JPS6124369B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to formulations containing novel prostaglandin analogs.

Prostaglandins are derivatives of prostanoic acid with the following structure.

Various types of prostaglandins are known, and the type depends on the structure and substituents of the alicyclic ring. For example, prostaglandin F
The alicyclic rings of (PGF), E (PGE) and A (PGA) have the following structures.

as well as A dotted line in the above structures or in other structural formulas herein indicates that the group to which it is attached is behind the ring plane, or in the α-configuration, in accordance with generally accepted nomenclature rules; The thick line indicates that the group attached to it is in front of the ring plane, that is, in the β-configuration;
A wavy line indicates that the group attached thereto is in the α- or β-configuration.

These compounds are subclassified according to the position of the double bond on the side chain at the 8th and 12th positions of the alicyclic ring. PG-1 compounds have a trans double bond (trans-Δ ¹³ ) between C ₁₃ and C ₁₄ , and PG-2 compounds have a cis double bond between C ₅ and C ₆ and a trans double bond between C ₁₃ and C ₁₄ . It has a double bond (cis-Δ ⁵ , trans-Δ ¹³ ). For example, prostaglandin F ₁
(PGF ₁ 〓) and prostaglandin E ₁ (PGE ₁ ) are represented by the following structural formulas () and ().

as well as The structural formulas of PGF ₂ 〓 and PGE ₂ as compounds of the PG-2 group correspond to those in which a cis double bond exists between the carbon atoms at the 5th and 6th positions in the structural formulas () and ().

Compounds of the PG-1 group in which the carbon atoms at the 13th and 14th positions are replaced with ethylene (-CH ₂ CH ₂ -) are dihydroprostaglandins, such as dihydroprostaglandins F ₁ (dihydro-
PGF ₁ 〓) and dihydroprostaglandin E ₁
(dihydro-PGE ₁ ).

Furthermore, when one or more methylene groups are added to or removed from the aliphatic group at position 12 of the cycloaliphatic ring of the prostaglandin, the compound is classified according to the general rules of organic nomenclature. Known as prostaglandins (when a methylene group is added) or nor-prostaglandins (when a methylene group is removed), and when more methylene groups are added or removed. The number is indicated by the prefix ``homo'' or ``nor'', such as ``di-'' or ``tri-''.

Prostaglandins generally have pharmacological properties. For example, they have antihypertensive effects, diuretic effects, platelet aggregation inhibitory effects, gastric acid secretion and gastrointestinal ulcer inhibitory effects, bronchodilator effects, lipolysis inhibitory effects, smooth muscle contraction stimulating effects, luteal regression effects, and egg deposition effects. Has a bed inhibiting effect. Therefore, treatment of hypertension, peripheral circulation disorders, asthma and gastric ulcers,
It is effective in treating and preventing thrombosis and myocardial infarction, inducing labor and abortion in pregnant mammals, improving fertilization in female mammals, regulating estrus, contraception and normalizing menstruation, and is also effective as a diuretic. They are fat-soluble substances that exist in extremely small amounts in each tissue that secretes prostaglandins into the living body of an animal.

For example, PGE and PGA inhibit gastric acid secretion and are therefore used to treat gastric ulcers. They are also effective in preventing arteriosclerosis and hyperlipidemia because they inhibit the release of free fatty acids caused by epinephrine and thus lower the free fatty acid concentration in the blood. PGE ₁ suppresses platelet aggregation, removes blood clots, and prevents thrombosis. PGE and PGF have smooth muscle stimulatory effects and increase intestinal spiral movement. These effects indicate that it is effective in treating post-surgical intestinal obstruction and as a laxative. Furthermore, with PGE
PGF is used as a labor stimulant, an abortifacient during early and mid-pregnancy, and expulsion of the placenta after birth, and is also used as an oral contraceptive to regulate the estrous cycle in female mammals. PGE and PGA have vasodilatory and diuretic effects, and because they increase cerebral blood flow, they are effective in improving diseases of the cerebral vascular system.
It is also effective in treating asthma due to its bronchodilatory action.

Over the past decade there has been a wide range of efforts to find new compounds that have the pharmacological effects of "natural" prostaglandins, or that have stronger activity in one or more of their properties, or that have completely unknown activities. Research has been conducted.

As a result of intensive research by the present inventors, the compound of the present application has an extremely effective pharmacological effect unique to prostaglandins, particularly the activity of stimulating uterine muscle contraction and the activity of inhibiting abortion, luteal involution, and egg implantation. It has further been discovered that the compounds of the present invention are useful as agents for abortion and induction of labor in pregnant mammals and for contraception and induction of menstruation in female mammals, i.e., as myometrial contraction agents, or The present invention has been based on the discovery that the present invention is useful as a drug for inducing abortion and labor in women, improving fertility in female mammals, regulating estrus, synchronizing the estrous cycle, contraceptives, and inducing menstruation, that is, as a luteostatic agent. completed.

According to the invention, the general formula [In the formula, B represents an oxygen atom or a sulfur atom,
R ¹ and R ² are the same or different, and each represents a hydrogen atom, a halogen atom, or a trifluoromethyl group, and R is of the formula -
A group represented by COOR ³ (wherein R ³ represents a straight-chain alkyl group having 1 to 12 carbon atoms) or the formula -
represents a group represented by CH ₂ OH, 〓 represents α-configuration or β-configuration or a mixture thereof;
The double bonds between C ₂ and C ₃ , between C ₅ and C ₆ , and between C ₁₃ and C ₁₄ are trans, cis, and trans, respectively. ] The novel prostaglandin-like compound represented by and the cyclodextrin clathrate of such prostaglandin-like compound have been shown to have strong uterine muscle contraction activity and abortifacient, corpus luteum involution, and egg implantation inhibiting activity in animal experiments. was found to have the following.

In the general formula (), B is an oxygen atom,
Preferably, R ¹ is a hydrogen atom, R ² is a hydrogen atom, a chlorine atom, or a trifluoromethyl group, and R ³ is a straight-chain alkyl group having 1 to 4 carbon atoms (particularly a methyl group). Also, in equation (), α−
Alternatively, the hydroxyl group expressed in the β-configuration is preferably in the α-configuration.

The results of the animal experiments are shown below. For example, in laboratory experiments, (i) 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester, 16-phenoxy-17, 18,19,20-tetranor-trans-
Δ ² -PGF ₂ 〓Methyl ester, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓Methyl ester, 16-(3
-chlorophenoxy)17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓alcohol, 16-
phenoxy-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓alcohol and 16-phenylthio-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓methyl ester, respectively, per day. When administered subcutaneously on the 3rd, 4th and 5th day of pregnancy at doses of 50, 10, 20, 100, 50 and 200 μg/Kg of animal body weight, egg implantation in pregnant rats was inhibited in all cases, (ii ) 16−
(3-trifluoromethylphenoxy)-17, 18,
19,20-tetranor-trans-Δ ² -PGF ₂ 〓
Methyl ester, 16-phenoxy-17, 18, 19,
20-tetranor-trans-Δ ² -PGF ₂ 〓methyl ester and 16-(3-chlorophenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ 〓Methyl ester 10 each per day,
When 2 and 5.0 μg/Kg of animal body weight were administered, an abortive effect was observed in all animals, and (iii) in an experiment on the effect of luteal regression, [pregnancy (the day when sperm was confirmed was defined as day zero of pregnancy)5 On day 1, the uterus of the rat is removed, and the compound used in the experiment is administered subcutaneously from the second day after hysterectomy. The luteal period is observed by plaque examination. The compound is administered daily until the first oestrus occurs, and the compound is considered to have a luteal regression effect when the first oestrus occurs within 5 days after the start of administration. ], 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-
Δ ² -PGF ₂ 〓Methyl ester, 16-phenoxy-17,18,19,20-tetranor-trans-Δ ²
-PGF ₂ 〓Methyl ester and 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓Methyl ester at 0.2, 0.1 and 0.5 μg/Kg animal per day, respectively. showed a luteal regression effect in 60% of the number of animals tested at the dose of body weight, (iv)
16-(3-trifluoromethylphenoxy)-17,
18,19,20-tetranor-trans-Δ ² −
PGF ₂ 〓Methyl ester, 16-phenoxy-17,
18,19,20-tetranor-trans-Δ ² −
PGF ₂ 〓Methyl ester, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓Methyl ester, 16-(3-chlorophenoxy)-17,18 ,19,20-tetranol-
When trans-Δ ² -PGF ₂ 〓alcohol and 16-phenoxy-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓alcohol were administered intravenously to female rats on the 20th day of pregnancy, 50% of each ,2
Doses of ~5, 2, 5-10 and 2-5 μg/Kg animal body weight stimulated myometrial contractions in all pregnant rats. These compounds also have relatively low diarrheal activity compared to their activity with regard to the valuable pharmacological properties mentioned above. For example, when administered orally to rats, the amount of 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranol-trans-Δ required to cause diarrhea in 50% of the rats is ² -PGF ₂ 〓Methyl ester, 16-phenoxy-17,18,19,20-tetranor-trans-
Δ ² -PGF ₂ 〓Methyl ester, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓Methyl ester and 16-
(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ The dosage of alcohol is 1-5, 0.47, 0.62 and 0.74μ, respectively.
g/Kg animal weight. Also, its acute toxicity is relatively low compared to its valuable pharmacological properties. For example, when administered intravenously to rats, 7
16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester required to cause mortality in 50% of the mice after 1 day. , 16-phenoxy-17,18,19,20-tetranor-trans-Δ
The dosages of ^2- PGF ₂ methyl ester and 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester were 120, 0.35 and 14 mg/Kg, respectively. It was the weight of the animal.

The compound of general formula () can be produced by the method described in JP-A-52-25745, which the present inventors have already synthesized and are currently applying for.

Effective administration methods for the present invention include oral, intravaginal, subcutaneous, intrauterine, intravenous, intramuscular and extra-amniotic administration.

Solid formulations for oral administration include tablets, pills, powders and granules. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as calcium carbonate, potato starch, alginic acid, mannite or lactose. The formulations may contain additives other than diluents, for example lubricants such as magnesium stearate, in a conventional manner. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, including commonly used inert diluents such as water or liquid paraffin. including. In addition to inert diluents, the formulations may also contain auxiliary agents, such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or preservatives. Preparations for oral administration according to the invention also include capsules of absorbable materials such as gelatin with or without one or more active substances and diluents or excipients. Solid formulations for rectal administration include suppositories containing one or more active substances and formulated in a manner known per se.

Solid formulations for intravaginal administration include petusari containing one or more active substances and formulated by methods known per se.

Products for parenteral administration according to the invention include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Non-aqueous solvents or suspending agents include:
Examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate. Such formulations can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of disinfectants, or by irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use.

The content of active substance in the formulations according to the invention can be varied and the proportions should be adjusted so as to obtain a dosage suitable for the desired therapeutic effect. Of course, several units of dosage can be administered at approximately the same time. In general, the products will usually contain at least 0.025% by weight of active substance when administered by injection and at least 0.1% by weight of active substance for oral administration. The dosage used depends on the desired therapeutic effect, the method of administration, and the duration of treatment.

In adults (or adult animals), the dosage per person (or animal) is generally for the purpose of abortion and induction of labor in pregnant female mammals, including humans, and for the fertility rate of female mammals, including humans. Oral, intravaginal, intrauterine, intravenous, subcutaneous, intramuscular, and extra-amniotic administration for improvement of oestrus, regulation of estrus, synchronization of sexual cycle, contraception, and induction of menstruation is from 0.05 μg to 50 mg.

Next, the present invention will be explained in more detail with reference to the following examples.

Example 1 16-phenoxy dissolved in 10 ml of ethanol
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ = 2 mg of methyl ester and 18.5 g of mannitol
Mix and pass through a 30-mesh sieve at 30℃ at 90℃.
After drying for a minute, pass through a 30-mesh sieve, add 200 mg of Aerosil (Micropore Silica), fill 100 No. 2 hard gelatin capsules, and fill each capsule with 20 μg of 16-phenoxy-17.
18,19,20-tetranor-trans-Δ ² −
Gastric soluble capsules containing PGF ₂ methyl ester were obtained.

Example 2 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF 2 dissolved in 10 ml of ethanol ₂ mg of alcohol was mixed with 18.5 g of mannitol, and 30-mesh Pass through a sieve, dry at 30°C for 90 minutes, pass through a 30-mesh sieve, and apply Aerosil (microfine silica).
Add 200 mg of 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓alcohol. Gastric soluble capsules containing the following were obtained.

Example 3 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ = Add 500 mg of methyl ester, 2 g of carboxymethyl cellulose calcium, 0.2 g of silicon dioxide, 0.2 g of stearic acid, 2 g of magnesium stearate, and dried mannitol to make 100 g. Mix thoroughly until homogeneous, then use a mortar with a diameter of 6.5 mm using a conventional method. 1000 tablets containing 0.5 mg of active substance in each tablet were obtained by direct compression using the same method.

Example 4 16-(3-chlorophenoxy)-17, 18, 19, 20
Using 400 mg of -tetranor-trans-Δ ² -PGF ₂ methyl ester, 1000 tablets each containing 0.4 mg of the active substance were obtained in the same manner as in Example 3.

Example 5 16-phenoxy-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ = 70 mg of alcohol
Add the solution dissolved in 1 ml of ethanol to 80 g of Witepsol S-52 dissolved at 30 to 40°C, mix well until homogeneous, and then add 0.9 ml using the usual method.
containers to obtain 100 petusari containing 0.7 mg of active substance in each tablet.

Example 6 16-(3-chlorophenoxy)-17, 18, 19, 20
Using 60 mg of -tetranor-trans-Δ ² -PGF ₂ methyl ester, 100 petals containing 0.6 mg of the active substance in each tablet were obtained in the same manner as in Example 5.

Example 7 16-phenylthio-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓Methyl ester 50
mg dissolved in 10 ml of ethanol to a thickness of 0.25 mm.
0.1 ml per 100 sheets of silicone rubber with an area of 10 cm ² and 100 mm, dried under reduced pressure, pasted together two sheets using appropriate gelatin as an adhesive, and then metal-packed using the usual method. Each piece contains 1 mg of active substance. Obtained 50 silicone rubber petusari including.

Example 8 α-Cyclodextrin in 300ml of distilled water for injection
Dissolve 1.75g and then 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-
70 mg of Δ ² -PGF ₂ methyl ester was added and thoroughly stirred to dissolve. After sterilization, the solution was lyophilized to give 16-(3-chlorophenoxy)-17, 18,
19,20-tetranor-trans-Δ ² -PGF ₂ 〓
1.82 g of powder of α-cyclodextrin clathrate of methyl ester was obtained.

600ml of pre-warmed distilled water for injection
1.8g of methylparaben and propylparaben
After cooling, 50 g of propylene glycol, 0.53 g of anhydrous sodium carbonate and 2.1 g of anhydrous citric acid were added and dissolved.
1.82 g of α- ^cyclodextrin clathrate _of methyl ester was added and dissolved. Add distilled water for injection to make a total volume of 1
After sterilization, 1 ml was dispensed into 1 ml sterile ampoules to obtain 1000 injections containing 0.07 mg of the active substance.

Example 9 α-cyclodextrin clathrate of 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester obtained in the same manner as in Example 8 Using 20.8 g, 1000 injections containing 0.8 mg of active substance per ampoule were obtained in the same manner as in Example 8.

Example 10 α-cyclodextrin clathrate of 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester obtained in the same manner as in Example 8 Using 3.25 g, 1000 injections containing 0.125 mg of active substance per ampoule were obtained in the same manner as in Example 8.

Example 11 The injection prepared in Example 9 was intramuscularly administered once to 50 cows weighing 276 to 576 kg, which were diagnosed by rectal examination to be 5 days or more after ovulation.
As a result, estrus occurred in 90.2% of the mice within 5 days after treatment, and ovulation occurred in 94% of the mice within 6 days. The pregnancy rate during the estrous period synchronized in this way was 68.0%.

Example 12 The injection prepared in Example 8 was intramuscularly administered once to each of 15 pregnant pigs on day 111, day 112, and day 113 of pregnancy. As a result, the time required from administration to the start of labor was 26.50±6.09 hours in all cases, with labor concentrated on the day after administration. In the control natural birth
It lasted between 111 and 118 days. In addition, the survival rate of farrowed piglets was good, exceeding 96%, and no adverse effects were observed on return of sows to heat or conception rates after weaning.

Example 13 Example 9 for 18 aestrous cows due to permanent corpus luteum
After one injection of the injectable solution manufactured in 2008 was administered intramuscularly, 17 (94.4%) of the cows came into heat, and 16 of them were artificially inseminated and 11 (61.1%) of the cows became pregnant.

Example 14 When the injection prepared in Example 9 was intramuscularly administered once to 51 anoestrous cows due to ovarian insufficiency, 40 cows (78.4%) came into oestrus, of which 25 cows came into oestrus.
Artificial insemination was performed on the head, and 24 (47.0%) became pregnant.

Example 15 When the injection prepared in Example 10 was intramuscularly administered once to six female sheep weighing 56.5 to 70.2 kg, all sheep developed estrus by the second day, and this first estrus was observed. 5 (83.3%) were conceived during mating.

The following reference example shows the production of prostaglandin-like compounds, which are the active ingredients of the present invention, in which "IR", "NMR" and "TLC" are respectively "infrared absorption spectrum" and "nuclear magnetic resonance spectrum". spectrum” and “thin layer chromatography”.
Solvent ratios in chromatography are volume ratios.

Reference example 1.1 9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprostasis-5, trans −13−
Dienoic acid methyl ester 9α-acetoxy-11α-(2-tetrahydropyranyloxy)-15 dissolved in 3.18 ml methanol
α-Hydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprostasis-5, trans-13-dienoic acid methyl ester (JP-A-50-123642) 137 mg of potassium carbonate was added to 481 mg of potassium carbonate, stirred at 40°C for 2.5 hours, neutralized with 1.69 ml of 1N hydrochloric acid, diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution and brine, After drying over magnesium sulfate and concentrating under reduced pressure, 447 mg of the title compound having the following physical properties was obtained.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.2.

IR (liquid film method) ν: 3400, 2940, 1740, 1600,
1500,980cm ^-1 .

NMR (CCl ₄ solution) δ: 7.7−6.9 (4H, m), 6.1
−5.55 (2H, m), 5.55−5.0 (2H, m).

Reference example 1.2 2-phenylzeleno-9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprosta-
Cis-5, trans-13-dienoic acid methyl ester 0.391 ml of diisopropylamine dissolved in 7 ml of tetrahydrofuran was cooled to -78°C, and 2.08 ml of 1.35 molar n-butyllithium dissolved in n-hexane was added dropwise to -78 The mixture was stirred at ℃ for 15 minutes to obtain lithium diisopropylamide. 9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)- was dissolved in 3 ml of tetrahydrofuran at -78°C to the obtained lithium diisopropylamide.
16-(3-trifluoromethylphenoxy)-17,
18,19,20-tetranorprostasi-5, trans-13-dienoic acid methyl ester (reference example
Manufactured with 1.1. ) 447 mg was added dropwise over 10 minutes and stirred at the same temperature for 20 minutes, then 920 mg of diphenyl diselenide dissolved in 4 ml of tetrahydrofuran was added dropwise and stirred at the same temperature for 1 hour. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, an aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (5:1) as an eluent to obtain 219 mg of the title compound having the following physical properties.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.3.

Reference example 1.3 9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprosta-trans-2,cis -5,
Trans-13-trienoic acid methyl ester 2-phenylzeleno- dissolved in 8 ml of a mixed solvent of ethyl acetate and tetrahydrofuran (1:1)
9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprostasi-5, trans-13- Dienic acid methyl ester (produced in Reference Example 1.2) 219 mg
Add 0.191 ml of 30% hydrogen peroxide to the solution and stir at 30°C for 40 minutes, then pour into water. The organic layer is washed with an aqueous sodium carbonate solution, water, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. 198 mg of the title compound with properties were obtained.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.18.

IR (liquid film method) ν: 3400, 2440, 1730, 1660,
1600, 1500, 980cm ^-1 .

NMR (CCl ₄ solution) δ: 7.6−6.3 (5H, m), 6.2
−5.0 (5H, m).

Reference example 1.4 9α, 11α, 15α-trihydroxy-16-(3
-trifluoromethylphenoxy)-17, 18,
19,20-tetranorprosta-trans-2,
Cis-5, trans-13-trienoic acid methyl ester [16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester] in 5 ml of tetrahydrofuran Melted 9α, 15α
-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprosta-trans-2, cis-5, trans-13 -Trienoic acid methyl ester (produced in Reference Example 1.3)
To 198 mg was added 2 ml of 1N hydrochloric acid, stirred at 40°C for 1 hour, poured into water, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was eluted with ethyl acetate.
Purification by silica gel column chromatography using cyclohexane (1:1) gave 64 mg of the title compound with the following physical properties.

TLC (developing solution, chloroform:tetrahydrofuran:acetic acid=10:2:1) Rf=0.21.

IR (liquid film method) ν: 3350, 2900, 1720, 1660,
1600, 1500, 980cm ^-1 .

NMR (CDCl ₃ solution) δ: 7.50−7.08 (4H, m),
6.42 (1H, d-t), 5.80 (1H, d), 5.77-
5.60 (2H, m), 5.60−5.20 (2H, m), 4.65
−4.35 (1H, m).

Reference example 2.1 9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-phenoxy-
17, 18, 19, 20-tetranorprostasis-
5. Trans-13-dienoic acid methyl ester 9α-acetoxy- dissolved in 8 ml of methanol
11α-(2-tetrahydropyranyloxy)-15α
-Hydroxy-16-phenoxy-17, 18, 19, 20
-tetranorprostasis-5, trans-13
-200 mg of potassium carbonate was added to 701 mg of dienoic acid methyl ester (produced by the method described in Reference Example 24 of JP-A-50-123642), stirred at 50°C for 1 hour, neutralized with acetic acid, and diluted with ethyl acetate. It was diluted, washed with water, aqueous sodium carbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 655 mg of the title compound having the following physical properties.

TLC (Developing solution, benzene: ethyl acetate = 1:
1) Rf=0.38.

IR (liquid film method) ν: 3450, 2940, 2860, 1730,
1595, 1580, 1485, 1425, 1240, 1165,
1125, 1065, 1030, ^{965 cm -1} .

NMR (CDCl ₃ solution) δ: 7.65−6.60 (5H, m),
5.90−5.56 (2H, m), 5.56−5.20 (2H,
m), 4.95-4.30 (2H, m), 4.30-3.20
(9H, m).

Reference example 2.2 9α,11α,15α-tris(2-tetrahydropyranyloxy)-16-phenoxy-17,18,
19,20-tetranorprostasis-5,trans-13-dienoic acid methyl ester 9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-phenoxy-17,18 dissolved in 10 ml of methylene chloride ,19,20-tetranorprostasis-5,trans-13-dienoic acid methyl ester (produced in Reference Example 2.1)
647 mg with 3 mg of p-toluenesulfonic acid and 2,3
- 0.4 ml of dihydropyran was added, stirred at room temperature for 30 minutes, neutralized with an aqueous sodium bicarbonate solution, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (6:1) as an eluent to obtain 735 mg of the title compound having the following physical properties.

TLC (developing solvent, benzene: ethyl acetate = 1:
1) Rf=0.65.

IR (liquid film method) ν: 2940, 2865, 1740, 1600,
1585, 1495, 1450, 1435, 1355, 1245,
1200, 1130, 1075, 1020, ^{980cm -1} .

NMR (CCl ₄ solution) δ: 7.50−6.45 (5H, m),
5.90−5.05 (4H, m), 4.95−4.20 (4H,
m), 4.20−2.95 (13H, m).

Reference example 2.3 2-phenylzeleno-9α, 11α, 15α-tris(2-tetrahydropyranyloxy)-16-
Phenoxy-17,18,19,20-tetranorprostasis-5, trans-13-dienoic acid methyl ester 0.27 ml of diisopropylamine dissolved in 10 ml of tetrahydrofuran was cooled to -78°C, and 1.4 mol was dissolved in n-hexane. Concentration of n-butyllithium 1.2
ml was added dropwise and stirred at the same temperature for 15 minutes to obtain lithium diisopropylamide. To the obtained lithium diisopropylamide was added 9α, 11α, 15α-tris (2
-Tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprostasis-5,trans-13-dienoic acid methyl ester (produced in Reference Example 2.2) 723mg was added dropwise to the same amount. 20 in
After stirring for a minute, 530 mg of diphenyl diselenide dissolved in 8 ml of tetrahydrofuran at -78°C was added dropwise at the same temperature for 30 minutes. The mixture was further stirred for 30 minutes at room temperature ^cm2 , acidified with dilute hydrochloric acid, extracted with ethyl acetate, and the extract was The mixture was washed with water, an aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure.
The residue was used as an elution solvent with benzene-ethyl acetate (9:
1) was purified by silica gel column chromatography to obtain the title compound having the following physical properties:
Obtained 665 mg.

TLC (developing solvent, benzene: ethyl acetate = 3:
1) Rf=0.63.

IR (liquid film method) ν: 2950, 2880, 1740, 1602,
1590, 1495, 1438, 1355, 1250, 1200,
1135, 1075, 1020, ^{980cm -1} .

NMR (CCl ₄ solution) δ: 7.80−6.60 (10H, m),
6.00−5.03 (4H, m), 5.03−4.32 (4H,
m), 4.32−3.05 (13H, m).

Reference example 2.4 9α, 11α, 15α-(2-tetrahydropyranyloxy)-16-phenoxy-17, 18, 19, 20
-tetranorprosta-trans-2,cis-
5. Trans-13-trienoic acid methyl ester Mixed solvent of ethyl acetate and methanol (3:2)
2-phenylzeleno-9α,11 dissolved in 10ml
α,15α-tris(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprostasi-5, trans-13-dienoic acid methyl ester (produced in Reference Example 2.3). )
0.7 ml of 30% hydrogen peroxide was added to 665 mg, stirred at 30°C for 1 hour, diluted with ethyl acetate, washed with water, an aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (9:1) as the eluent to obtain the title compound 392- having the following physical properties.

TLC (developing solvent, benzene: ethyl acetate = 3:
1) Rf=0.58.

IR (liquid film method) ν: 2940, 2860, 1725, 1650,
1600, 1585, 1490, 1435, 1325, 1245,
1200, 1130, 1075, 1030, 1020 ^{, 980cm -1} .

NMR (CCl ₄ solution) δ: 7.75−6.50 (6H, m),
6.20−5.15 (5H, m), 5.10−4.40 (4H,
m), 4.40−3.18 (13H, m), 3.18−2.75
(2H, m).

Reference example 2.5 9α,11α,15α-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-trans-2, cis, -5, trans-13-
Trienoic acid methyl ester [16-phenoxy-
17,18,19,20-tetranor-trans- ^Δ2
-PGF ₂ 〓Methyl ester〓Tetrahydrofuran 0.5ml and 65% acetic acid water 5ml
9α,11α,15α-tris(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprosta-trans-2, cis-5, trans-13- dissolved in a mixed solvent of Trienoic acid methyl ester (produced in Reference Example 2.4) 390
After stirring the mixture at 60° C. for 1 hour, the mixture was diluted with ethyl acetate, washed with water, an aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane-ethyl acetate (2:3) as an eluent to obtain 171 mg of the title compound having the following physical properties.

TLC (developing solvent, ethyl acetate) Rf = 0.30.

IR (liquid film method) ν: 3400, 3020, 2940, 1725,
1655, 1600, 1590, 1495, 1435, 1335,
1280, 1250, 1175, 1080, 1045 ^{, 975cm -1} .

NMR (CDCl ₃ solution) δ: 7.45−6.66 (6H, m),
5.96−5.20 (5H, m), 4.63−4.35 (1H,
m), 4.25−3.78 (4H, m), 3.69 (3H,
s), 2.95 (2H, t) Reference example 3.1 9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-(3-chlorophenoxy)-17,18,19,20-tetranorprosta -cis-5, trans-13-dienoic acid methyl ester 9α-acetoxy-11 in the same manner as in Reference Example 2.1
α-(2-tetrahydropyranyloxy)-15α-
Hydroxy-16-(3-chlorophenoxy)-17,
From 845 mg of 18,19,20-tetranorprostasi-5,trans-13-dienoic acid methyl ester (produced by the method described below), 776 mg of the title compound having the following physical properties was obtained.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.28.

IR (liquid film method) ν: 3450, 2950, 2870, 1740,
1600, 1580, 1480, 1435, 1250, 1135,
1075, 1030, 975 cm ^-1 .

NMR (CCl ₄ solution) δ: 7.45−6.50 (4H, m),
5.90−5.50 (2H, m), 5.50−5.05 (2H,
m), 4.95-4.20 (2H, m), 4.20-3.10
(9H, m), 2.90 (2H, s).

9α-acetoxy-11α-(2-tetrahydropyranyloxy)-15α-hydroxy-16-(3-chlorophenoxy)17,18,19,20-tetranorprostasis used as starting material in the above method -5, trans-13-dienoic acid methyl ester was produced as follows.

25.6 g of 3-chlorophenol was added dropwise to a sodium ethoxide solution prepared from 4 g of sodium and 150 ml of ethanol, stirred at room temperature for 30 minutes, and then 16 g of ethyl bromoacetate was added dropwise at room temperature.
After refluxing for an hour, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution, water, and brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 9.2 g of ethyl (3-chlorophenoxy) acetate having the following physical properties. .

NMR (CCl ₄ solution) δ: 7.3−6.5 (4H, m), 4.50
(2H, s), 4.19 (2H, q), 1.26 (3H,
t).

Add n- to 16 g of dimethylphosphonate dissolved in 200 ml of anhydrous tetrahydrofuran while keeping at -60℃.
100 ml of 1.3 molar n-butyllithium dissolved in hexane was added dropwise, stirred for 15 minutes, and then ethyl lithium (3
11.9 g of -chlorophenoxy)acetate (prepared above) was added dropwise and stirred at -70°C for 2 hours and at 4°C overnight, then adjusted to pH 4 with acetic acid and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was distilled under vacuum to give dimethyl 2-oxo-3-(3-chlorophenoxy)propylphosphonate having the following physical properties 12.0 I got g.

Boiling point: 175℃-180℃/0.1-0.05mmHg.

NMR (CCl ₄ solution) δ: 7.35−6.5 (4H, m),
4.70 (2H, s), 3.72 (H, d), 3.18 (2H,
d).

1.03 g of sodium hydride (63% content) suspended in 120 ml of anhydrous tetrahydrofuran under nitrogen atmosphere
While stirring at 30°C, add 8.76 g of dimethyl 2-oxo-3-(3-chlorophenoxy)propylphosphonate (prepared above) dissolved in 40 ml of tetrahydrofuran, stir for 20 minutes, and then add 1α- dissolved in 40 ml of tetrahydrofuran. Acetoxy
2α-(6-methoxycarbonylhex-cis-
Add 4.16 g of 2-enyl)-3β-formyl-4α-(2-tetrahydropyranyloxy)-cyclopentane (produced by the method described in Reference Example 19 of JP-A-50-123642) and heat to 1.5 g at 30°C. After stirring for 1 hour at 45°C and 2 hours at 60°C, the mixture was acidified with acetic acid, filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (20:1, 15:1, 10:1 and 8:1) as the eluent to obtain 9α-acetoxy- 11α
-(2-tetrahydropyranyloxy)-15-oxo-16-(3-chlorophenoxy)-17, 18, 19,
20-tetranorprostasis-5, trans-
2.94 g of 13-dienoic acid methyl ester was obtained.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.78.

IR (liquid film method) ν: 3000, 2930, 2850, 1740,
1695, 1625, 1600, 1585, 1480, 1250,
1050, 980, 700 cm ^-1 .

NMR (CDCl ₃ solution) δ: 7.45−6.4 (6H, m),
5.7-5.25 (2H, m), 5.25-5.0 (1H, m),
4.80 (2H, s), 4.75−4.4 (1H, m), 3.70
(3H, s), 2.10 (3H, s).

9α-acetoxy-11α dissolved in 50 ml of a mixed solvent of methanol and tetrahydrofuran (1:1)
-(2-tetrahydropyranyloxy)-15-oxo-16-(3-chlorophenoxy)-17, 18, 19,
20-tetranorprostasis-5, trans-
760 mg of sodium borohydroxide was added to 2.87 g of 13-dienoic acid methyl ester (prepared above).
The mixture was carefully added at a temperature of 40°C to -45°C, stirred for 10 minutes, adjusted to pH 4 with acetic acid, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was eluted with benzene.
Purification by silica gel column chromatography using ethyl acetate (3:1) yielded 9α-acetoxy-11α-(2-tetrahydropyranyloxy)-15
α-hydroxy-16-(3-chlorophenoxy)-
17, 18, 19, 20-tetranorprostasis-
5. Trans-13-dienoic acid methyl ester
1.05 g and 1.16 g of its 15β-hydroxy isomer were obtained. The 15α-hydroxy compound had the following physical properties.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.38 (15β-hydroxy isomer Rf=
0.45).

IR (liquid film method) ν: 3430, 2925, 2850, 1740,
1600, 1585, 980, 780, ^{700cm -1} .

NMR (CDCl ₃ solution) δ: 7.4−6.7 (4H, m),
5.95−5.65 (2H, m), 5.65−5.3 (2H,
m), 5.3-4.9 (1H, m), 4.9-4.4 (2H,
m), 4.0 (2H, d), 3.72 (3H, s), 2.10
(3H, s).

Reference example 3.2 9α,11α,15α-tris(2-tetrahydropyranyloxy)-16-(3-chlorophenoxy)-17,18,19,20-tetranorprosta-
Cis-5, trans-13-dienoic acid methyl ester 9α,15α-dihydroxy-11α-(2-tetrahydropyranyloxy)-16-(3-chlorophenoxy)-17,18,
From 776 ml of 19,20-tetranorprostasis-5, trans-13-dienoic acid methyl ester (produced in Reference Example 3.1), 1063 mg of the title compound was obtained as a crude product. The obtained crude product was purified by silica gel column chromatography using benzene-ethyl acetate (9:1) as an elution solvent to obtain 937 mg of the title compound having the following physical properties.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.52.

IR (liquid film method) ν: 2950, 2870, 1740, 1600,
1580, 1480, 1440, 1355, 1255, 1200,
1160, 1135, 1080, 1035, ^{1025, 980cm -1} .

NMR (CCl solution) δ: 7.45-6.50 (4H, m),
5.95−5.10 (4H, m), 5.00−4.30 (4H,
m), 4.30−3.05 (13H, m).

Reference example 3.3 2-phenylzeleno-9α,11α-15α-tris(2-tetrahydropyranyloxy)-16-
(3-chlorophenoxy)-17,18,19,20-tetranorprostasis-5, trans-13-
Dienic acid methyl ester 1.4 molar n-butyryl lithium 2 dissolved in n-hexane by cooling 0.45 ml of diisopropylamine dissolved in 10 ml of tetrahydrofuran to -78°C
ml was added dropwise and stirred at the same temperature for 15 minutes to obtain lithium diisopropylamide. 9α, 11α, 15α-tris(2-tetrahydropyranyloxy)-16-(3
-chlorophenoxy)-17,18,19,20-tetranorprostasi-5, trans-13-dienoic acid methyl ester (produced in Reference Example 3.2) 937
After adding mg dropwise and stirring for 20 minutes at the same temperature, −78
Add dropwise 900 mg of diphenyl diselenide dissolved in 5 ml of tetrahydrofuran at -78°C, stir for 30 minutes at room temperature, acidify with diluted hydrochloric acid, extract with ethyl acetate, and add the extract to water and an aqueous sodium bicarbonate solution. The mixture was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (9:1) as an eluent to obtain 736 mg of the title compound having the following physical properties.

TCL (developing solvent, benzene: ethyl acetate = 3:
1) Rf=0.57.

IR (liquid film method) ν: 3070, 2950, 2870, 1735,
1597, 1580, 1475, 1435, 1350, 1245,
1200, 1155, 1130, 1070, ^{1020, 980cm -1} .

NMR (CCl ₄ solution) δ: 7.72−6.45 (9H, m),
6.00−5.02 (4H, m), 5.02−4.28 (4H,
m), 4.28−3.00 (13H, m).

Reference example 3.4 9α,11α,15α-tris(2-tetrahydropyranyloxy)-16-(3-chlorophenoxy)-17,18,19,20-tetranorprosta-
trans-2, cis-5, trans-13-trienoic acid methyl ester 2-phenylzeleno-
9α,11α,15α-tris(2-tetrahydropyranyloxy)-16-(3-chlorophenoxy)-
17, 18, 19, 20-tetranorprostasis-
5, 510 mg of the title compound having the following physical properties was obtained from 736 mg of trans-13-dienoic acid methyl ester (prepared in Reference Example 3.3).

TLC (developing solvent, benzene: ethyl acetate = 3:
1) Rf=0.50.

IR (liquid film method) ν: 2960, 2880, 1730, 1655,
1595, 1580, 1480, 1435, 1325, 1280,
1200, 1160, 1135, 1080, 1035, 1025, 985
cm ^-1 .

NMR (CCl ₄ solution) δ: 7.40−6.50 (5H, m),
6.00−5.10 (5H, m), 4.93−4.30 (4H,
m), 4.30-3.10 (13H, m), 3.10-2.70
(2H, m).

Reference example 3.5 9α, 11α, 15α-trihydroxy-16-(3
-chlorophenoxy)-17,18,19,20tetranorprosta-trans-2,cis-5,trans-13-trienoic acid methyl ester [16-
(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester] Tetrahydrofuran 1 was prepared in the same manner as in Reference Example 2.5.
9α dissolved in a mixed solvent of ml and 65% acetic acid water 10ml,
11α,15α-tris(2-tetrahydropyranyloxy)-16-(3-chlorophenoxy)-17,
18,19,20-tetranorprosta-trans-
From 510 mg of 2, cis-5, trans-13-trienoic acid, methyl ester (prepared in Reference Example 3.4), 230 mg of the title compound having the following physical properties was obtained.

TLC (developing solvent, ethyl acetate) Rf = 0.32.

IR (liquid film method) ν: 3400, 3030, 2940, 1720,
1655, 1600, 1580, 1480, 1435, 1335,
1290, 1175, 1040, ^{975 cm -1} .

NMR (CDCl ₃ solution) δ: 7.40−6.60 (5H, m),
5.97-5.20 (5H, m), 4.64-4.33 (1H,
m), 4,30−3.79 (4H, m), 3.69 (3H,
s), 2.95 (2H, t).

Reference example 4 16-phenoxy-17,18,19,20-tetranorprosta-trans-2, cis-5, trans-13-triene-1,9α,11α,15α-tetrol [16-phenoxy-17,18 ,19,20-tetranor-trans-Δ ² -PGF ₂ 〓alcohol] 16-phenoxy- dissolved in 8 ml of anhydrous toluene
17,18,19,20-tetranor-trans- ^Δ2-
64 mg of PGF ₂ methyl ester (synthesized in Reference Example 2.5) was cooled to -78°C, and while stirring under a nitrogen atmosphere, 1.5 ml of 25% (w/v) diisobutylaluminum hydride dissolved in toluene was added dropwise.
After stirring at the same temperature for 40 minutes, 1 ml of methanol was added, and after heating to 0°C, 3 ml of water was added and stirred to form a precipitate. The resulting precipitate was filtered off, and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-cyclohexane (2:1) as an eluent to obtain 42 mg of the title compound with the following physical properties.

TLC (developing solvent, ethyl acetate) Rf = 0.20.

IR (liquid film method) ν: 3450, 3030, 2940, 1602,
1590, 1495, 1450, 1380, 1250, 1175,
1080, 1040, 975 cm ^-1 .

NMR ( _CDCl3 + acetone- _d6 solution) δ: 7.45-
6.75 (5H, m), 5.90-5.20 (6H, m), 4.63
−4.34 (1H, m), 4.30−3.60 (6H, m),
2.90−2.55 (2H, m).

Reference example 5 16-(3-chlorophenoxy)-17, 18, 19, 20
-tetranorprosta-trans-2,cis-
5, trans-13-triene-1,9α,11
α,15α-tetrol [16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓alcohol] 16-(3-chlorophenoxy) 46 mg of the title compound having the following physical properties was obtained from 83 mg of -17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester (produced in Reference Example 3.5).

TLC (developing solvent, ethyl acetate) Rf = 0.17.

IR (liquid film method) ν: 3450, 3030, 2940, 1600,
1580, 1480, 1425, 1290, 1250, 1140, 975
cm ^-1 .

NMR ( _CDCl3 + acetone- _d6 solution) δ: 7.40-
6.65 (4H, m), 5.90-5.20 (6H, m), 4.65
−4.35 (1H, m), 4.30−3.63 (6H, m),
2.90−2.60 (2H, m).

Reference example 6.1 1α,4α-bis(2-tetrahydropyranyloxy)-2α-(6-phenylzeleno-6-methoxycarbonylhex-cis-2-enyl)
3β-(3-hydroxypropertrans-1
-enyl)cyclopentane 1α,4α-bis(2
-tetrahydropyranyloxy)-2α-(6-methoxycarbonylhex-cis-2-enyl)-
3β-(3-hydroxypropertrans-1-
7.73 g of the title compound having the following physical properties were obtained from 7.06 g of enyl)cyclopentane (prepared by the method described below).

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.35.

1α, 4α used as starting materials in the above method
-bis(2-tetrahydropyranyloxy)-2
α-(6-methoxycarbonylhex-cis-2
-enyl)-3β-(3-hydroxypropertrans-1-enyl)cyclopentane was produced by the following method.

Add chromium trioxide to a mixture of 140 ml of anhydrous methylene chloride and 16.1 ml of anhydrous pyridine at room temperature under a nitrogen atmosphere.
Add 10g and stir for 30 minutes, then add 20g of diatomaceous earth
2-oxa-3-oxo-6-syn-hydroxymethyl- dissolved in 20 ml of methylene chloride after cooling to ℃.
7-anti-acetoxy-cis-bicyclo[3,
3,0] Octane [J.Amer.Chem.Soc., 92,
397 (1970). ]
Add 2.14g and stir at 0℃ for 15 minutes, then add 25g of sodium hydrogen sulfate and stir at 0℃ for 10 minutes.
Passed through magnesium sulfate. liquid at 0℃
Concentrate under reduced pressure as follows to obtain 2-oxa-3-oxo-6
-cis-formyl-7-anti-acetoxy-cis-bicyclo[3,3,0]octane was obtained.

Trimethylphosphonoacetate [CRAcad.Sci.Paris.A, B, 262B, 515] was suspended in 60 ml of anhydrous tetrahydrofuran with stirring at room temperature under a nitrogen atmosphere to suspend 369 mg of sodium hydride (65% content).
(1966). ]Add 1.82g and stir for 30 minutes, then add 30ml of tetrahydrofuran.
formyl compound (prepared above) dissolved in
was added while keeping the temperature below 15℃, stirred at 15℃ for 2 hours, then added 2ml of acetic acid to bring the pH to 5, concentrated slightly, added 20ml of water, extracted twice with 80ml of ethyl acetate (total volume: 160ml), and extracted the organic layer with salt. The mixture was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-benzene (1:4) as the elution solvent to obtain 2-oxa-3-oxo-6-syn-(2-methoxy) having the following physical properties. carbonyl-trans-vinyl)-7-anti-acetoxy-cis-
2.0 g of bicyclo[3,3,0]octane was obtained.

TLC (developing solvent, ethyl acetate:benzene = 1:
2) Rf=0.38.

IR (liquid film method) ν: 2970, 1775, 1735, 1710,
1650, 1240, 1160, 1037, ^{980cm -1} .

NMR (CDCl ₃ solution) δ: 6.77 (1H, d), 5.87
(1H, d), 5.00 (2H, m), 3.70 (3H,
s), 3.0−1.9 (6H, m), 2.04 (3H, s).

2-oxa-3 dissolved in 30 ml of absolute methanol
1.38 g of potassium carbonate was added to 2.68 g of -oxo-6-syn-(2-methoxycarbonyl-trans-vinyl)-7-anti-acetoxy-cis-bicyclo[3,3,0]octane (prepared above). The mixture was stirred at room temperature for 15 minutes, cooled in an ice bath, neutralized with 2 ml of 1N hydrochloric acid, added with 260 ml of ethyl acetate and 27 ml of an aqueous sodium hydrogen carbonate solution, and separated. The organic layer obtained was washed with brine and washed with magnesium sulfate. After drying, it was concentrated under reduced pressure to obtain 2-oxa-3-oxo-6-syn-(2-methoxycarbonyl-trans-vinyl)-7-anti-hydroxy-cis-bicyclo[3,3, 0] 1.96 g of octane was obtained.

TLC (developing solvent, methylene chloride: methanol =
19:1) Rf=0.38.

IR (liquid film method) ν: 3430, 1786-1690 (wide range),
1650cm ^-1 .

NMR (CDCl ₃ solution) δ: 6.82 (1H, dd), 5.90
(1H, d), 4.95 (1H, m), 3.72 (3H,
s), 4.30−3.25 (2H, m), 2.90−1.70
(6H, m).

2-oxa-3- dissolved in 30 ml of methylene chloride
Oxo-6-syn-(2-methoxycarbonyl-
trans-vinyl)-7-anti-hydroxy-
20 mg of p-toluenesulfonic acid to 2.31 g of cis-bicyclo[3,3,0]octane (prepared above)
Add 3 ml of 2,3-dihydropyran and stir at room temperature for 15 minutes.
After stirring for a minute, the mixture was neutralized by adding an aqueous sodium bicarbonate solution, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-benzene (1:3) as the eluent to obtain 2-oxa-3-oxo-6-syn-(2-methoxy) having the following physical properties. Carbonyl-trans-vinyl)-7-anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3,3,
0] 3.0 g of octane was obtained.

TLC (developing solvent, ethyl acetate:benzene = 1:
2) Rf=0.34.

IR (KBr tablet method) ν: 2930, 1770, 1710, 1650,
1343, 1240, 1152 cm ^-1 .

NMR (CDCl ₃ solution) δ: 6.78 (1H, dd), 5.84
(1H, d), 4.97 (1H, m), 4.63 (1H,
m), 3.71 (3H, s), 4.30−3.20 (3H,
m).

2-oxa-3-oxo-6-syn-(2-methoxycarbonyl-trans-vinyl)-7-anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3,3,
0] 3.10g of octane (produced above) at -65℃
Cool to -60℃ and add 23ml of 25 (w/v)% diisobutylaluminum hydride dissolved in toluene.
After stirring for 20 minutes, methanol and water were added to destroy excess diisobutylaluminum hydride, the precipitate was filtered off, the filtrate was dried and concentrated under reduced pressure to obtain 2-oxa-3-hydroxy-6-synthine having the following physical properties. -(3-hydroxyprop-trans-1-enyl)-7-anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3,3,
0] 2.8 g of octane was obtained.

TLC (developing solvent, methylene chloride: methanol =
19.1) Rf=0.23.

IR (liquid film method) ν: 3390, 2930, 1350, ^{1120cm -1} .

NMR (CDCl ₃ solution) δ: 5.75−5.5 (3H, m),
4.75−3.34 (8H, m).

2.94 g of sodium hydroxide (65% content) was suspended in 40 ml of dimethyl sulfoxide and stirred at 65° C. for 40 minutes to obtain sodium methylsulfinyl methylide. The resulting reaction mixture was cooled to room temperature from 20°C to 25°C.
18.5 g of (4-carboxybutyl)triphenylphosphonium bromide dissolved in 40 ml of dimethyl sulfoxide was added while keeping the temperature at trans-1-enyl)-7-anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3,
Add 2.84 g of 3,0] octane (prepared above) and stir vigorously at 25°C for 1 hour, then mix with 500 g of ice-water.
ml, extract with ethyl acetate-diethyl ether (1:1) to remove neutral substances, adjust the aqueous layer to pH 3 with saturated oxalic acid water, and extract with ethyl acetate-diethyl ether (1:1). The product was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 2α-(6-carboxyhex-cis-
2-enyl)-3β-(3-hydroxyprop-trans-1-enyl)-4α-(2-tetrahydropyranyloxy)-cyclopentan-1α-ol was obtained as a crude product.

TLC (developing solvent, methylene chloride: methanol =
19:1) Rf0.23.

IR (liquid film method) ν: 2930, 1720, 1240, ^{1120cm -1} .

NMR (CDCl ₃ solution) δ: 5.70−5.25 (4H, m),
4.62 (1H, m).

The obtained acid was dissolved in 40 ml of methylene chloride, cooled to 0°C, and a solution of diazomethane in diethyl ether was added until the reaction mixture turned pale yellow, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-cyclohexane (1:1) as the elution solvent to obtain 2α-(6-methoxycarbonylhex-cis-2-enyl)- having the following physical properties. 2.87 g of 3β-(3-hydroxyprop-trans-1-enyl)-4α-(2-tetrahydropyranyloxy)cyclopentan-1α-ol was obtained.

TLC (developing solvent, ethyl acetate: cyclohexane = 2:1) Rf = 0.31.

IR (liquid film method) ν: 3420, 2930, 1740, 1435,
1020cm ^-1 .

NMR (CDCl ₃ solution) δ: 5.75−5.20 (4H, m),
4.67 (1H, m), 4.10−3.30 (6H, m), 3.67
(3H, s).

2α-(6-methoxycarbonylhexa-) dissolved in 60ml of anhydrous methylene chloride and 19ml of anhydrous pyridine.
cis-2-enyl)-3β-(3-hydroxyprop-trans-1-enyl)-4α-(2-tetrahydropyranyloxy)cyclopentane-1α-
From -20℃ to 14g of oar (prepared above)
3.7 g of acetyl chloride dissolved in 40 ml of methylene chloride was added dropwise over 1 hour at 30°C, stirred for 45 minutes at -30°C, then 10 ml of methanol and 40 g of sodium hydrogen sulfate monohydrate were added, and the yellow precipitate was filtered out. is concentrated under reduced pressure to obtain 2α-
(6-methoxycarbonylhex-cis-2-enyl)-3β-(3-acetoxyprop-trans-1-enyl)-4α-(2-tetrahydropyranyloxy)cyclopentan-1α-ol 12.6 g
I got it.

TLC (developing solvent, benzene: ethyl acetate = 1:
1) Rf0.64.

IR (liquid film method) ν: 3450, 1740, 1440, 1030, 980
cm ^-1 .

NMR (CDCl ₃ solution) δ: 5.80−5.20 (4H, m),
4.75−4.45 (2H, m), 4.35−3.95 (2H,
m), 3.76 (3H, s), 2.03 (3H, s).

2α-(6-Methoxycarbonylhex-cis-2-enyl)-3β-(3-acetoxyprop-trans-1) in 100 ml of methylene chloride containing 81 mg of p-toluenesulfonic acid and 2.6 g of 2,3-dihydropyran. -enyl)-4α-(2-tetrahydropyranyloxy)cyclopentan-1α-ol (prepared above) was stirred at room temperature for 10 minutes, then 7.9 g of pyridine was added to stop the reaction, and the mixture was diluted with ethyl acetate. Washed with aqueous sodium carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1α,4α-bis(2-
Tetrahydropyranyloxy)-2α-(6-methoxycarbonylhex-cis-2-enyl)-3
9.4 g of β-(3-acetoxyprop-trans-1-enyl)cyclopentane was obtained.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf0.60.

1α, 4α− dissolved in 120 ml of anhydrous methanol
Bis(2-tetrahydropyranyloxy)-2α
-(6-methoxycarbonylhex-cis-2-
4.0 g of anhydrous potassium carbonate was added to 9.4 g of (prepared above) -3β-(3-acetoxyprop-trans-1-enyl)cyclopentane, and the mixture was heated at room temperature.
After stirring for 30 minutes, the mixture was acidified with acetic acid, diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was eluted with benzene-ethyl acetate (2:
1) purified by silica gel column chromatography using 1α, 4α with the following physical properties.
-bis(2-tetrahydropyranyloxy)-2
α-(6-methoxycarbonylhex-cis-2
7.1 g of -enyl)-3β-(3-hydroxyprop-trans-1-enyl)cyclopentane were obtained.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.22.

IR (liquid film method) ν: 3450, 1740, 1440, 1030, 980
cm ^-1 .

NMR (CDCl ₃ solution) δ: 6.00−5.20 (4H, m),
5.00−4.55 (2H, m), 3.76 (3H, s).

Reference example 6.2 1α,4α-bis(2-tetrahydropyranyloxy)-2α-(6-methoxycarbonylhex-cis-2, trans-5-dienyl)-3
β-(3-hydroxyproper-trans-1-
enyl) cyclopentane 1α,4α-bis(2
-tetrahydropyranyloxy)-2α-(6-phenylzeleno-6-methoxycarbonylhexa-
From 7.73 g of cis-2-enyl)-3β-(3-hydroxyprop-trans-1-enyl)cycupentane (prepared in Reference Example 6.1), 5.74 g of the title compound having the following physical properties were obtained.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.25.

IR (liquid film method) ν: 3450, 1730, 1660, 1440,
1030cm ^-1 .

NMR (CDCl ₃ solution) δ: 7.32−6.75 (1H, m),
6.15−5.30 (5H, m), 4.90−4.50 (2H,
m), 3.76 (3H, s), 3.15−2.80 (2H,
m).

Reference example 6.3 1α,,α-bis(2-tetrahydropyranyloxy)-2α-(6-methoxycarbonylhex-cis-2,trans-5-dienyl)-3
β-(2-formyl-trans-vinyl)cyclopentane 1α,4α-bis(2-tetrahydropyranyloxy)-2α- dissolved in 130 ml of methylene chloride
5.74 g of (6-methoxycarbonylhex-cis-2, trans-5-dienyl)-3β-(3-hydroxyprop-trans-1-enyl)cyclopentane (produced in Reference Example 6.2) and manganese dioxide
40 g was added, stirred at room temperature for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (4:1) as an eluent to obtain 3.85 g of the title compound having the following physical properties.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf0.50.

IR (liquid film method) ν: 1730, 1690, 1660, 1440,
1030, 980, 760 cm ^-1 .

NMR (CDCl ₃ solution) δ: 9.72 (1H, d), 7.40−
5.35 (6H, m), 4.90−4.50 (2H, m), 3.80
(3H, s).

Reference example 6.4 9α,11α-bis(2-tetrahydropyranyloxy)-15ξ-hydroxy-16-phenylthio-17,18,19,20-tetranorprosta-trans-2, cis-5, trans-13-triene Acid methyl ester To 1.17 ml of thioanisole dissolved in 20 ml of anhydrous tetrahydrofuran, 8.4 ml of 1.2 molar n-butyllithium dissolved in n-hexane was added at -20°C and stirred for 1.5 hours at the same temperature to obtain 0.28 molar phenylthio. A solution of lithium in tetrahydrofuran was obtained. 1 dissolved in 18 ml of anhydrous tetrahydrofuran
α,4α-bis(2-tetrahydropyranyloxy)-2α-(6-methoxycarbonylhex-cis-2,trans-5-dienyl)-3β-(2-
To 980 mg of (formyl-trans-vinyl)cyclopentane (produced in Reference Example 6.3) was added 8.4 ml of the previously obtained 0.28 molar phenylthiomethyllithium solution in tetrahydrofuran at -70°C.
After stirring for a while and adding 0.3 ml of acetic acid, the mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (4:1) as an eluent to obtain 740 mg of the title compound having the following physical properties.

TLC (developing solvent, benzene: ethyl acetate = 2:
1) Rf=0.48.

IR (liquid film method) ν: 3450, 1740, 1660, 1590,
1480, 1030cm ^-1 .

NMR (CDCl ₃ solution) δ: 7.55−6.70 (6H, m),
6.10−5.25 (5H, m), 4.82−4.45 (2H,
m), 3.72 (3H, s).

Reference example 6.5 9α,11α,15α-trihydroxy-16-phenylthio-17,18,19,20-tetranorprosta-trans-2, cis-5, trans-13-
Trienoic acid methyl ester [16-phenylthio-17,18,19,20tetranor-trans- ^Δ2
-PGF ₂ 〓Methyl ester〓9α, 11α dissolved in 12ml of tetrahydrofuran
-bis(2-tetrahydropyranyloxy)-15
ξ-hydroxy-16-phenylthio-17, 18,
Add 4 ml of 1N hydrochloric acid to 740 mg of 19,20-tetranorprosta-trans-2, cis-5, trans-13-trienoic acid methyl ester (produced in Reference Example 6.4).
After stirring at 35°C for 4 hours, the mixture was extracted with ethyl acetate, and the extract was washed with an aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (2:3) as the elution solvent to obtain 150 mg of the title compound having the following physical properties, its 15β-hydroxy isomer 120
mg and their mixture 125 mg were obtained.

TLC (developing solvent, ethyl acetate) Rf = 0.15 (15β
-hydroxy isomer Rf = 0.23).

IR (liquid film method) ν: 3400, 1730, 1660, 1590,
1480, 980, 750 cm ^-1 .

NMR (CDCl ₃ solution) δ: 7.45−7.07 (5H, m),
6.95 (1H, dt), 5.82 (1H, d), 5.70−5.30
(4H, m), 4,30−3.80 (3H, m), 3.70
(3H, s), 3.06 (2H, d).

Claims (1)

[Claims] 1. General formula [In the formula, B represents an oxygen atom or a sulfur atom, R ¹ and R ² are the same or different, and each represents a hydrogen atom, a halogen atom, or a trifluoromethyl group, and R is a compound of the formula -
COOR ³ (wherein, R ³ represents a straight-chain alkyl group having 1 to 12 carbon atoms) or the formula -
represents a group represented by CH ₂ OH, 〓〓 represents α-configuration or β-configuration or a mixture thereof;
The double bonds between _C2 and _C3 , between _C5C6 and between _C13 and _C14 are trans, cis and trans _, respectively. ] A luteal degeneration agent or a uterine muscle contracting agent containing a novel prostaglandin-like compound represented by the above formula or a cyclodextrin clathrate of such a prostaglandin-like compound. 2. Claim No. 2 in which the compound is 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester or its cyclodextrin inclusion compound The corpus luteum involution agent or myometrial contraction agent according to item 1. 3 The compound is 16-(3-chlorophenoxy)-17,
18,19,20-tetranor-trans-Δ ² −
The luteal retraction agent or myometrial contraction agent according to claim 1, which is PGF ₂ methyl ester or a cyclodextrin clathrate thereof. 4 The compound is 16-phenoxy-17,18,19,20-
The luteal degeneration agent or uterine muscle contracting agent according to claim 1, which is tetranor-trans-Δ ² -PGF ₂ methyl ester or a cyclodextrin inclusion compound thereof. 5 The compound is 16-(3-chlorophenoxy)-17,
18,19,20-tetranor-trans-Δ ² −
The luteal retraction agent or myometrial contraction agent according to claim 1, which is PGF ₂ =alcohol or its cyclodextrin inclusion compound. 6 The compound is 16-phenoxy-17,18,19,20-
The luteal degeneration agent or uterine muscle contracting agent according to claim 1, which is tetranor-trans-Δ ² -PGF ₂ alcohol or its cyclodextrin inclusion compound. 7 The compound is 16-phenylthio-17, 18, 19, 20
-tetranor-trans- ^Δ2 - _PGF2〓 methyl ester or its cyclodextrin inclusion compound, the luteal degeneration agent or uterine muscle contracting agent according to claim 1.