NL7810862A - Prostacyclin analogues - useful as smooth-muscle stimulants, antifertility agents and antiulcer agents - Google Patents

Abstract

Prostacyclin analogues of formula (I) and their isomers and salts are new. In (I) L is (CH2)3, (CH2)2CF2 or trans-CH2CH=CH; Q is H OH, H OH, I or Me OH; Y1 is H and Y2 is OH, or Y1 + Y2 is a bond; R1 is COOH, COOMe or CONHBu; R2 is C5H11, R2 is C5H11. C(Me)2C4H9 or phenoxymethyl; X is CH2CH2, trans-CH=CH or C=C. Cpds. (I) have smooth-muscle stimulating, antifertility and/or anti-ulcer activity, often with great specificity than known PGI, cpds. E.g., (6R)-13,14-didehydro-PGI (Ia) has about the same uterus-stimulating activity as PGI, methyl ester and 15-methyl-PGI, but lower colon-stimulating, antifertility and antiulcer activity.

Description

• · κ

The Upjohn Company, Kalamazoo, Michigan, Ver. St. v. America 5 6-Didehydroprostacycline analogs, pharmaceutical preparations thereof, and methods for preparing the one.

Prostacylic, derivatives and analogs thereof are active in eliciting various biological responses such as prevention of platelet accumulation, smooth muscle stimulation, inhibition of gastric juice secretion, and reduction of undesirable effects on the gastrointestinal system when administered systemically. prostaglandin synthetase inhibitors.

Because of these biological responses, prostacycline and prostacycline-type compounds are useful for studying, preventing, combating or reducing a wide variety of diseases and CNG-10 conditions in mammals, including humans, beneficial pets, pets and animals in in a zoo and in laboratory animals, for example, mice, rats, rabbits and monkeys. Prostacycline and prostacycline-type compounds are useful when it is desired to prevent platelet build-up, reduce the sticky nature of platelets, and eliminate or prevent thrombi formation in mammals such as humans, rabbits and rats. . These compounds are useful, for example, in the treatment and prevention of myarardial infarctions, the treatment and prevention of thrombosis after surgery and for the treatment of conditions, such as atherosclerosis, arteriosclerosis, blood clotting defects caused by lipemia and other clinical conditions, of which the underlying etiology is associated with lipid nhalans or hyperlipidemia. Other in vivo applications take place in geriatric patients for the prevention of cerebral ischemic attacks and long-term prophylaxis after myarardial infarctions and strokes. For these purposes, these compounds are administered systemically, for example, intravenously, intravenously, subcutaneously intramuscularly and in the form of sterile prolonged action implants. For rapid response, especially in emergencies, the intravenous route of administration is preferred. Doses of about 0.01-10 mg / kg body weight / day are used, the appropriate dose depending on the age, weight and condition of the patient or animal and on the frequency and mode of administration.

The addition of prostacycline and prostacycline-type compounds to whole blood provides in vitro applications, such as storage of whole blood to be used in heart-lung machines.

Furthermore, whole blood containing these compounds can be circulated through limbs and organs, for example the heart and kidneys, which are either connected to or removed from the original body and preserved or prepared for transplantation or attached. to a new body. The presence of these compounds prevents blockage by clumped blood platelets. For this purpose, the compound is added gradually or in single or multiple doses to the circulating blood, the blood of the donor (human or animal) or the perfused body part, which may or may not be attached to the recipient in a total constant dose of about 0.01-1.0 µg / ml whole blood, These compounds are also useful in preparing platelet-rich blood concentrates for use in the treatment of thrombocytopenia or in chemotherapists.

Prostacycline and prostacycline type 25 compounds are exceptionally potent in stimulating the smooth muscle and are also highly effective in enhancing the action of other known smooth muscle stimulants, for example, oztoic agents, for example, oxytocin and the various ergot alkaloids, with including derivatives and analogues. Therefore, they are useful in place of or in combination with less than the usual amounts of these known smooth muscle stimulants, for example to reduce the symptoms of paralytic ileus or to prevent or prevent atomic bleeding from the uterus after abortion or redemption as an aid during the expulsion of the placenta and during childbirth. For the latter purpose, the compound is administered by 7810862 3 intraven · intravenous infusion immediately after the abortion or delivery at a dose between approximately 0.001 and 50 µg / kg body weight / minute until the desired effect is achieved. Subsequent doses are given during childbirth by intravenous, subcutaneous or intramuscular injection or infusion at a dose of 0.01-2 mg / kg body weight / day, the appropriate dose depending on the age, weight and condition of the patient or animal.

Prostacycline and prostacycline-type compounds are also useful in mammals, including humans, and certain animals, for example dogs and pigs, to reduce and combat excessive gastric secretion, thereby preventing the formation of ulcers in the gastrointestinal tract is reduced or avoided and the healing of such ulcers already present in the gastrointestinal tract is accelerated. For this purpose, these compounds are injected intravenously, subcutaneously or intranruscularly or infused in an infusion dose of approximately 0.1 µg / kg body weight / minute or in a total daily dose by injection or infusion of approximately 0.01-10 mg / kg body weight / day. the appropriate dose depending on the age, weight and condition of the patient or patient and on the frequency and method of administration.

These compounds are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors and are used for that purpose by co-administration of the prostacycline or compounds of the prostacycline -25 type and the anti-inflammatory prostaglandin synthetase inhibitor.

See U.S. Pat. No. 3,781.U29 for a discussion of the ulcerogenic effect caused in rats by certain non-steroidal anti-inflammatory agents and prevented by concomitant oral administration of certain E and A 30 series prostaglandins, including of PGE ^, PCrEg, PGE ^, 13.1 U-dihydr o - PC-E ^ and the corresponding 11-deoxy-PGE and PC-A compounds. For example, prostacycline and prostacycline-type compounds are useful for reducing the undesirable effects on the gastrointestinal tract resulting from the systemic administration of indomethacin, phenylbutazone and aspirin. These materials are specifically mentioned in the above 7810862

U.S. Patent Listed as Non-Steroidal Inflammation Against Agents. They are also known as prostaglandin synthetase inhibitors, r k

The anti-inflammatory synthetase inhibitor, for example indomethacin, aspirin or phenylbutazone, is administered in any manner known to relieve an inflammatory condition, for example in a given dosage and by one of the known routes for systematic administration.

The prostacycline or compound of the prostacycline -10 type is administered together with the anti-inflammatory prostaglandin synthetase inhibitor in the same way or not. For example, when anti-inflammatory agent is administered orally, the prostacycline or the compounds of the prostacycline type is also administered orally. administered either rectally in the form of a suppository or a vaginal drug for slow release of the drug, as described, for example, in U.S. Pat. When the anti-inflammatory agent is administered rectally, the prostacycline or the compounds of the hebprostacycline type can also be administered rectally. Furthermore, the prostacycline derivative can easily be administered orally or, in 20 women, vaginally. It is particularly convenient when both the anti-inflammatory agent and helprostacycline or the prostacycline-type compounds are to be administered in the same manner, combining both in a single dose.

The dosage of the prostacycline or the prostacycline type compound in this treatment depends on several factors, including nature; the age, weight, sex and medical condition of the mammal, the nature and dosage of the anti-inflammatory synthetase inhibitor administered to the mammal, the sensitivity of the particular mammalian to the prostacy-cline or compound of the prostacycline type to be administered.

Not every person who needs an anti-inflammatory substance experiences the same adverse effects on the gastrointestinal system when taking the substance. These often vary considerably in type and extent.

However, it is within the reach of the attending physician, or veterinarian, to ascertain whether administration of the anti-inflammatory agent is undesirable 7810882. 5 'effects on the gastrointestinal tract causing man or animals and prescribe an effective amount of the prostacyelin or the prostacycline-type compound which reduces and subsequently practically eliminates these undesirable effects, 5 Prostacyelin and prostacyclin-compounds type are also useful in treating asthma. These compounds are useful, for example, as bronchodilators or as inhibitors or mediators, such as SHS-A and histamine, released from the cells activated by an antigen-antibody complex. Thus, these compounds counteract cramps and facilitate breathing in conditions such as bronchial asthma, bronchitis bronchiectasis, pneumonia and emphysema. For these purposes, the compounds are administered in various dosage forms, for example, orally in the form of tablets, capsules or liquids; rectally in the form of suppository-15 lön; parenteral, subcutaneous or intrsmuscular, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers or by insufflation in the form of powder. Doses of about 0.01-5 mg / kg body weight are used 1-U times daily. the appropriate dose depending on the age, weight and condition of the patient and on the frequency and mode of administration. For the above use, the prosta-cycline or the compound of the prostacycline type can advantageously be combined with other anti-asthmatics, such as sympatomimetics (isoproterenol, phenylephrine, ephedrine, etc.); ranthine derivatives (theophyiline 25 and aminophyiline) and corticosteroids (ACTE and predbisolone).

Prostacyeline or prostacycline-type compounds are successfully administered to people with asthma by oral inhalation or aerosol inhalation.

For administration by the oral inhalation route with conventional nebulizers or by oxygen aerolization, it is convenient to give the prostacyclin component in dilute solution, preferably at a concentration of about 1 part drug to form 100-200 parts by weight of total solution. Quite common additives can be used to stabilize these solutions or to provide isotonic media, for example sodium chloride, sodium citrate, 7810862 citric acid and the like,

For administration as a self-propelled metering unit for the administration of the active ingredient in aerosol form, suitable for inhalation therapy, the composition may contain the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavors, fragrances and stabilizers. A dispersant such as oleyl alcohol may also be used in plate 3 of a co-solvent. Suitable agents for applying the aerosol inhalation therapy technique are, for example, fully described in U.S. Pat. No. 2,868,691.

Prostacycline or compounds of the prostacycline type are useful in mammals and also humans as nasal canal release agents and are used for this purpose in a dosage of about 10 µg / ml of a pharmacologically acceptable liquid carrier or as aerosol sprays, both for topical administration.

Prostacycline or compounds of the prostacycline type are also useful in the treatment of peripheral vascular disease in humans. Peripheral vascular disease is here understood to mean an infection of one of the 20 blood vessels outside the heart and lymphatic disease, for example, freezing, ischemic cerebrovucular disease, arteriovenous fistulas, ischemic leg ulcers, phlebitis, insufficiency of the veins, gangrene, hepatic syndrome, ductus arteriosis, non-obstructive mesenteric ischemia, lynphangitis arteritis. and such. These conditions are mentioned by way of example only and do not limit the term peripheral vascular disease. For these conditions, the prostacyclinic oral or parent is administered either by injection or infusion directly into a vein or artery,

The dosage of these compounds is 0.01-1.0 yug, administered by infusions at a rate per hour or by injection on a basis per day, ie 1 ^ times a day, the correct dose depending on the dose. age, weight and condition of the patient, and frequency and method of administration. Treatment is continued for 1 to 5 days, although 3 days is usually sufficient to achieve a long-lasting therapeutic effect. If systemic or side effects are observed, the dose is reduced to "below the level where such effects occur.

Prostacycline and prostacycline-type compounds are therefore "useful for treating peripheral vascular diseases in the hands and feet of humans, which exhibit circulation insufficiencies, such treatment providing pain relief and ulcer healing. .

For a full discussion of the nature and clinical manifestations of human peripheral vascular disease and the hitherto known treatment method with prostaglandins, see South African Patent 7/01/9 and Elliott et al, Lancet, 18. January 1975, p.

1IK) -1U2.

Prostacycline or compounds of the prostacycline type are useful in place of oaytocin to induce labor in pregnant women and female mammals, such as cows, sheep and pigs, shortly before or at the end of the gestational period or if the fetus is in pregnancy. uterus has died from about 20 weeks before the end to the end of the gestational period. For this purpose, the compound is infused intravenously at a dose of 0.01-50 µg / kg body weight / minute until or near the termination of the second stage of labor, i.e. fetal expulsion .

These compounds are particularly useful when the woman has given birth one or more weeks earlier and no natural labor has started or 12 to 60 hours after the membranes have ruptured and the natural labor has not yet begun. Another mode of administration is oral.

Prostacycline or compounds of the prostacycline type are further applicable for controlling the reproductive cycle in menstruating women and female mammals. Menstruating female mammals are understood to be animals which are mature enough to menstruate 30 cm but not yet so old that regular menstruation has ceased. For that purpose, the prostacyclin compound is systematically administered at a dose of 0.01 to about 20 mg / kg body weight of the female mammal, advantageously during a period beginning approximately at the time of ovulation and approximately ending at the time of menstruation or just before menstruation. Other modes of administration are intravaginal and intranterus. Furthermore, an embryo or fetus is ejected upon similar administration of the compound during the first or second third of the normal gestational period of the mammal.

Prostacycline or prostacycline type compounds are further useful for cervical removal in pregnant and non-pregnant female mammals in gynalogy and obstetrics. This widening of the cervix is also observed upon initiation of labor and in clinical abortions obtained by these compounds. In case of infertility, widening of the cervix by these compounds is helpful in promoting the movement of the sperm to the uterus. Widening of the cervix by prostacyclinic compounds is also useful in surgical gynecology, such as in the widening of the cervix and eurecture of the ute-15, as mechanical widening may cause perforation of the uterus, rupture of the cervix or infections. It is also useful in diagnostic methods where dilation is necessary for tissue research. For these purposes, the prostacyclin compound is administered locally or systemically.

The prostacyclin compound is administered orally or vaginally in doses of about 5-50 mg per treatment of an adult woman with 1-5 treatments per 2k hour period. The compound is also administered intramuscularly or subcutaneously in doses of about 1-25 mg per treatment. The appropriate dosages for these purposes depend on the age, weight and condition of the patient or animal.

Furthermore, prostacycline and prosta-cyclin type compounds are useful in pets as a miscarriage agent (especially for fattening heifers) as a means of promoting estrus sensing and controlling or synchronizing estrus. Pets include horses, livestock, sheep and pigs.

Regulating or synchronizing oestrus allows more efficient control of both conception and childbearing, by enabling the farmer to breed with all of her female animals at short predetermined intervals. This synchronization leads to a higher percentage of live births than is achieved by natural regulation. 7810852 9. The prostacyclin compound is injected or administered into a feed at a dose of 0.1-100 mg / animal and can be combined with other agents such as steroids. Dosage schedules depend on the treated species. For example, mares get the prostaeycline compound 5-8 days after ovulation and return to estrus. Cattle are treated at regular intervals for 3 weeks, with all cattle advantageously being brought to estrus simultaneously.

Prostacycline or compounds of the prostacycline type increase blood flow through the kidneys of the mammal, thereby increasing the volume and electrolyte content of the urine. Therefore, these compounds are useful in treating cases where the function of the kidneys is inadequate, especially those in which the renal vascular bed is blocked. These compounds are useful, for example, in alleviating and ameliorating edema cases, for example, resulting from major surface burns and in the treatment of shock. For these purposes, these compounds are preferably administered first by intravenous injection at a dose of 10-1000 µg / kg body weight or by intravenous infusion at a dose of 0.1-20 µg / kg body weight / minute until the desired result is obtained. -20 reaches. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion at a dose of 0.05-2 mg / kg body weight / day.

Prostacycline or compounds of the prostacycline type are useful in treating expanding skin diseases in humans and in pets, including psoriasis, atopic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and scaly cell cancers. skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun-induced keratosis, non-malignant keratosis, acne and seborrheic dermatitis in humans and atopic dermatitis and mange in pets. These compounds relieve the symptoms of these spreading skin diseases, for example, psoriasis is relieved when a scale-free psoriasis damage decreases markedly in thickness or becomes conspicuously but incompletely clean or completely clean.

For these purposes, these compounds are used topically as preparations containing a suitable pharmaceutical carrier, for example, as a spread, lotion, paste, jelly, spray, or aerosol, using topical bases such as petrolatum, lanolin, polyethylene glycols, and alcohols. As the active ingredients, these compounds form about 0.1-15% by weight of the composition, preferably about 0.5-2% by weight. In addition to topical application, injection can be used, such as intradermal, intra- or perilesional or subcutaneous using suitable sterile brine-containing preparations.

Prostacycline or prostacycline type 10 compounds are useful as anti-inflammatory agents for preventing chronic inflammation in mammals, including swelling and other unpleasant effects thereof, using the treatment methods and dosages generally described in the U.S. Patent 3,885.0 ^ -1.

In Dutch Patent Application 77.05991 laid open to public inspection, 5,6-didehydroprostacycline analogs with pharmacological properties are described.

It has been found that a particular group of these have remarkable therapeutic properties. This group of 5,6-didehydroprostacy-20 cline analogs has the general formula 1, wherein L is a group of the formula - (CH ^ -, - (CH ^ CP ^ - or H ^

C = C

-CE ^ X E ^ *

Q represents a group of the formula H 0E, H 0E, 0 or CH 2 OH

25, fk / Q represents a group of the formula 2 or ^, represents a group of the formula -C00E, -COOCH ^ or -CONHC ^ H ^, R ^ represents a group of the formula -CiLCH_, or a green of the formula 3 represents, 5 η i 3 -CC, ï 1 k 9 CH 3 30 X represents a group of the formula -CH ^ CE ^ -, trans-CH = CH- or -C = C-, and a bond in indicates α or β configuration, and its pharmacologically acceptable salts.

Formula 1 as shown is understood to include all possible isomers.

The following explains the results of animal experiments with compounds of the formula 1 and two compounds from the aforementioned Dutch patent application TT.05991.

A. Smooth kidney test on desert snring mulseolon.

The contraction of isolated desert hawk mouse colon 5 is tested in vitro at two concentrations of PG4. The concentration of test compound which gives a response almost equal to that of one of the GE concentrations or in between is determined.

B. Hamster anti-festivity test,

The test compound is administered to 6 pregnant hamsters on the. a a 10 4 day of pregnancy administered subcutaneously. On the 8th day, the uteri are examined for implantations. A compound is considered inactive, moderately active, or very active when no implants are found in 3 or less, h or 5, or 6 hamsters, respectively. The test compound is administered in a decreasing range of concentrations of 1000 µg, 100 µg, 10 µg, etc., When the compound is very active at a dose of 1000 µg, it is retested at a dose of 100 µg, when a compound is very active at a dose of 100 µg, it is retested at a dose of 10 yug, etc. Once a dose is reached, in which the compound is inactive or moderately active (the so-called longest 20 dose tested), the test is terminated, C. uterine activity test in monkeys.

The stimulating effect on the uterine muscle is investigated in mid-trimester pregnant rhesus monkeys (Macaca mnlatta). The ut eras motility is recorded on a Grass polygraph. An open-ended, liquid-filled catheter is inserted trans-abdominally into the amniotic sac; the distal end of the catheter is connected to the polygraph. The test compounds are administered intravenously as a phosphate buffer containing solution in ethanol. It is used as a reference.

30 D. Gastro-erosion test in ratsé

Gastromucosal erosion is examined in rats 3 hours after indomethacin (20 mg / kg s.c.) administration with an erosion score determined for each mucosa based on the incidence and severity of the lesions. The test compounds are dissolved in 50 mM Tris just before test 35 and administered subcutaneously at a dose of 500 7810862 12 µg / kg, immediately followed by indomethecin. PGEg is used as a reference.

The results are summarized in the table below.

As reference compounds, 5 A. PGI.J, methyl ester were used

B. 15-methyl-PGI

(both compounds according to Dutch patent application 77.05991).

Table ^ Test method

Connection Name A B C D

from example XI (6r) -16,16-dimethyl 1-PGI ^ + + + (6s) -16,16-dimethyl-PGI1 + - + = 15 IV (6s) -1,66-dimethyl-PGI1s methyl ester + + VIII (6r) -13,1U-dihy dro-PGI1 - XI (6s) -d2-PGI1, methyl ester - XIII (6Η) -Δ ^ -16,1 6-dimethyl-PGI1 + - + - 20 (6δ) -Δ2-16,16-dimethyl-PGI ^ + - + = XVI (6r) -16-phenoxy-PGI, methyl ester + + = (6s) -16-phenoxy-PGI, methyl ester + + + 25 XVII (6s) - 16-phenoxy-PGI + + + +

A plus sign (+) means that the test compound in question has a higher activity than A and B, a minus sign (-) has a lower activity, and an equal sign (=) about the same activity. The results show that the compound of Example VIII is equivalent to the reference compounds in Test C and exhibits a lower smooth muscle stimulating effect making this compound more suitable for reducing side effects such as intestinal crows.

The compound of Example XI is equivalent to the reference compounds 7810862 13 in Test D and "has a lower smooth muscle toning effect so that this compound is even more suitable to reduce side effects such as intestinal cramps,

The compounds according to the invention of the formula [15] can be prepared by methods which are conventional or known for preparing analogous compounds, in particular as described in the aforementioned Dutch patent application TT.05991, as well as in the American patent application Ser. No. 85T.203. The preparation methods and reaction schemes shown therein are considered incorporated herein.

The following examples relate to the preparation of compounds of the formula 1 wherein L is a group of the formula - (ΟΗ ^) ^ -, Q a group of the formula H ÓH, (g) a group of the formula 2, a group of the formula -C ^ H ^ - and X represent a group of the formula trans-CH = CH-, unless otherwise indicated.

Example I

9-Deoxy-6,9a-epoxy-16,16-dimethyl-PGFj, less polar and more polar isomer, R is -C00E, R is GH_ * d 4 3 20 CH3 1 See Scheme J in the Netherlands patent application TT.05991.

A solution of 16,16-dimethyl-PGF, 11,15-bis (tetrahydropyran-2-yl ether) (U.S. Patent 3,995,033, 1.02 g) in 20 ml of chloroform 25 is treated with a solution of mercury (II) acetate (1.15 g) in t / ml acetic acid. The mixture is left in the dark for 5 hours.

Then TO ml of toluene are added after which the mixture is concentrated. The residue is dissolved in T5 ml of diethyl ether, washed with water and an aqueous sodium chloride solution, dried and concentrated. The residue is taken up in a mixture of acetic acid, water and tetrahydrofuran (20: 10: 3) and heated for 2.5 hours at a temperature of ^ 5 ° C. After adding ^ 0 ml toluene, the mixture is concentrated . The mixture of isomers obtained shows R 2 values of 0.30 and 0.33 (thin layer chromatography on silica gel in a Α-ΓΧ system).

2. The product prepared above under 1. is dissolved in 7810862

1U

a mixture of 10 ml tetrahydrofuran and 10 ml water and treated with 10 ml aqueous 3M sodium hydroxide and 10 ml aqueous 0.5M sodium borohydride in 3M sodium hydroxide, Then the mixture is stirred at a temperature of 25 ° C for 1 minute, cooled in an ice bath , and treated with 100 ml ethyl acetate, 10 ml water, 12 g solid potassium hydrogen sulfate and finally sodium chloride until saturation. The organic phase is separated, dried and concentrated. The oily residue is chromatographed on silica gel to afford the title compounds, which is the less polar isomer (0.025g) with an F. 10 value of 0.28 (thin layer chromatography on silica gel in an A-IX solvent system) and the more polar isomer (0.18 g) with an Rf value of 0.2¼ (thin layer chromatography on silica gel in A-IX), high-resolution mass spike peak (TMS derivative) 583.3656, and infrared absorption at 3hk0, 17UQ, 1580, 1135 and 1365 cm. The more polar isomer is referred to as (6s) -16,16-dimethyl-PGi.

Example II

9-Deoxy-6,9a-epoxy-16,16-dimethyl-PGF 2, less polar isomer of the compound of Example I.

1. See Scheme J in Dutch patent application 77 * 05991.20 A solution of 2.0 g of l6, 16-dimethyl-PGF2a in 1) -0 ml of tetrahydrofuran is added to a solution of 3.6 g of mercury (ll) acetate in a mixture of 30 ml water and 20 ral tetrahydrofuran. the mixture is stirred at a temperature of 25 ° C for 2 hours.

2. The product prepared under 1. above is treated with a solution of 0.75 g of sodium borohydride in 30 ml of sodium hydroxide and stirred at a temperature of about 25 ° C for 20 minutes. The mixture is then acidified with 10% hydrochloric acid, diluted with 100 ml diethyl ether and saturated with solid sodium chloride. The organic phase is separated, washed with brine, dried and concentrated. The residue is chromatographed on silica gel, eluting with acetone (20-66%) methylene chloride. The chromatography is repeated until the title compound is pure. The title compound, obtained in an amount of 0.2¼ g, shows an Rf value of 0.55 (thin layer chromatography on silica gel in a mixture of ethyl acetate, cyclohexane 35 and acetic acid (20: 30: 1)}, high resolution mass spectrum (TMS derivative) 7 8 1 0 8 6 2 15 583.3673, and infrared absorption at 3 ^ 00, 2680, 1720, 11 * 65, 1l * 05, 1385, 1365 , 1215, 1085, 1020, 1000 and 970 cat '' *, The Blinder polar isomer is referred to as (6R) -1,66-dimethyl-PGI3, also the more polar isomer (0.58 g) having an R ^ value of 0.1 * 7 in the same 5 system.

Example III

9-Deo3y-6,9a-epozy-16,16-dimethyl-PGP1, methyl ester, less polar isomer, R1 is -C00CH3, R2 is -C (CH3) g CuHg.

The title compound is obtained by reacting the corresponding acid (Example II) with excess ethereal diazo methane. The product is designated as (6R) -16,16-dimethyl-PGI, methyl ester.

Example IV

9-Daoxy-6,9a-epoxy-1,66-dimethyl-PGP4, beet ethyl ester, more polar isomer 15 of the compound of Example III.

1, See Scheme H in Dutch patent application 77-05991. A mixture of 16,16-dimethyl-PGF 2, methyl ester (U.S. Patent 3,995,833, 1.85 g) in 35 ml of methylene dichloride and 35 ml of saturated sodium bicarbonate is treated with 1.1 * 2 g with cooling in an ice bath. iodine in 89 ml of methylene dichloride, added over 15 minutes.

The mixture is stirred for 1 hour. After demolition, the organic phase is separated, washed with sodium sulfite and brine (backwashed with chloroform), dried and concentrated. The oily residue (2.9¾ g) is chromatographed on silica gel eluting with ethyl-25 acetate (50-100 #) - Skellysolve 3 with the mixed C-5 isamers of the 5-iodine compound (2.1 * 0 g ) is acquired. RF value 0.37 (thin layer chromatography on silica gel in ethyl acetate (60 *) - hexane), infrared absorption 31 * 20, 1735, 1260, 1230, 1195, 1170, 1090, 1075, 1050, 1020 and 1000 cm * , and NMR peaks at 3.65, 5.5, 1 *> 5 and 0.9 6.

2. A solution of the product prepared above under 1. (2.1 * 0 g) in 1 * 0 ml absolute ethanol is treated with 2.5 ml tributyltin chloride and a solution of 0.5 g sodium borohydride in 20 ml. absolute ethanol. The mixture is stirred at a temperature of about 25 ° C for 2.5 hours. Afterwards, it is carefully acidified with 35 dilute hydrochloric acid to a pH of about 3, after which the mixture is concentrated to about one third of the volume. After adding water, the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetate (33-100 #) - Skellysolve B to obtain 1.01 g of the title compound.

Rf value 0.65 (thin layer chromatography on silica gel eluting with ethyl acetate), mass spectrum peaks (TMS derivative) at 525.3411, 509, 450, 441, 41, 351 and 201, infrared absorption at 3400, 1740, 1665, 1460 , 1435, 1380, 1360, 1240, 1200, 1175, 1055, 1020, and 970 cm -1 and NMR-10 peaks at 5.5, 4.44, 3.65, and 0.95. This more polar isomer is referred to as (6s) -16-16-dimethyl-PGI-methyl ester.

Example V * 9-Deoxy-6c, 9ot-epoxy-16-phenoxy-17,18,19,20-tetranor-PGF 2, methyl ester, less polar isomer and more polar isomer, is -COOCH 4, is 15 H ' 'OH, is group with formula 3.

A mixture of isomers obtained according to example XII of Dutch patent application 77.05991 is separated by silica gel chromatography. The less polar isomer is designated as (6R) -17,18,19,20-tetranor-16-phenoxy-PGI1, methyl ester. The more polar isomer is designated (6s) -17,18,19,20-tetranor-16-phenoxy-PGI, methyl ester.

Example VI

9-Ββοχν-6ξ, 9ct-epoxy-PGF.j, n-butyl agent mixture of isomers, is com Cj ^ Hp.

25 1 · Scheme I ir. Dutch patent application 77.05991.

A solution of 5C-iodo-9-deoxy-65,9a-epoxy-PGF1, mixed isomers (example XV of Dutch patent application 77.05991 5.0 g) in 50 ml of acetone is treated with 2.0 ml of triethvlamine and ge-30. cooled in a mixture of methanol and ice. 1.9 ml of isobutyl chloroformate are added with stirring and stirring is continued for 6 minutes. Then 15 ml of n-butylamine in 20 ml of acetone are added. The mixture is then heated to a temperature of about 25 ° C and stirred for 3 hours. After completion, the reaction mixture is concentrated. Est residue is dissolved in ethyl acetate 7810862, washed with water and brine, dried and concentrated.

The residue is chromatographed on silica gel eluting with acetone (5 -00 #) methylene chloride. The duller oily residue (5.3 g) is purified by chromatography to obtain U.8 g of the 5-5 iodine compounds.

2. A solution of the 5C-iodo-9 "deoxy-6c; 9ct-epoxy-PGP, n-butylamide, mixed isomers (0.70 g) prepared in 25 ml of ethanol prepared in 25 ml of ethanol above is prepared with approximately 1, 0 ml of tributyltin chloride and 0.15 g of sodium borohydride in 5 ml of ethanol at a temperature of about 25 ° C. The progress of the reaction is monitored by thin layer chromatography on silica gel, eluting with a mixture of equal parts by volume of acetone and methylene chloride. After about 1.5 hours, the reaction mixture is diluted with ice water and extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated! The residue is chromatographed on silica gel eluting with acetone (25-65 #} methylene chloride to give 0.60 g of the title compounds. R ^ value 0.62 (thin layer chromatography on silica gel in acetone), high resolution mass spectra he 553.3993 , and infrared absorption peaks at 3300, 3100, 17 ^ 0, 1715, 16 ^ 5, 1555 ._____ 20 li * 60, 1375, 1330, 1070, 1055 and 9 ^ 5 cm "1.

Example VII

(6s} -13.1 k-Didehydro-PGI.j, X is -C = C-, ^ is -C00H and -C00CH3 the methyl ester is -COOCH ^.

1, See Scheme N in U.S. Patent Application No. 25 Sar.Ho, 857,203. A solution of 1U-bromo-PGF, methyl ester (Preparation 2 in U.S. Patent Application Ser. No, 857,203, 1.02 g) in 10 ml of tetrahydrofuran is treated with a suspension of mercury (II) acetate (1.8 g) in water (1¾ ml) and tetrahydrofuran (8.5 ml) at a temperature of 25 ° C for 15 minutes. Afterwards, the suspension is cooled in an ice bath, after which a solution of sodium borohydride (0.65 g) in sodium hydroxide (6.5 ml) is added dropwise. The mixture is diluted with diethyl ether, freed by decanting the mercury compound, washed with water, dried and concentrated to form a mixture of C-6 isomers. The isomers are separated by silica gel chromatography eluting with a mixture of methylene chloride and 7810862 acetone. (85:15). Thereby, the 6R compounds are first obtained (0 = 183 g) with an R ^ value 0.38 (thin layer chromatography on silica gel eluting with a mixture of methylene chloride and acetone (3: 1)), infrared absorption at 1CA0, 1075 , 108ö, 1170, 1195, 1710, 17 ^ 0 and 3300 cm "1.5 BMR peaks at 0.90 1.05-3.1, 3.65, 3.5-1 *, 25 and 5.79 δ and mass spectrum peaks (TMS derivative) at 590.21 * 50, 575, 551, 519, 511, 500, 1 * 21> 03, 38l *: 305 and 173,

An intermediate fraction (0.20 g) is obtained followed by the 6S compound (0.1 * 52 g) with an R 2 value of 0.31, infrared absorption-10 at 101 * 0, 1095, 1160, 1710 , 17l * 0 and 3300 cm "1, HMR peaks at 0.89, 1, 5-3.1, 3.65, 3.5-1 *, 25, 1 *, 1 * 3 and 5.585 δ and mass spectrum peaks at .590.21 * 1 * 0 and as found for the 6R compound, 2, Het (6S) -13,11 * -didebydro-PGI ^ is obtained by the 6s isomer (see above under 1., 0.275 g) Treat in 10 ml of methanol 15 with 5 ml of 1N aqueous sodium hydroxide at 25 ° C for 20 hours. After completion, the reaction solution is cooled and acidified with cold dilute phosphoric acid, then the mixture is extracted with a mixture of diethyl ether and ethyl acetate ( 2: 1) The organic phase is separated, washed with 57% sodium chloride, dried and concentrated to give 14-bromo-20 in the acid of the 1 * -bromo compound (0.2l * g). value 0.36 (thin layer chromatography on silica gel in Solvent A, which is a mixture of ethyl acetate, acetic acid, cyelohexane and water (9: 2: 5: 10)), and infrared absorption 950, 10l * 5, 1080, 1100, 12l * 0, 1280, 1710, 265Ο-3100, and 3l * 00 cm- 1. The acid is dissolved in a mixture of 10 ml of dimethyl sulfoxide and 1.0 ml of methanol and treated with potassium tert.butoxide (0.31 g) at a temperature of about 25 ° C for 26 hours. Afterwards, the reaction solution is diluted with cold water, acidified with 0.2 M potassium hydrogen phosphate and extracted with a mixture of diethyl ether and ethyl acetate (2: 1). The organic phase is separated, washed with 5% sodium chloride, dried and concentrated to yield 0.225 g of the title compound. R ^ value 0.1 * 3 (thin layer chromatography on silica gel in Solvent A), infrared absorption at 1) 55, 1080, 1095, 1710, 2220, 2550, 3100 and 3350 cm 1, NMR peaks at 0.90, 1 .05-2.9, 3.96, 1 +, 21 and 6.38 δ and mass spectrum peaks (TMS-deri-35 vessels) at 568.31 * 20, 533, 1 * 97, 1 + 78, U63, 1 * 07 , 395, 388, 362, 173, and 117.

78 1 G8 «2 19

The acid is converted into the corresponding methyl ester by reaction with an excess of ethereal diazomethane. The methyl ester of (6s) -13, 1H-didehydro-PIG formed has an R 2 value of 0.59 in ethyl acetate and shows infrared absorption peaks at 1015, 10 * 5, 1065, 5 1090, 1170, 1725, nbO, 2220 and 3 ^ 00 cm ”1, HMR peaks he 0.90, 1.1-2.9, 3.1 * 5, 3.65, 3.65-1 *, 2, and 1 *, 2- 1 *, 65 δ and mass spectrum peaks he 510.3209, 1 * 95, 1 * 79, 1 * 39, 1 * 20, 395, 337, 330, 323, 313, 30l +, 225 and 173. Example Till (6r) -13, 1H-Didehydro-PGI 4 and its methyl ester, isomers of the compounds of Example VII,

In the manner described in example VII but starting from the corresponding 6R-isomer, i.e. the methyl ester of 9-deoxy- (6r), 9a-epoxy-1 * brom-PGF ^ Q, (0.16 g) the corresponding acid of the 11 * -bromo compound (0.1¾ 0.1 * 0 in Solvent A) is obtained and then the title compound (0.11g). R ^ value 0.53 in Solvent A, infrared absorption at 1020, I050, 1075, 1225, I7I0, 1725, 2220, 26OO-2800 and 3350 cm-1 and HMR peaks at 0.90, 1.1-2, 9, 3.66, and 1 *, 33 5.

The acid is converted to the methyl ester with excess ethereal diazomethane. The obtained methyl ester of (ÖR) -13,11 * - didehydro-20 PGI ^ has an R ^ value of 0.67 in ethyl acetate and shows infrared absorption peaks at 1010, 1050, 1070, 1080, 1095, 1155, 1170 , 1725, 17l * 0, 2220 and 3l * 00 cm ”1, NMR peaks at 0.90, 1.1-2.9, 3.5-l *, 0, 3.65 and 1 *, 0- 1 *, 55 5 and mass spectrum peaks at 510.3193, 1 * 95, 1 * 79 and others found for the 6S compound of Example VII.

Example IX

(ÊSj ^ J-ISil ^ -Oidehydro-PGI ^, Q is OH, X is -C = C- and R ^ is -C00H and -COOCE ^ and the methyl ester.

The title compounds are obtained according to the embodiment of Example VII using the corresponding methyl ester of 1 * stream (15R) (Preparation 2 in U.S. Patent Application Ser, Ho. 857,203). First, the 9-deoxy-6 (R and S), 9a-epozy-11 * -bromo (15R) -PGF 2 a methyl esters are prepared and separated chromatographically. The 6R isomer is less polar and has an Rf value of 0.63 in a mixture of methylene chloride and acetone (7: 3) compared to the 6S isomer which has an R 2 value of 0.55. The 6R isomer exhibits 7810862 20 MR peaks at 0.89, 1.05-3.2, 3.66, 3.1 * -! *, 2 and 5.80 δ, and mass spectrum peaks "at 590.21 * 52, 575, 559, 519 and others, The 6s isomer exhibits MR peaks at 0.89, 1.1-3.5, 3.65, 3.6-1 *, 35, 1 *, 1 * 6 and 5.90 δ.ϋβ corresponding acids are prepared as described in Example VII using a methanolic solution of sodium hydroxide.

The (6s) title acid is obtained by dehydrohalogenation with potassium tert-butoxide. The acid has an R 2 value of 0.32 in a 0.25's acetic acid-containing mixture of methylene chloride and acetone (7: 3) and shows infrared absorption peaks at 1710, 2220, 2550 and 3 ^ 00 10 cm -1, MR peaks at 0.90, 1.08-2.90, 3.60-1 *, 20, 1 *, 20-1.71 and k, 90-5.85 δ and mass spectrum peaks at 568.3 ^ 1 ^, 553, 1 * 97, 1 * 78, 1 * 63, 395, 388, 381 and 173,

The title methyl ester is obtained by reacting the acid with an excess of ethereal diazomethane. The ester lives an R 1 value of Q. 60 in a 0.25 acetic acid-containing mixture of methylene chloride and acetone (7: 3) and exhibits infrared absorption peaks at 1735, 2220, 2850, 2930 and 3100 cm -1, NMR peaks at 0.90, 1.08-2.75, 3.30-3.62, 3.67, 3.68-1 *, 22 and 1 *, 22-1 *, 73 Sen mass spectral peaks at 510.3193, 1 * 95, 1 * 79., U39 »1 * 20, 395, 32h, 305 and 173.

Example X

(6r, 15R} -13,1H-Didehydro-PGI 4 and its methyl ester, isomers of the compounds of Example IX.

In the same manner as in Example VII but using (6Rf15R) -1U-bromo-PGI (Example IX) and dehalogenation thereof with potassium tert-butoxide, the title acid (6r) is obtained. The acid has an R ^ value of 0.1 * 0 in a 0.25 acetic acid-containing mixture of methylene chloride and acetone (7: 3), and shows absorption peaks at 1710, 2220, 2650, 2850, 2930, and 3 ^ 00 cm "1, MR peaks at 0.90, 1.05-3.0, 3.1 * 5-3.95, 3.95-1 *, 53 and 5.08 δ, and mass spectrum peaks at 568.31 * 19 , 553, 1 * 97, 30 V78, 1 * 63, 395, 388, 371, 362 and 173.

The corresponding methyl ester is obtained by reacting the acid with an excess of ethereal diazomethane.

Example XI

Trans-PGI, methyl ester, less uolar isomer and more uolar isomer.

L is C = C ^, R is -C00CH.

-CHg H 1 3 7810862 21 1, See Scheme O in U.S. Patent Application Ser.No. 857,203. The phenyl selenidyl ethers (Formula XCVIII in Scheme 0) are prepared from the compounds of the formula XCYII as their 11,15-bis (tert-butyl-dimethylsilyl] ethers thereof. They are prepared from the mixed PGI-5 isomers ( Example XVII in Dutch patent application 77.05991) by reaction with hexamethyldisilazane and trimethylchlorosilane.

A solution of the aforementioned PGI-methyl esters, bis (silyl ethers) (1.1 + 25 g) in 20 ml of tetrahydrofuran is added to a mixture of isopropyleyclohexylamine (1.17 g), 30 ml of tetrahydrofuran and n-1Q butyl lithium ( 1.7 ml of 1.6 M in hexane) which has been prepared at a temperature of -78 ° C. The mixture is stirred at a temperature of -78 ° C for 0.5 hours, after which a solution of diphenyl diselenide (1, 76 g) in 15 ml of tetrahydrofuran is added. Stirring at a temperature of -70 ° C is continued for 1 hour after which the temperature of the reaction mixture is allowed to rise to 0 ° C. The reaction mixture is then poured into 150 ml of saturated aqueous ammonium chloride and 150 ml of diethyl ether. The organic phase is separated, washed with ice water and brine, dried and concentrated. The residue is purified by high pressure liquid column chromatography using 3 Merck "B" 20 columns in series eluting with a mixture of benzene and ethyl acetate (Uo: 1) to give the phenylselenidyl ethers as mixed C-6 isomers. 0.52 and 0.1 + 8 (thin layer chromatography on silica gel in a mixture of benzene and ethyl acetate (20: 1)) and NMR peaks at 7.55, 7.30, 5.1 + 5, 50 -3.1 + 0, 3.60, 2.50-1.10, 0.90 and 0.03 δ.

2. The bis (silyl ethers) of the title compounds are obtained by oxidative removal of phenylselenide from the compounds prepared above under 1.. In accordance with the embodiment of Example LX in Dutch patent application 77.05991, from the product prepared above under 1. (0.961 + g) 0.707 g of trans-Δ-PGI, methyl ester, 11,15-bis (tert-butyldimethylsilyl ether) ), mixed isomers.

R ^ values 0.1 + 1 and 0.39 (thin layer chromatography on silica gel in a mixture of benzene and ethyl acetate (20: 1))) and HMR peaks at 6.90, 5.90, 5.63, 5, 1 + 2, 1 +, 50-3.50, 3.61+, 2.50-1.10, 0.90 and 0.02 δ.

3. The title compounds are obtained by removing the protecting groups from compounds prepared above and separating the C-8 isomers by chromatography. The product prepared above under 2 (0.707 g) is treated in 6 ml of tetrahydrofuran with tetra-n-butyl-ammonium fluoride (3.5 ml of a 1.2 M solution in tetrahydrofuran) at a temperature of about 25 ° C for 19 hours. The mixture is diluted with 250 ml of ethyl acetate, washed with brine, dried and concentrated. The oily residue is purified by high pressure liquid column chromatography using 3 Merck "B" columns in series eluting with a mixture of methylene chloride and acetone (1: 2).

The resulting less polar isamer (0.125 g) has a melting point of 10-9 ° -71.5 ° C and shows NMR peaks at 7.00, 5.97-5.70, 5.50, if, 35-2, 90, 3.68, 2.50-1.10 and 0.90 δ, and the more polar isomer (0.09 g) NMR peaks at 7.00, 5.97-5.70, 5.50, M3 , U, 17-2.90, 3.68, 2.60-1.10 and 0.90 $.

Example ΧΊΓ 2 '15 Trans-A- ^ j ^ -dimethyl-PGI ^, methyl ester, less polar isomer and more polar isomer, R ^ is -COOCH ^, R2 is

CH_ H

«3 n y

- C - C. H, L is C = C I H 3 / N

ch3 -ch2 H

20 1, See scheme J in Dutch patent application 77.05991.

A solution of 16,16-dimethyl-PGF2a, 11,15-bis (tetrahydropyran-2-yl ether, 7.83 g) in 180 ml of acetonitrile is mixed with 25 diisopropylethylamine (if · ^ 7 g) and treated with methyl iodide (29.5 µg) at a temperature of about 25 ° C in the dark for 25 hours.

Afterwards, the reaction mixture is poured into 500 ml of brine and extracted with diethyl ether. The organic phase is separated, washed with ice water, dilute sodium thiosulfate and brine, dried and concentrated. The obtained methyl ester (7.81 g) shows infrared absorption peaks at 3 ^ 00, 2900, 1730, 1U30, 1350, 1190, 1120, 1070, 1010, 975, 900, 865, 810 and 725 cm -1 MR peaks at 5.80-5.02, U.85-M7, 1 ^, 26-3.17, 3.83, 2.78-1.05 and 0.88 δ.

2, The acetone mercury (II) compounds are prepared from a solution of the product prepared above under 1 (7.0 g) in 30 ml of tetra-7810862 23 hydrofuran by adding the solution dropwise to an ice-cooled yellow suspension of mercury (II) acetate (5.92 g) in a mixture of 2h ml vessel and 2k ml tetrahydrofuran, followed by stirring at a temperature of about 25 ° C for 2 hours. Afterwards, the mixture is poured into an ice-cooled sodium boron solution.

hydride (2.83 µl in 7 ^, ** ml 1N hydroxide and stirred for 10 minutes. Then the mixture is diluted with 750 ml brine and extracted with diethyl ether. The organic phase is separated, dried, filtered and concentrated. oily residue is chromatographed on silica gel eluting with a mixture of ethyl acetate and Skellysolve B

(1: 3) to obtain 5.65 g of 16,16-dimethyl-PGI-methyl ester, 11,15-bis (tetrahydropyran-2-yl ether) mixed isomers as a colorless oil. R 2 value 0. kh (thin layer chromatography on silica gel using a mixture of ethyl acetate and toluene (Γ, 3)), infrared 15 absorption peaks at 2950.1730, 1H30, 1370, 13k0, 1310, 1250, 1190, 1125, 1070, 1020, 975, 910, 905, 865, 815, 730, and 705 cm @ 1 and NMR peaks at 5.71-5.32, fc, 85-U, 53, U, 53-3.04, 3, 6h, 2.72-1.05 and 0.87 δ.

3. See Scheme 0 in U.S. Patent Application Ser.No. 857 * 203. The phenyl selenidyl ether is prepared by adding a solution of the compound prepared above under 2. (5.03 g) in 50 ml of trahydrofuran to a mixture of diisopropylamine (1.08 g) in 125 ml of tetrahydrofuran and n-butyl lithium. (6.5 µm) of a 1.5M solution in hexane) prepared at -78 C followed by stirring at said temperature for 1.2 hours. Afterwards, a solution of phenylselenyl chloride 25 (1.79 g) in 30 ml of tetrahydrofuran is added dropwise over 7 minutes.

The mixture is stirred at -78 ° C for 1.25 hours and then poured into a mixture of 300 ml saturated aqueous ammonium chloride and 00 ml ice water and extracted with diethyl ether.

The organic phase is dried and concentrated. The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene (1: 8) to obtain 3.01 g of the mixed C-6 isamers as an oil. R value 0.53 (thin layer chromatography on silica gel eluting with a mixture of ethyl acetate and toluene (1: 3)) infrared absorption peaks at 2950, 1730, 1570, 1530, 1360, 1310, 1230, 35 1200, 1130, 1070, 1020 , 975, 910, 905, 870, 815, 7 * 10 and ¢ 90 cm'1, and m®.

7810862 2k peaks at 7.78-7, ½. 7, 5-7. / 5, 5.7 ^ -5.27, U, 8Mi, 53, fc, 53-3.17, 3.62, 2.66-1.06 and 0.85 5.

The bis (tetrahydropyran-2-ylethers) of the title compounds are obtained by oxidative removal of phenylselenide 5 to lift the mixed C-6 isomers (3.01 g) prepared above under 3. by treatment in a solution of 65 ml of methylene chloride with hydrogen peroxide (0.99 g of a 10% aqueous hydrogen peroxide solution) at a temperature of about 25 ° C for 1 hour. At the end, the organic phase is separated, washed with a 5 # sodium bicarbonate solution, 10 saturated sodium bicarbonate aqueous solution and brine, dried and concentrated. The oily residue (2.0 g) is chromatographed on silica gel eluting with a mixture of ethyl acetate and Skelly-solve B (1: 3) to give 1.86 g of the mixed C-6 decontamination. Infrared absorption peaks at 2950, 1730, 1660, 1 ^ 0, 1380, 1310, 15 1260, 1200, 1120, 1070, 1020, 975, 905, 870 and 830 cm -1 and HMR peaks at 7.38-6.73, 6 0.06-5.29, U, 85-3.1fc, 3.72, 2.75-1.06 and 0.88 d.

5. The title compounds are obtained by removing the protecting groups from the product prepared above under U and separating the C-6 isomers by chromatography. The top under t. the prepared product (1.86 g) is hydrolysed in a mixture of acetic acid, water and tetrahydrofuran (20: 10: 3) at a temperature of about 10 ° C. Then the reaction mixture is poured into brine and extracted with ethyl acetate. The organic phase is separated, washed with ice water, dried and concentrated to yield 1.5 µg of the mixed isomers of the title compound as an oil. The product is purified by high pressure liquid column chromatography using Merck "B" columns in series eluting with a mixture of acetone and methylene chloride of gradually increasing polarity (from 1: 9 to 1: 5).

The yield of the less polar isomer is 0.352 g and of the more polar isomer 0.536 g. The less polar isomer shows infrared absorption peaks at 3 ^ 50, 2950, 1730, 1660, 1U30, 1310, 1270, 1210, 1170, 1060, 970, 85Ο and 720 cm ”1, HMR peaks at 7, ^ 2-6, 72, 6.06-5.35, ^, 38-2.8¾. 3.70, 2.66-1.06, 0.86 and 0.82 δ and a high resolution mass spectrum peak at 523.3263 (TMS derivative). The more polar isomer shows infrared absorption peaks at 3 ^ 50, 2950, 1730, 1660, 1 ^ 30, 1310, 7810862 25 1270, 12U0, 1210, 1180, 100Uo, 97Q, 850 and 725 on 1, HMR peaks at 7, ^ 7-6.12, 6.11-5.35, M6-3.0, 3.70, 2.70-1.08, 0.88 and 0.83 δ and a high-resolution mass spectrum at 523.32 ^ 3.

Example XTTI

5 Trans-16-16,16-dimethyl-PGI ^} less polar isomer and more polar isomer, R ^ is -COOS,

CH- H

1 3 \ / R2 is -C-C ^, L is C-C '

ch3 -ch ^ N H

10

The methyl esters prepared in Example XII are individually hydrolysed in tertiary butanol with 3N potassium hydroxide and extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated. The less polar acid shows infrared absorption at 3 ^ 00, 2900, 1700, 1650, 1 ^ 20, 1250, 1060, and 970 cm -1, and NMR peaks at 7.38-6.68, 6.13 , 6.0.1-5.33, ^ 1-3.52, 2.65-1.05, 0.88 and 0.83 5, The less polar * acid is referred to as (2E, 6R) -16.16 -dimethyl - ^ - PC-Ij.

The more polar acid shows infrared absorption peaks 20 at 3, 00, 2900, 1700, 1650, lb20, 1250, 1060 and 970 cm -1 and NMR peaks at 7.39-6.76, 6.25, 6.03-5 , 39, ^, 72 ^ 3.35, 2.77-1.06, 0.88 and 0.83 δ.

The more polar acid is referred to as (2E, 6s) -16,16-dimethyl-1β - PGIr

Example XIV

9-Deoxy-6, 9a-epoxy-13, 10U-dihydro-PGF, more polar isomer, X is -C1 ^ CHg-, R1 is -C00H.

A solution of the more polar isomer of 9-deoxy-6t, 9 -epoxy-PGF.j (example XXXVIII in Dutch patent application 77.05991, 1.00 g). in 100 ml of ethyl acetate is mixed with 50 mg of palladium (5%) on carbon and hydrogenated for 7 hours. Afterwards, the reaction mixture is filtered and the filtrate is concentrated. The oily residue has an Rf value of 0.37 (thin layer chromatography in Solvent A-IX) and shows NMR peaks at 6.12, 3.3- b, 6 and 0.9 δ. This more polar acid is referred to as (6s) -13.1 ^ -35 dihydro-PGI ^.

78 1 0 8 6 2 26

Proced XV

-— I -............... »mimm * 9-Βεοχ3τ-6ξ, 9a-epoxy-2,2-difluoro-16-phenoxy-17,18,19,20- tetranor-PGF ^, methyl ester, less polar isomer and more polar isomer, L is Rj is -COOCH ^, R2 is group of formula 3.

According to the embodiment of Example XXXVIII

in Dutch patent application 77 * 05991 but replacing the methyl ester of PGF2 as a starting compound with the methyl ester of 2,2-di-fluoro-16-f-enoxy-17,18,19, 20-tetranor-PGF2a (U.S. Pat. ^ .001,300} the title compounds are obtained.

0 Example XVI

9-Deoxy-6C, 9a-epoxy-16-phenoxy-17,18,19,20-tetranor-PGF ^, methyl ester, less polar isomer and more polar isomer, is -COOCH ^, R ^ is group of formula 3 .

1. See scheme H in Dutch patent application 15 77 * 05991 * A solution of the methyl ester of 16-phenoxy-17,18,19,20-tetranor-PGF2a (1.0 g) in 25 ml of methylene chloride is cooled in an ice bath treated with 25 ml of a saturated aqueous sodium bicarbonate solution and a solution of 1.0 g of iodine in 50 ml of methylene chloride is added dropwise over 20 minutes. The mixture is stirred for 1.5 hours and then diluted with 50 ml of methylene chloride. After washing with a 5% aqueous sodium sulfite solution and brine, it is dried and concentrated. The mixed 5-iodo isomers are separated by chromatography on silica gel eluting with acetone (20-30%) methylene chloride. The less polar isomer (0.0¼ g) 25 has an R 2 value of 0.31 (thin layer chromatography on silica gel in acetone (30%) methylene chloride) and is referred to as the öR isomer. Masa spectrum peaks (TMS derivative) at 567 * 1 ^ 62, 580, 5 ^ 7, 5 ^ 6, 1 * 77 and 2U3. The more polar isomer (0.7¼ g) has an R 2 value of 0.28 (thin layer chromatography on silica gel in acetone (30 / O-methylene chloride) 30 and is referred to as the 6S isomer.

2. The less polar iodine compound as prepared above under 1. (0.37 g) is treated in about 20 ml of methanol with about 0.8 ml of tributyltin chloride. After stirring for 5 minutes, 0.37 g of sodium boron hydride are carefully added over 10 minutes. The mixture is stirred for 1.5 hours at a temperature of about 25 ° C and then diluted with 125 ml of brine and extracted with ethyl acetate. The organic phase is separated, washed with brine, dried and Concentrated The residue is chromatographed eluting with a mixture of acetone ($ 30) and methylene chloride to give 0.2 µg of the less polar title compound, namely, the methyl ester of (6R) -16-phenoxy-17,18 »19 20-tetranor-PGI 2 are obtained, R 2 value 0.20 (thin layer chromatography on silica gel in a mixture of acetone (30 #) and methylene chloride).

Likewise, the corresponding more polar (6s) title compound is prepared replacing the less polar iodine compound with the more polar iodine compound as prepared above under 1. (0tb0 g), Ha chromatography, the more polar title compound is 0.28 g were obtained. R ^ value 0.19 (thin layer chromatography on silica gel in a mixture of acetone (30%) and methylene chloride). Mass spectrum peaks (TMS derivative) at IA1.2U98, ^ 5¾, ^ 23, 15 and 351, and HMR peaks (in CCl ^) at 6.68-7.5.6, ^, 3 ^, 3.7- 0.05 and 3.55 5, Le more polar title compound is referred to as the methyl ester of (6s) -16-phenozy-17,18,19,20-tetranor-PGI1.

Example XVII

9-Deoxy-6g, 9a-epoxy-16-phenoxy-17,18,19,20-tetranor-PGFj, less polar isomer and more polar isomer, is -C00H, Rg is group of formula 3.

To a solution of the less polar methyl ester of Example XVT (0.15 g) in 6 ml of methanol, a solution of 0.3 g of sodium carbonate in 3 ml of water is added and the mixture is stirred at a temperature of about 25 ° for 16 hours C. At the end of 25, the reaction mixture is filtered through Celite (a calcium aluminum silicate filter medium) and concentrated. The residue is acidified with 1N potassium hydrogen sulfate, diluted with 20 ml of brine and extracted with ethyl acetate. The organic phase is separated, washed with brine, dried and concentrated. The oily residue (0.18 g) is chromatographed eluting with acetone (25-35 $) methylene chloride to give 0.11 g of the less polar title compound. HMR peaks at 6.73-7.5, 5.67-5.9, M8 and 3.5-1.5 (in acetone). The product is referred to as (6R) -16-phenoxy-17,18,19,20-tetranor-PGII.

In the same manner, starting from the more polar methyl ester (0.52 g) and using 0.8 g of sodium carbonate, 0.38 g of the 7810862 28 more polar title compound are obtained. Mass spectrum lines at 591.3005, 5T3, 512, 1 * 99, 1 * 09 and 2U3 and NMR peaks at 6.75-7.5, 5.3-5.83, 1 *, 17-1 *, 6¼ and 3, 3-1 *, 17 (in CDCl 3), This product is referred to as (6S5-16-fenaxy-17,18,19,20-tetraoro-PGI.

.5 Example XVIII

9-Deo2ty-6C, 9a-enoxy-15-epi-1β-phenoxy-17,18,19,20-tetranor-PGF, methyl ester, less polar isomer and more polazr isomer, Q is H OH, R ^ is -COQCH ^ ,. Rg is group with formula 3.

In the same manner as in Example XVI but replacing the starting compound with the methyl ester of 15-epi-16-phenoxy-17,18,19,20-t etranor-PGF4, the corresponding 5-iodo compounds are replaced: egen. These are reduced to the title compounds, namely the methyl ester of (62.15S) -16-phenoxy-17,18,19,20-tetranor-PGI ^ and the methyl ester of (63.15S) -16-phenoxy-17 , 18,19,20-tetranor PGI.

15 Example XIX

9-Deoxy-6C, 9a-epoxy-15-epi-16-phenoxy-17,18,19,20-tetranor-PGF1, less - '' N 1 polar isomer and more polar isomer, Q is H OH, R ^ is -C00E, R ^ is group of formula 3.

In the same manner as in Example XVII, the methyl esters of Example XVIII are hydrolyzed to the title compounds (6R, 15S) -16-phenoay-17,18,19,20-tetranor-PGI and (6s, 15S) -16-phenoxy-17,18,19,2O-tetranor-PGI 4.

Example XX

(6ξ) -9-Deoxy-6,9a-epoxy-11-deoxy-10,11-didehydro-PGF ^, methyl ester, mixed isomer and, (lt) is group of formula 1 *, R ^ is -COOCH ^.

1. See scheme H in Dutch patent application 77.05991. First, the corresponding 5-iodo intermediates are prepared, viz. The mixed isomers of the methyl ester of (5'-iodo-9,11-dideoxy-6,9a-epoxy-10,11-didehydro-PGF). A mixture of the methyl ester 3Q of 11-deoxy-10,11-didehydr o-PGF, (obtained by reduction of the methyl ester of PGA with 9-boron-bicyclo-3.3.1-nonane and separation of the C-9 isomers , 0.1 * 5 g) and 15 ml of saturated aqueous sodium bicarbonate solution in 10 ml of methylene chloride at a temperature of about 0 ° C are treated with a solution of iodine (0.35 g) in 25 ml of methylene chloride 35 portionwise adding the latter solution in 1 * 0 minutes. The mixture is stirred for an additional 10 minutes after which the organic phase is separated, washed with aqueous sodium sulfite to colorless and with brine, dried and concentrated. The oily residue (0.6 g) has an R value of 0. 1 * 8 and 0.52 (thin layer chromatography J 5 on silica gel eluting with a mixture of ethyl acetate and cyclohexane (1: 1)), and showing NMR peaks 5.78, 5.5, 5.2, 1 *, 5, 1 *, 05, 3.67, 3.1 and 0.9 5.

2, The iodine compound (0.32 g) obtained above under 1 is treated together with 0.3 ml of tributyltin chloride in 5 ml of ethanol with a solution of 0.10 g of sodium borohydride in k ml of ethanol while slowly adding the latter solution in 15 minutes after which the mixture is stirred for an additional 1 hour. Afterwards, the reaction mixture is acidified with dilute hydrochloric acid, diluted with brine and extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated. The oily residue formed is chromatographed eluting with ethyl acetate (20-h0%) - Skellysolve 3 to obtain 0.11 * g of the title compound as mixed C-6 isomers. R 1 value 0.61 (thin layer chromatography on silica gel in a mixture of equal parts by volume ethyl acetate and cyclohexane (1: 1)), NMR peaks at 5.77, 5.55, 5.18, 3.8-4, 25, 3.63, 3.1 and 0.9 high resolution mass spectrum line at 1 * 22.2852, and infrared absorption at 3 ^ 0, 17 ^ 0, 1625, 12l * 5, 1200, 1175, 1050, 1025 and 975 cm ”1.

Example XXI

(6S) -15-Keto-9-deoxy-6,9a-epoxy-PGF, methyl ester, Q is 0), is -C00CH3.

A solution of the more polar isomer of 9-deoxy-6 3pa-epoxy-PGF ^ (example XXXIX in Dutch patent application 77.05991, 2.00 g) in 66 ml of acetone is treated with 3 ml of Jones reagent at a temperature for 30 minutes. from -7 ° C. At the end, isopropanol is added to the reaction mixture, after which it is concentrated, diluted with brine and extracted with diethyl ether. The organic phase is separated, washed with brine, dried and concentrated. The oily residue is chromatographed eluting with acetone (20-100%) methylene chloride and re-chromatographed to yield 1.39 g of the title compound. R ^ value 0.35 (thin layer chrome-7810862 silica gel matography in an A-DC system "consisting of a mixture of ethyl acetate, acetic acid, 2,2,1 * trimethylpent and water (90: 20: 50: 100 ), M, Hamberg et al., J. Biol.Chem.21 * 1, 2kj (1966) 1, NMR peaks at 7.1 *, 6.93, 6.67, 6.31, 6.03, 1 *, 1 * 8, 3.9, 2.1-2.8 and 0.9 d, mass spectrum lines 5 at 1φ6.3θ66, 1 * 81, 1 * 25, 1 * 06, 380, 365 and 11 * 3 , and infrared absorption at 3l * 20, 3180, 2660, 1730, 1710, 1675, 1630, 1230, 1180, 1080, 1060, 985 and 730 cm ”1.

Example XXII

(6S1-15-Ejato-9-deo2y-6,9a-epoxy-13,1 l * -dihydro-PGF, methyl ester, 10Q is 0.X is -CHgCHg-, Rj is -COOCH ^.

A solution of the methyl ester of (6s) -15-keto-9-deoxy-6,9a-epoxy-PGF ^ prepared in Example XXI (0.75 g) in a mixture of ethyl acetate and 95% ethanol (3: 1) is hydrogenated for 6 hours in the presence of 100 ml of 5% palladium-on-carbon catalyst. At the end, the catalyst material is removed by filtration, after which the filtrate is concentrated. The oily residue is chromatographed eluting with acetone (20 µmethylene chloride to give 0.70 g of the title compound. R1 value 0.1 * 0 (thin layer chromatography on silica gel in A-IX ), and IMR peaks at 7.3l *, Λ,! *, __ 20 3.96, 3.6, 3.0-2.7 and 0.9 <5, mass spectrum peaks at 1 * 98.3228, 1 * 83, 1 * 80, 1 * 65, 1 * 27, 1 * 08, 393, 325, 318, 235 and 99, infrared absorption at 3l * 20, ^ 2660 ~ 1735, 1755, 11 * 10 and 1380 cm "1.

Example XXIII, '^ (6s) -9-Deoxy-6,9a-epoxy- (15B) "15-methyl-PGF1, Q is CH ^ OH, R ^ is 25 -C00H, 1. See scheme H in the Dutch patent application 77.05991. First, the corresponding 5-iodine intermediates, i.e., the mixed isomers of the methyl ester of (5ξ) -iodo-9-deoxy-6,9a-epoxy- (15R) -15-methyl-PGF 2, are prepared. A solution of the methyl ester of 30 (15R) -15-methyl-PGF2a in 100 ml of methylene chloride is mixed with 150 ml of a saturated aqueous sodium bicarbonate solution, followed by a solution of 3.0 g of iodine in 200 ml of methylene chloride in 1 * 0. minutes are added dropwise at a temperature of -5 ° C. After stirring for an additional 20 minutes, the organic phase is separated, washed with aqueous sodium sulfite and brine, dried and concentrated. The iodine 7810862 31 intermediate has an R 2 value of 0.22 (thin layer chromatography on silica gel in ethyl acetate).

2. To a solution of iodine intermediate prepared (1.00 µl in IJ ml of ethanol and 0.9 ml of tributyltin chloride 5), a solution of 0.3 g of sodium borohydride in 12 ml of ethanol is prepared portionwise over 15 minutes. After stirring for an additional 1 hour, the mixture is neutralized with aqueous potassium hydrogen sulfate, diluted with brine and extracted with ethyl acetate. The organic phase is separated, washed with brine, dried and concentrated. The residue is chromatographed eluting with ethyl acetate (20). -60 #) - Skellysolve "B" to give 0.60 g of the methyl esters of the title compounds (mixed C-6 isomers). R 2 value 0.36 (thin layer chromatography on silica gel eluting with ethyl acetate), NMR peaks at 5.57, 3, 2, 3.63, 3.2, 1.23 and 0.9 µ.

3. The mixed methyl esters prepared above under 2. are converted to the corresponding free acids by treatment in methanol with 3 ml of a 3N sodium hydroxide solution at a temperature of about 25 ° C for 3 hours. Afterwards, the reaction mixture is concentrated to half the volume, diluted with brine and ice, acidified with aqueous potassium hydrogen sulfite and immediately extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried and concentrated to give 0.6 g of a mixture of the title compounds. Rf value Q, 2h (thin layer chromatography on silica gel in A-IX system). The product is chromatographed on 0.037-0.062 m silica gel eluting with acetone (20-0.0 #) methylene chloride to obtain 0.52 g of the title compounds. R ^ value 0.1 * 0 (thin layer chromatography on silica gel eluting with a mixture of acetone, methylene chloride and acetic acid (33: 66: 2)), mass spectrum lines at 58k.3753, 569, 513 and b23, and infrared-30 absorption peaks at 3380, 26 ^ 0, 1710, 1U60, 1375, 1230, 1085, 1055 and 975 cm 1.

Example XXIV

(6s) -2,2-Difluoro-9-deaxy-6,9a-epoxy-13,1H-didehydro-PGF, j, methyl ester and the (6r) isomer, L is -CH ^ CH ^ -CF ^ -, X 1 -C * C-, R 3 is -CQOCH 3, 35 1, See Scheme J in Dutch patent application 78 1 0 8 6 2 32 77.05991. First, the 1-chloro compounds, namely (6s) -2,2-difluoro-9-deaxy-6,9a-epoxy-1-chloro-PGF, and the (6R) isomer, are prepared by cyclizing the mercury (XI) derivative of the corresponding methyl ester of 2,2-difluoro-1l-chloro-PGF, to a solution of the methyl 2a-5-ester of 2,2-difluoro-A-chloro-PGP U.S. Patent 2a (1, Q29,681, 0.35 g) in 6 ral tetrahydrofuran is added with a mixture of mercury (11) acetate (0.53 g), water (6 ral) and tetrahydrofuran (6ml).

The mixture is stirred at a temperature of about 25 ° C for 5.5 hours and then cooled to 0 ° C, after which a solution of 0.12 M 10 sodium borohydride in 1N sodium hydroxide solution (25 ml) is added dropwise. suspension is acidified with 0.2M aqueous potassium hydrogen sulfate and extracted with ethyl acetate. The organic phase is separated, washed with a 5% sodium chloride solution, dried and concentrated to give 0.5 g of the mixed 15 C-6 isomers of 2,2-difluoro-9-deoxy-6,9a-epoxy. 1H-chloro-PGF4 are obtained.

R ^ value 0.17 (thin layer chromatography on silica gel in a mixture of ethyl acetate, acetic acid, cyclohexane and water (9: 2: 5: 10)).

2. A solution of the 1U-chloroic acids (0.9X gLin 3¾ml dimethyl sulfoxide prepared above under 1.) is treated with potassium tert -butoxide (0.66 (g) for 15 hours. JTa run is neutralized with cold 0.2M potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic phase is separated, washed with a 5 # sodium chloride solution, dried and concentrated. The oily residue (0.76 g) consisting of the isomeric acids of the title compound, 25 is converted with ethereal diazomethane to the mixed methyl esters (0.72 g) with an R 2 value of 0.13 and 0.52 in a mixture of ethyl acetate and cyclohexane (2: 1). The isomers are separated by chromatography eluting with a mixture of hexane and ethyl acetate (3: 2) to give 0.202 g of the less polar (6R) isomer of the title compound. IMR peaks at 0.23, 3.68, 3.71, 3.23, 1.1-3.0 and 0, Q0 5, infrared absorption peaks at 3500, 22 ^ 0, 1765, 1U60, 1 ^ 0, 1310, 12 ^ - 5, 1200, 1170, 1135, 10 ^ -5-1100, 1020, and 965 cm -1, and mass spectrum lines he 5 ^ 6,2998, 531, ¾75, ¾56, ^ 30, 359 and 173. The more polar (6s ) isomer (0.298 g) shows DMR peaks at ^, ^ 0, 3.86, 3, ^ - ^, 15, 1.1-3.1 and 0.90 <5.35 The infrared and mass spectrum are the same as for the (6R) isomer.

7810862

Claims (27)

1, Prostacycline analogs, characterized by the formula 1, wherein H _ ^ / 5. represents a group of the formula - (CE ^ -, - (CEgJgCFg- or C = C ^, - CE ^ H / X II Q a group of the formula Η OH, H OH, 0 or CH ^ OH, 10 (r) represents a group of the formula 2 or b, Rj represents a group of the formula -C00H, -COOCH ^ or -C0NHC ^ HQ, ? = 3 Rn represents a group with the formula -C_ff_ - c - C, H_ or a group with the 2 pill j 4 y & 3 15 formula 3, X represents a group with the formula -CE ^ CE ^ -, trans-CE = CH- or -C = C-, and r \ j represents a bond in the α or δ configuration, and its pharmacologically acceptable salts. 2. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (Cig) ^ -, Q a group of the formula E Ö &, (r) a group of the formula 2, a group of the formula -C00H, R4 represent a group of the formula ch3 -é-Vg and X a group of the formula trans-C12 -CH- (compound according to example I), and the pharmacologically acceptable salts thereof. Isomer of the compound according to claim 2 (compound according to example II), and the pharmacologically acceptable salts thereof, Compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH 2) ) Q a green with the form - / 'nv — V 2 3 mule ïï 0H, (Jjyeen group of the formula 2, R ^ a group of the formula -COOCH 2, Rg represent a group of the formula 7810862 3k? 3 - ® - CkH9 O¾ and X a group of the formula trans-CH = CH- (compound according to Example III), and the pharmacologically acceptable salts thereof . Isomer of the compound of claim k (compound of example IV), and the pharmacologically acceptable salts thereof. 6. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH_) _-, Q a group of the formula KOS, (γene group of the formula 2, a group of the formula -COOCH ^, Rg represent a group of the formula 3 and X a group of the formula trans-CH = CE- (compound according to example V), and the pharmacologically acceptable salts thereof, T. Compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CHOL-, Q a group of the formula H OH, (R; a group of the formula 2, R ^ a group with the formula -C0MC, H-, R a green with the formula -C_H and X represent a group with the for-4 y 2 mule trans-CH = CE- (compound according to example VI), and the pharmacologically acceptable salts thereof. 8. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH) Q a group of the formula H 0H, (r) a group of the formula 2, R ^ a group of the formula -C00H or -COQCH ^, R ^ a group of the formula 1 and X represent a group of the formula -C = C- (compound according to example VII), and the pharmacologically acceptable salts thereof. Isomers of the compounds of claim 8 (compounds of example VIH) and the pharmacologically acceptable salts thereof, A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CEL), Q a group of the formula É OH, a group of the formula 2, R ^ a group of the formula -C00H or -COOCII, Rg represent a group of the formula -C ^ and X a group of the formula -C = C- (compound according to example IX), and the pharmacologically acceptable salts thereof, 7810862 V ν ' . · 11, Isomers of the compounds of claim 10, (compounds of Example X} and the pharmacologically acceptable salts thereof, A compound according to claim 1, characterized in that Bet is 5 in formula 1 L is a group of the formula E. n "" / e-c \. -Chrt h 2 _ Q a group with the formula ff Off, yp a group with the formula 2, R _ represents a group of the formula -C00CH, R represents a group of the formula -C E 1 32 5 Π and X represents a group of the formula trans-C * CH- (compound of Example XI) and its pharmacologically acceptable salts, A compound according to claim 1, characterized in that in formula 1 L a group of the formula 15 / V 0 = 0 N 1 AXQ a group of the formula ff 0II, Qyeen group of the formula 2, R 1 a group with the formula -COOCE ^, R ^ a group of the formula 20. f3 '- C - C, BL 1 ^ 9 CH3 and X represent a group of the formula trans-C * CH- (compound according to example XII) and the pharmacological acceptable salts thereof. 25 1¾. A compound according to claim 1, characterized in that in formula 1 L a group with the formula: 0¾ ^ “3 ° Q a group with the formula ff 0t, Qpen a group with the formula 2, R ^ a group with the formula -COOff , Rg is a group with the formula f3 - = -¾¾ K. J and X represent a group of the formula trans-C = CH- (compound according to 7810862 Example XIII) and its pharmacologically acceptable salts. A compound according to claim 1, characterized in that in formula 1.1 a group of the formula "(CHglg-, Q a group of the formula E ok, (R) a group of the formula 2, R ^ a group of the formula -C00H, R represent a group of the formula -CE and X a group of the 2 5 Π formula -CHgCHg- (compound according to example XIV), and the pharmacologically acceptable salts thereof. characterized in that in formula 1 L a group of the formula - (CH_) FQ a group of the d cc 10 formula H 0E, (r) a group of the formula 2, R1 a group of the formula -COOCH ^, R 1 represents a group of the formula 3 and X a group of the formula trans-CH = CH- (compound according to example XV) and its pharmacologically acceptable salts. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH-) Q a group of the formula H 0H, (RJ a group of the formula 2, R ^ a group of the formula -COOCHg, Rg a group of the formula 3 and X represent a group of the formula trans-CE = CE (compound according to example XVI), and the pharmaceutically acceptable salts thereof. A compound according to claim 1, characterized in that in formula 1 L a group of the formula Q a group of the formula E OH, ^ a group of the formula 2, R ^ a group of the formula -C00H, a group of the formula 3 and X represent a group of the formula trans-CH = CH- (compound according to example XVII), and the pharmaceutically acceptable salts thereof. Compound according to claim 1, characterized in that in formula 1 L a salute) of the formula - (CHOL-, Q a group with the formula "2 3 mule E 0H, (R) a group of the formula 2 , R ^ a group of the formula -COOCH ^ j, Rg represent a group of the formula 3 and X a group of the formula trans-CH = CR- (compound according to example XVIII), and the pharmacologically acceptable salts thereof. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH0) - - Q a group of the formula H 0Η / £ / a group of the formula 2, R ^ a group of the formula -C00E, R2 a group of the formula 3 and X represent a group of the formula trans-7810862% J * CH = CH- (compound of Example IXI), and the pharmacologically acceptable salts thereof. 21. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH 2) - -, Q a group of the formula H OH, Qj) a group of the formula i? 1 represent a group of the formula -COOCH 4, Rg «and group of the formula -C 1 H 1 ^ and X a group of the formula trans-CH = CH- (compound according to example XX), and the pharmacologically acceptable salts thereof. 22. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH *) -, Q a group of the formula O, (a group of the formula II, R1 a group of the formula -COOCH ^, Rg a group of the formula -C ^ H ^ ^ and X represent a group with the formula trans-CH * CH- (compound according to example XXI), and the pharmacologically acceptable salts thereof. Compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CH _) _-, Q a group of the formula 0, (£) a group of the formula 2, R1 a group of the formula -COOCHg, Rg represent a group of the formula -C ^ H ^ ^ and X represent a group of the formula -CHgCHg- (compound of Example XXII), and the pharmaceutically acceptable salts thereof. 2k. A compound according to claim 1, characterized in that in formula 1 L represents a group of the formula - (CHg) - -, Q represents a group of the formula CH - 'OH, (5) represents a group of the formula 2 R 1 a group of the formula -COOH, Rg represents a group of the formula "C5Hii, X represents a group of the formula trans-CH * CH- (compound of Example XXIII), and the pharmacologically acceptable salts thereof. A compound according to claim 1, characterized in that in formula 1 L a group of the formula - (CHgJgFg-, Q) a group of the 7810862 formula E o! E, a group of the formula 2, a group of the formula -C00CIL, Rr represents a group of the formula -CH and X a group of the -3 2.5 Ji formula -C = C- (compound according to example XXIV), and the pharmacologically acceptable salts thereof. 5 26, T-Terkvij them for the preparation of prostacycline analogues, characterized in that a compound of the formula I, used in L, Q, m Rp Rg and X enrj, has the meaning indicated in claim 1, in particular a compound according to any one of claims 2-25, as well as the pharmacologically acceptable salts thereof, prepared in a manner conventional for the preparation of analogous compounds, or as indicated in the description and described in the examples. 27. Pharmaceutical preparation containing as active ingredient a prostacycline or pharmacologically acceptable salt thereof, characterized in that the active ingredient preparation contains a compound of the formula 1, wherein L, Q, (II), Rj, Rg X and r have the meaning defined in claim 1, in particular a compound according to any one of claims 2-25, or a pharmacologically acceptable salt thereof, 28. A process for the preparation of a pharmaceutical composition according to claim 27, characterized in that a compound of the formula 1, wherein L, R, Rg, X and J have the meaning indicated in claim 1, in particular a compound according to any one of claims 2-25, or a pharmacologically acceptable salt thereof, in a dosage form suitable for therapeutic use. 78 1 0 8 62 ƒ O - CH ~ CHrL- R, X-C-R. 1 Q & OH 2 - ° v ° -0 3 Ü "i t 7810862