SE432101B - PROSTACYCLINE DERIVATIVES FOR USE TO REGULATE THE REPRODUCTION CYCLE OF MENSTRUCTING DOGS - Google Patents

Description

"only for the treatment and prevention of myocardial infarctions in cohabitation 1 1-42-4 In the formulas, broken lines connecting to the cyclopentane ring or side chain indicate that the substituent is in alpha configuration, i.e. below the plane of the ring or side chain. Thick lines indicate that the substituents are in beta configuration, ie above the plane of the line.

Similar compounds have been shown by Pace-Asciak and co-workers in Biochemistry, volume_10, p. 3657-3664 (1971) and includes, for example: II OH Prostacyclin and prostacyclin-type compounds, including derivatives and analogs, are extremely active in causing various biological responses. For this reason, the compounds are useful for pharmacological purposes. A few of these biological responses are: inhibition of platelet aggregation ability, stimulation of smooth muscle and inhibition of gastritic secretion and reduction of undesirable gastrointestinal effects from systemic administration of prostaglandin synthetase inhibitors.

Depending on these biological responses, prostacyclin and prostacyclin-type compounds are useful for studying, preventing, regulating or alleviating a large number of diseases and undesirable physiological conditions in mammals including humans, useful pets, pets and zoological animals, as well as in laboratory animals. , for example mouse, rat, rabbit and monkey.

Prostacyclin and prostacyclin-type compounds are useful in all cases where it is desirable to prevent platelet aggregation and to reduce the aggressive nature of platelets, and to remove or prevent the formation of thrombi in mammals including humans, rabbits and rats. These compounds are, for example, used with postoperative conditions and to prevent conditions such as atherosclerosis, arteriosclerosis, blood coagulation defects due to lipidemia and other clinical conditions where the underlying etiology is associated with lipidobalance or hyperlipidemia.

Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and for long-term prophylaxis after myocardial infarction and stroke. For these purposes, these compounds are administered systemically, e.g. intravenously, subcutaneously, intramuscularly and in the form of sterile implants with prolonged action. Where prompt response is desirable, especially in emergencies, intravenous administration is preferred. Doses in the range of about 0.01 to about 10 mg per kg of body weight per day were used, the exact dose depending on the age, weight and condition of the patient or animal, as well as the frequency and route of administration.

The addition of prostacyclin and prostacyclin-type compounds to whole blood enables in vitro applications the storage of whole blood for use in cardiopulmonary bypass machines. Furthermore, whole blood containing these compounds can be circulated through limbs and organs, e.g. heart and kidneys, whether they are connected to the original body, removed and prepared for transplantation or connected to a new body. Blockage by aggregate platelets is avoided by the presence of these compounds. For this purpose, the compounds are added gradually or in a single or several doses to the circulating blood, to the blood of the donor or animal to the perforated body part, connected or withdrawn, to the recipient or to two or all of these with a total continuation dose. of about 0.001 - 1.0 pg / ml whole blood. These compounds are also useful for preparing platelet-rich concentrates from blood for use in the treatment of thrombocytopenia or in chemotherapy.

Prostacyclin or prostacyclin-type compounds are extremely active in causing stimulation of the smooth muscle and are also extremely active in potentiating other known stimulators of the smooth muscle, e.g. oxytoxic agents, e.g. oxytocin and various ergot alkaloids including derivatives and analogs thereof. Therefore, they are usually useful for or in combination with less than usual amounts of these known stimulators of the smooth muscle, for example to relieve symptoms of paralytic ileus or to regulate or prevent atonic uterine bleeding after abortion or childbirth, to facilitate ejection of the placenta and during puerperium. For the latter purpose, the compound is administered intravenously by infusion immediately after abortion or delivery at a dose in the range of from about 0.01 to about 50 pg per kg of body weight per minute until the desired effect is obtained. Subsequent doses are given intravenously, subcutaneously or by intramuscular injection or infusion during puerperium in the order of 0.01 to 2 mg per kg body weight per day, the exact dose depending on the age, weight and condition of the patient or animal. .

Prostacyclin and prostacyclin-type compounds are also useful in mammals including humans and certain useful animals, such as dogs and pigs, to reduce or regulate excess gastric secretion and thereby reduce or avoid gastrointestinal ulceration and accelerate wound healing. already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously or intramuscularly with an infusion dose of about 0.1 mg per kg of body weight per minute or in a total daily dose by injection or infusion in the range of 0.01 to about 10 mg per kg body weight per day, the exact dose depending on the patient's or animal's age, weight and condition and on the frequency and route of administration.

Prostacyclin and prostacyclin-type compounds are also useful in reducing undesirable gastrointestinal effects due to systemic administration of anti-inflammatory prostaglandin synthetase inhibitors and are used for this purpose by co-administration of prostacyclin or prostacyclin-type compounds and the anti-inflammatory synthesis prostag. See Partridge and co-workers, U.S.P. No. 3,781,429 to discuss that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by co-administration of certain E- and A-type prostaglandins, including PGE1, PGE2, PGE3 , 13,14-dihydro-PGE1 and the corresponding 11-deoxy-PGE1 and PGA compounds. Prostacyclin and prostacyclin-type compounds are useful, for example, to reduce undesirable gastrointestinal effects due to systemic administration of indomethacin, phenylbutazone and aspirin. These are substances that are specifically mentioned in Partridge and co-workers, such as non-steroidal, anti-inflammatory drugs. They are also known as prostaglandin synthetase inhibitors. 73.1 1 1 42-4 The anti-inflammatory synthetase inhibitors, for example indomethacin, aspirin or phenylbutazone, are administered in any of the ways known to alleviate an inflammatory condition, e.g. in each dose regimen and on each per se known route for systemic administration.

Prostacyclin or prostacyclin-type compounds are co-administered with the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by another route. For example, if the anti-inflammatory agent is administered orally, prostacyclin or prostacyclin-type compounds are also administered orally or alternatively it is administered rectally in the form of suppositories or in the case of women vaginally in the form of suppositories or a slow release vaginal device, e.g. type described in U.S. Patent 3,545,439. Alternatively, if the anti-inflammatory agent is administered rectally, prostacyclin or prostacyclin-type compounds may also be administered rectally.

Furthermore, prostacyclin derivatives may conveniently be administered orally or, in the case of women, vaginally. It is particularly suitable when the route of administration is to be the same for both the anti-inflammatory substance and prostacyclin or prostacyclin-type compounds to combine both in a single dosage form.

The dosage regimen of prostacyclin or prostacyclin-type compounds according to this treatment depends on various factors such as the type, age, weight, sex and medical condition of the mammal, the nature and the dosage regimen of the anti-inflammatory synthetase inhibitor administered to the mammal. , the sensitivity to the particular prostacycline or prostacyclin-type compound to be administered.

For example, not everyone in need of an anti-inflammatory agent needs to have the same troublesome gastrointestinal effects when taking the substance. The gastrointestinal effects often vary significantly in nature and degree. However, it is within the scope of a physician's or veterinarian's experience to determine which administration of the anti-inflammatory substance causes undesirable gastrointestinal effects in humans or animals and to prescribe an effective amount of prostacyclin or prostacyclin-type compound to reduce and essentially eliminate these undesirable effects.

Prostacyclin or prostacyclin-type compounds are also useful in providing the prostacyclin ingredient in dilute solution, preferably for the treatment of asthma. The compounds are useful, for example, as bronchodilators and as inhibitors of mediators, such as SRS-A and histamine, which are released from cells activated by an antigen-antibody complex. Thus, these compounds regulate seizures and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, penumonia and emphysema. For these purposes, the compounds are administered in a large number of dosage forms, e.g. orally in the form of tablets, capsules or liquids, rectally in the form of suppositories, parenterally, subcutaneously or intramuscularly with intravenous administration preferred in emergencies, by inhalation or in the form of aerosols or solutions for spray bottles or by snuff in the form of powder. Doses in the range of about 0.01 to 5 mg per kg of body weight per day are used 1-4 times daily, the exact dose depending on the patient's age, weight and condition, as well as the frequency and route of administration. For the above application, prostacyclin or prostacyclin-type compound can be either combined with other anti-asthmatic agents, such as symptomatimetics (isoproteinol, phenylephrine, ephedrine, etc); xanthine derivatives (theophylline and; aminophylline); and drug steroids (ACTH and prednisolone).

Prostacyclin or prostacyclin-type compounds can be effectively administered to human asthma patients by oral inhalation or by aerosol inhalation.

For administration by oral inhalation, conventional vials are used or by oxygen aerosolization, it is convenient to dissolve in concentrations from about 1 part of drug to form 4 of 100-200 parts by weight of total solution. Completely conventional additives can be used to stabilize these solutions or provide isotonic media, for example sodium chloride, sodium citrate, citric acid and the like can be used.

For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy, the composition may consist of the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent such as ethanol. materials and stabilizers. Instead of a co-solvent, a dispersant such as oleyl alcohol can also be used. Suitable devices for using aerosol inhalation therapy techniques are described in U.S. Pat. No. 2,868,691.

Prostacyclin or prostacyclin-type compounds are useful in mammals, including humans, as nasal decongestants and were used for this purpose in a dose range from 10 pg to about 10 mg per ml of a pharmacologically suitable liquid carrier as an aerosol spray, in both cases. for local application.

Prostacyclin or compounds of prostacyclin types are also useful for the treatment of peripheral vascular diseases in humans.

The term peripheral vascular disease is used herein to denote any blood vessel outside the heart and diseases of the lymphatic vessels, such as frostbite, ischemic cerebrovascular disease, arteriovenous fistula, ischemic leg ulcers, phlebitis, venous disease, cold sores, hepatorus arthritis, non-obstructive mesenteric ischemia, arteritis lymphangitis and the like. These examples are used to illustrate and should not be construed as delimiting the term peripheral vascular disease.

For these purposes, prostacyclin compounds are administered orally or parenterally via injection or infusion directly into a vein or artery.

The doses of these compounds range from about 0.01 to 1.0 pg and are administered by infusion over a period of hours or by injection per day with e.g. 1-4 times, with the exact dose depending on the age, weight and condition of the patient and the frequency and route of administration. Treatment is continued for 1-5 days, although three days is usually sufficient to achieve a long-lasting therapeutic effect. In case systemic or side effects are observed by the dose, this is lowered below the threshold at which such systemic or side effects can be observed.

Accordingly, prostacyclin or prostacyclin-type compounds are useful for the treatment of peripheral and vascular diseases of the extremities of people with unsatisfactory circulation in said extremities, such as treatment for the removal of residual pain and healing of wounds.

For a full discussion of the nature and clinical manifestations of human peripheral vascular disease and procedures previously used for their treatment with prostaglandins, reference may be made to South African Patent 74/01414, Derwent Farmdoc No. 58,400V. See Elliott and co-workers, Lancet, January 18, 1975, p. 14ø-'14â.

Prostacyclin or prostacyclin-type compounds are useful in place of oxoxytocin for inducing pain in pregnant women and pregnant animals, including humans, cattle, sheep and pigs, at or near delivery or delivery, or in pregnant animals with intrauterine death in fetuses from about the 20th week to estimated birth. For this purpose, the compounds are infused intravenously at a dose of from about 0.01 to 50 pg per kg of body weight per minute to or near the end of the second stage of labor, ie the expulsion of the fetus. These compounds are especially useful when the woman has gone one or more weeks over time and natural pains have not started or 12-60 hours after the placenta has ruptured and natural pains have not yet begun. An alternative route of administration is oral administration.

~ Prostacyclin or prostacyclin-type compounds are further useful in controlling the reproductive cycle of menstruating female mammals, including women. The term menstruating female mammals * refers to animals which are old enough to menstruate but not so old that -regular menstruation has ceased. For this purpose, the prostacyclin compounds are administered systemically at a dose level in the range of 0.01 mg to about 20 mg per kg of body weight of the female mammal, preferably for a period of time beginning approximately at the time of ovulation and ending approximately at the time of menstruation or just before menstruation.

Intravaginal and intrauterine routes are alternative routes of administration.

In addition, embryo or fetal rejection is obtained during similar administration of compounds during the first or second third of a normal mammalian gestation period.

Prostacyclin or prostacyclin-type compounds are further useful for causing cervical dilation in pregnant or non-pregnant female mammals for gynecological and absterical purposes. In pain induction and in clinical abortion induced by these compounds In case of infertility, cervical dilation induced by these compounds may be a pain, cervical dilation has also been observed. and aids for the movement to the uterus. Cervical dilation of 7811142-4 prostacyclin compounds are also useful in surgical gynecology, such as D and C (cervical dilation and uterine ligation) where mechanical dilation can cause penetration of the uterus, cervical secretions or infections. It is also useful for diagnostic purposes where dilation is necessary for tissue examination. For this purpose, the prostacyclin association is administered locally or systemically.

For example, the prostacyclin compounds are administered orally or vaginally at doses from about 5 to 50 mg in the treatment of adult women with from one to five treatments per 24 hours. Alternatively, the compounds are administered intramuscularly or subcutaneously at doses from about 1 to 25 mg per treatment. The exact dose depends on the age, weight and condition of the patient or animal.

Prostacyclin and prostacyclin-type compounds are also useful in pets as abortifacients (especially for hepatocellular heifers), as an aid in oestrus detection and regulation or synchronization of oestrus. Pets include horses, cattle, sheep and pigs.

The regulation or synchronization of oestrus allows a more efficient management of both conception and pain that enables the breeder to give birth to all female animals within a short predefined time. This synchronization results in a higher number of live births than the percentage obtained by natural regulation. The prostacyclin compounds are injected or applied to the diet at doses from about 0.1 - 100 mg per animal and can be combined with other agents such as steroids. The dosing schedule depends on the species being treated. For mares, prostacyclin compounds were used 5 to 8 days after ovulation and reuse for oestrus. Livestock are treated at regular intervals over a 3-week period in order to get everyone in oestrus at the same time in the most appropriate way.

Prostacyclin or prostacyclin-type compounds increase blood flow through the mammalian kidneys, thereby increasing the volume and electrolyte content of the urine. For this reason, the compounds are used to treat cases of renal dysfunction, especially those involving renal pelvic blockage. Illustrative is that these compounds are useful for relieving and curing edema due to, for example, massive burns and in the treatment of shock conditions. For these purposes, these compounds are suitably administered intravenously by injection at a dose of from about 10 to 1000 pg per kg of body weight or by intra- 7575. 1 42- 4- 10 venous infusion at a dose range of 0.1 to 20 pg per kg of body weight per minute until the desired effect is obtained. Subsequent doses are given intravenously or by subcutaneous injection in the range of från ß to 2 mg per kg body weight per day.

These prostacyclin or prostacyclin-type compounds are useful in treating growing skin diseases in humans and domestic animals including psoriasis, atopic dermatitis, non-specific dermatitis, primarily induced contact kermatitis, allergic contact dermatitis, basal and squamous cell carcinoma of the skin, - dermolytic hyperkeratosis, premalignant sun-induced keratosis, non-malignant keratosis, acne and soborrheic dermatitis in humans and atopic dermatitis and scabies in domesticated animals. These compounds relieve the symptoms of these growing skin diseases, psoriasis, for example, can be alleviated when a scaly psoriasis noticeably increases in thickness or noticeably but is completely free or completely free.

For these purposes, these compounds are applied topically as compositions comprising suitable pharmaceutical carriers, for example as a liniment, a lotion, a paste, a jelly, a paste, an aerosol using local bases such as letrolatum, lanolin, polyethylene glycols and alcohols. These compounds constitute as the active ingredient from 0.1 to about 15% by weight of the composition, preferably from 0.5 to 2% by weight. In addition to topical administration, injections may be used as intradermial, intra- or perilesional or subcutaneous injections using sterile saline compositions.

Prostacyclin or prostacyclin-type compounds are also useful as anti-inflammatory agents for preventing chronic inflammation in mammals, including swelling and other undesirable effects thereof, using methods and treatments and dosages generally described in U.S. Patent No. 3,885,041.

According to the present invention there are obtained new products with pharmacological activity: These new products comprise cyclic ethers of the following formula: 737111 42-4 11 cnz-L-cooR17 III / 'III' I xcR Ho - 25 Qz where L represents - (CH2 ) 3-, -CH = CH-, -CH2 ~ CH = CH- or -CH2-O-CH2 ~; wherein R 17 represents hydrogen or methyl; R 25 represents - (CH 2) 4 -CH 3; CH 3 I -C- CH -CH; -CH -O 11 -CH CH; d "X bt ck- I (2) 3 3 2 e er 2 2 ar ee CH3 when trans-CH = CH-, -CH2CH2- or -CsC- and where Q2 represents /" * / \ H \ OH or CH3 OH .

The novel 5,6-dihydro-prostacyclin-type compounds of formula III have qualitatively the same pharmacological properties as described above for prostacyclin or prostacyclin-type compounds and can be used for the same purpose and in the same manner as described above. Quite surprisingly, these new compounds of the 5,6-dihydro-prostacyclin type are significantly more specific in terms of potency in causing prostacyclin-like biological responses. Therefore, each of these new prostacyclin analogues is more useful than prostacyclin for at least some of the pharmacological purposes listed above. Use of these new analogs for this purpose results in less undesirable side effects than when prostacyclin was used for the same purpose. Depending on their prolonged activity, fewer and smaller doses of the new analogues can be used regularly to achieve the desired result.

These 5,6-dihydro-prostacyclin-type compounds are especially useful for preventing platelet aggregation in blood, in blood in vivo or in vitro applications described above.

To obtain an optimal combination of biological responses, specificity, potency and duration of the activity, certain compounds are preferred within the framework of formula III. The compounds of the invention are prepared in accordance with the following.

Reaction Scheme A IV cH2-coo31 2 VI 78-11 ä 42-4 13 o-í '2.

I ', VII CH -CHO oí 2 I _,' I VIII fl, __ Ho _ * TF 1125 92 CH2-CH = CH-COOR17 IX \\ 73111 1 42- 4 14 CH2- (CH) 3 ~ COOR17 Reaction Scheme A clarifying steps, in which a cyclic ether of formula VI is prepared starting from a lactone of formula IV which is reduced to a lactol of formula V, which is then reduced with a substituted acetate of formula R12OOC-CH2-R13, wherein R12 represents alkyl having 1-8 carbon atoms and R 13 the group -P (C 6 H or) L 3 -P (O) (OR 12) 2 to give a compound of formula VI.

Reaction Scheme A further shows reduction of the compound of formula VI to a hydroxyethyl compound of formula VII, oxidation of this alcohol of formula VII to an aldehyde of formula VIII.

This aldehyde Wittig is alkylated either with an acetate R12OOC-CH2-R13 where R12 and R13 have been previously defined, or with an anion of the formula I1 'Hal' I (C6H5) 3-P-CH2-COOH, where Hal represents chlorine, bromine or iodine to form a compound of formula IX, which may then be subjected to a selective reduction to a compound of formula X.

The alcohol of formula VII is obtained from the ether of formula VI in a manner known per se by using lithium aluminum hydride or lithium trimethoxyaluminum hydride in a solvent such as diethyl ether or tetrahydrofuran.

The aldehyde of formula VIII is obtained by oxidation of -CH 2 -OH to CHO while avoiding decomposition of the cyclic ether ring, with, for example, pyridinium chlorochromate, Jones reagent, Pfetzner-Moffaths reagent and especially Collins reagent (pyridine-CrO 1s ° c.

The aldehyde of formula VIII formed is then alkylated to the compound of formula according to procedures described by, for example, Wadsworth et al., Et al., J. Org. Chem. 30, 680 (1965), Organic Reactions, Volume 14, Chap. 3, New York The ethylene group will be mainly in trans form.

Reaction Scheme B lists alternative methods for the preparation of compounds of the invention in which L represents -CH-CH = CH-.

Reaction Scheme B XI 1 (C 6 H 5) 312 = cH-cH = cH-coco3 CH 2 -CH = CH-COOCH 3 XII The alcohol of formula XI is reacted with methyl 4- (triphenylphosphoranylidene) crotonic acid ester to give a compound of formula XII. The reaction takes place at a temperature of 70-12,000, preferably under refluxing of benzene. The compound can, if desired, be saponified to the corresponding acid.

A further alternative process for the preparation of the compounds of the invention is shown in Reaction Scheme C. Reaction Scheme C 16 OH \ / _cH -cH = cH-L-cooR 2 17 XIII É33 CH-L-COOR17 xiv cH2-L-coo317 XV 7§11142-4 17 The starting materials, the compound of formula XIII, are per se known or readily available PGFZQ compounds.

For example, for PGFZU, see USP 3,706,789, for 15-methyl and 15-ethyl-PGFZG, see USP 3,728,382; for 16,16-dimethyl-PGF2α, see USP 3,903,131, for 16,16-difluoro-PGF2Q, see USP 3,969,380; for 2-decarboxy-2-hydroxymethyl compounds, see USP 3,636,120, for 2-decarboxy-2-tetrazyl derivatives, see USP 3,883513 and 3,932,389, for 2,3-didehydro-PGF2a, see Derwent Farmdoc no. 46497W and German Publication No. 2,460,285, relating to 11-deoxy-11-hydroxymethyl-PGF2α, see U.S. Patents 3,931,282 and 3,950,363; for 16-methylene-PGFZG, see Derwent Farmdoc no. 19594W and USP 3,953,495; for the 17,18-didehydro-PGF2α compounds see USP 3,920,726; for the 3- (or 4-) -oxa-17,18-didehydro-PGF2u compounds see USP 3,920,723; for 15-oxo-PGF2α see USP 3,728,382, for 15-deoxy-PGF2Q see Derwent Farmdoc no. 09239W, for 11-deoxy-15-deoxy-PHF2a see Derwent Farmdoc no. 05694U and USP 3,853,951; regarding the w ~ homo-PGF2a compounds, see Derwent Farmdoc no. O4728W, for the 2-decarboxy-2-amino-PGF2α compounds see Preparation 1 below; for 16-phenoxy-17,18,19,20-tetranor-PGF2α see Derwent Farmdoc no. 73279U, for 17-phenyl-18,19,20-trinor-PGF2u, see USP no. 3,987,087; for 13 ~ cis-PGF2α, see USP 3,932,479; for 13,14-dide-hydro-PGF2α, see Derwent Farmdoc no. 20717X and 59715X; regarding 11-deoxy-PH for see Derwent Farmdoc no. 10695V, for PGE2 see USP 3,767,813; regarding 2a, 2b-dihomo-PGF2u see Derwent Farmdoc no. 614128; for 3-oxo-PGF2α see USP 3,923,861; for 3-oxa-17-phenyl-18,19,2O-trinor-PGF2α, see USP no. 3,931,289; for 2,2-difluoro-PGF2α see USP 4,001,300; for 113-PGFZG see USP 3,890,371; and for 11B-17-phenyl-18,19,20-trinor-PGF2Q see Derwent Farmdoc 13090X.

The compound of formula XIII is halogenated and cyclized to give halogen compounds of formula XIV where hal represents iodine or bromine. Similar cyclization procedure see Staninets and Shilov, Chem. Abs. 64, 12615h (1966). For the iodination, either an aqueous system containing iodine, potassium iodide and an alkali carbonate or bicarbonate or an organic solvent system such as dichloromethane containing iodine is used in the presence of an alkali metal carbonate.

The reaction is carried out at temperatures below 2500 ° C, preferably about 0-5 ° C for 10-20 hours. Thereafter, the reaction is quenched with sodium sulfite and sodium carbonate, and the compound of formula XIV is separated from the reaction mixture. For bromination, N-bromosuccinimide or N-bromoacetamide was used. See Fieser and co-workers, Reagents for Organic Synthesis, Volume I, p. 74-78, Volume IV, p. 51, John Wiley and Sons, Inc., New York.

Thereafter, the halogen compound of formula XIV is subjected to reductive dehalogenation to form the compound of formula XV. Common reagents include tributyltin hydride, triphenyltin hydride, sodium borohydride in dimethyl sulfoxide and zinc in acetic acid. Particularly preferred are newly produced tributyltin hydride from tributyltin chloride and lithium aluminum hydride. The reaction is carried out in a solvent such as benzene at about 15 DEG-5 DEG C. and is followed by thin layer chromatography.

The invention will be illustrated below with the following examples, in which all temperatures are given in OC.

Infrared absorption spectra have been recorded on a Perkin-Elmer Model 421 infrared spectrophotometer. Unless otherwise indicated, undiluted samples have been used.

Nuclear spin resonance spectra have been recorded on a Varian A-60, A-60D, T-60 or XL-100 spectrophotometer in deuterochloroform solutions with tetramethylsilone as internal standard.

Mass spectra are recorded on a mass spectrometer of type Varian, model.

MAT CH7 and a double-focusing high-resolution mass spectrophotometer of type CEC, model 110B or LKB model 9000 GAS. Chromatograph mass spectrometers (ionization voltage 22 or 70 eV.) Were usually run as TMS (trimethylsilyl) derivatives.

"Salt" below means a saturated aqueous solution of sodium chloride.

"Skellysolve B" denotes the mixed isomer of hexanes.

Silica gel chromatography is used below including elution, collection of fractions and pooling of these fractions, which on thin layer chromatography are found to contain the desired product free of starting materials and impurities.

"Concentration" is used herein to denote_concentration under H T fi ffll 42 "4 19 reduced pressure, preferably less than 50 mm Hg and at temperatures below 35 ° C.

"Lower alkanoate" hereinafter refers to an ester of an alkanoic acid having 1-8 carbon atoms.

Example 1 9-deoxy-6β, 9α-epoxy-2,3,4-trinor-PGF1-ethyl ester. Mixed isomers.

I. Reference Scheme A. First, 9-deoxy-6β, 9α-epoxy-2,3,4-trinor-PGF1-ethyl ester-bis-tetrahydropyranyl ether, mixed isomers were prepared. A solution of triethylphosphonoacetate (3.58 g) in 40 ml of tetrahydrofuran was treated at 0 ° C with a solution of potassium t-butoxide (1.79 g) in 40 ml of tetrahydrofuran followed by a solution of 2u, 4a-dihydroxy. 5B- (3'a-hydroxy-1'-trans-octenyl) -α-cyclopentylacetaldehyde-γ-lactol-3'4-bistetrahydropyran-2-yl ethers of formula V (EJ Corey and co-workers, J. Am. Chem. Soc. 92, 397 (1970)) (5.6 g) in 20 ml of benzene was added over a period of one minute. Then the mixture was stirred at 0-25 ° C for 25 minutes and diluted with 500 ml of ether-methylene chloride (3: 1). The resulting mixture was washed with water, dilute potassium hydroxide solution, water and brine, dried and concentrated to a compound of formula IV as a crude product, 8.1 g.

The above product was subjected to silica gel chromatography, eluting with 40-75% ethyl acetate in Skellysolve B to give bis-tetrahydropyranyl ether of formula IV, 4.7 g, with nuclear magnetic resonance peaks at 5.4-5.7, 3.2-4. 8, 2.42 and 2.565.

II. The mixed isomers of the compound of formula VI (1.0 g) were hydrolyzed in 15 ml of acetic acid and 7.5 ml of water at 37-39 ° C for 3 hours. The mixture was cooled, mixed with diethyl ether-methylene chloride (3: 1) and shaken with ice-cold dilute potassium hydroxide solution. The organic phase was washed with brine, dried and concentrated. The residue was subjected to silica gel chromatography, eluting with 0-5% ethanol in ethyl acetate to give the title compound of formula III as a mixture of less polar and more polar isomers, 0.55 g, with nuclear magnetic resonance peaks at 5.27-5.47. 3.3-4.5, 2.4 and 2.526, and mass spectral peaks at 322, 304, 278, 251 and 235. 7061 51 1. 4.2 - 4-20 _.

Example 2 29-deoxy-65,9a-epoxy-2,3,4-trinor-PGF1-ethyl ester, bis (tetrahydropyran-2-yl-ether), mixed isomers and 9-deoxy-6,9a-epoxy- 2,3,4-tri-nor-PGF1-ethyl ester, less polar isomer and more polar isomer.

-IN. Reference to Reaction Scheme A. First, the bis (tetrahydropyranyl ether) of Compound VI was prepared. A mixture of 2d, 4a-dihydroxy--58- [13S) -3-hydroxy-trans-1-octenyl] -1α-cyclopentane-acetaldehyde-Y-lactol-bis- (tetrahydropyran-2-yl-ether) (10 g) of formula V, ethyl (triphegylphosphoranylidine) acetate (10 g) and 150 ml of ethanol were stirred for 3 days under a nitrogen atmosphere. The mixture was concentrated and the residue was chromatographed on silica gel, eluting with ethyl acetate-Skellysolve B (1: 1) to give the isomeric title compound of formula VI, 9.0 g. The product had an Rf value of 0.34 and 0.39 for the mixture (thin layer chromatography on silica gel in ethyl acetate-hexane (1: 3)), and nuclear magnetic resonance peaks at 5.35-5.69, 4.69, 3.98-4.34 and 2.48-2.66.

II. To remove the THP blocking groups, a mixture of the compound of the above formula VI (6.95 g), 100 ml of acetic acid, 50 ml of water and 10 ml of tetrahydrofuran was stirred at 40 ° C for 4 hours.

The mixture was cooled, diluted with 500 ml of ethyl acetate and washed with a mixture of 72 g of sodium hydroxide in 500 ml of ice and water, then with brine, dried and concentrated. The residue was chromatographed on a column of 500 g of fine silica gel (40-63'pm, Merck) previously deactivated with acetone-methylene chloride (60:40). The column was eluted with the acetone-methylene chloride mixture as follows: 3 liters of 30:70, 0.5 liters of 35:65 and 1.5 liters of 40:60. The first 500 ml of the eluent were discarded and then the 40 ml fractions were collected. Fractions 40-46 gave the less polar isomer of formula III of the title compound, 0.21 g with an Rf value of 0.39 (thin layer chromatography on silica gel in acetone-methylene chloride (40: 60D and nuclear magnetic resonance peaks at 5.43). -5.54, 3.98-4.33 and 2.57-2.716.

Fig. 1 shows the 1H nuclear magnetic resonance spectrum. Fractions 47-62 gave a mixture of the isomers. Fractions 63-100 gave the more polar isomer of formula VI of the title compound, 2.03 g, with an Rf value of 0.32 (thin layer chromatography on silica gel in acetone-methylene chloride (40:60)), and nuclear magnetic resonance peaks at 5.47 -5.58, 4.34-4.64, 3.98-4.34 and 2.48-2.63. See Fig. 2 for the 1H nuclear magnetic resonance spectrum and note peaks at 4.4-4.66 for the mercury isomer. Example 11 (9-deoxy-6,9a-epoxy-2,3,4-ran-2-yl-ether), mixed isomers and 9-deoxy-6,9d-epoxy-2,3,4- -trinor-PGF1-methyl ester, the less polar isomer and the more polar isomer.

I. Reference Scheme A. A solution of trimethylphosphonoacetate (7.11 g) in 75 ml of tetrahydrofuran was treated with a solution of potassium t-butoxia (4.10 g) in 75 ml of tetrahyarofuran at 0 ° C. The mixture was stirred at 0 DEG-5 DEG C. for 10 minutes and then a solution of 2α, 4d-dihydroxy-58-1135) -3-hydroxy-trans-1-octenyl; 7-1-cyclopentane-acetaldehyde was added. Γ-lactolbis (tetrahydropyran-2-yl ether) (13.2 g) in 60 ml of tetrahydrofuran for one minute. The mixture was then stirred at about 25 ° C for 1 hour and diluted with 600 ml of diethyl ether-methylene chloride (3: 1). The organic phase was washed with brine, dried and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate-Skellysolve B (1: 1) to give the product of formula VI mixed in C-6 isomers, 12.15 g with an Rf value of 0.62 (thin layer chromatography on silica gel in ethyl acetate-hexane (1: 1 »and nuclear magnetic resonance peaks at 5.3-5.71, 4.71, 3.67 and 2.5-2.616.

Example 4 4a 3a, 4,5,6,6aas-hexahydro-Su-hydroxy-2E- (2'-hydroxyethyl) -4β- (3'-α-hydroxy-trans-1-octenyl) 2H-cyclopenta [ b7furan-3 ', 5'-bistetrahydropyranyl ether, mixed isomers (Formula VII: Q1 represents H OTHP, R25 represents n-pentyl and OH 11 11-position is OTHP, where THP represents tetrahydropyranol and A / represents alpha or beta ).

Reference to Reaction Scheme A. A solution of 9-deoxy-6§, 9a-epoxy-2,3,4-trinor-PGF1-ethyl ester-bistetrahydropyran-2-yl ether (4.0 g) in 40 ml of diethyl ether was added to a slurry of lithium aluminum hydride (0.50 g) in 100 ml of anhydrous diethyl ether. The mixture was then heated at reflux with stirring for 2 hours. After cooling, it was treated successively with 0.70 ml of aqueous 0.70 ml of a 15% aqueous solution of sodium hydroxide and 0.8 ml of water. The mixture was filtered and the filtrate was concentrated to give the title compound of formula VII, 3. 7 g, with nuclear magnetic resonance peaks at 5.2-5.6, 4.6 and 3.0-4.06. An alternative name for these compounds is {3aR- [guy 4a (1E, 3 $ x), 5ß, 6aqñš-hexahydro-5- [Rtetrahydro-2H-pyran-2-yl) oxy-7811142-4 22 -4- α-17-tetrahydro-2H-pyran-2-yl) oxy7-1-octenyl-2H-cyclopenta [alpha] -4-furan-2H-ethanol, where E represents an unknown configuration.

Example 5 9-deoxy-3,4-trans-didehydro-6g, 9a-epoxy-17-phenyl-2,18,19,20-tetranon-PGF1-methyl ester, mixed isomers (formula IX: Q represents / XH OH, R17 represents methyl, R2 represents -CH2CH2% <::>).

I. Reference Scheme B. A mixture of 2d, 4a-dihydroxy--56- (3'a-hydroxy-5'-phenyl-1'-trans-heptenyl) -α-cyclopentylacetaldehyde-γ-lactol-3 4-bistetrahydropyran-2-yl ether (2.28 g) and methyl 4- (triphenylphosphoranylidene), crotonate (Buchta et al., Chem.

Ber. 92, 3111 (1959 », (3.46 g) in 100 ml of benzene were heated at reflux for 16 hours: The mixture was concentrated to a dark orange semi-solid, the residue was subjected to silica gel chromatography, eluted with acetone (5%) - dichloromethane to give the bistetrahydropyran-2-yl ether of the title compound as a yellow oil, 1.55 g.

The above material was hydrolyzed in acetic acid-water-tetrahydrofuran (20:10:10) at about 42 ° C for 4.5 hours. Then 5U ml of water were added, after which the mixture was frozen and then freeze-dried. The resulting residue of the oil was subjected to silica gel chromatography, eluting with acetone (30%) - dichloromethane to give the title compound of formula IX as a mixture between a less polar and a more polar isomer as an oil, 0.444 g. with mass spectral peaks at 336, 363, 350, 324, 287, 277, 269, 233, 133, 105 and 91; infrared absorption peaks at 3390,1720,1655,16QO, 1445, 1446 1325, 1275, 1215, 1195, 1175, 1060, 975, 750 Cm-1; AND Nucleotide Residues At 1 | 2'3r2, 3.7, 3.8-4.6, 5.4-5.65, 5.7-6.1, 6.7-7.1 and 7 , 26. Example 9 6-9-deoxy-6§, 9q-epoxy-PGF1-methyl ester, mixed isomers (formula XV; Q2 represents / V \\, R25 represents n-pentyl, R17 represents methyl OH, L represents - (CH2 ) 3 and / v denote alpha or beta); and 9-deoxy-6,6, 9a-epoxy-PGF1, mixed isomers (formula XV: CgH2g, d, Q, R5, R6, W and the same as above and R1 represents hydrogen).

I. Reference to Reaction Scheme C. First, the halogen compound of formula X10 was prepared. A solution of Pf2a-11,15-bistetrahydropy 731.1 1 1 42-4 23 ran-2-yl ether (2.1 g) in 10 ml of methanol was converted to methyl ester with 20 ml of diethyl ether solution in diazomethane at about 25 ° C for 15 minutes. Then the mixture was concentrated to an oil. The resulting 11,15-bistetrahydropyran-2-yl-PGF2α methyl ester (2.0 g) was suspended in 23 ml of water and treated with sodium bicarbonate (0.7 g) and cooled on an ice bath. To the resulting solution was added potassium iodide (1.93 g) and iodine (2.28 g) and stirring was continued for 16 hours at 0 ° C. Then sodium sulfite (1.66 g) and sodium carbonate (0.76 g) in 10 ml of water were added. After a few minutes, the mixture was extracted with chloroform. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give the iodine compound of formula XIV as bis (tetrahydropyran-2-yl ether) -mixed isomers, 2.2 g, as an oil having an Rf value of 0.75 (thin layer chromatography on silica gel 1 A-IX system).

II. The above 9-deoxy-65,9a-epoxy-5-iodo-PGF1-methyl ester-bistetrahydropyranyl ether (2.2 g) was dissolved in 15 ml of benzene and treated with 15 ml of an ethereal solution of tributyltin hydride (freshly prepared from tributyltin chloride and lithium aluminum hydride containing about 0.145 g per ml) was added dropwise over 20 minutes and after about 30 minutes an additional 20 ml of tributyltin hydride in ether was added while stirring was continued for 1 hour. The reaction mixture was concentrated.

The residue, above mainly the bistetrahydropyranyl ether with the methyl ester of formula XV was converted to the title compound in the following manner. The oily residue was treated with 40 ml of acetic acid-water-tetrahydrofuran (20: 10: 3) for about 16 hours at 25 ° C. Then 250 ml of toluene were added and the mixture was concentrated, which procedure was repeated. The residue was again treated in 40 ml of acetic acid-water-tetrahydrofuran (20: 10: 3) at 40-45 ° C for 2 hours and taken up in 250 ml of toluene and concentrated. The residue was dissolved in 25 ml of dichloromethane and subjected to silica gel chromatography, eluted with ethyl acetate (50-80%) - Skellysolve B. A fraction, 0.77 g, was again subjected to silica gel chromatography, eluted with acetone (20-40%) - dichloromethane to give 9-deoxy-65,9a-epoxy-PGF1-methyl ester-mixed isomers of the formula XV, 0.19 g, with an Rf value of 0.26 (thin layer chromatography in ethyl acetate); [Α] D + 27 ° (chloroform); nuclear magnetic resonance peaks at 0.9, 1.15-2.8, 3.3-4.4, 3.8, 4.63 and 5.65-5856; mass spectral peaks (TMS derivatives) at 512, 497, 481, 441, 391, 351, 325 and 1 7311114-2-4- 24 323 and a high resolution mass spectral peak at 512.3333.

Ill. The methyl ester of formula XV above was converted to the acid of formula XV in the following manner. A solution of the methyl ester (1.0 g) in 30 ml of methanol was treated with 20 ml of 3N potassium hydroxide at about 25 ° C for 1.5 hours. Then the mixture was acidified to pH 1 with 45 ml of 2N potassium hydrogen sulphate and diluted with 50 ml of water. The mixture was saturated with sodium chloride and extracted with ethyl acetate.

The organic phase was washed with brine, dried over sodium sulfate and concentrated to give an oil containing the free answer of formula XV, which gradually crystallized. The product was subjected to silica gel chromatography, eluted with acetone (30-50%) - dichloromethane to give the title compound, 9-deoxy-GE, 9α-epoxy-PGF1α-mixed isomers as less polar and more polar isomers. 84 g, m.p. 79.2-84.500, with infrared absorption at 3340, 3220, 2620, 1715, 1695, 1360, 1320, 1235, 1210, 1080, 990, 975 and 950 cm -1; [Α] D + 28 ° (chloroform); and mass spectral peaks (TMS derivatives) at 555, 499, 480, 465, 409 and 173 with a high resolution mass spectral peak at 570.3569.

Example 7 9-deoxy-6g, 9'-epoxy-PGF1-methyl ester, mixed isomers (formula XV: as in Example 6).

I. Reference to Reaction Scheme C. First, the halogen compound of formula XIV was prepared. One solution of PGF2u methyl ester (9.0 g) in 125 ml of dichloromethane, cooled on an ice bath and treated with anhydrous sodium carbonate (5.3 g) and iodine (6.35 g) and stirred for one hour.

The mixture was then allowed to warm to 25 ° C with stirring for 16 hours. The reaction mixture was diluted with 250 ml of dichloromethane and then 100 ml of 10% aqueous sodium sulfite solution was added. When the iodine color disappeared, the organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting oil, 13.5 g, was subjected to silica gel chromatography, eluting with acetone (20-50%) - dichloromethane to give 9-deoxy-65,9a-epoxy-5-iodo-PGF1-methyl ester mixed isomers. 'of formula XIV, 4.76 g, with an Rf value of 0.40 (thin-layer chromatography on silica gel in acetone-dichloromethane (3: 7)); [Α] D + 22 ° (chloroform); mass spectral peaks (TMS derivative) at 623, 567, 548, 517, 511, 477, 451, 521, 199 and 173; high resolution spectral peaks at 638.2314 78711142-4 and infrared absorption peaks at 3380, 2960, 2940, 2860, 1740, 1440, 1365, 1230, 1195, 1175, 1075, 1055 and 1020 cm -1.

II. Then the title compound of formula XV was prepared. A solution of the above 5-iodo-compound of formula XIV (0.98 g) in 10 ml of benzene was treated at about 15 ° C with 5 mg of 2,2-azobis- (2-methylpropionitrile) and a solution of 0.58 g of tributyltin hydride in 4 ml of diethyl ether added dropwise over 2 minutes. The mixture was allowed to warm to room temperature of about 25 ° C with stirring for a period of 1.25 hours. The second batch of tributyltin hydride (0.58 g) was added and stirring was continued for a further 0.75 hours. The reaction mixture was concentrated and then diluted with 25 ml of Skellysolve B and 25 ml of water, stirred for 0.5 hours and filtered through diatomaceous earth. The aqueous phase together with aqueous washings of the organic phase was mixed with 50 ml of ethyl acetate, saturated with sodium chloride and stirred for one hour. The organic phase together with the ethyl acetate liquids and the aqueous phase comprising a solution in Skellysolve B were dried over sodium sulfate and concentrated.

The resulting oil was subjected to silica gel chromatography, eluting with acetone (25-50%) - dichloromethane to give the title compound of formula XV as mixed compounds, 0.48 g, having the same properties as the product of Example 6.

Example 8 9-Deoxy-65,9a-epoxy-17-phenyl-18,19,20-trinor-PGF1-methyl ester mixed isomers (formula XV: Q2 represents 1H OH, R17 represents methyl, R25 represents -CH2-CH2 - <:: 3>.) I. Reference to Reaction Scheme C. First, the 5-iodine compound of formula XIV was prepared. A solution of 17-phenyl-18,19,20-trinor-PGF1α methyl ether (2.3 g) in 25 ml of dichloromethane, cooled on an ice bath, treated with anhydrous sodium carbonate (1.06 g) and iodine (1.27 g) and stirred for one hour. The mixture was then allowed to warm to 25 ° C with stirring for 16 hours. The reaction mixture was diluted with 50 ml of dichloromethane and treated with 20 ml of 10% aqueous sodium sulfite solution. After the iodine color disappeared, the organic phase was dried together with the organic extracts from washing the aqueous phase with dichloromethane, dried and concentrated to a pale yellow oil, 2.64 g. This oil was subjected to silica gel chromatography to give 9-deoxy. 65,9u-epoxy-5-jpdoj11-phenyl-7611142-4 26 -18,19,20-trinor-PGF1-methyl ester-mixed isomers, of formula XIV, 1.57 g, with an Rf value of 0.24 thin layer chromatography on silica gel in acetone-dichloromethane (3: 7D; nuclear magnetic resonance peaks at 1.5-2.1, 2.1-2.8, 3.5, 3.66, 3.7-4.2, 4.3 -4.6, 5.4-5.7 and 7.26, mass spectral peaks (TMS derivatives) at 657, 582, 567, 545, 477, 455, 389, 337 and 259 and infrared absorption at 3390, 1735, 1600, 1495, 1455, 1435, 1360, 1305 and 975.

II. Then the title compound of formula XV was prepared. A solution of the above 5-iodo-compound of formula XIV (1.0 g) in 9 ml of benzene was treated with 3 mg of 2,2-azobis- (2-methylpropionitrile) and to the cold mixture was added 10 ml of ether solution of tribdtyltin hydride (recently prepared and containing about 0.145 g per ml) dropwise over 5 minutes. The mixture was allowed to warm to 22-25 ° C and stirred for about 45 minutes until the reaction was complete by thin layer chromatography. The mixture was concentrated and the residue was stirred with 25 ml of Skellysolve B and 25 ml of water for 0.5 hours. The aqueous phase, together with the aqueous washes of the Skellysolve B phase, was saturated with sodium chloride and extracted with ethyl acetate. The organic phase, together with the ethyl acetate extracts of the aqueous phase, was dried and concentrated to an oil, 0.87 g. The oil was subjected to silica gel chromatography, eluted with acetone (20-50%) - dichloromethane to give the title compound of formula XV , as a mixture of less polar and more polar isomers, 0.568 g, with an Rf gel in acetone-dichloromethane (3: 7 »; nuclear magnetic resonance peaks at 1.2-2.9, 3.69, 3.7-4.6 , 5.4-5.65 and 7.26, mass spectral peaks at 546, 531, 515, 456, 441, 432, -425 and others and infrared absorption at 3400, 1735, 1495, 1450, 1435, 750 and other cm value of 0.17 (thin layer chromatography on silica- Example 9 5-E-iodo-9-deoxy-6§, 9u-epoxy-PGF1-mixed isomers (formula XIV: R17 represents hydrogen).

A solution of S6-iodo-9-deoxy-6§, 9a-epoxy-PGF1-methyl ester-mixedH isomers of formula XIV (Example 7, 1.00 g) in 25 ml of methanol treated. . was added at about 0 DEG C. with 20 ml of 3N aqueous sodium hydroxide solution.

(After 15 minutes, the cooling bath was removed and stirring was continued for 2 hours. Crushed ice was added together with an aqueous solution of potassium hydrogen sulphate for acidification. The mixture was extracted with ethyl acetate and the organic phase was washed with cocalt, dried over magnesium sulphate and concentrated. The residue was subjected to silica gel chromatography using acid-washed silica gel, eluting with acetone (40-100%) - methylene chloride to give the title compound consisting of mixed isomers, with a [@] D = + 20 ° (C = 0.992 in chloro- roform); infrared absorption at 3360, 2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050 and 970 cm -1; and mass spectral peaks at 696.2554, 681, 625, 606, 569, 535 , 479 and 173.

Example 10 (5S, 6S) -5-Iodo-9-deoxy-6,9a-epoxy-PGF1-methyl ester, less polar isomer and (5R, 6R) -5-iodo-9-deoxy-6,9a- epoxy-PGF1 methyl ester, more polar isomer (Formula XIV).

A suspension of PGF2α methyl ester (3.0 g) in 60 ml of water was treated with sodium carbonate (1.7 g) and cooled in an ice bath. To the resulting solution was added potassium iodide (2.7 g) and iodine (4.14 g) and stirring was continued for 3 hours at about 0 ° C. Then sodium sulfite (2.5 g) and sodium carbonate (0.8 g) were added to decolorize the mixture. After a few minutes, the mixture was extracted with chloroform. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give mixed isomers of the title compound as an oil, which was further purified by silica gel chromatography, eluting with methylene chloride (15-50%) - acetone to give the less polar (5S, 6S) the title compound, 0.29 g with an Rf value of 0.44 (thin layer chromatography on silica gel in ethyl acetate); and the more polar (5R, 6R) title compound, 3.36 g, with an Rf value of 0.41 (thin layer chromatography on silica gel in ethyl acetate).

Example 11 9-deoxy-6,9a-epoxy-PGF1-methyl ester, less polar isomer and more polar isomer (formula XV, L represents - (CH 2) 3 -, R 17 represents methyl, B 25 '(CH 2) 4'CH 3 Reference Scheme C. A solution of the less polar isomer of iodine of formula XIV (Example 10, 0.247 g) in 3 ml of absolute ethanol was treated with tributyltin chloride (0.12 g) and then with a freshly prepared solution. of sodium borohydride (0.050 g) in 3 ml of absolute ethanol. After 45 minutes, the reaction mixture was diluted with ethyl acetate and water. The organic phase was separated, washed, dried and concentrated to an oil, 0.14 g, having properties (identical to those obtained with the title compound. 7§¶? 142-4 28 Exemgel 12 9-deoxy-6š, 9a- epoxy-13,14-dihydro-15-deoxy-PGF1-methyl ester (formula III: Q represents / and X 'represents -CH CH -) 2. HH 2 2 and 9-deoxy-6š, 9d-eoxy-13, 14-dihydro-PGF1-methyl ester (formula III, where Q2 represents / fi x and X 'represents -CH2CH2-).

H OH A solution of 9-deoxy-6E, 9d-epoxy-PGF1-methyl ester (Example 7, estimated 10 mg) in 3 ml of methanol was hydrogenated at atmospheric pressure in the presence of platinum oxide until the starting material could no longer be detected. by thin layer chromatography. There was obtained the title compound: the 15-deoxy compound of formula III with an Rf value of 0.60 (thin layer chromatography on silica gel in acetone-methylene chloride (3: 7U and mass) spectral peaks at 426, 336, 311 and 221 and 9- deoxy-6§, 9u-epoxy-13,14-dihydro-PGF1-methyl ester of formula III and an Rf value of 0.24 (thin layer chromatography on silica gel in acetone-methylene chloride (3: 7)) and mass spectral peaks at 443,425,424AJ4A09, 399, 353, 334, 309, 267, 219, 177 and 173.

Example Gel 9 9-Decoxy-6,9a-epoxy-16,16-dimethyl-PGF1-methyl ester, more polar isomer, Formula XV: R17 represents methyl, Q2 represents I +, R25 represents (CH2) 4-CH3 ). H OH I. Reference to Reaction Scheme C. First, the 5-iodo compound of formula XIV is prepared. A mixture of 16,16-dimethyl-PGF2α-methyl ester (U.S. Pat. No. 3,954,833, 1.85 g) in 35 ml of methylene dichloride and 35 ml of saturated sodium bicarbonate was cooled on an ice bath, treated with 1.42 g of iodine in 89 ml of methylene dichloride which was added over 15 minutes. The mixture was stirred for one hour. The organic phase was separated, washed with sodium sulfite and brine (re-washed with chloroform), dried and concentrated to an oil, 2.94 g. The product was chromatographed on silica gel, eluting with ethyl acetate (50-100%) - Skellysolve B, to give the mixed C-5 isomers of the 5-iodine compound, 2.40 g, with an Rf value of 0.37 (thin layer chromatography on silica gel in ethyl acetate (60% hexane), infrared absorption at 3420 g , 1735, 1260, 1230, 1195, 1170, 1090, 1075, 1020 and 10000 if "0.96., And nuclear magnetic resonance peaks at 3.65, 5.5, 4.5 and II. A solution of the fi roduct from I above ( 2.40 g) in 40 ml of absolute ethanol was treated with 2.5 ml of tributyltin chloride and a solution of 0.5 g of 7.501 l of 42-4 sodium borohydride in 20 ml of absolute ethanol, the mixture was stirred at about 25 ° C for 2 Then carefully dilute aqueous solution of hydrogen chloride was added until the mixture became acidic (pH about 3) and the mixture was concentrated to about 1/3 volume.

Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate (33-200%) - Skellysolve B to give the title compound, 1.01 g, with an Rf value of 0.65 (thin layer chromatography on silica gel in ethyl acetate), mass spectral peaks (TMS derivative) at 525,3411, 509, 450, 441, 419, 351 and 201, infrared absorption at 3400, 1740, 1665, 1460, 1435, 1380, 1360, 1240, 1175, 1055, 1020 and 970 cm -1 and nuclear spin resonance peaks at 5, 4, 4.44, 3.65 and 0.96. The more polar isomer is called (65) -16,16-dimethyl-PGI1-methyl ester.

Example gel 14 9-deoxy-65,9a-epoxy-16-phenoxy-17,18,19,20-tetranor-PGF1-methyl ester, less polar isomer and more polar isomer.

(Formula XV, d represents 3, Q2 represents ¿f \\, R17 represents methyl, H OH R25 represents -CH2-O {<::>, L represents - (CH2) 3-J The mixed isomers, obtained according to Example 6 , but with 16-phenoxy-17,18,19,20-tetranor-PGFZG as starting material, separated on silica gel by chromatography. The less polar isomer is designated (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-PGI1-methyl ester.

Example 15 9-deoxy-6§, 9a-epoxy-16-phenoxy-17,18,19,20-tetranor-PGF1-methyl ester, less polar and more polar isomers (formula XV; Q represents H \ OH, R17 represents methyl , L represents - (CH2) 3- and I. Reference to Reaction Scheme C. First, 5-iodo-precursor R25 represents the compounds of formula XIV. A solution of 16-phenoxy-17,18,19,20-tetranes -PGF2u methyl ester (1.0 g) in 25 ml of methylene chloride, cooled in an ice bath, was treated with 25 ml of saturated sodium bicarbonate solution and a solution of 1.0 g of iodine in 50 ml of methylene chloride added dropwise over 20 minutes. an additional 1.5 hours, after which it was diluted 42-4 with 50 ml of methylene chloride, washed with 5% aqueous sodium sulfite and brine, dried and concentrated, the residue, mixed 5-iodine isomers, of formula XIV , chromatographed on silica gel, eluting with acetone (20-30%) - methylene chloride to give the separated isomers The less polar isomer, 0.04 g, had an Rf value of 0.3 1 (thin layer chromatography on silica gel in acetone (30%) - methylene chloride) and was identified as the 6R isomer. It had mass spectral lines (TMS derivatives) at 567,1462, 580, 547, 546, 477 and 243. The more polar isomer, 0.74 g, had an Rf value of 0.28 in the same system and was identified as the 6S isomer. II. Then the title compound of formula XV was prepared, first the less polar (6R) compound. Continuing with the less polar iodine compound of formula XIV from Part I above, combined with other amounts of the same material (0.37 g) in 20 ml of methanol, the solution was treated with about 0.8 ml of tributyltin chloride, stirred for 5 minutes and then 0.37 g of sodium borohydride was carefully added over 10 minutes. The mixture was stirred at about 25 ° C for 1.5 hours, then diluted with 125 ml of brine and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The residue was chromatographed, eluting with acetone (30%) - methylene chloride to give the less polar title compound of formula XV, namely (6R) f16-phenoxy-17,18,19,20-tetranor-PGI1-methyl ester, 0.24 g. This had an Rf value of 0.20 (thin layer chromatography on silica gel in acetone (30%) - methylene chloride).

The corresponding more polar (63) compound of formula XV was prepared in a similar manner, followed by the procedure of Part II, but instead of the iodine compound the more polar iodine compound of formula XIV, from Part I above (0.40 g) was used. There was obtained after chromatography, the more polar title compound, 0.28 g, with an Rf value of 0.13 (thin layer chromatography on silica gel in acetone (30%) - methylene chloride), with mass spectral lines (TMS derivatives) at 441.2498, 454. 423 and 351 and nuclear spin resonance peaks (in CCl 4) at 6.68-7.4, 5.6, 4.34, 3.7-4.05 and 3.556. It was named (6S) -16-phenoxy-17,18,19,20-tetranor-PGI1- x methyl ester.

Example 16 9-deoxy-6:, 3d-epoxy-16-phenoxy-17,18,19,20-tetranor-PGF1, * less polar and more polar isomers. (Formula XV: R17 represents hydrogen, Q2 represents H OH and R25 represents -CH2-O-).

The methyl esters were hydrolyzed to the acids. The less polar compounds of formula XV (Example 15, 0.15 g) in 6 ml of methanol were treated with 3 ml of water and 0.3 g of sodium carbonate and the mixture was stirred at about 25 ° C for 16 hours. The mixture was filtered through Celite® (a calcium aluminum silicate filter material) and concentrated. The residue was acidified with 1N potassium hydrogen sulphate, diluted with 20 ml of brine and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The residue, an oil, 0.18 g, was chromatographed, eluting with acetone (25-35%) - methylene chloride to give the less polar title compound of formula XV, 0.11 g, with nuclear magnetic resonance peaks at 6.73 ~ 7.5. 5.67-5.9, 4.38 and 3.5-4.76 (in acetone). The compound was called (6R) -16-phenoxy-17,18,19,20-tetranor-PGI1. The above procedure was followed but instead the more polar methyl ester of formula XV (Example 15, 0.52 g) was used and 0.8 g of sodium carbonate to give the corresponding more polar title compound of formula XV, 0.38 g, with mass spectral lines at 591.§005, 573, 512, 499, 409 and 243 and nuclear magnetic resonance peaks at 6.75-7.5, 5.3-5.83, 4.17-4.64 and 3.3-4.176 (in CDCl3 ). The compound was called (6S) -16-phenoxy-17,18,19,20-tetranor-PGI1.

Example 17 9-deoxy-6β, 9α-epoxy-15-epi-16-phenoxy-17,18,19β20-tetranor-PGF1-methyl ester, less polar and more polar isomers (formula XV, Q) I 1 (\ draws OH).

The procedure of Example 15 was followed, but instead of the starting material, 15-epi-16-phenoxy-17,18,19,20-tetranor-PGF2α-methyl ester was obtained to give the corresponding 5-iodine compounds, which upon reduction gave the title compound namely (6R, 15S) -16-phenoxy-17,18,19,20-f-tetranor-PGI1-methyl ester and (6S, 15S) -16-phenoxy-17,18,19,20-tetranonor- PGI1 methyl ester. Example 18 9-deoxy-6β, 9α-epoxy-15-epi-16-phenoxy-17,18,19,20-tetranor-PGF1, less polar and more polar isomers.

The procedure of Example 16 was followed to hydrolyze the methyl esters of Example 17 to the title compounds, namely (6R, 15S) -16-phenoxy-17,18,19,20-tetranor-PGI1 and (6S, 15S) -16-phenoxy-17 , 18,19,20- -tetranor-PGI1.

Example 19 (6š) -9-deoxy-6,9a-epoxy-11-deoxy-10,11-didehydro4PGF1-methyl ester, mixed isomers (formula XV: Q represents H XOH, L represents - (CH2) 3-, R25 represents - (CH2) 4-CH3, R1 represents methyl and / V 'denotes alpha and beta). I. Reference to Reaction Scheme C. First, the corresponding 5-iodine intermediate of formula XIV was prepared, namely (5š) -iodo-9,11-dideoxy-6,9a-epoxy-10,11-didehydro-PGF1-methyl ester , mixed isomers.

A mixture of 11-deoxy-10,11-didehydro-PGF2Q methyl ester (obtained by reduction of PGA2-methyl ester with 9-borobicyclo-3,3,1-nonane and separation of the C-9 isomers, 0.45 g) and 15 ml of saturated aqueous solution of sodium bicarbonate in 10 ml of methylene chloride are treated at about 0 ° C with a solution of iodine (0.35 g) in 25 ml of methylene chloride added in portions over 40 minutes. The mixture was stirred for a further 10 minutes, after which the organic phase was washed with an aqueous solution of sodium sulfite until it became colorless, washed with brine, dried and concentrated with an oil, 0.64 g, with Rf values of 0.48 and 0.52 (thin layer chromatography on silica gel in ethyl acetate-cyclohexane (1: 1)) and nuclear magnetic resonance peaks at 5.78, 5.5, 5.2, 4.5, 4.05, 3.67, 3.1 and 0.96.

II. The above iodine compound (0.32 g) together with 3 ml of tributyltin chloride in 5 ml of ethanol was treated with a solution of 0.10 g of sodium borohydride in 4 ml of ethanol for 15 minutes and the mixture was stirred for another hour. The reaction mixture was acidified with dilute hydrochloric acid, diluted with brine and extracted with ethyl acetate.

The organic phase was washed with brine, dried and concentrated. The resulting oil was chromatographed, eluting with ethyl acetate (20-40%) - Skellysolve B to give the title compound as mixed C-6 isomers, 0.14 g, with an Rf value of 0.61 (thin layer chromatography). on silica gel in ethyl acetate-cyclohexane (1: 1)), nuclear magnetic resonance peaks at 5.77, 5.55, 5.18, 3.8-4.25, 3.63, 3.1 and 0.96, high resolution mass spectral line at 422.2852 and infrared absorption at 3440, 1740, 1625, 1245, 1200, 1175, 1050, 1025 and 975 cm -1.

Example 20 (6S) -9-deoxy-6,9a-epoxy- (15R) -15-methyl-PGF1 [formula XV: / Q2 represents CH3 R17_ represents hydrogen) OH, L represents - (CH2) 3-, R25 represents - (CH2) 4-CH3, I. Reference to Reaction Scheme C. First, the corresponding 5-iodine intermediate of formula XIV was prepared, namely (55) -iodo-9-deoxy-6,9d-epoxy- (15R) -15- methyl-PGF1-methyl ester, mixed isomers. A solution of (15R) -15-methyl-PGFZÜ-methyl ester in 100 ml of methylene chloride was mixed with 150 ml of saturated aqueous sodium bicarbonate solution and treated around -SOC with a solution of about 3.0 g of iodine in 200 ml of methylene chloride added dropwise under 40 minutes. The mixture was stirred for another 20 minutes. The organic phase was washed with an aqueous solution of sodium sulfite and brine, dried and concentrated.

The iodine intermediate had an Rf value of 0.42 (thin layer chromatography on silica gel in ethyl acetate). _II. A solution of: the above iodine intermediate (1.00 g) in 15 ml of ethanol together with 0.9 ml of tributyltin chloride was treated with a solution of 0.3 g of sodium borohydride in 12 ml of ethanol added portionwise over 15 minutes. The mixture was stirred for an additional hour, neutralized with an aqueous solution of potassium hydrogen sulfate, diluted with brine and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The residue was chromatographed, eluting with ethyl acetate (20-60%) - Skellysolve B to give the corresponding methyl esters (mixed C-6 isomers) of the title compound, 0.60 g, with an Rf value of 0.36 ( thin layer chromatography on silica gel in ethyl acetate) and nuclear magnetic resonance peaks at 5.57, 4.4, 3.4-4.2, 3.63, 3.2, 1.23 and 0.96.

III. The above mixed methyl esters were converted to the free acids by treatment in a methanol solution with 3 ml of 3N sodium hydroxide at about 25 ° C for 3 hours. The mixture was concentrated to half volume, diluted with brine and ice, acidified with an aqueous solution of potassium hydrogen sulfite and extracted immediately with ethyl acetate. The extracts were washed with brine, dried and concentrated to the mixed title compounds, 0.6 g, with an Rf value of 0.24 (thin layer chromatography on silica gel in the A-IX system). The product was chromatographed on 230-400 mesh silica gel, eluting with acetone (20-40%) - methylene chloride, to give the title compound, 0.52 g, with an Rf value of 0.40 in acetone in acetone-methylene chloride-acetic acid (33: 66: 2), mass spectral lines at 584.3753, 569, 513 and 423 and infrared absorption at 3380, 2640, 1710, 1460, 1375, 1230, 1085, 1055 beh 975 om *. '

Claims (1)

Claim Cyclic ether for use in regulating the reproductive cycle of menstruating female mammals, characterized by the general formula CH 2 -L-COOR 17 Ho 'X'ff'R 25 Q 2 wherein L represents - (CH 2) 3 -, -CH = CH-, -CH2-CH = CH- or ECH2-O-CH2-; where B17 represents hydrogen or methyl; H25 represents - (CH2) u-CH5; CH - 3,: ~; / \\ 'I. ul -ç- (CH2) 3-CH5; -CH 2 O ((/ ïïf or -CH2CH2jš ::: ¿); where X represents -CH 2 - 3 when trans-CH = CH-, -CH CH 2 - or -CëC- and where Q 2 represents 2 4% / ^ \ ~ \ or 4 * / ^ \ ~ \ CH H OH 3 OH '