ml). The crude product obtained by a conventional treatment was purified by a silica gel column (n-hexane / ethyl acetate = 4/1) to give the title compound.
(2-15) was obtained. Yield: 1.169 g (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
In 1), debenzylation was performed using 5% palladium-carbon (0.230 g) and hydrogen gas. Silica gel column purification
(n-hexane / ethyl acetate = 100 / 0-40 / 60)
Then, the title compound (2-16) was obtained. Yield: 0.731 g (78%) n. m. r. (CDCl ₃ ) δ: 0.92 (6H, d, J =
6.0Hz), 1.20 to 2.13 (22H, m), 2.
26 (1H, dd, J = 17.5 Hz, J = 11.5H
z), 2.60 (1H, dd, J = 17.5 Hz, J = 7.
0 Hz), 4.19 (1H, m) mass m / z: 404 (M ⁺ ), 386 (M ⁺ -H
^{_{2 O), 368 (M +}} -2H 2 O),

Embedded image

Synthesis Example 3 3 : 7-[(1R, 2R, 3R) -2- {4,4-difluoro-5 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] Heptanoic acid
(13,14-dihydro-15-keto-16,16-difluoro--17 (R) - methyl -PGE ₁₎ (3-10)

Embedded image

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)

Embedded image Two types of amides obtained from (d.l) -2,2-difluoro-3-methylhexanoic acid and (R)-(+)-phenylethylamine were separated by normal phase column chromatography, and the retention time Dimethyl (3,3-difluoro-4 (R) -methylheptyl) phosphonate (3-
2) To a solution of (0.796 g) in THF (5 ml), potassium t-butoxide (1MTHF solution, 2.63 ml) was added, and the mixture was stirred at room temperature for 30 minutes.
Stirred for hours. An aldehyde obtained in the same manner as in Example 2 except that methyl iodide was used instead of isopropyl iodide, 7-[(1R, 2R, 3R, 5S) -5-acetoxy-2-formyl-3- (Tetrahydropyranyloxy) cyclopentyl] heptanoic acid methyl (3-1) (0.8
A solution of 25 g) in THF (5 ml) was added and the mixture was heated under reflux for 3 days. Crude product obtained by conventional treatment is purified by silica gel column
(n-hexane / acetic acid = 3/1) to give the title compound (3-3)
I got Yield: 0.664 g (59%)

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

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

3-3 : 7-[(1R, 2R, 3R, 5S)
-5-acetoxy-2- {4,4-difluoro-3 (R
S) -Hydroxy-5 (R) -methyloctyl {-3- (tetrahydropyranyloxy) cyclopentyl] heptanoic acid methyl (3-5)

Embedded image Compound (3-4) (0.630 g) was added to methanol (10 ml).
Medium, at -40 ° C, sodium borohydride (0.044g)
Reduced. The crude product obtained by a conventional method was purified by a silica gel column (n-hexane / ethyl acetate = 2/1) to obtain the title compound (3-5). Yield: 0.619 g (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 Ethanol (11 ml) of compound (3-5) (0.619 g)
A 1-N sodium hydroxide solution (11.3 ml) was added to the solution, and the mixture was stirred at room temperature. Yield: 0.583 g

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

Embedded image Compound (3-6) (0.583 g) was added to acetonitrile (10
ml), diisopropylethylamine (0.79 ml)
And benzyl bromide (0.54 ml) to give the title compound (3-7). Silica gel column purification (n-hexane / ethyl acetate = 3
/ 2). Yield: 0.633 g (96% in two reaction steps)

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

Embedded image Compound (3-7) (0.633 g) in dichloromethane (7 m
l) The solution was swarmed using oxalyl chloride (0.47 ml) in dichloromethane (10 ml), DMSO (0.77 ml) and triethylamine (1.89 ml). The crude product obtained by a conventional treatment was purified by a 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-
{4,4-Difluoro-5 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] benzyl heptanate (3-9)

Embedded image Acetic acid (20 ml) and water (10 ml) were added to a solution of compound (3-8) (0.590 g) in THF (5 ml), and the mixture was added at 45 ° C.
For 3.5 hours. A crude product obtained by a conventional method was purified by a silica gel column (n-hexane / ethyl acetate = 7/3).
Then, the title compound (3-9) was obtained. Yield: 0.407 g (81%)

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

Embedded image Compound (3-8) (0.407 g) was added to ethanol (15 ml).
In 10% palladium-carbon (0.080 g) and hydrogen gas. Silica gel column purification (n-
Hexane / ethyl acetate = 100 / 0-30 / 70)
The title compound (3-10) was obtained. Yield: 0.153 g (46%) n. m. r. (CDCl ₃ ) δ: 0.91 (3H, t, J =
7.0Hz), 1.00 (0.6H, d, J = 7.0H)
z), 1.10 (0.4 H, d, J = 7.0 Hz), 1.1
3 to 2.30 (21H, m), 2.34 (2H, t, J = 7.
5 Hz), 2.58 (1H, dd, J = 17.5 Hz, J =
7.5Hz), 2.62 (1H, dd, J = 17.5Hz,
J = 7.5 Hz), 2.90 (1 H, t, J = 7.5 H)
z), 4.02-4.28 (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 types of amides obtained from (d, l) -2,2-difluoro-3-methylhexanoic acid and (R)-(+)-phenylethylamine were separated by normal phase column chromatography. Dimethyl (3,3-difluoro-4 (S) -methylheptyl) phosphonate (4-2) obtained using a substance having a long retention time

Embedded image Was used in the same manner as in Synthesis Example 3 except that
1) was obtained. n. m. r. (CDCl ₃ ) δ: 0.90 (3H, t, J =
7.0 Hz), 0.98 (0.6 Hz, d, J = 7.0 H)
z), 1.09 (0.4 H, d, J = 7.0 Hz), 1.1
4 to 2.30 (21H, m), 2.34 (2H, t, J = 7.
5 Hz), 2.67 (1H, dd, J = 17.5 Hz, J =
7.5 Hz), 2.70 (1H, dd.J = 17.5 Hz,
J = 7.5 Hz), 2.90 (1 H, t, J = 7.5 H)
z), 4.04 to 4.26 (1H, m) mass m / z: 404 (M ⁺ ), 386 (M ⁺ -H
₂ O), 368 (M ⁺ -2H ₂ O)

Embedded image

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

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

Embedded image Was used in the same manner as in Synthesis Example 3 except that
1) was obtained. n. m. r. (CDCl ₃ ) δ: 0.86 (4H, d, J =
7.0 Hz), 0.94 (2H, d, J = 7.0 Hz),
0.98 (0.7H, d, J = 7.0Hz), 1.08
(0.3H, d, J = 7.0 Hz), 1.13 to 2.43
(20H, m), 2.34 (2H, t, J = 6.5Hz),
2.58 (1H, dd, J = 17.5 Hz, J = 7.5H
z), 2.71 (1H, dd, J = 17.5 Hz, J = 7.
5Hz), 3.91 (1H, t, J = 7.5Hz), 4.03
~ 4.30 (1H, m) mass m / z: 418 (M ⁺ ), 400 (M ⁺ -H
^{_{2 O), 382 (M +}} -2H 2 O),

Embedded image

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)

Embedded image 7-[(1R, 2R, 3R) -3 obtained in the same manner as in Synthesis Example 2.
-Hydroxy-2- (4,4-difluoro-7-methyl-
(3-Oxooctyl) -5-oxocyclopentyl] heptanoic acid (6-1) (0.533 g) was dissolved in acetic acid (10 ml) and kept at 70 ° C. overnight. The crude product obtained by a conventional method was purified by a silica gel column (dichloromethane / methanol = 20/1) to obtain the title compound (6-2). Yield: 0.3969 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 carried out using 10% palladium on carbon (0.0281 g) and hydrogen gas. Purify on a silica gel column (dichloromethane / methanol = 20/1) to give the title compound (6-3)
I got Yield: 0.4576 g (81.0%) n. m. r. (CDCl ₃ ) δ: 0.92 (6H, d, J =
6.0 Hz), 1.17 to 2.23 (22 H, m), 2.3
4 (3H, 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-16,1
6- difluoro -17 (R), 19- dimethyl -PGE ₁₎
Synthesis of:

Embedded image

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

Embedded image Commercially available corey lactone, (1S, 5R, 6R, 7R) -6
-(Hydroxymethyl) -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3,3,0] octane-3
-One (7-1) and (5,000 g) were converted to compound (7-2) using imidazole (2.9 g) and t-butyldimethylsilane chloride (4.28 g) in DMF (7 ml).

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

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

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

Embedded image Compound (7-3) (2,500 g) was added to dichloroethane (20 m
In 1), thiocarbonyldiimidazole (2.273 g)
Was used as 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] octan-3-one (7-5)

Embedded image Tributyltin hydride (5.06 g) in toluene (13
Compound (7-4) (3,450) under reflux with heating.
g) was added to give compound (7-5).

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

Embedded image Compound (7-5) was dissolved in concentrated hydrochloric acid (3.5 ml) in THF (70 ml).
0 ml) to give compound (7-6). Purification by silica gel column (ethyl acetate). Yield: 1.206 g (88.8 g)

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

Embedded image Compound (7-6) (1.200 g) was treated with oxazalyl chloride
(2.93 g) in dichloromethane (40 ml), DMS
Swonic acidation using O (3.60 g) and triethylamine (6.22 g) gave the title compound (7-7). Yield: 0.9109 g (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 Two kinds of amides obtained from (dl) -2,2-difluoro-3,5-dimethylhexanoic acid and (R)-(+)-phenylethylamine were separated by normal phase column chromatography, and the retention time was determined. Dimethyl (3.3)
-Difluoro-4 (R), 6-dimethyl-2-oxoheptyl) phosphonate (7-9) (phosphonate in Example 5
(Same as (5-2)) (0.882 g)

Embedded image THF (2.4 ml) was added to sodium hydride (6 mL).
Treatment with a suspension of 3.8%, 0.1103 g) in THF (1.5 ml), to which compound (7-7) (0.5202 g) was added.
Of THF (4 ml) was added. The title compound
(7-8) was obtained. Yield: 0.6651 g (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%
Hydrogenation was performed using Pd-carbon. Used for 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
-ON (7-11)

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

7-10 {(1S, 3 (RS), 5R, 6R}
-6- {4,4-difluoro-5 (R), 7-dimethyl-3
(RS) -Hydroxyoctyl} -2-oxabicyclo [3.3.0] octan-3-ol (7-12)

Embedded image Compound (7-11) (0.6495 g) was dissolved in toluene (3 ml).
Diisobutylaluminum hydride (-1.
5M toluene solution, 2.86 ml). The title compound (7-12) was obtained by a 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)

Embedded image The compound (7-12) was added to an ylide formed from a suspension of (4-carboxybutyl) triphenylphosphonium bromide (3.16 g) in THF (9 ml) and potassium t-butoxide (1MTHF solution, 14.3 ml). THF (9m
l) The solution was added to obtain the title compound (7-13). 7-12 Z-7-[(1R, 2R, 5S) -2- ｛4,4
-Difluoro-3 (RS) -hydroxy-5 (R), 7-dimethyloctyl {-5-hydroxycyclopentyl] benzyl hepto-5-enoate (7-14)

Embedded image Compound (7-13) was dissolved in acetonitrile (19 ml) in benzyl bromide (1.57 g) and diisopropylamine (1.
19g) to give the title compound (7-14). A crude product obtained by a conventional method was purified by a silica gel column. Yield: 0.9257 g (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) (0.9255 g) was added to dichloromethane.
(35 ml) was swane-oxidized with a solution of oxalyl chloride (1.19 g) in dichloromethane (20 ml), DMSO (1.46 g) and triethylamine (2.37 g).
The crude product obtained by the usual treatment was purified by silica gel column (n
-Hexane / ethyl acetate = 8/1). Yield: 0.8701 g (94.8%)

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

Embedded image Compound (7-15) (0.8695 g) was added to ethanol (9 m
l) reducing with 10% Pd carbon and hydrogen gas in
The title compound (7-16) was obtained. Yield: 0.5569 g (77.8%) n. m. r. (CDCl ₃ ) δ: 0.86 (3H, d, J =
6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 0.
98 (3H, d, J = 7.1 Hz), 1.11 to 2.50
(22H, m), 2.34 (2H, t, J = 7.6Hz),
2.74 (2H, t, m), 7-9 (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) Synthesis of (13,14-dihydro-15-keto-16,16-difluoro-18 (S) -methyl PGE ₁ ):

Embedded image

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

Embedded image Commercially available 2 (S) -methyl-1-bromobutane (8-1) (1
0.0 g) in ether (10 ml) and ether (20
2 (S) -Methyl-1-butylmagnesium bromide was prepared from magnesium (1.61 g) in 1 ml.
This was reacted with diethyl oxalate (7.74 g) to obtain compound (8-2). Yield: 4.82 g (53%)

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

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

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

Embedded image Dimethylmethylphosphonate (5.23 g) in THF (6
Compound (8-3) (4.09 g) was reacted with a phosphonate anion prepared at −78 ° C. from a 0 ml solution and n-butyl lithium (25.8 ml of a 1.6 M hexane solution). Silica gel column purification (ethyl acetate / hexane = 7
/ 3). 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, 5) obtained in the same manner as in Example 3 except that hydrogenation was not performed on the double bond.
S) -5-acetoxy-2-formyl-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-enoate methyl (8-5) and dimethyl [3,3-difluoro-5 (S) -methyl-2 -Oxoheptyl] phosphonate
Compound (8-) was prepared in the same manner as in Example 3 using (8-4).
6) was obtained. n. m. r. (CDCl ₃ ) δ: 0.89 (3H, t, J =
7.6 Hz), 1.01 (3H, d, J = 5.6 Hz), 1.
12 to 2.14 (21H, m), 2.26 (1H, dd, J =
17.7 Hz, J = 10.1 Hz), 2.35 (2H, t, J)
= 7.6 Hz), 2.58 (1H, dd, J = 17.7H)
z, J = 7.6 Hz), 4.18 (1 H, 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 Synthesis of) -methyl-PGE ₁ ):

Embedded image

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

Embedded image 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)
Of acetic acid (15 ml) was kept at 70 to 80 ° C. for 20 hours to obtain compound (9-2). Purification by a silica gel column (ethyl acetate / hexane = 1/4). Yield: 0.399 g (79%)

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

Embedded image Compound (3) (0.399 g) was added to ethanol (20 ml).
Medium, reduction was carried out using 5% palladium / carbon and hydrogen gas. Purify on a silica gel column to give the title compound (9
-3) was obtained. Yield: 0.260 g (80%) n. m. r. (CDCl ₃ ) δ: 0.90 (3H, t, J =
7.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.
13-2.50 (23H, m), 2.35 (2H, t, J =
7.6 Hz), 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
Synthesis of -difluoro-17 (R) -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-−２4,
Benzyl 4-difluoro-5 (R) -methyl-3-oxooctyl {-3-hydroxy-5-oxocyclopentyl] heptanoate (10-1) was prepared in the same manner as in Example 9 to give a colorless oily compound (10-3). ). n. m. r. (CDCl ₃ ) δ: 0.92 (3H, t, J =
6.6 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.
08-2.50 (23H, m), 2.34 (2H, t, J =
7.6 Hz), 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- 17 (S), 19-dimethyl-
Synthesis of PGE ₁ ):

Embedded image

The two amides obtained from (d.l) -2,2-difluoro-3,5-dimethylhexanoic acid and (R)-(+)-phenylethylamine were separated by normal phase column chromatography. And dimethyl (3.3-difluoro-4 (S), 6-dimethyl-2) obtained by using a sample having a long retention time.
-Oxoheptyl) phosphonate (11-2)

Embedded image The title compound (11) was prepared in the same manner as in Example 5 except that
-1) was obtained. n. m. r. (CDCl ₃ ) δ: 0.86 (3H, d, J =
6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 0.
98 (2H, d, J = 7.1 Hz), 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 (1H,
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),

Embedded image

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 ):

Embedded image

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

Embedded image n. m. r. (CDCl ₃ ) δ: 0.86 (3H, d, J =
6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 0.
98 (3H, d, J = 7.1 Hz), 1.11 to 2.50 (2
2H, m), 2, 34 (2H, t, J = 7.6 Hz), 2.7
5 (2H, m), 8 to 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)

Embedded image 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.

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

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

Embedded image

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] octan-3-one (15-3)

Embedded image (1S, 5R, 6R, 7R) -6- (1S, 5R, 6R, 7R) 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] octan-3-one
(15-1) (2.285 g) in methanol (50 ml)
The title compound (15-3) was obtained using sodium borohydride in the presence of cesium chloride heptahydrate. 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 dissolved in toluene (40 ml).
The title compound (15-4) was obtained using diisobutylaluminum hydride in the middle.

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-butoxycali
(1MTHF solution, 33.8 ml) and to the ylide prepared above were added a THF solution of the compound (15-4) obtained above to obtain the title compound (15-5).

15-4 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 Benzyl (15-6)

Embedded image Compound (15-5) was converted to the title compound (15-6) using diisopropylethylamine (2.68 ml) and benzyl bromide (1.83 ml) in acetonitrile (30 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-
Oxohept-1-enyl) -5-oxo-3- (tetrahydropyranyloxy) cyclopentyl] hept-5-
Benzyl enoate (15-7)

Embedded image Compound (15-6) (1.613 g) was treated with oxazalyl chloride.
(2M dichloromethane solution, 7.14 ml) in dichloromethane (70 ml), DMSO (2.47 ml) and triethylamine (4.2 ml) were used to perform Swern oxidation. Yield: 1.218 g (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] benzyl hepto-5-enoate (1
5-8)

Embedded image Compound (15-7) (1.150 g) was treated with acetic acid, THF and water (3.
/ 1/1) It was dissolved in a mixed solvent and kept at 50 ° C for 2 hours to give the title compound (15-8). Yield: 0.812 g (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 m
In 1), hydrogenation was performed using 5% Pd-carbon to obtain the title compound (15-9). Yield: 0.5053 g (83.4%) n. m. r. (CDCl ₃ ) δ: 1.00 (6H, d, J =
6.1 Hz), 1.2 to 2.15 (20 H, m), 2.24
(1H, dd, J = 17.7 Hz, J = 11.6 Hz),
2.33 (2H, t, J = 7.1 Hz), 2.56 (1H, d
d, J = 17.7 Hz, 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 (1
6-2) (13,14-dihydro-15-keto-16,1
Synthesis of 6-difluoro-18 (R) -methyl-PGE ₁ )

Embedded image The title was the same as in Example 8 except that dimethyl {3,3-difluoro-5 (R) -methyl-2-oxoheptyl} phosphonate (16-1) prepared from (R) -2-methylbutanol was used. Compound (16-2) was obtained. n. m. r. (CDCl ₃ ) δ: 0.90 (3H, t, J =
7.1 Hz), 1.00 (3H, d, J = 6.6 Hz),
1.15 to 2.15 (22H, m), 2.25 (1H, dd,
J = 17.7 Hz, J = 11.1 Hz), 2.35 (2H,
t, J = 6.6 Hz), 2.58 (1H, dd, J = 17.
7 Hz, J = 6.6 Hz), 4.18 (1 H, m) mass m / z: 404 (M ⁺ ), 386 (M ⁺ -H
^{_{2 O), 368 (M +}} -2H 2 O),

Embedded image

Synthesis Example 17 17: 7-[(1R, 2R, 3R) -2- (4,4-difluoro-8-methyl-3-oxononyl) -3-hydroxy-5-oxocyclopentyl] heptanoic acid (17 -2)
Synthesis of (13,14-dihydro-15-keto-16,16-difluoro-20,20-dimethyl-PGE ₁ )

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 =
6.1 Hz), 1.15 to 2.15 (23H, m), 2.2
4 (1H, dd, J = 17.7 Hz, J = 11.1 Hz),
2.36 (2H, t, J = 6.6 Hz), 2.59 (1H, d
d, J = 17.7 Hz, J = 6.6 Hz), 4.18 (1
H, m) mass m / z: 502 (M ⁺ ), 484 (M ⁺ -H
₂ O),

Embedded image

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

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 =
6.6 Hz), 1.15 to 2.25 (27 H, m), 2.3
6 (2H, t, J = 7.1 Hz), 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
-Difluoro-18 (R) -methyl-PGE ₁ )

Embedded image Synthetic intermediate obtained in Example 16, 7-[(1R, 2R, 3R)
Example 6 using benzyl-2- {4,4-difluoro-6 (R) -methyl-3-oxooctyl} -3-hydroxy-5-oxocyclopentyl] heptanoate (19-1).
In the same manner as in the above, the title compound (19-2) was obtained.

Embedded image n. m. r. (CDCl ₃ ) δ: 0.88 (3H, t, J =
7.1 Hz), 0.97 (3H, d, J = 6.1 Hz),
1.1 to 2.25 (25H, m), 2.34 (2H, t, J =
6.6 Hz), 2.76 (1 H, m) mass m / z: 404 (M ⁺ ), 386 (M ⁺ -H
₂ O), 368 (M ⁺ -2H ₂ O)

Test Example 1 Crj: Wister rats (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 intraperitoneal administration of 800 mg / kg of D-galactosamine hydrochloride. Twenty-four hours after galactosamine administration, blood was collected under ether anesthesia and serum was separated. Serum was measured by 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 administered by oral gavage using an oral probe for rats 30 minutes, 2 hours, and 6 hours before the administration of galactosamine. Serum biochemical liver function tests were performed on the following four items. -Glutamate oxaloacetate transaminase (GO
T) Glutamate pyruvate transaminase (GPT) Lactate dehydrogenase (LDH) Total bilirubin (T-Bil)

On the basis of the results of the serum biochemical liver function test,
The extent to which the increase was suppressed by the administration of the test substance was determined as the inhibition rate (%) by galactosamine administration. The suppression rate was determined by the following formula.

(Equation 1) The occurrence of diarrhea and loose stool was observed until 2 hours after the third test substance administration, and the number of individuals with diarrhea and loose stool were recorded. Table 1 shows the results.

[0114]

[Table 1]

Test substance 1: 13,14-dihydro-15
-Keto-16,16-difluoro-PGE ₂ (compound described in Publication A) Test substance 2: 13,14-dihydro-15-keto-16,
16-difluoro-19-methyl-PGE ₂ (Compound of Synthesis Example 1) Based on the above results, 30% of test compound 1 which is a known compound was obtained.
While diarrhea was observed in 3/10 cases with μg / kg administration, test compound 2 which is a compound of the present invention did not show any diarrhea in all cases. Therefore, it can be seen that the test substance 2 clearly separates the diarrhea action which is a side effect of the test substance 1.

Test Example 2 The test was performed in the same manner as in Test Example 1. However, the following test substances were used. Table 2 shows the results.

[0117]

[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 test compound 3 which is a known compound showed diarrhea in 1/6 cases at 100 μg / kg administration,
While loose stool is observed in 6 cases, test compounds 4 and 5 which are compounds of the present invention do not show any diarrhea in all cases. Therefore, it can be seen that the test substances 4 and 5 clearly separate the diarrhea action which is a side effect of the test substance 3.

Test Example 3 The test was carried out in the same manner as in Test Example 1. However, the following test substances were used. Table 3 shows the results.

[0121]

[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
-Dehydroxy-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 compounds 6, 7 and 8, which are the compounds of the present invention, show no diarrhea in all cases even when administered at 1000 μg / kg. Therefore, it can be seen that the test substances 6, 7 and 8 very well separate the diarrhea action which is a side effect of the known substance.

Test Example 4 Test was carried out in the same manner as in Test Example 1. However, the following test substances were used. Table 4 shows the results.

[0125]

[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 test was performed in the same manner as in Test Example 1. However, the following test substances were used. Table 5 shows the results.

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

[0128]

Industrial Applicability The PG derivative of the present invention exhibits the same degree of improving effect on liver injury as compared with a compound having a straight chain ω known in the prior art, and has a clear side effect such as diarrhea. Are separated. Such advantages cannot be inferred from the prior art.

Continuation of front page (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 405/00 A61K 31/00 CA (STN) REGISTRY (STN)

Claims (18)

(57) [Claims] 1. A compound of the general formula (I) Wherein A is —COOH, a pharmaceutically acceptable salt thereof or an ester hydrolyzed by an esterase; B is —CH ₂ —CH ₂ —; X is a hydrogen atom or a hydroxyl group (provided that X has a hydrogen atom when it has a heavy bond); R ₁ is —CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ —
Or —CH ₂ —CH ＝ CH—CH ₂ —CH ₂ —CH ₂ —; R ₂ , R ₃ , R ₄ and R ₅ are a hydrogen atom, a methyl group or an ethyl group, 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 methylene or ethylene m is 0 or 1.]. 2. The compound represented by the general formula (I): wherein R ₁ is —CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ —
Or _{-CH 2 -CH = CH-CH 2} -CH 2 -CH 2 -; Q is A compound according to claim 1, wherein a single bond and m is 0 or 1. 3. The compound represented by the general formula (I): wherein R ₁ is —CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ —
Or _{-CH 2 -CH = CH-CH 2} -CH 2 -CH 2 -; Q is _{-CH 2 -, - CH 2 CH} 2 - and m is 0 or 1
The compound according to claim 1, which is 4. The compound according to claim 1, wherein the ester hydrolyzed by the esterase is selected from the group consisting of an aliphatic ester, an optionally substituted aryl ester and an aryl (lower) alkyl ester. . 5. The compound according to claim 4, wherein the aliphatic ester is selected from the group consisting of lower alkyl esters, lower alkenyl esters, lower alkynyl esters, hydroxy (lower) alkyl esters, lower alkoxy (lower) alkyl esters. . 6. The compound according to claim 1, wherein the compound of the formula (I) is 13,14-dihydro-15-keto-16,16-difluoro-19-methyl-PGE ₁ or PGE ₂ . 7. The compound according to claim ₁ , wherein the compound of general formula (I) is 13,14-dihydro-15-keto-16,16-difluoro-17-methyl-PGE1. 8. A compound of the formula (I) wherein the compound is 13,14-dihydro-15-keto-16,16-difluoro-17,19
The compound according to claim _1, which is -dimethyl-PGE1. 9. The compound is 13,14-dihydro-15-keto-16,16-difluoro-18-compound of claim 1 wherein the methyl -PGE ₁ of the general formula (I). 10. The compound of the general formula (I) is selected from the group consisting of 13,14-dihydro-15-keto-16,16-difluoro-18,1
The compound according to claim _1, which is 8-dimethyl-PGE1. 11. A compound of the formula (I) wherein the compound is 13,14-dihydro-15-keto-16,16-difluoro-18-
The compound according to claim _1, which is ethyl-PGE1. 12. A compound of the formula (I) wherein the compound is 13,14-dihydro-15-keto-16,16-difluoro-18-
The compound according to claim _1, which is methyl-20-nor-PGE1. 13. A compound of the formula (I) wherein the compound is 13,14-dihydro-15-keto-16,16-difluoro-20,2
The compound according to claim _1, which is 0-dimethyl-PGE1. 14. The compound of the formula (I) is selected from the group consisting of 13,14-dihydro-15-keto-11-dehydroxy-16,16
- Claim 1 difluoromethyl-19-methyl -PGE ₁
A compound as described. 15. The compound of the formula (I) is represented by the formula: 13,14-dihydro-15-keto-11-dehydroxy-16,16
- Claim 1 difluoromethyl-17-methyl -PGE ₁
A compound as described. 16. The compound of the formula (I) is selected from the group consisting of 13,14-dihydro-15-keto-11-dehydroxy-16,16
The compound according to claim _1, which is -difluoro-17,19-dimethyl-PGE1. 17. The compound of the formula (I) is represented by the formula: 13,14-dihydro-15-keto-11-dehydroxy-16,16
- Claim 1 difluoromethyl-18-methyl -PGE ₁
A compound as described. 18. The compound of the general formula (I) is selected from the group consisting of 13,14-dihydro-15-keto-11-dehydroxy-16,16
The compound according to claim _1, which is -difluoro-20,20-dimethyl-PGE1.