IE45604B1 - Prostacyclin derivatives - Google Patents

Abstract

Analogues of 5,6-dihydroprostacyclin of the formula in which the substituents are defined in claim 1, are prepared. These compounds are obtained by halogenating and cyclising a compound of the formula and subsequently reductively dehalogenating the reaction product, with the formation of the desired ether, or by converting the said compound LXII into a corresponding mercury compound and then subjecting the reaction product to the removal of mercury by reduction. The compounds which are obtained may be used for the same pharmacological purposes as the known prostaglandins.

Description

This invention relates to products having prostacyclin-like structure and to processes for preparing them. In particular this invention relates to 5,6-dihydro-prostacyclin analogs and to processes for preparing them.

Prostacyclin is an organic compound related to prostaglandins and identified as 9-deoxy-6,9a-epoxy-45-PGF^. It is particularly characterized as an enol ether from its chemical properties. See R.A. Johnson et. a/., Prostaglandins 12, 915 (1976).

Somewhat related compounds have been reported by C. Pace-Asciak et al., in Biochemistry, Vol. 10., pages 3657-3664 (1971), including, for example: 35604 Prostacyclin and prostacyclin-type compounds, including derivatives and analogs, are extremely potent in causing various biological responses. For that reason, these com5 pounds are useful for pharmacological purposes. A few of those biological responses are: inhibition of blood platelet aggregation, stimulation of smooth muscle, inhibition of gastric secretion and reduction of undesirable gastrointestinal effects from systemic )0 administration of prostaglandin synthetase inhibitors.

Because of these biological responses, prostacyclin and prostacyclin-type compounds are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

Prostacyclin and prostacyclin-type compounds are useful whenever it is desired to inhibit platelet aggre20 gation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post25 operative surgery, and to treat conditions such as -2atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral Ischemic attacks and long term prophylaxis following myocardial infarcts and strokes. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses of 0.01 to mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The addition of prostacyclin and prostacyclin-type compounds to whole blood provides in vitro applications such as storage of whole blood to be used in heart-lung machines. Additionally whole blood containing these compounds can be circulated through limbs and organs, e.g. heart, and kidneys, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. Blocking of aggregated plate25 lets is avoided by the presence of these compounds. For this purpose, the compound is_added gradually or in single or multiple portions to the circulating blood, to the blood of the donor person or animal, to the perfused body portion, attached of detached, to the recipient, or to two or all of these at a total steady state dose of -4- '>·. 0.001-1.0 ug./ml. of whole blood. These compounds ace also uselul in preparing plate let-rich concentrates from blood for use in treating thrombocytopenia or in chemotherapy.

Prostacyclin and prostacyclin-type compounds are 5 extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore, they are useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the fatter purpose, the compound is administered by intravenous infusion immediately after abortion or delivery at a dose of 0.01 to ug. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by 20 intravenous, subcutaneous, or intramuscular injection or infusion during puerperiUm and are from 0.01 to 2 mg. per kg. of 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 man and certain useful animals, e.g. dogs and pigs, to reduce and control excessive gastric secretion, thereby reduce or avoid gastrointestinal ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this >o purpose, these compounds are injected or infused intra-545604 S/ venously, subcutaneously, or intramuscularly in an infusion dose of about 0.1 gg. per kg. of body weight per minute, or in a total daily dose by injection or infusion of 0.01 to 10 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

Prostacyclin and prostacyclin-type 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 concomitant administration of the prostacyclin or prostacyclin-type compound and the anti-inflammatory prostaglandin synthetase inhibitor. See U.S. Patent Specification No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E and A series, including PGEj, PGE2, PGE3, 13,14-dihydro-PGEi, and the corresponding 11-deoxy-PGE and PGA compounds, Prostacyclin and,prostacyclin-type compounds are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in U.S. Patent Specification No. 3,781,429 as non-steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, for example indomethacin, aspirin, or phenylbutazone is adminis30 tered in any of the ways known in the art to alleviate an -6'v..45604 inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration.

The prostacyclin or prostacyclin-type compound is administered along with the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route. For example, if the antiinflammatory substance is being administered orally, the prostacyclin or prostacyclin-type compound is also administered orally, or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example as described in U.S. Patent Specification No. 3,545,438. Alternatively, if the anti-inflammatory substance is being administered rectally, the prostacyclin lp or prostacyclin-type compound is also administered rectally. Further, the prostacyclin derivative can be conveniently administered orally or, in the case of women, vaginally.

It is especially convenient when the administration route is to be the same for both anti-inflammatory substance and prostacyclin or prostacyclin-type compound to combine both into a single dosage form.

The dosage regimen for the prostacyclin or prostacyclin· type compound in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex 2|> and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular prostacyclin or prostacyclin-type compound to be administered. For example, not every human in need of an po anti-inflammatory substance experiences the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree. But it is within the skill of the attending physician or veterinarian to determine that admin5 istration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of the prostacyclin or prostacyclin-type compound to reduce and then substantially to eliminate those undesirable effects.

Prostacyclin or prostacyclin-type compounds are also useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety 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 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 0.01 to 5 rag. per kg. of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use the .prostacyclin or prostacyclin-type compound can be combined advantageously with other anti-asthmatic agents, such as -8! sympathcmimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophyl1ine); and corticosteroids (ACTH and prednisolone).

Prostacyclin or prostacyclin-type compounds are effec5 tively administered to human asthma patients by oral inhalation or by aerosol inhalation, For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient tc provide the prostacyclin ingredient in dilute solution, preferably at concentrations of about 1 part of medicament to form WO to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid, can be employed.

For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise L’Q the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetraf I uoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can a-lso be used a dispensing agent £5 such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technique are described fully i;n.. for example, d.S. Patent Specification No. 2,868,691.

Prostacyclin or prostacyclin-type compounds are useful in mammals, including man, as nasal decongestants and are used for this purpose in a dosage of 10 yg. to -94560 4 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

Prostacyclin or prostacyclin-type compounds are also useful in treating peripheral vascular disease in humans. The term peripheral vascular disease as used herein means disease of any of the blood vessels outside of the heart and to disease of the lymph vessels, for example, frostbite, ischemic cerebrovascular disease, arteriovenous fistulas, ischemic leg ulcers, phlebitis, venous insufficiency, gangrene, hepatorenal syndrome, ductus arteriosus; non-obstructive mesenteric ischemic and arteritis lymphangitis. For these conditions the prostacyclin compounds are administered orally or parenterally via injection or infusion directly into a vein or artery.

The dosages of these compounds are in the range of 0.01 to 1.0 pg. administered by infusions at an hourly rate or by injection on a daily basis, i.e. 1-4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration.

Treatment is continued for one to five days, although three days is ordinarily sufficient to assure long-lasting therapeutic action. In the event that systemic or side effects are observed the dosage is lowered below the threshold at which such systemic or side effects are observed, Prostacyclin or prostacyclin-type compounds are 4S6G4 accordingly useful for treating peripheral vascular diseases in the extremities of humans who have circulatory insufficiencies in said extremities, such treatment affording relief of rest pain and induction of healing of ulcers.

For a complete discussion of the nature of and clinical manifestations of human peripheral vascular disease and the method previously known of its treatment with prostaglandins see South African Patent Specification No 74/0149 referenced as Derwent Farmdoc No. 58,400V.

See Elliott et a_l., Lancet, January 18, 1975, ΡΡ· 140-142.

Prostacyclin or prostacyclin-type compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 gg. per kg. of body weight per minute until or near the termination of the second stage of labour, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labour has not yet started.

An alternative route of administration is oral, Prostacyclin or prostacyclin-type compounds are further useful for control 1ing the reproductive cycle in menstruating female mammals, including humans. By the term menstruating female mammals is meant animals which are mature enough to menstruate, but not so old that regular menstruation has ceased. For that purpose the prostacyclin compound is administered systemically at a dose level in the range 0.01 mg. to -1120 mg. Per ^9- °f body we'9bt °f tbe female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine routes are alternate methods of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administrati on of the compound during the first or second trimester of the normal mammalian gestation period.

Prostacyclin or prostacyclin-type compounds are further useful in causing cervical dilation in pregnant and nonpregnant female mammals for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases of infertility, cervical dilation produced by these compounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostacyclin compounds is also useful in operative gynecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause performation of the uterus, cervical tears, or infections. It is also useful for diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the prostacyclin compound is administered locally or systemica)ly.

The prostacyclin compound, for example, is administered orally or vaginally at doses of . 5 to 50 mg. per treatment of an adult female human, with from one to five treatments per 24 hour period. Alternatively the compound is administered intramuscularly or subcutaneously at doses of one to 25 mg. per treatment. The exact -12- 45604 dosages for these purposes depend on the age, weight, and condition of the patient or animal.

Prostacyclin and prostacyclin-type compounds are further useful in domestic animals as in abortifacients (especially for feedlot heifers), as an aid to estrus detection, and for regulation or synchronization of estrus. Domestic animals include horses, cattle, sheep, and swine. The regulation or synchronization of estrus allows for more efficient management of both conception and labour by enabling the herdsman to breed all his females in short pre-defined intervals. This synchronization results in a higher percentage of live births than the percentage achieved by natural control. The prostacyclin compound Is injected or applied in a feed at doses of 0.1-100 mg. per animal and may be combined with other agents suc'h as steroids.

Dosing schedules will depend on the species treated. For example, mares are given the prostacyclin compound 5 to 8 days after ovulation and return to estrus. Cattle are treated at regular intervals over a 3 week period to advantageously bring all into estrus at the same time.

Prostacyclin or prostacyclin-type compounds increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that reason, these compounds are useful in managing cases of renal dysfunction, especially those involving blockage of the renal vascular bed. Illustratively, these compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. For these purposes, these compounds are preferably first administered by intravenous injection at -13a dose in the range 10 to 1000 pg. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0,05 to 2mg. per kg. of body weight per day.

These prostacyclin or prostacyclin-type compounds are useful for treating proliferating skin diseases of man and domesticated animals, including psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun-induced keratosis, nonmalignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in domesticated animals. These compounds alleviate the symptoms of these proliferative skin diseases: psoriasis, for example, being alleviated when a scale-free psoriasis lesion is noticeably decreased in thickness or noticeably but incompletely cleared or completely cleared.

For those purposes, these compounds are applied topically as compositions including a suitable pharmaceutical carrier, for example as an ointment, iotion, paste, jelly, spray, or aerosol, using topical bases such as petrolatum, lanolin, polyethylene glycols, and alcohol?. These compounds, as the active ingredients, constitute from θ.1% to 15% by weight of the composition, preferably from 0.5% to 2%.

In addition to topical administration, injection may be employed, as intradermally, intra- or perilesionally, or -1445604 subcutaneously, using appropriate sterile saline compositions.

Prostacyclin or prostacyclin-type compounds are useful as antiflammatory agents for inhibiting chronic inflammation in mammals, including swelling and other unpleasant effects, using methods of treatment and dosages generally in accordance with U.S. Patent Specification Nc. 3,885,041.

According to the present invention, there are provided cyclic ether of the formula zo-ch~ch2- l1- r30 Γ------In X- C - R, /\ (I) Iq wherein L* is (1) a valence bond, (2)-(CH2)d -wherein d is an integer of from one to 5, (3) -(CH2)t-CF2- wherein t is 2, 3 or 4, (4)-(CH2)p -CH = CH-(CH2)^- wherein h is zero, one 2 or 3, and p is zero or one, or (Sj-CHg-tHCHg)^- wherein k is one, 2 or 3; wherein (i) Q1 and Q together are oxo, (ii) Q' and Q are both hydrogen, or (iii) one of Q‘ and Q is hydrogen or alkyl of one to 4 carbon atoms and the other is hydroxy; wherein wherein Rgg is (1) -CR5R6-CgH2g-CH3 wherein CgHgg is alkylene of one to 9 carbon atoms, with one to 5 carbon atoms in the chain between -CRgRg- and the terminal methyl, and Rg and Rg are the same or different and are each hydrogen, alkyl of one to 4 carbon atoms or fluorine, with the proviso that -CRgRg is not -CFAlkyl-; (2) -cr5r6-z (T)s wherein 1 is -0- or C.H,, wherein C.H,. is a valence bond or j Zj j zj alkylene of one to 9 carbon atoms optionally substituted with one or 2 fluorine atoms, with one to 6 carbon atoms in the chain between CR5R6“ ani* Pheny^ wherein T is alkyl or alkoxy of one to 4 carbon atoms, fluorine, chlorine or trifluoromethyl and s is zero, one, 2 or 3, with the provisos that not more than two T’s are other than alkyl and that when s is 2 or 3 the T’s may be the same or different; and wherein Rg and Rg are as ϊθ defined above with the proviso that neither Rg nor Rg is fluorine when Z is -0-; or (3) -cis-CH,-CH = CH-CH2CH3; wherein R^ is (1) -COOR^g wherein R^g is hydrogen, a pharmacologic ally acceptable cation, alkyl of one to 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, phenyl substituted with one, 2 or 3 chlorine atoms or alkyl radicals of one to 4 carbon atoms, £-(£iacetamidobenzamido)phenyl, £-benzamidophenyl, £-acetamidophenyl, £-ureidophenyl, £-semicarbazonomethylphenyl, 2-naphthyl or -CHRgg-COR,^ wherein R^ is phenyl, £-bromophenyl, £-biphenylyl, £-nitrophenyl, £-benzaminophenyl or 2-naphthyl and R3g is hydrogen or benzoyl, 4S®04 (2) -CHgOH, (3)-CH2N(R-jg)2 wherein the R-jg.’s are the same or different and are each hydrogen, alkyl of one to 12 carbon atoms, phenyl or benzyl, (4)-C0N(R^g)2 wherein the R1g’s are as defined above, or 5 (5) tetrazolyl: wherein X is trans-CH - CH-, cis-CH-CH-, -C = C-, or -CHgCHg-j and whereinindicates attachment in alpha or beta configuration; and alkanoates thereof which are derived from alkanoic acids of 2 to 18 carbon atoms; with the overall proviso that, when 1? is -CH = 0Η-(0Η2)^- wherein h is as defined above, then R2g is not cis-CHp-CH = CHgCH^ and/or Q' and Q together are not oxo.

In the above formulae, broken line attachments to the cyclopentane ring or side chain indicate substituents in alpha configuration, i.e. below the plane of the ring or side chain.

Heavy solid line attachments indicate substituents in beta configuration, i.e. above the plane.

In the compounds of this invention, the carbon atoms are numbered as for prostanoic acid, except that the carbon atoms in longer or shorter side chains are named, following the usual convention, as “nor or homo atoms.

By way of illustration, formula I represents 9-deoxy-6e,9a-epoxy-2,3,4-trinor-PFG1, ethyl ester, when I? is a valence bond; Q1 is hydrogen; Q1 is hydroxy; R22 is R25 is n-pentyl; X is trans-CH = CH-; and R3q is ethoxycarbonyl.

HO 4S604 For those compounds of formula I in which Q is hydroxy, i.e those in which a C-15 hydroxyl group is attached to the side chain in alpha configuration, the configuration at C-15 is identical to that of naturally occurring prostaglandins such as PGE^ obtained from mammalian tissues. The 15-epimer compounds are represented by formula I wherein Q' is hydroxy and are identified variously as 15-epi or 15g by the appropriate prefix in the name. As is known, R and S designations depend on the neighbouring substituents, See. R.S. Cahn, J. Chem. Ed. 41, 115 (1964).

As indicated above, indicates that the -CHg-L'-Rgg group may be in alpha or beta configuration.

The nomenclature for these isomers may refer to alpha or beta substitution at C-6 or, preferably, it may follow the R and S usage, for which see R.S. Cahn cited above. See Nelson, J. Medic. Chem. 17, 911 (1974).

Although these formulas represent specific optical isomers, it is intended that the compounds are claimed not only in their purified form but also in mixtures, including racemic mixtures or mixtures of the enantiomeric forms.

With regard to formula I, examples of alkyl of one to 4 carbon atoms are methyl, ethyl, propyl, butyl, and isomeric forms thereof. Examples of alkyl of one to 8 carbon atoms, inclusive, are those given above and pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. Examples of alkyl of one to 18 carbon atoms, inclusive, are those given above and nony), decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and Isomeric forms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms, which includes alkyl-substituted cycloalkyl, are cyclopropyl, 2-methyl cyclopropyl, 2.2- dimethyl cyclopropyl, 2.3- diethyl cyclopropyl, 2>butylcyclcpropyl, cyclobutyl, 2- methylcyclobutyl, 3- propylcyclobutyl, 2,3,4,-tri ethy lcyclobutyl, • cyclopentyl, 2,2-di methyl cyclopentyl, 2- pentylcyclopentyl, 3- tert-butyl cyclopentyl, cyclohexyl, 4-tert-butylcyc1ohexy1, 2-isopropy1cyclohexyl, 2,2-di methylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of aralkyl of 7 to 12 carbon atoms are benzyl, phenethyl, 1- phenylethyl, 2- pheny1 propyl, 4-pheny1 butyl, 2-phenylbuty1, 2-(l-naphthylethy1), and l-(2-naphthylmpthyl).

Examples of phenyl substituted by alkyl radicals of one to carbon atoms are (ο-, m-, or _p-)to1yl, β-ethylphenyl, p-tert-butylphenyl, ana 2,5-dimethylphenyl.

Examples of alkylene of one to 9 carbon atoms gf) with one to 5 carbon atoms in the chain, within the scope of CgH3g as defined above, are methylene, ethylene, trimethylene, tetramethylene, and pentamethylene, and those alkylene with one or more alkyl substituents on one or more carbon atoms thereof, e.g, -CH(CH3)-, -C -CH(CH2CH3)-, -CHs-CH(CH3)-, -CH(CHa)-CH(CHa)-, Λ3604 -CH2-C(CHa)2-, -CH2-CH(CHa)-CH3-, -CH2-CH2-CH(CH2CH2CH3)-, -CH(CHa)-CH(CHa)-CH2-CH2-, -CH2-CH2-CH2-C(CH3)2-CH2, and -CH2-CH2-CHa-CH2-CH(CH3)-. Examples of alkylene of one to 9 carbon atoms optionally substituted with one or 2 fluorine atoms, with one to 6 carbon atoms in the chain, within the scope of CjH2j as defined above, are those given above for CgH2g and hexamethylene, including hexamethylene with one or more alkyl substituents on one or more carbon atoms theredf, and including those alkylene groups with one or 2 fluorine atoms on one or 2 carbon atoms thereof, e.g. -CHF-CH2-, -CHF-CHF-, -CH2-CH2-CF2-, -CHs-CHF-CHs-, -CH2-CHa-CF(CH3)-, -CH2-CH2-CF2-CH2-, -CH(CHs)CHa-CH2-CHF -, -CH2-CH2-CH2-CH2-CFs-, -CHF-CH2’CH2-CH2-CHs-CHF-, -CF2-CH2-CHS-CH2-CHfi-CHs-, -CH2-CH2-CH2-CF2-CH2-CH2-, and -CH2-CH2-CH2-CHa-CH2-CF2.· Examples of Λ-^-(Τ)δ -Cy as defined above are phenyl, . ! (o«, m-, or £-)to1yl, (ο-, m-, or j3-)ethy1phenyl, (o-j ffi-j or j3-)propylphenyl, (ο-, m-, or £-)butylphenyl, (ο-, ¢-, or_p-)isobutylphenyl, (o-,jn-, or p-)tert-butylphenyl, 2,5-xylyl, . 2,4-xylyl, 2.5- xylyl, 2.6- xylyl, 3,4-xylyl, 6 0 4 2,6-diethy1pheny), 2-ethyl-p-tolyl, 4- ethy1 -o.-tol yl, - ethyI ^n-toiyl, 2- propyl-(ο-, _m--· or £-)tolyl, 4-butyl -_m-tolyl, 6- tert-butvl -_rn_-to’y 1, 4-isopropyl-2,6-xylyl, 3- propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenyl, (2-, 21’, or ja-)fluorophenyl, 2-f luoro-(o.-, m-, orj3-)tolyl, 4- fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (ο-, m-, or j)-)chlorophenyl, 2-chloro-p-tolyl, (5-, 4-, 5-, or 6-)chloro-_o-tolyl, 4-ch1oro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xy1yl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)01 chlorophenyl, 4-chloro-3-fluorophenyl, (3-, or 4-)chloro-2-fluorophenyl, α,α,α-trlfluoro-(o-, m-, or_g-)tolyl, (ο-, m-, or £-)methoxyphenyl, (ο-, m-, or j3_-)ethoxypheny 1, (4- or 5-)chloro-2-methoxyphenyl, and 2,4-dlchloro(5- or 6-)methoxyphenyl.

Included within the scope of in formula I, and following the above nomenclature, are Πβ compounds, ll-deoxy-ll-oxo (PGDj compounds, ll-tfeoxy-ll-methylene compounds, Π-deoxy compound, ll-deoxy-10,11-di dehydro compounds, and 11-deoxy-11-hydroxymethyl compounds.

Considering the srapa of R^q in formula I, there are included acids, esters, salts, 2-decarboxy-2-hydroxymethyl compounds, 2-decarboxy-2-aminomethyl compounds, amides, and 2-decarboxy-2-tetrazolyl compounds.

Included in this invention are the pharmacologically acceptable salts when R1 is hydrogen. Pharmacologically acceptable salts of these formula I compounds useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.; Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines.

Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutyiamine, triisopropylamine, N-methyl hexyl amine, decyl amine, dodecylamine, allylamine, crotyiamine, cyclopentylamine, dicyclohexylamine, benzylamine, di benzyl amine, α-pheny1 ethyl amine, β-phenylethy1 amine, ethylenediamine, diethylenetriamlne, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., 1- methyIpiperidine, 4-ethy!morpholine, 1-isopropylpyrro)tdine, 2-methyIpyrrolidine, 1,4-dtmethylpfperazine, 2-methylpi peri dine, ’as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amlno-l-butanol, 2-amino-2-ethy 1:-1,5-,l>f»pand1ol> 2- ami no-2-methy1-1-propanol, tris(hydroxymethyl)ami nomethane, N -phenyl ethanol ami ne, N-(p-tert-amyl phenyl)diethanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine. or procaine.

Examples of suitable pharmacologicalJy acceptable xq quaternary ammonium cations are tetramethylammoniurn, tetraethyl ammonium, benzyl tri methyl ammonium and phenyl tri ethylammoni um.

The novel 5,6-dihydro-prostacyclin-type compounds of formula I can be used for the same purposes as the prostacyclins described above, and in the same manner. The invention therefore provides pharmaceutical compositions comprising compounds of formula I in association with pharmaceutically acceptable carriers.

The novel 5,6-dihydro-prostacyclin-type compounds are especially useful for the inhibition of platelet aggregation in blood for either in vivo or in vitro applications of the type described above.

To obtain the optimum combination of biological response specificity, potency, and duration of activity, certain compounds of formula I are preferred. For example it is preferred that one of Q' and Q is hydrogen or alkyl and the other is hydroxy. More preferably one is hydrogen and the other hydroxy.

Another preference is that Rig in -COORig is hydrogen or alkyl. of one to 12 carbon atoms (especially methyl or ethyl for optimum absorption on administration) or a salt of a pharmacologically acceptable cation. For the purposes of stability on long storage, it is preferred that R^g in -COOR^g is amido-substituted phenyl or substituted phenacyl.

For oral administration of the novel compounds it is preferred that Rg0 is -CONJR^gJg wherein each R-jg is as defined above. Preferably each R^g is hydrogen or alkyl of one to 4 carbon atoms, more preferably hydrogen or methyl. 4S604 When R25 is -CRgR6-CgH2g-CH3, ii: is Preferred that CgH2g is alkylene of 2, 3 or 4 carbon atoms, and especially that it is trimethylene. It is further preferred that Rg and Rg are each hydrogen, methyl, ethyl or fluorine, being the same or different. It is further preferred, when Rg and Rg are not hydrogen, that Rg and Rg are both methyl or fluorine.

It is especially preferred that R25 is n-pentyl, 1,1-dimethylpentyl or 1,1-di fluoropentyl.

When R25 is it is preferred that s is either zero or one. When s is not zero, it is preferred that T is methyl, chlorine, fluorine, trifluoromethyl or methoxy with meta or para attachment to the phenyl ring.

When Z is -0-, it is preferred that Rg and Rg are each hydrogen, methyl or ethyl, being the same or different.

It is further preferred, when Rg and Rg are not hydrogen, that Rg and Rg are both methyl. -jHgp it is preferred that is a valence bond, methyl, or ethylene. Rgg is phenokymethyl It is especially preferred that or phenethyl.

As to variations in it is preferred that and most preferably the first of these.

It is preferred that L1 is -(CHgJg-» “(CHg)^ or “(CH2)5-, and especially “(CH2)3-.

The following Charts show synthetic routes for the preparation of compounds of formula I. 6 0 4 CHART A XXXVII 4' XXXVII I XXXIX 604 in Chart A, —' is as defined above Q is OR. or ‘4 R wherein R3 is hydrogen or alkyl of one to 4 carbon atoms, and R^ is hydrogen, tetrahydropyran-2-yl, tetrahydrofuran-2-yl, or a group of the formula Rg— 0 - C - C — R-j ( wherein Rg is alkyl of one to 18 caroon atoms, cycloalky! of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, or phenyl substituted with one, 2 or 3 alkyl radicals of one to 4 carbon atoms; either Rg and R-|0 are the same or different and are each hydrogen, alkyl of one to 4 carbon atoms, phenyl or phenyl substituted with one, 2 or 3 alkyl radicals of one to 4 carbon atoms, or Rg and R^ are taken together and are -(CHg)a- or -(CH2)b-0-(CH2)c- wherein a is 3, 4 or 5, lb b is one, 2 or 3, and c is one, 2 or 3 with the proviso that b plus c is 2, 3 and 4; and is hydrogen or phenyl.

R, is hydrogen or alkyl of one to 8 carbon atoms.

Rg is as defined above for Rgg but is not cis-CHg-CH = CH-CHg-CHg. 4S604 is wherein Rg is as defined above and R^o is the same as R. defined above except that 5 it does not include hydrogen, but includes only the blocking groups such as tetrahydropyran-2-yι, R}2 is alkyl of one to 8 carbon atoms.

CH20R4 wherein R4 is as defined above. (R^p is the same as (R20) defined above except that R4 therein is replaced with R4o as defined above, i.e. excluding hydrogen.

The formula-XXXVII lactone reactants are known in the art or are available by processes known in the art. For example, when 1 s CL / THPO where THP is tetrahydropyran-2-yl and Ra is alkyl, see Corey et a_I., J. Am. Chem. Soc. 92, 397 (1970), and U.S. Patent No. 3,931,279 when Rg is phenyl-substituted, see U.S. Patent No. 3,987,087,.. - -----------------------When (Rs 1 j ϊ s OR 40 these IIP lactones are obtained by isomerizing a correspond20 ing lactone having the 11« configuration, with suitable blocking at the C-15 position if desired, b.y methods known in the art, such as by way of the 11-mesylate or 11-tosylate. For application of the 11-benzoate for example, see Mitsunobu et al., J. Am. Chem. Soc. 94, 679 (1972). and R2 is alkyl, see U.S. Patent No. 3,931,279 when R2 is phenyl-substituted, also see U.S. Patent specification No. 3,931,279.

When a suitable starting material is OCHS LXXI I CHO See E.J. Corey et a_l., Tetrahedron Lett. 107 (1972). After 20 introduction of the R2-containing side chain by known methods including the Wittig reaction and reduction of the 15-oxo group, the methyl ether is hydrolyzed to the lactone in acid, CHsOH the lactone is available or prepared by processes known in 4S604 the art. See German Offenlegungsschrift No. 2,437,622. . For example, the carboxy group in a compound of the formula LXXI11 H C “R2 11 Q * C=C. COOH / X Π is reduced to the corresponding -CHgOH compound using diborane; when When (Rai) is CHa the hydroxymethyl compound immediately .above is converted first to a · tosylate by known methods such as reaction with £-toluenesu1fonyl chloride in 50# excess in the presence of pyridine at about 25° C.; the tosyl group is then exchanged with iodide, e.g. sodium iodide in acetone at 25-40°C. to form the corresponding iodomethyl compound. 6 0 4 That iodomethyl compound is then dehydroiodinatcj, for example with potassium tert-butoxide in tetrahydrofuran at -50° C. or below, to yield the methylene compound: Q LXXXV The formula-XXXVI11 lactol is obtained on reduction of lactone XXXVil without reducing the ethylenic group. For this purpose, diisobutylaluminum hydride is used as known in the art. The reduction is preferably done at -60° to -78° C.

The formula-XXXIX intermediate is obtained from the lactol by reaction with an anion derived from either a phosphonoacetate of the formula RiZOOC-CH2-P(O)(OR12)e LXXIV or a carboxymethylpbosphoniuffl compound of the formula R12OOC-CH2*P(CeHs)a Hal® LXXV wherein Ria is alkyl of one to 8 carbon atoms. ar*d Hal is chlorine, bromine or iodine. Alternatively, the phosphonium compound may be referred to by its yl td form, R12OOC-CH= P(CgH5J3. LAAVa The reaction is done in the presence of a base, preferably potassium t-butoxide or sodium hydride for LXXIV, or potass.i urn t-butoxide, sodium ethoxide, benzyltrimethyl5 ammonium hydroxide, or, preferably, an alkali metal hydroxide for LXXV, usually at 0-25° c.

The formula-XL product is obtained on replacement of the R40 blocking groups with hydrogen, by acid hydrolysis, for example in dilute acetic acid, aqueous citric acid, or lu aqueous phosphoric acid-tetrahydrofuran. When Rj in the product is different than.Ri2, transformation is brought about by methods known in the art, including saponification to yield the acid, optionally followed by esterification. Esters are conveniently prepared by interaction of the acid with an . appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane, and l-diazo-2-ethylhexane for example, gives the ethyl, butyl, and 2-ethyl hexyl esters, respectively. Of these esters, it is preferred that Ri be methyl or ethyl.

Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than 48604 necessary to effect the desired esterification, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example Organic Reactions, John Wiley & Sons, Inc., New York, N.Y., Vol 8, pp. 389-394 (1954).

Ar. alternative method for esterification of the acid compounds herein comprises transformations of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, and isobutyl iodide. The silver salts are prepared by conventional methods, for example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of silver nitrate.

As for all of the reactions described herein, the duration of the reaction is readily determined by monitoring with TLC (thin layer chromatography).

XXXIX CHART Β •ψ XLI , 0 -CH CHS -CH=CH-A -COOR ι (Rai/· _CHs XLI 11 S XH C=CX H C-Rs via several steps 5604 GHART B (continued) Qi XLIV H z.0-CH-^(CH&)s-A-C00Ri / -CH2 /H C=C, xC-Rs XLV in Chart B and in the following charts, tne term Q> Q-|» R·] > Rg* Ri2* h and have the same meaning as for Chart A.

R is hydrogen or alley I of one to 8 carbon atoms; R^ represents hydrogen or an alkali metal cation, e.g. sodium, potassium or lithium.

In Chart B, the formula-XxXIX intermediates are produced by the steps in Chart A above.

A formula-XLl alcohol is obtained from a formula-XXXIX ester on reduction, by methods known in the art, for example using lithium aluminium hydride or lithium trimethoxyaluminium hydride in a solvent such as diethyl ether or tetrahydrofuran.

The formula-XLII aldehyde is obtained by oxidation of the -CHgOH of XLI to -CHO, avoiding decomposition of the cyclic ether ring. Useful for this purpose are pyridinium chlorochromate, Jones reagent, Pfitzner-Moffatt reagent and, especially, Collins' reagent (pyridine-CrOgj at U-15°C. 2u The formuia-XLIII compound is obtained by Wittig alkylation using an anion derived from an appropriate phosphonate or phosphonium compound. When h is zero, a compound of the formula RjgOOC-CHg-R·^ is used, wherein R^g is alkyl of one to 8 carbon atoms and R13 is the group “P(c6h5)3 8 6 0 4 or -f(0j(0R.|2)2. See for example D.H. Wadsworth et aL, J. Org. chem. 30,680 (i96b') as to phosphonates. See also Organic Reactions Vol. 14, Chapter 3, John Wiley and Sons, Inc,, N.Y. (1965) as to the Wittig reaction, when h is zero, the 3,4-ethylenic group of the XLIII compound is predominately in the trans form. When h is one, 2 or 3, the appropriate reagent for the Wittig alkylation is an anion derived from an ω-carboxyalkyltriphenylphosphonium halide of the formula + © (CgH5)3-P-CH2-M-C00H Ha 1^ LXXVIII wherein M is (CHgjh and Hal is chlorine, bromine, or iodine.

The resulting 3,4-ethylenic group of compound XLIII is then predominately in the cis form.

The formula-XLIlI compounds are useful intermediate for preparing compounds of the invention, following hydrolysis of the blocking groups and conversion of R^z to R1 as required. Isomerization of cis to trans or trans to cis, if desired, is accomplished, for example, by ultraviolet radiation as disclosed in U.S. Patent Specification No. 3,759,978, followed by separation of the product as by chromatography.

Continuing with Chart B, the formula-XLIV compounds are obtained from the formula-XLilI compounds by selective reduction of the 3,4-ethylenic unsaturation. For this purpose several methods are available: when h is zero, that of Dennis et_al.j Tetrahedron Lett. 1821 (1968), utilizing for the acids or salts a cyanonickel complex and sodium borohydride, or preferably, catalytic reduction over 5# palladium (or rhodium) on carbon at about 0° C. for the esters.

Finally, the formula-XLV products are obtained by hydrolysis of the blocking groups and conversion of Ri4 to Ri as required.

Methods of separating the products similar to those known in the art are employed, including extraction, chroma15 tography and crystal Iization.

Chart C shows the steps for preparing a cyclic ether of formula XLVII by starting with a formula-XXXVI11 lactol of Chart A, reacting that lactol with a 4-(triphenylphosphoranyIidene) crotonic acid ester, for example the methyl , ester (Buchta et aj., Chem. Ber. 92, Jill (1959)) obtained from the corresponding phosphonium compound. The reaction is done in a temperature range of 70-120° C. and is conveniently done in refluxing benzene to yield the formulaXLVI intermediate. The product XLVII is obtained on hydrolysis of the blocking groups and conversion of R12 to Ri as required.

Chart D shows the steps for preparing a cyclic ether of formula LlI by starting with a formula-XXXIX ester of Chart A, (a) saponifying that ester to form acid XLVI11, (b) forming a mixed anhydride of formula XLIX, (c) forming 6 0 4 CHART C XXXVI11 (CeH5)sP=CH-CH=CH-COORia V .0-CH/v CHaCH=CH-C00Ris R21 J CHa tt ^C-Ra XLVI Qi XLVI I CHART D XXXIX XLVIII II ch3 -c-o-ch2-ch< XCHS XLIX (conti nued) V· CHART D (continued) il XO-CH~ CH2-C-CHN2 (Ci/· S> =Cv^ Hx C-R2 il Qi Ll H ^O-CH'vCHeCHe-COORi / -ch2 xc=<H Lx sC-Ra 56© A a diazoketone of formula L, (d) forming a compound of formula Ll, and (e) forming the desired formula-LII product.

The formula-XXXlX compound is saponified to yield the acid XLVIIl, for example in an aqueous alkaline medium, such as sodium hydroxide to form an alkaline salt which is then acidified to yield the free acid.

The acid XLVIIl is converted to anhydride XLIX by reaction with isobutylchioroformate in the presence of an organic tertiary amine. The anhydride is formed readily at temperatures in the range -40° to +60° C., preferably at -10° to +10° C. so that the rate is reasonably fast and yet side reactions are minimized. The isobutylchioroformate reagent is preferably used in excess, for example 1.2 molar equivalents up to 4.0 per mole of the acid XLVIIl. The reaction is preferably done in a solvent and for this purpose acetone is preferred, although other relatively nonpolar solvents are used such as acetonitrile, di chloromethane and chloroform. The reaction is run in the presence of a tertiary amine, for example triethylamine, and the co20 formed amine hydrochloride usually crystallizes out, but need not be removed for the next step.

Diazoketone L, obtained by reaction of anhydride XLIX with diazomethane, yields compound Ll on contact!ng with water ahd a catalyst such as colloidal silver, platinum, or copper. See Bachmann et al., Org. Reactions Vol. 1, page ρθ (1942). Thereafter compound Ll yields a 6^,9“epoxy ether within the scope of the invention by methods described herein.

CHART £ 0-CH—' CH2CHs-OH z .

H II z0 -CH/— CHaCHa-OTs LXXXVI Hz VC-R2 II Qi (b) 'O-CHzv'CHaCHa-OTs LXXXVII ll (conti nued) CHART E (continued) Ί- (c) LXXXVI11 (d) ,0-CHx^CHsCHa-COOH Q-CHa <** ti' C-Rs (e) O-^lWCHaCHs-COORi Rao )* -CH2 >=C< C-R2 LXXXIX Ll 1 Chart E illustrates an alternative process tor preparing a formula Lll cyclic ether, starting with a formula-XLI hydroxyethyl compound of Chari B, (a) transforming that formula-XLI alcohol to tosylate LXXXVI, (b) optionally removing blocking groups such as THP groups by acid hydrolysis to form compound LXXXVI1, (c) exchanging tosylate groups with nitrile groups to form nitrile LXXXVIII, (d) hydrolyzing that nitrile to acid LXXXIX, and (e) optionally forming esters within the scope of formula Lll. In Chart E the terms Q, Qi, Ri, R2, (Rso) j , andxJ are as used above for Chart A, and Ts represents the p-toluenesulfonyl (tosyl) group.

Tosylate LXXXVI is formed by treating the alcohol XLI with p-toluenesulfonyl chloride in excess tertiary amine, Ij, preferably pyridine, at room temperature. Thereafter blocking groups are optionally removed, as by acid hydrolysis, to form a compound represented by formula LXXXVII.

Nitrile LXXXVIII is obtained on treating the tosylate with sodium or potassium cyanide in a solvent such as hexamethylphosphoramide, dimethylformamide, dimethylsulfoxide, or N-methyl pyrrolidone. The reaction proceeds smoothly at room temperature.

Acid LXXXIX is formed by alkaline hydrolysis of the nitrile, with subsequent acidification as known in the art.

Finally, esters within the scope of Lll are made if desired by methods known or disclosed herein.

Charts F, G .and H relate to preparation of oxa (-0-)type compounds. Chart E shows the steps for preparing a cyclic ether or formula LIV by starting with a hydroxyethyl 3U compound of formula XLI, and (a) subjecting that compound to a Williamson synthesis to form a compound of formula LllI, and (b) transforming LllI to the desired formula-LIV 4δβθ4 CHART F .O-CH-^CHsCHs -0 -CHa -COORis Rad- -CHa h L, ,, zC=CV HZ XC-Ra Qt ,0 -CH^ CHaCHs -0 -CHa -COOR i / 1 ’( R20 1— CHa ,H ,C=C^ XC-Ra LIV 4S604 CHART G O-CH^CHsCHs -OH XL1 ,O-CH~CHsCHs-0-CHs-CH=CHs / , R21 J-~ CHs LV \ -·χ ZH NC=C< Hx C-Re Qi -CH ~CHsCHs-0 -(CHe)2-CHSOH (RsH- -CH£<~>c=cx' Hx C-Re LVI (conti nued) 4S604 CHART 6 (cont i nued) I ZO-CH—* CH2CH2 -0-(CHs)a-C00H 7r2i/- -CH2 LVII >=< H - C-R2 II Qi _O-CH~- CH2CHs-0-(CH2)2-C00R1 I ^20 } GH2 LVI 11 *c=c„ H' xC-R2 4S604 CHART Η (CH2)3-C(OR1S LIX )s -0-CH^CH2CH2-0-(CH2)3-COORi (r2J--ch2k 1 zH LX H^^C-Ra 8, ,0-CH—' CHaCHa-0-(CHa)s-COOR t / R„« -—CH, Rao !—CHa ^c=c\ H \-Ra LXI 6 0 4 Intermediate alcohol XLI of Chart B is transformed to compound LIII by the Williamson synthesis employing a haloacetate, Hal-CH2-COOR1S or a haloacetic acid salt, for ex5 ample lithium chloroacetate. See for example U.S. Patent Specification no. 3,920,723. In Chart F, represents alkyl of one to 3 carbon atoms and Hal is chlorine, bromine or iodine.

The condensation is done in the presence of a base, for example, n-butyl 1 i thi um, phenyl 1ίthiurn, triphenyImethyl10 lithium, sodium hydride, or potassium t-butoxide. The acetate is employed in about 100$ excess. The condensation is conveniently done in a solvent such as dimethyl formamide tetrahydrofuran, dimethyl sulfoxide, or hexamethylphosphoramide. Thereafter, if a salt has been used, the formula-LIli compound is obtained by methods known in the art. Product LIV, which includes products VII and XI 11, is obtained by the usual steps of hydrolyzing off the blocking groups and converting Ris to Ri if required.

Chart G shows the steps in preparing a cyclic ether of formula LVi!I by starting with a hydroxyethyl compound of formula XLI, and (a) subjecting that hydroxyethyl compound to a Williamson synthesis with an allyl halide to form a compound of formula LV, (b) forming an alcohol of formula LVI, (c) oxidizing the terminal hydroxyl group of that' alcohol to yield a carboxylic acid of formula LVII, and (d). thereafter transforming that acid to the desired formula-LVl1 I product.

Intermediate alcohol XLI of Chart B is transformed to compound LV by a Williamson ether synthesis, employing allyl chloride. See for example U.S'. Patent Specification No. 3,920,723. 6 0 4 Thereafter, hydroboration yields alcohol LVI. See, for example, Hydroboration, H.C. Brown, W.A. Benjamin, Inc., New York, 1962. The formula-LVIl acid is obtained by oxidation, for example with the Jones reagent. Finally, blocking groups are removed by methods described above. The product is esterified if desired to yield the formula-LVI11 product.

Chart H shows the steps in preparing a cyclic ether of formula LXi by starting with a hydroxyethyl compound of formula XLI, and (a) condensing that hydroxyethyl compound with an omega-halo ortho ester of the formula Hal-(CH2)3-C(0Ris)3, wherein Hal and RiS are as defined for Chart E, to form a compound of formula LIX, (b) transforming compound LIX to a compound of formula LX, and (c) thereafter transforming compound LX to the desired formulaLXI product.

Compound LIX is obtained from alcohol XLI by a Williamson synthesis preferably employing an ortho-4-bromobutyrate of the formula Hal-(CHg)s-C(0Ri5)3 wherein Hal is chlorine, bromine or iodine and R|g is as defined above. See for example U.S. Patent Specification No. 3,921,279. The condensation is done in the presence of a base and a solvent, for example potassium t-butoxide and tetrahydrofuran, or n-butyllithium and hexamethylphosphoramide. The reaction proceeds smoothly at -20° to +50° C. but is preferably done at about 25° C, for convenience. Following the condensation, the formulaLX compound is obtained by methods known in the art, for example by hydrolysis in cold dilute mineral acid. Finally, oroduct LXI, which is within the scope of tbe invention is obtained by hydrolysis of blocking groups and conversion of Rl5 to Rt as required. 6 0 4 The compounds of the invention include oxo compounds.

For their preparation, the processes of Charts A-Hare employed, nut the starting materials XXXVII, XXXVlll, XXXIX, and XLI are replaced by corresponding compounds wherein (R21) is replaced by OS i (CHa )a (t -C4H9 ) Such compounds are available by methods known in the art or described herein. For this purpose there are prepared lactones of the formula OR2g H C-Ra II Qi wherein Q'r and 'Ra are as defined above and Rss is a carboxyacyl blocking group: (1) -(R27 )c wherein Rg? is alkyl of one to 4 carbon atoms, phenylalkyl of 7 to 10 carbon atoms, phehyl or nitro, and g is zero or an integer of from one to 5, the Bg^/s are other than alkyl, and that the total number of carbon atoms in the does not exceed 10; S6 Ο 4 (2) 0 .COOR28 wherein R2s is alkyl of one to 4 carbon atoms or wherein R27 and g are as defined above. Starting materials for these formula-LXXIX lactones are known or readily available. See for example U.S. Patent Specification No. 3,931, 279.

The formula-LXXIX lactone is transformed to the silylated starting material by replacing R2e with hydrogen, as with sodium methoxide in methanol, and blocking at the latent C-ll position with t-butyldimethylsilyl. See E.J. Corey _et al., J. Am. Chem. Soc. 94, 6190 (1972).

Thereafter, the procedures of Charts A-H yield compounds bearing the t-butyldimethylsilyl group at C-ll.

This group is then replaced with hydrogen usi ng tetrabutyianmonium fluoride. See Corey et al. cited above. Next the 11-hydroxy group is oxidized to 11-oxo, for example by Jones oxidation, and finally the R40 groups at C-15 are replaced, if desired, by acid hydrolysis.

The compounds of the invention include Π-methyl ene compounds. Alternative methods for their preparation, other than those included within Charts A-G utilize those processes of Charts A-H by replacing starting materials XXXVII, XXXVI11, XXXIX, and XLI with corresponding S 6 Ο 4 compounds wherein (Rei) is replaced by CHa-O-Si(CH3)a(t-C4Hg) Such compounds are readily prepared from the hydroxymethyl lactones wherein (R21) is ; CHaOH described herein for the starting materials of Chart A, using the procedures of Corey g.t al. cited above.

Thereafter the procedures of Charts A-H yield compounds 15 bearing the t-butyldimethylsilyloxymethyl group at C-ll.

It is preferred that Rt is alkyl. Next the silyl groups are replaced with hydrogen using tetrabuty1ammonium fluoride, and the resulting hydroxymethyl groups are converted to iodomethyl groups by way of tosylation and iodide exchange, Finally dehydroiodination, as with potassium tert-butoxide in tetrahydrofuran, yields the 11-methylene compounds.

The compounds of the invention include 15-deoxy compounds. For their preparation, the products of Charts A-H where!n Q is X'· z\ H 'OH or H OH, in their free acid form,- are used. They are (l) silylated, e.g. with t-butyldimethylsilyl chloride and imidazole, (2) hydrolyzed to remove silyl ester groups at C-l, e.g. with aqueous potassium hydroxide, (3) reduced with lithiumneopentyl alcohol-methyl amine at about -30° C., and (4) hydrolyzed to remove silyl ether groups, thereby yielding 15-deoxy products.

Alternatively, a lactone of the formula LXXX wherein R2 and R2e are as defined above is (1) transformed to the 3a-bromo compound, (2) reduced with sodium borohydride in dimethylsulfoxide, (3) treated with potassium carbonate to replace -0R2e with hydroxyl and (4) blocked at the hydroxyl sites with -0R4o wherein R4o is as defined above. Thereby a lactone is obtained of the formula LXXX1 which is used to replace lactone XXXVil in Chart A and the 15 processes of Charts A-H for preparing 15-deoxy products.

An alternative method for preparing the compounds is by reductive dehalogenation of a compound ot the formula <_z wherein L is' (I) a valence bond, (2) - {CHgJj- wherein d is an integer of from one to 5, (3)-(CH2)t -CF2 wherein t is 2, 3 or 4, (4) - OHg-CH = CH-(CH2)n~ wherein h is zero, one, 2 or 3, or (δι-Οι^-Ο-ίΟΗ^- wherein k is one, 2 or 3; wherein Q2 is II o, Η H, or R' wherein Rg and R^ are as defined above; wherein R(6 is (1) -coor17 (2) -CK20H (3) -CH2N(R18)2 (4) “GON|R18)2 or (5) tetrazolyl, wherein R17 is (a; hydrogen, |b) alkyl of one to i2 carbon atoms, (c) cycloalKyl of 3 toio carbon atoms, (dj aralkyl ot 7 to 12 carbon carbon atoms, (e) phenyl, )g, R25 and S'-' are as defined above, and wherein wherein R4 is as defined above. Certain compounds of formula lXIII are described and claimed in our Patent Specification No. 243/77.

Chart 0 shows the steps by which a PGFg -type compound of formula LXII is (a) halogenated and cyclized to form a compound of formula LXIII, and the compound LXIII is subjected to reductive dehalogenation to form the formula LXIV product. In Chart J the terms are defined as for compound LXIII above. 456Q4 S.

CHART J Q2 C=C ^.L-Rie XH LXII (b) ^O-CHfvCHa-L-Rm ( R22)·· - CHs' Sc-G-flas II·.· ·· q.2 LX IV The starting materials of formula LXII are prostaglandins or prostaglandin-like materials known in the art or readily available by processes known in the art. Either the compounds in which R^ of and Q2 is hydrogen or those in which R^ may be used. For example, as to PGF2o Specification (USPS) No. 3,706,789; as to 15-methvl- and 15-ethvl-PGF„ . see is a blocking group see U.S. Patent SPS No. 3,728,382; as to 16,16-dimethyl-PGF2a, see USPS No. 3,903,131; as to 16,-6;dif1uoro-PGF2a> see USPS No. 3,969,380; as to 2-decarboxy-2-hydroxyraethyl compounds, see USPS No. 3,636,120; as to 2-decarboxy-2-tetrazolyl derivatives, see USPS Nos. 3,883,513 and 3,932,389; as to 2,3-didehydro-PGF2a. see German Offenlegungsschrift No. 2,460,285; as to 11-deoxy-Π-hydroxymethyl-PGF2q, see USPS Nos. 3,931,282 and 3,950,363; as to 16-methylene-PGF2a, see USPS No. 3,953,495; as to 17,18-didehydro-PGF2a compounds, see USPS No. 3,920,726; as to 3- (or 4-)oxa-17,18-didehydro-PGF2a compounds, see 20 USPS No. 3,920,723; as to 15-oxo-PGF2a, see USPS No. 3,728,382; as to 15-deoxy-PGF2c(, see Derwent Farmdoc No. 09239W; as to Π-deoxy-15-deoxy-PGF^ see U.S. Patent No. 3,853,951; as to ω-homo-PGFau compounds, see Derwent Farmdoc No. 04728W; as to 2-decarboxy-2-aminoPGF2a compounds, see Patent Specification No. 53739/76 as to l6-phenoxy-17,l8,19,20-tetranor-PGF2a, see Derwent Farmdoc No. 73279U; as to 17-phenyl-18,19,20-trinor-PGF2a, see U.S.Patent No. 3,987,087; as to 13-cis-PGFec, see U.S. Patent No. 3,932,479; as to 13,14-didehydro-PGFsa, see Derwent Farmdoc No. 20717X and 59715X! as to ll-deoxy-PGF2a, see Derwent Farmdoc No. 10695V; as to PGD2, see U.S. Patent No, 3,767,8135 as to 2a,2b-dihomo-PGF2a, see Derwent Farmdoc No. 61412S; as to 3-oxa-PGF2ct, see U.S. Patent No. 3,923,861; as to 3-oxa-17-phenyl-18,19,20-trinor-PGF2a, see U.S. Patent No. 3,931,289; as to 2,2-di fl uoro-PGF2ci, see U.S. Patent No. 4,001,300; as to HP-PGF2a, see U.S. Patent No. 3,890,371; and as to llB-17-pheny Γ-Ι8,19,20-trinor-PGF2a, see Derwent Farmdoc No. 13090X, In step a of Chart J the starting material LX 11 is subjected to halogenation and cyclization to yield the formula-LXIίI halo compounds. For related cyclization procedures see Staninets and Shilov, Chem. Abs. 64, 12625h (1966). For iodination there is used either an aqueous system containing iodine, potassium iodide, and an alkali carbonate or bicarbonate, or an organic solvent system such as dichloromethane containing i.odine in the presence of an alkali metal carbonate. The reaction is carried out at 0 0 temperatures below 25 C., preferably about 0-5 C. for 10-20 hr. Thereafter the reaction is quenched with sodium sulfite and sodium carbonate and the formula-LXl11 compound separated from the reaction mixture. For bromination N64 ” 45904 V bromosuccinimide or N-bromoacetamide are used. See Fieser et al., Reagents for Organic Synthesis, Vol. I, pp. 74 and 78, Vol. IV p. 51, John Wiley and Sons, Inc., New York.

In step b of Chart J the halo compound LXIII is sub5 jected to reductive dehalogenation. Useful reagents include tributyitin hydride, triphenyitin hydride, sodium borohydride in dimethyl sulfoxide, and zinc in acetic acid. Especially preferred is tributyltin hydride freshly prepared from tributyltin chloride and lithium aluminum hydride.

The reaction is run in a solvent such as benzene at about 15-35° C. and monitored by TLC.

Thereafter, any blocking groups are removed by methods known in the art and the product isolated by methods described herein or known in the art, for example by chromatography on si 1ica gel.

A preferred method for preparing amides of formula LXVII wherein L, Qg, R-j^ and Rg5 are as defined above, is by the steps shown in Chart K. The halo acid LXV is converted to amide LXVI and thence, by reductive dehalogenation to the formula-LXVII amide.

CHART Κ Rs3 Q2 LXVI I CHART L -OH J V- ch2 .L-R, '36 LXVIII K.

\ H^ xh X-C-R2s II Qa (θ) Hg-G O-CH~CH-L-R3S / ^22 ~ CHg ^X-C-Ras II Q2 LXIX (b) , O-CH^V' CH2*L“R se R221)- “·ΟΗ2 X-C-Ras II Qa LXX 4S60.4. is as An alternative process by reductive demercuration shown in Chart L, wherein for preparing compounds of the invention of a compound of the formula LXIX, L, Q2 R25’ X^and are as defined above, G is nitrato, iodine, chlorine, bromine, acetoxy, trifluoroacetoxy or benzoyloxy, and R36 13 (1) — ccor37 (2) — CH20H (3) - CH2N(R18)2 (4) - C N(R·^)^ or (5) tetrazolyl wherein R^g is as defined above and R37 is (a) alkyl of one to 12 carbon atoms, (b) cycloalkyl of 3 to 10 carbon atoms, (c) aralkyl of 7 to 12 carbon atoms, (d) phenyl, (e) phenyl substituted one to 3 times by chlorine atoms or alkyl radicals of one to 4 carbon atoms, (f) £-(p'-acetamidobenzamide)phenyl, (g) £-benzamidophenyl, (h) ]3-acetamidophenyl, (i) £-ureidopheny1, (j) £-serai carbazonomethy1 phenyl, (k) 2-naphthyl II (1) -CR-C-R,, wherein Rg^ and Rgg are as defined above, or (m) hydrogen.

Chart L shows the steps by which a PGF^-type compound of formula LXVIII is (a) converted to a mercury compound of formula LXIX and (b) compound LXIX is subjected to reductive demercuration to form the formula-LXX product. In Chart L the terms are defined as for compound LXIX above.

Reference to Chart L will make clear the steps of this process. For background on this mercuration-demercuration cyclization see, for example, H.C. Brown eta/., Organometal. Chem. Syn. 1, 7 (1970) and Fieser and Fieser, Reagents for Organic Synthesis, Vol. 3, p. 194, Wiley, N.Y., 1972.

Many of the formula-LXVIII starting materials have been discussed above for Chart J. As to substituted phenyl esters, see U.S. Patent Specification No. 3,890,372; and as to 4560 4 substituted phenacyl esters, see Derwent Farmdoc No. 16828X and German Offenlegungsschrift No. 2,535,693. In step A of Chart L, the starting material is reacted with an appropriate mercury (II) salt corresponding to Hg(G)2, for example mercuric nitrate, chloride, or acetate. Preferred is either mercuric acetate or trifluoroacetate. The reagent is dissolved in either water or acid, e.g. acetic acid, and combined with a solution of the formula-LXVIII starting material in a convenient solvent such as chloroform or tetrahydrofuran. The reaction is conveniently carried out at 15-35°C.

In step b of Chart L the mercurio compound is subjected to reductive demercuration. Useful reagents for this step include sodium borohydride, sodium amalgam, and hydrazine. Especially - preferred is sodium borohydride in alkaline solution, e.g. aqueous sodium hydroxide. The reaction is carried out in a solvent such as tetrahydrofuran at 15-35°C. Thereafter the mercury is separated, blocking groups removed if necessary, and the product isolated by methods described herein.

G may be varied, for example, by suitable choice of reagent Hg(G)2 or by replacement, for example of acetoxy by chlorine by ion exchange.

The intermediates of Charts A-L, including those compounds represented by formulas XLI, XLII, XLIIl, XLIV, XLVI, XLVill, XLIX, L, Ll, LIII, LV, LVI, LVII, LIX, LX, LXIII, LXVI, LXIX, LXXXVI, LXXXVII, and LXXXVII I are frequently not isolated but used directly for a subsequent process step.

When they are isolated, they are purified by methods known in the art, for example partition extraction, fractional crystal ization, and, preferably, silica gel column chromatography.

The compounds of Charts A-L wherein Q, Qt, or Q2 are in either alpha or beta configuration, for example OH Λ or H OH represent 15-« and 15-β isomers. The transformations shown herein generally have no effect on the stereochemistry at this position and therefore the final products have the same stereo configuration at C-15 as in the starting materials at the corresponding carbon atoms. Should it be necessary to separate 15« and 153 isomers, this can be done by methods known in the art, for example by chromatography on neutral silica gel.

When an optically active Intermediate or starting material is employed, subsequent steps yield optically active intermediates or products. That optical isomer of bicyclo lactone XXXVII is preferred which will yield product XL, for example, in the configuration corresponding to that of the 45804 naturally occurring prostaglandins. When the racemic form of the intermediate or starting material is employed, the subsequent intermediates or products are obtained in their racemic form. Optically active and racemic forms of the intermediates or starting materials are known or available by methods known in the art.

Compounds of this invention occur in two isomeric forms wherein is in alpha or beta configuration, i.e. endo or exo relative to the heterocyclic ring.

There two isomers differ in their mobility on TLC silica gel plates or on a silica gel column. The members of each pair of isomers are distinguished herein as less polar or more polar isomers, considering that mobility.

The alkanoates of the compounds disclosed herein are prepared from those compounds by replacing any blocking groups (R^q) with hydroxy, and thereafter reacting the hydroxy compound with a carboxyacylating agent, preferably the anhydride of an alkanoic acid of 2 to 8 carbon atoms. . For example, use of acetic anhydride gives the corresponding diacetate. Similar use of propionic anhydride, isobutyric anhydride, and hexanoic acid anhydride gives the corresponding carboxyacylates.

The carboxyacylation is advantageously carried out by mixing the hydroxy compound and the acid anhydride, preferably in the presence of a tertiary amine such as pyridine or triethylamine. A substantial excess of the anhydride is used, preferably 2 to 10 moles of anhydride per mole of the hydroxy compound reactant. The excess anhydride 456 0 4 serves as a reaction diluent and solvent. An inert organic diluent, for example dioxane, can also be added. It is preferred to use at least enough of the tertiary amine to neutralize the carboxylic acid produced by the reaction, as well as any free carboxyl groups present in the hydroxy compound reactant.

The carboxyacylation reaction is preferably carried out at 0° to 100°C. The necessary reaction time will depend on such factors as the reaction temperature, and the nature of the anhydride; with acetic anhydride, pyridine, and a 25° C. reaction temperature, a 12 to 24-hour reaction time is used.

The carboxyacylated product is isolated from the reaction mixture by conventional methods. For example, the excess anhydride is decomposed with water, and the resulting mixture acidified and then extracted with a solvent such as diethyl ether. The desired carboxylate is recovered from the diethyl ether extract by evaporation. The carboxylate is then purified by conventional methods, advantageously by chromatography.

Compounds of the invention may be interconverted by methods known in the art. Accordingly, a compound wherein i s OH may be transformed to another compound wherein (R22) is another ring within the scope of , for example an 11-methylene 46604 compound, by methods known or described herein. A compound wherein the C^-C^ group is trans-CH 2 CH- is transformed to another compound wherein the group may be cis-CH = CH-, -C — CT, or -CHgCHg-. For example, -CSC- is obtained by selective bromination and dehydrobromination.

A compound wherein the Cg substituent is -COOR^g» e.g. a methyl ester,’ may be transformed by known methods to another compound having another Cg substituent within the scope of R30, as defined herein, for example -CHgOH or -C0N(R18)g.

The following Preparations and Examples illustrate how the compounds of this invention may be prepared.

All solvent proportions are by volume.

Infrared absorption spectra are recorded on a Perkin-Elmer model 421 infrared spectrophotometer. Except when specified otherwise, undiluted (neat) samples are used.

The NMR spectra are recorded on a *Varian A-60, A-60D, T-60, or XL-10C spectrophotometer in deuterochloroform solutions with tetramethyl si lane as an internal standard.

Mass spectra are recorded on a Varian Model MAT CH7 Mass Spectrometer a CEC Model HOB Double Focusing High Resolution Mass Spectrometer, or a LKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ev.), and are usually run as TMS (trimethylsilyl) derivatives.

Brine, herein, refers to an aqueous saturated sodium chloride solution.

Skellysolve B, herein, refers to mixed isomeric hexanes, TLC, herein, refers to thin layer chromatography.

*Varian isa trade mark Silica gel chromatography, as used herein, is understood to include elution, collection of fractions, and combination of those fractions shown by TLC to contain the desired product free of starting material and impurities. 8 L°Jd ^Presents the rotation observed when sodium D is passed through 1 decimeter of a 1 g./c.c. solution of the relevant material at 25°C.

Concentrating, as used herein, refers to concentration under reduced pressure, preferably at less than 50 mm. and at temperatures below 53°C.

Lower alkanoate, herein, refers to an ester of an alkanoic acid of 2 to 8 carbon atoms.

Example 1 9-Deoxy-6£,9a -epoxy-2,3,4-trinor-PGFp Ethyl Ester, Mixed Isomers I. Refer to Chart A. There is first prepared the formula-XXXIX 9-deoxy-65,9a-epoxy-2,3,4-trinor-PGF^, ethyl ester, bis(tetrahydropyran-2-y1 ether), mixed isomers. A solution of triethyl phosphonoacetate (3.58 g.) in 40 ml. of tetrahydrofuran is treated at 0°C. with a solution of potassium t-butoxide (1.79 g) in 40 ml. of tetrahydrofuran, followed by a solution of the formula-XXXVIII 2α, 4a-dihydroxy-5g-(3a-hydroxy-1-trans-octeny1)la-cyclopentaneacetaldehyde-y-lactol, bis-(tetrahydropyran-2-yl ether) (E.J. Corey et al., 4560 4 4. Am. Chem. Soc. 92, 397 (1970), (5.6 g)) i n 20 nil. of benzene added over a one-minute period. Thereafter the mixture is stirred at 0-25° C. for 25 min. and diluted with 500 ml. of diethyl ether-methylene chloride (3;l). The resulting mixture is washed with water, dilute potassium hydroxide solution, water, and brine, dried, and concentrated to the formula-XXXIX compound in a crude product, 8.1 g.

The above product is subjected to silica gel chromatography, eluting with 40-75$ ethyl acetate in Skellysolve B, to obtain the formula-XXXIX compound 4.7 9·, having NMR peaks at 5.4-5.7, 3.2-4.8, 2.42 and 2.56 6.

II. The above mixed isomers of the formula-XXXIX compound (1.0 g.) are hydrolyzed in 15 ml. of acetic acid and 7.5 ml. of water at 37-39° C. for 3 hr. The mixture is cooled, mixed with diethyl ether-methylene chloride (3;l), and shaken with ice-cold dilute potassium hydroxide solution.

The organic phase is washed with brine, dried, and concentrated. The residue is subjected to silica gel chromatography, elut20 ing with 0-5$ ethanol in ethyl acetate, to obtain the formula-ill title compound as mixed less polar and more polar isomers, 0.55 g., having NMR peaks at 5.27-5.47, 3.3-4.5, 2.4, and 2.52 6j and mass spectral peaks at 322, 304, 278, 251, and 235.

Example 2 9-Deoxy-6^,9“-epoxy-2,3,4-tri nor-PGFf, Ethyl Ester, Bis(tetrahydropyran-2-yl ether), mixed isomers (Formula XXXIX wherein R40 of Qi and (rT^Is THP (tetrahydropyran-2-yl); and 9-Deoxy-6,9a-epoxy-2,3,4-trinor-PGFi, ‘ Ethyl Ester, less polar isomer and more polar isomer (Formula I wherein R4 of Q and W is hydrogen).

I. Refer to Chart A. There is first prepared the formula-XXXIX bis(tetrahydropyran-2-yl ether). A mixture of the formula-XXXVI 11 2a,4a-dihydroxy-5P-[(3S)-3-hydroxy-jxan5-loctenyl]-la-cyclopentane acetaldehyde, y-lactol, bis(tetrahydropyran-2-y1 ether) (10 g.), ethyl (triphenylphosphoranylidine)acetate (10 g.) and 150 ml, of ethanol is stirred for 3 days under nitrogen. The mixture is then concentrated and the residue is chromatographed on silica gel, eluting with ethyl acetate-Skellysolve B (l:l) to yield the formula-111 mixed isomer title compound, 9.0 g.

The product has Rf 0.34 and 0.39 for the mixture (TLC on silica gel in ethyl acetate-hexane (1:3)), and NMR peaks at 5.35-5.69, 4.69, 3.98-4.34, and 2.48-2.62 fi.

II. To remove the THP block!ng groups, a mixture of the above formula-XXXIX compound (6.95 g.), 100 ml. of acetic acid, 50 ml. of water, and 10 ml. of tetrahydrofuran is stirred at 40° C. for 4 hr. The mixture is 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 is chromatographed on a column of 500 g. of fine silica gel (40-63 μ, Merck) previously deactivated with acetone-methylene chloride (6θ:4θ). The column is eluted with acetone-methylene chloride mixtures as follows: liters of 30:70, 0.5 liter of 35:65, snd 1.5 1iter of 40:60. The first 500 ml. of eluant is discarded, and thereafter 40 ml. fractions are collected. Fractions 40-46 yield the formula “I less polar isomer of the title com77 56 0 4 pound, 0.21 g., having Rf 0.39 (TLC on silica gel in acetone-methylene chloride (40:60)), and NMR peaks at 5.43-5.54, 3.98-4.33, and 2.57-2.71 6. See FIGURE 1 for the 1H NMR spectrum. Fractions 47-62 yield a mixture of the isomers. Fractions 63-100 yield the formula -I polar isomer of the title compound, 2.03 g., having Rf Ο.32 (TLC on silica gel in acetone-methylene chloride (4θ:6θ)), and NMR peaks at.5.47-5.58, 4.34-4.64, 3.98-4.34, and 2.482.63. See FIGURE 2 for the ΧΗ NMR spectrum, noting peaks at 4.4-4.6 δ for this more polar isomer.

Example 3 9-Deoxy-6, gct-epoxy-2,3,4-tri nor-PGFx, Methyl Ester, Bis(tetrahydropyran-2-yl Ether), mixed isomers (Formula XXXIX); and 9-Deoxy-6,9a-epoxy-2,3,4-tri nor'-PGFi,.

Methyl Ester, less polar isomer and more polar isomer (Formula I) I. Refer to Chart A. A solution of trimethylphosphonoacetate (7.11 g.) in 75 ml. of tetrahydrofuran is treated at 0° C. with a solution of potassium t-butoxide (4.05 g.) in 75 ml. of tetrahydrofuran. The mixture is stirred at 0-5° for 10 min. and then a solution of 2α,4adi hydroxy-5P-[(5S)-3-hydroxy-tran5-l-octenyl]-lct-cyclopentane acetaldehyde, y-lactol, bis(tetrahydropyran-2-yl ether) (13.2 g.) in 60 ml. of tetrahydrofuran is added within one min. Thereafter the mixture is stirred at about 25° C. for 2 hr., then diluted with 600 ml. of diethyl ether-methylene chloride (3:1)- The organic phase is washed with brine, dried, and concentrated. The residue is chromatographed on silica gel, eluting With ethyl acetate-Skellysolve B (1:1), to yield the formula-XXXlX product as mixed C-6 isomers, 12.15 9·> having Rf? 0.62 (TLC on silica gel in ethyl acetate-hexane (1:1)), and NMR peaks at 5-55-5.71, 4.71, 5.67, and 2.5-2.61 6.

II. To prepare the formula-I product, a mixture 5 of the above formula-XXXIX bis(tetrahydropyran-2-yl ether) (12.15 g-) in 200 ml. of acetic acid, 100 ml. of water, and 10 ml. of tetrahydrofuran is stirred at 40° C, for 4 hr. The mixture is cooled and diluted with 800 ml. of cold (-10° C. ) ethyl acetate. The organic phase is washed with a mixture of sodium hydroxide (150 g.) in 800 ml. of ice and water, then with brine, dried, and concentrated. The residue, 11.8 g.) is chromatographed on a column of about 500 g. of fine silica gel (40-63 μ, Merck). The column is eluted with acetone-methylene chloride mixtures as follows: 8 liters of 40:60, and 4 liters of 6θ:4θ. The first 2 liters of eluant is discarded, thereafter 17 200 ml. fractions and 18 300 ml. fractions are collected. Fractions 6-22 yield a mixture of the formula-I less polar isomer and more polar isomer, 3.9 g<, later separated below.

Fractions 23*32 yield the formula-I more polar isomer of the title compound, 3.55 g.

Rechromatography of the mixed-isomer fraction, again on fine (40-63 p) silica gel, followed by further rechromatography of a mixed-isomer fraction so-obtai.ned, yields the less polar isomer and more polar isomer which, with the amounts above, total: for the less polar isomer, 1.25 g.,.and for the more polar isomer 5.44 g.

The formula-I less polar isomer of the title compound has m.p. 47-48° C. (from diethyl ether-hexane), Rf 0.41 (TLC on silica gel in acetone-methylene chloride (4O:6o))j NMR peaks at 5-50-5.61, 3.86-4.46, 3.72, and 2.61-2.75 6; and mass spectra] peaks at 470.2898, 4^5, 439. 399, 3θΟ, 265, 219, 199, and 173.

The formula-! more polar isomer has Rf 0.35 (TLC on 5 silica gelin acetone-methylene chioride (40:60)); NMR peaks at 5-50-5-61, 3.88-4.67, 3-72, and 2.52-2.63 δ; and mass spectral peaks at 470.2903, 455, 399, 380, 309, 199, and 173.

Preparation 1 9-Deoxy-65,9a-epoxy-2,3,4-trinor-PGF.|, Methyl Ester, Bis(tetrahydropyran-2-yl ether), Mixed Isomers, by Michael Addition I. There is first prepared 2,3,4-trinor»5,6-trans-didehydro5 pGFla’ aster, II,I5-bis(tetrahydropyran-2-yI ether).

A mixture of 2a,4a-dihydro-5g- [(3S)-3-hydroxy-trans-T-octenyT]1a-cyclopentaneacetaldehyde, γ-lactol·, bi s(tetrahydropyran-2-yl ether) (8.8 g.) methyl(triphenylphosphoranylidine)acetate (10.0 g.) and 100 ml. of tetrahydrofuran is stirred until homogeneous and then left at about 25°C.for 7 days. The mixture is concentrated. The residue is chromatographed on silica gel deactivated with ethyl acetate, eluting with ethyl acetateSkellysolve B (1:1) to yield the above 5,6-trans compound, 9.6 g., having Rf 0.59 (TLC on silica gel in ethyl acetate15 hexane (1:1)); NMR peaks at 6.80-7.20, 5.77-6.01, 5,38-5.67, 4.71, and 3.70 6; and infrared absorption at 3600, 1730, and 1670 cm-1.

II. To prepare the title compound, a solution of the above ,6-trans compound (0.300 g. ) in 3 ml. of methanol and approximately 0.15 ml. of a methanol solution of sodium methoxide is stirred for minutes, whereupon the reaction is complete as shown by TLC.

The mixture is diluted with 35 ml. of diethyl ether, washed with brine, dried over magnesium sulfate, and concentrated. The oily residue, 0.290 g., consists of the mixed isomers of the formula-XXXIX title compound, having identical properties to those reported above in Example 3. 6 0 4 ^Z Preparation 2. 3,3ag,4,5,6ag - Hexahydro - 5a - hydroxy - 2ξ - (2‘ - hydroxyethyl) 4g - (3‘a - hydroxy - trans - 1 -octenyl) -2/cyclopenta[b] furan, 3',5 - bistetrahydropyranyl Ether Mixed Isomers (Formula-XLI: is /'x H 'bTHP Rg is n-pentyl, OTHP where THP is 2-tetrahydropyranyl, and^ is alpha and beta).

Refer to Chart B. A solution of formula-XXXIX, 9-deoxy-65,9a-epoxy-2,3,4-trinor-PGFp ethyl ester, bis(tetrahydropyran-2-yl ether) (Example 1-1, 4.0 g.) in 40 ml. of diethyl ether is added to a slurry of lithium aluminium hydride (0.50 g.) in 100 ml .· of anhydrous diethyl.ether. The mixture is heated at reflux with stirring, for 2 hours. After cooling it is treated successively with 0.70 ml. of water, 0.70 ml. of 15% aqueous sodium hydroxide solution and 0.8 ml. of water. The mixture is filtered and the filtrate is concentrated to yield the formula-XLI title compounds, 3.7 g., having NMR peaks at 5.2-5.5, 4.6, and 3.0 4.0 s. An alternate name for these compounds is f3aR’-[3a,4a(IE,3S*), 5g,6aaJ|- hexahydro - 5 - βtetrahydro - 2H pyran - 2 - yl)oxo -4 - { 3 - Q(tetrahydro - 2H - pyran - 2 - yl)oxy] - 1 - octenyl^ - 2H - cyclopenta[ajfuran - 2ξ - ethanol, where ξ indicates unknown configuration.

Preparation 3 3,3as, 4, 5j 6,6ag 1 Hexahydro - 5a - hydroxy - 2ξ - (formylmethyl)4g - (3'a - hydroxy - trans - 1 - octenyl) - 2H - cyclopenta (b] furan, 3',5 - bis(tetrahydropyran - 2 - yl Ether) Mixed Isomers, Formula XLII: Qp Rg, and -v are as defined in preparation 2) and 9-0eoxy-3,4-trans-didehydro-6g,9a-epoxy-2-nor-PGF^, Ethyl Ester, Bis(tetrahydropyran-2-yl Ether) Mixed Isomers (Formula XLIII: h is zero, Rj is ethyl and Qp and ~ are as defined above).

I. Refer to Chart B. A solution of the formulaXLI 3,3ag4,5,6,6ag - hexahydro - 5a - hydroxy - 2ξ 15 (2' - hydroxyethyl) - 4g - (3'a - hydroxy - trans - 1 - octenyl) 604 2H,- cyclopenta £b] furan, 3' ,5 - bis (tetrahydropyran - 2 yl ether) (Preparation 2, 2.3 g.) in 15 ml. of diehloromethane is added (in 15 seconds) to a solution of chromium trioxide (3.8 g.) in 100 ml. of diehloromethane and 6 ml. of pyridine. The mixture is stirred at 15°C. for 10 minutes, then 25 ml. of benzene is added and the mixture filtered.

The filtrate and washings are concentrated to about 15 ml. and taken up in 50 ml. of diehloromethane. The mixture is contacted with CC-4 silica gel and diatomaceous earth and filtered. The filtrate is concentrated to yield the formula-XLII title aldehyde, as mixed isomers.

II. A solution of the above formula-XLII aldehyde in 10 ml. of benzene is cooled to 10°C. and added to a previously prepared mixture of 1.1 ml. of triethyl phosphonoacetate and 0.60 g. of potassium t-butoxide in 30 ml. of tetrahydrofuran which has been stirred at 0°C for 10 minutes. Thereupon the ice-bath is removed and the mixture stirred for.30 minutes as it gradually warms to about 25°C. Finally the mixture is diluted with diethyl ether-methylene chloride (3:1) and shaken with water. The 6 0 4 organic phase is washed with dilute aqueous potassium hydroxide, water and brine, dried, and concentrated to a residue, 3.8 g. The residue is subjected to silica gel chromatography, eluting with ethyl acetate-Skellysolve 8 (1:1), to yield the formula-XLIII title compound mixed less polar and more polar isomers, 2.3 g,, having NMR peaks at 5.4 - 7.2, 4.7, and 3.2 - 4.5 δ.

Example 4 9-Deoxy-3,4-trans-didehydro-6?,9a-epoxy-2-nor-PGF^, Ethyl Ester, Mixed Isomers The formula-XLIII bis(tetrahydropyranyl ether) (Preparation 3-11, 0.5g.) is hydrolyzed in a mixture of 12 ml. of acetic acid and 6 ml. of water at 37-39°C. for 2.5 hours. The mixture is cooled and shaken with diethyl ether-dichloromethane (3:1) and a mixture of cold brine and aqueous potassium hydroxide.

The organic phase is washed with brine, dried and concentrated.

The residue is subjected to silica gel chromatography, eluting with 0-5% ethanol in ethyl acetate to yield the formula-V title compounds, 0.29 g., having NMR peaks at 5.7, 5.97, 6.68 - 7.28, 5.32 - 5.57, and 3.4 - 4.54s and mass spectral peaks (for the TMS derivatives) at 510, 495, 481, 465, 429, 420, 411, 397 and 349.

Example 5 9-Deoxy-6?,9a -epoxy - 2 - nor - PGFp Methyl Ester Mixed Isomers Refer to Chart B. The acid form of the formula-XLIII compound is first prepared. A mixture of the formula-XLIII 9-deoxy-3,4-trans-didehydro-6g,9a-epoxy-2-nor-PGF^, ethyl ester, bistetrahydropyran-2-yl ether (Preparation 3-11 1.7 g.) and ml. of methanol is treated with a solution of 0.25 g of sodium hydroxide in 6 ml. of water. The mixture is stirred at about °C. fcr 5 hours. Chipped ice is added and the mixture shaken with diethyl ether-dichloromethane (3:1) and cold dilute hydrochloric acid to acidity. The organic phase is washed with brine, dried, and concentrated to yield the formula-XLIII acid, as mixed isomers.

The acid above is dissolved in aqueous sodium hydroxide (0.2 g. in 25 ml. of water) and the resulting solution adjusted to pH 9 with dilute hydrochloric acid. Following the procedure of Dennis et al_., Tetrahedron Lett. 1821 (1968), this solution is treated with a freshly prepared mixture of nickel chloride hexahydrate (0.30 g.) and potassium cyanide (0.41 g. in 25 ml. of water followed by a fresh solution of sodium borohydride (1.0 g.) in 5.0 ml. of water. The mixture is stirred at about 25°C. for hours and then cooled in an ice bath while acidifying with cold dilute hydrochloric acid to pH 1-2. (Danger; evolution of 2b hydrogen and hydrogen cyanide). The resulting mixture is immediately extracted with diethyl ether-dichloromethane (3:1) ahd the organic phase is washed with dilute acid, water, and brine, dried, and concentrated to the acid form of the formula-XLIV bis(tetrahydropyran-2-yl ether), as mixed isomers. •86 The above formula-XLIV acid is converted to the methyl ester by treatment in diethyl ether solution with diazomethane, thereafter separating the formula-XLIV methyl ester, bistetrahydropyran-2-yl ether, having NMR peaks at 5.3 - 5.6, 4.63, 3.61, and 3.2-4.5 d.

The above formula-XLIV methyl ester, bis(tetrahydropyran-2-yl ether) is hydrolyzed to the title compound in 25 ml. of acetic acid and 12.5 ml. of water at 37-40°C for 2.5 hours. Thereafter the product is worked up as for Example 7 and subjected to silica gel chromatography, eluting with 4-5% ethanol in ethyl acetate.

There is finally obtained the title product, as mixed less polar and more polar isomers, 0.200 g., having NMR peaks at 5.32 - 5.57, 3.61 and 3.3 - 4.5 6; and mass spectral peaks at 336, 322, 292 and 264.

Example 6 9-0eoxy-3,4-ci£-didehydro-6c,9a-epoxy-PGFi, Bis(tetrahydropyran2-yl Ether), Mixed Isomers (Formula XLIII; h, Qp R2 and are as defined in Preparation 2 and R^ is hydrogen). 9-Deoxy-65,9a-epoxy-PGFp Mixed isomers and 9-Deoxy-65,9a*epoxy-PGFp Ethyl Ester, Mixed Isomers.

I. Refer to Chart B. A mixture of the formula-XLII aldehyde, namely 3, 3ag, 4, 5, 6, 6ag - hexahydro - 5a hydroxy - 2ς - (formylmethyl) - 4g - (3'ct - hydroxy - trans - 1 octenyl) - 2H - cyclopenta [b] furan, 3',5 - bis(tetrahydropyran - 2 yl ether) Preparation 3-1, equivalent of 4.64 g.) and (2-carboxyethyl)triphenylphosphonium chloride (see Howard S. Corey, Jr. etal., J. Am. Chem. 4SS0 4 Soc. 86, 1884-.(1964), 3.71 g.) in dimethylsul I'oxi de-tetrahydrofuran (1:1) is added under nitrogen, with stirring, to a slurry of sodium hydride (0.84 g. of 57$) in the same solvent system. The reaction is monitored fay TLC and after about 6 hr. water is added and the mixture extracted with diethyl ether. The aqueous layer is mixed with a suspension of ammonium chloride (5 g.) in 25 ml, of brine and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with magnesium sulfate, and con10 centrated. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (25-50$)-hexane to yield the formula-XLl 11 title compound, as mixed isomers.

II. The formula-XLl 11 compound above is reduced in ethyl acetate solution with hydrogen at slightly above atmos15 pheric pressure in the presence of 5$-pa1ladium-on-carbon catalyst. The reaction is terminated when one equivalent of hydrogen has been taken up. The catalyst is filtered off and the formula-v(LIV compound recovered, as mixed isomers.

It I. Following the procedure of Example 7, the tetra20 hydropyranyl groups· are next removed by hydrolysis in dilute acetic acid at about 40° C. and the formula-IV title compound recovered, as mixed isomers.

IV. The formula-IV title ester is obtained by treating the above acid ϊn ethanol-diethyl· ether solution with diazoethane at about 25° C. for 15 min. and thereafter separating the product, as mixed isomers.

Example 7 9 - Deoxy -3,4-trans - d i dehyd r0-6 S, ga-epoxy -17phenyl-2,l8,19,20-tetranor-PGFi, Methyl Ester, Mixed Isomers, I. Refer to Chart C. A mixture of the formula-XXXVIίI 2a,4a-dihydroxy-5P-(3'a-hydroxy-5'-phenyl-1'-trans-heptenvl)α-cyclopenty lacetaldehyde-y-lactoi, 3' ,4- bis(tetrahydropyran2-yl-ether)(2.28 g. ) and methyl 4-( tripheny1phosphorany 1 i5 dene) crotonate (Buchta et ., Chem. Ber. 92, 3111 (1959), 3.46 g,) in 100 ml. of benzene is heated at reflux for 16 hr. The mixture is concentrated to a dark orange semi-sol id. The residue is subjected to silica gei chromatography, eluting with acetone (5/.)-dichloromethane to yield the bistetra10 hydropyran-2-yl ether of the title compound, a yellow oil, 1.55 g.

The above material is hydrolyzed in acetic acidwater-tetrahydrofuran (20:10:10) at about 42° C. for 4.5 hr. Thereupon 50 ml. of water is added, the mixture Is frozen, and then freeze-dried. The resulting residual oil Is subjected to silica gel chromatography, eluting with acetone (30/)-dichloromethane, to. yield the formu)a-XI title compound, mixed less polar and more polar isomeis, an oil, 0,444 g., having mass spectral peaks at 386, 368, 350, 324, 287, 277, 26g, 233, 133, 105, and 91ί infrared absorption peaks at 3390, 1720, 1655, l600, 1445, 1455, 1440, 1325, 1275, 1215, 1195, 1175, 1θ6θ, 975, 750 cm'1; and NMR peaks at 1.2-3.2, 3.7, 3.8-4.6, 5.4-5-65, 5.7-6.1, 6.7-7.1, and 7.2 δ.

Example 8 . ; 9-Deoxy-6£,Sa-epoxy-3-oxa-PGF.j, Methyl Ester, Mixed Isomers I. Refer to Chart F. There is first prepared the bistetrahydropyran-2-yl ether of the title compound, A solu10 tion of the formula-XLI 3,3a3,4,5,6,6ap-hexahydro-5c£hydroxy-2^-(21-hydroxyethy1-4β-(3'«-hydroxy-trans-1-octeny1) 2H-cyclopenta[bIftiran, 3',5*bistetrahydropyran-2-y1 ether (Preparation 2, 0.80 g.) in 10 ml. of dimethyl sulfoxide and 5 ml. of tetrahydrofuran is treated at about 0-5° C. with 1.1 ml, of 1.6 M n-butyl1ithrum in hexane added dropwise over a one-minute period. Thereafter the mixture is stirred at about 10° C. for 5 min., followed by additions of 8 ml. of dimethylformamide and 0.35 g. of lithium chloroacetate. The mixture is stirred at about 25° C. for 22 hr., then diluted with 125 ml. of ice and water containing 3 ml, of concentrated hydrochloric acid. The resulting mixture Is extracted with dichloromethane and the organic phase is washed with cold water and brine, and concentratad. The residue containing the acid form of the formula-LIII bistetrahydropyran-2-y1 ether, is'converted to the methyl ester in diethyl ether by reaction with diazomethane. After 3 min., the excess diazometfiane is destroyed with acetic acid and the mixture is washed with dilute potassium hydroxide solution and brine, dried, and concentrated to yield the formula-LIII bistetrahydropyran-2-yl ether of the title compound, as mixed isomers.

II. The above ether is hydrolyzed in 15 ml. of acetic acid and 7.5 ml. of water at 37-39° C. for 2,5 hr. The mixture is diluted with ice and water and extracted with diethyl ether-dich1oromethane (3:1). The organic phase is washed with dilute aqueous potassium hydroxide and brine, dried, and concentrated. The residue is subjected to silica gel chromatography, eluting with 2-5^ methanol in ethyl acetate, to yield the title compound, as mixed ( less polar and more polar isomers, 0.400 g,, having NMR peaks at 5.3-5-55, 4.01, 3.69, and 3.4-4,5ί and mass spectral peaks (for the TMS derivative) at 514, 499, 455, W, 424, and 355.

Example 9 9-Deoxy-6i;,9a-epoxy-PGFi Methyl Ester, Mixed isomers 4SS04 I. Refer to Chart J. There is first prepared the formula LXI i l halo compound. A solution of ΡΘΡεα, 11,15bis(tetrahydropyran-2-yl ether) (2.1 g.) in 10 ml. of methanol is'converted to the methyl ester with 20 ml, of a diethyl ether solution of diazomethane at about 25° C, for 15 min. Thereafter the mixture Is concentrated to an oil. The resulting 11,15-bistetrahydropyran-2-y1-PGPaa, methyl ester (2.0 g.), suspended in 2^ ml. of water, is treated with sodium bicarbonate (0.7 g.) and cooled' in an ice bath. To the resuiting solution is added potassium iodide (l.93 g.) and iodine (2.28 g.) and stirring continued for 16 hr. at about 0° C. Thereafter a solution of sodium sulfite (1.66 g.) and sodium carbonate (0.76 g.) in 10 ml. of water is added. After a few minutes the mixture is ex15 tracted with chloroform. The organic phase is washed with brine, dried over sodium sulfate, and concentrated to yield mainly the formula-LXIII iodo compound as the bis(tetrahydropyran-2-yl· ether), mixed isomers, 2.2 g., an oil, having Rf 0.75 (TLC on si 1Jca gel i n A -f X system). 2° 11. The above formuta-LXIII 9-deoxy-6jf,9“-epoxy-5iodo-PGFi, methyl ester, bis(tetrahydropyranyl ether) (2.2 g.) is dissolved in 15 ml. of benzene and treated with 15 ml. of an ether solution of tri butylti n hydride (freshly prepared from tributyltin chloride and lithium aluminum hy25 dride and containing about 0.145 g, per ml.) added dropwise over 20 min. after about 30 min. an additional 20 ml. of tributyltin hydride in ether is added and stirring continued for 1 hr. The reaction mixture is concentrated.

The residue above, largely the bistetrahydropyrany1 ether of the formula-LXlV methyl ester, is converted to the title compound as follows. The oily residue is treated with 40 ml. of acetic acid-water-tetrahydrofuran (20:10:3) for about 16 hr. at 25° C. Then 250 ml. of toluene is added and the mixture is concentrated, repeating this procedure again. The residue is again treated in 40 mi, of acetic acid-water-tetrahydrofuran (20:10:3) at 40-45° c. for 2 hr., taken up in 250 ml. of toluene, and concentrated. The residue is dissolved in 25 m). of di chloromethane and subjected to silica gel chromatography, eluting with ethy! acetate (50-80$)-Skellysolve B. One fraction, 0.77 g., is again subjected to silica gel chromatography, eluting with •acetone (20-40$)-dlchloromethane, to yield the formula-IV 9-deoxy-6^,9a-epoxy-PGFt methyl ester, mixed isomers, 0.19 g.>< having Rf 0.26 (TLC on silica gel in ethyl acetate); [a]D+27° (chloroform); NMR peaks at 0.9, 1.15-2.8, 3.3-4.4, 3-8, 4.63, and 5.65-5-85 δ; and mass spectral peaks (TMS derivative) at 512, 497, 48l, 44l, 391, 351, 325, and 323; and high-resolution mass spectral peak at 512.3333.

III. The methyl ether above is converted to the free acids as follows. A solution of the methyl ester (1,0 g.) in 30 ml. of methanol is treated with 20 ml. of 3N. potassium hydroxide at about 25° C, for 1.5 br. Thereafter the mixture is acidified to pH 1 with 45 ml. of 2N. potassium hydrogen sulfate and diluted with 50 ml· of water. The mixture is saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed I with brine, dried over sodium sulfate, and concentrated to yield an oil containing the fofmula-IV free acid, which gradually crystal 1izes. The product is subjected to silica gel chromatography, eluting with acetone (?0-50jt)-dichloromethane, to yield the title compound, 9-deoxy-6^,901-epoxyPGFia, mixed less polar and more polar isomers, 0.84 g. melting 79-2-84.5° c., having infrared absorptions at 3340, 3220, 2620, 1715, 1695, 1360, 1320, 1235, 1210, 1080, 990, 975, and 950 cm 1; [tt]jj+28° (Chloroform); and mass spectral peaks (TMS derivative) at 555, 499, ^θ, 465, 409, and 173; with high resolution mass spectral peak at 570.3569, Following the procedures of Examples, but replacing the PGFaa, 11,15-histetrahydropyran-2-y1 ether starting material with the following formula-LXIi compounds or their C-ll and C-15 ethers, there are obtained the corresponding formula-LXII I iodo compounds: -Methyl-PGFaa - Ethyl-PGFaa 16.16- Di methyl-PGFaa 16.16- Dif1uoro-PGFaa 16- Phenoxy-17,18,19,20-tetranor-PGFaa 17- Phenyl-18,19,20-trinor-PGFaa 11-Deoxy-PGFaa 2a,2b-Dihomo-PGFaa 3-0xa-PGFaa 3-0x3-17-phenyl-18,19,20-trinor-PGFaaThereafter, following the reductive dehalogenation procedures of Example 9 and subsequent work-up of the product, there are obtained the corresponding formula-LXIV products, as mixtures of less polar and .more polar isomers:. 6 Od 9-Deoxy-6$,9®-epoxy-15-methyl -PGFi 9-Deoxy-6 9®-epoxy-15-ethy 1-PGFi 9-Deoxy-61;,9®-epoxy-16, l6-dimethyl -PGFi 9-Deoxy-6£,9«-epoxy-16, l6-d! fluoro-PGFi 9-Deoxy-61^, 9a-epoxy-l6-phenoxy-17,18,19,20-tetranorPGFi 9-Deoxy-6f,9®-epoxy-17-phenyl -18,19,20-tri nor-PGFj 9-Deoxy-6^, 9a-epoxy-11-deoxy-PGF j 9-Deoxy-6ij, 9a-epoxy-2a,2b-dihomo-PGFi 9-Deoxy-6^,9a-epoxy-3-oxa-PGF1 9-Deoxy-6^,9«-epoxy-3-oxa-17-phenyi-18,19,20-tri norPGFi.

Example ]Q 9-Deoxy-6^,9a-epoxy-PGFi, Methyl Escer, Mixed Isomers , I. Refer to Chart J and consider R4 on (Res) and Q2 to be hydrogen. There is first prepared the formulaLXIII halo compound. A solution of PGFaa, methyl ester (9.0 g.) in 125 ml, of diehloromethane, cooled in an ice bath, is treated with anhydrous sodium carbonate (5.3 g.) and iodine (6.35 9·) and stirred for one hr. Then it is allowed to warm up to 25° C. while stirring for 16 hr.

The reaction mixture is diluted with 250 mi. of dichloromethane and then 100 ml, of 10$ aqueous sodium sulfite is added. When the iodine color disappears the organic phase is separated, and the aqueous phase is extracted with dichioromethane. The organic phases are combined, washed with brine, dried over sodium sulfate, and concentrated.

The resulting oil, 13.5 g., is subjected to silica gel chromatography, eluting with acetone (20-50$) dichltfromethane 6 0 4 to yield the formula-LX111 9'deoxy-6^,Qa-epoxy-5iodo-PGFi, methyl ester, mixed isomers, 4.76 g., having Rf 0.40 (TLC on silica gel in acetone-dichloromethane (3:7)); [a]^+22° (chloroform); mass spectral peaks (TMS derivative) . at 623, 567, 548, 517, 511, 477, 451, 521, 199, and 173; high resolution mass peak at 638.2314; and infrared absorption peaks at 3380, 2960, 2940, 2860, 1740, 1440, 1365, 1230, 1195, 1175, 1075, 1055, and 1020 cm'1.

II. Next, the title compound is prepared.

A solution of the above formula-LXiJf 5-iodo compound (0.98 g.) in 10 ml. of benzene is treated at about 15° C. with 5 mg, of 2,2razobis-(2-methylpropionitrile) and a solution of 0,58 g. of tributyl tin hydride in 4 ml. of diethyl ether added dropwise over about 2 min. The mixture isallowed to warm to about 25° C. while stirring for 1.25 hr. Another portion of tributyl tin hydride (0.58 g. j is added and s timing continued for 0.75 hr. The reaction mixture is concentrated, then di luted with 25 ml. of Skellysolve B and 25 ml. of water, stirred for 0.5 hr. and filtered through diatomaceous earth. The aqueous phase together with aqueous washes of the organic phase, is mixed with 50 ml. of ethyl acetate, saturated with sodium chloride, and stirred for 0.5 hr. The organic phase, together with ethyl acetate washes of the aqueous phase and including the solution in Skellysolve B, is dried over sodium sulfate and concentrated. The resulting oil is subjected to silica gel chromatography, eluting with acetone (25-50<)-dichloro methane, to yield the formula-IV title compound, mixed. : isomers, 0,48 g., having the same properties as the pro5° duct of Example g.

Example Π 9-Deoxy-6£,9a -epoxy-I7-phenyl-18,19,20-trinor-PGF, Methyl Ester, Mixed Isomers.

!, Refer to Chart J, There is first prepared the formula-LX111 5-iodo compound. A solution of 17-phenyl18,19,20-trinor-PGFltu methyl ester (2.3 g.) in 25 ml. of dichloromethane, cooled in an ice bath, is treated with anhydrous sodium carbonate (1.06 g,) and iodine (1.27 g.) ]θ and stirred for one hr. Thereafter the mixture is allowed to warm to 25° C., with stirring for 16 hr. The reaction mixture is diluted with 50 ml. of dichloromethane and treated with 20 ml. of 10% w/v aqueous sodium sulfite. After the iodine color has disappeared, the organic phase, together with organic extractions of the aqueous phase with dichloromethane, is dried and concentrated to a pale yellow oil, 2.64 g. The oil is subjected to silica gel chromatography to yield the formula-LXl 11 9deoxy-6^,9aepoxy-5-iodo-17-phenyl-18,19,20-trinor-PGFi, methyl ester, go mixed isomers, 1.57 g., having Rf 0.24 (TLC on silica gel in acetone-dichloromethane (3:7)), NMR 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 7.2 6; mass spectral peaks (TMS derivative) at 657, 582, 567, 545, 477, 455’ 38$> 257j and 259; and infrared absorption at 53‘JO. 1735, 1600, 1495, 1455, 1435, 1360, 1305, and 975.

II. Next, the title compound is' prepared.

A solution of the above formula-LXIII 5-i.odo compound (1.0 g,) in 9 ml. of benzene is treated with 3 mg. of 2,2-azobis(2-methyl propionitrile) and to the cold mixture is added -10 ml, of an ether solution of tributylti n hydride (freshly-prepared and containing about 0.145 g. per ml.) dropwise over about 5 min. The mixture is allowed to warm to 22-25° C. and stirred for- about 45 min. until the reaction is shown complete by TLC. The mixture is concentrated and the residue stirred with 25 ml. of Skellysolve B and 25 ml. of water for 0,5.hr. The aqueous phase, together with aqueous washes of the Skellysolve B layer, is saturated with sodium chloride and extracted with ethyl acetate. The organic phase, together with ethyl acetate extractions of the aqueous phase, is dried and concentrated to an oil, 0,87 g. The oil is subjected to silica gel chromatography, eluting with agetone (20-50#)'-di chloromethane to yield the title compound, mixed less polar and more polar isomers, 0.568 g., having Rf 0.17 (TLC on silica gel in acetone-di chloromethane (3:7); NMR peaks at 1.2-2.9, 3.69, 3.7-4.6, 5.4-5.65, and 7.2 δ; mass spectral peaks at .546, 531, 515, 456, 44Ϊ, 432, 425, and others; and in25 frared absorption at 3400, 1735, 1495, 1450, 1435, 750, and others cm'1.

Preparation 4 5-^*1 odo-9-deoxy-6^,9a-epoxy-PGFi, Mixed Isomers, (Formula LXII): Rie is -COOH).

A solution of the formula-LXIII 5^-iodo-9-deoxy-6^,9a30 epoxy-PGFi, methyl ester, mixed isomers (Example 10, 1.00 g.) in 25 ml. of methanol is treated at about 0° C. with 20 ml. of 3 N aqueous sodium hydroxide. After 15 min. the cooling bath is removed and stirring continued for 2 hr. Crushed ice is added, together with aqueous potassium hydrogen sulfate to acidify. The mixture is extracted with ethy] acetate and the organic phase is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to silica gel chromatography using acidwashed silica gel, eluting with acetone (40-100$)-methylene chloride. There is obtained the title compound, consisting of mixed isomers, having [α]θ=+20° (C = 0.992 in chloroform); infrared absorption at 33βθ, 2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050, and 970 cm’1; and mass spectral peaks at 696.2554, 68l, 625, 6o6, 569, 535, 479, and 173.

Preparation 5 (5S, 6S) -5 -1 odo-9-deoxy -6,9a-epoxy-PGF 1, Methy] Ester, Less Polar Isomer, and (5R, 6R) -5 -1 odo-9 -deoxy -6,901-epoxy - PGF 1, Methyl Ester, More Polar Isomer (Formula LXI 11 ).

A suspension of PGF2CiJ methyl ester (3.0 g.) i n 60 ml. of water is treated with sodium carbonate (1.7 .9.) and cooled in an ice bath. To the resulting solution is added potassium iodide (2.7 g.) and iodine (4.14 g.) and stirring continued for 3 hr. at about 0° C. Thereafter sodium sulfite (2.5 g.) and sodium carbonate (0,8 g.) are added to decolorize the mixture. After a few minutes the mixture is extracted with chloroform, The organic phase is washed with hrine, dried over sodium sulfate, and concentrated to yield the mixed isomers of the title compounds, an oil, which is further -45604 purifled by si 1ica gel chromatography, eluting with methylene chloride (15-50$)-acetone to yield the less polar (5S,6s) titie compound, 0,29 g., having Rf 0.44 (TLC on silica gel in ethyl acetate); and the more-polar (5R,6R) title com5 pound, 3.36 g., having Rf 0.4l (TLC on silica gel in ethyl acetate).7 Example Ί2 - 9-Deoxy-6J9a-epoxy-PGF1, Methyl Ester, lesspolar isomer and more-polar isomer.

Refer to Chart J. A solution of the less-polar TO isomer of the formula-LXII I iodo ether (Example 16j 0.247 g.) in 3 ml. of absolute ethanol is treated with tributyl tin 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 min. the reaction mixture is diluted with ethyl acetate and water. The organic phase is separated, washed, dried, and concentrated to an oil, O.l4.g., having properties identical· to those of the title compound, lesspolar isomer, of Example below.

Likewise following the above procedure but starting with the more-polar formula-LXIII iodo ether, there is obtained an oil, 0.14 g., having properties idential to those of the title compound, more-polar isomer, of Example. 21 below.

Example ra. 9-Deoxy-6,9a-epoxy-PGF1, Amide, less polar and more polar isomers I. Refer to Chart κ. There is first prepared the formula-LXVI 5-iodo-9-deoxy-6,9a-epoxy-PGF!, amide, less polar and more polar isomers. A solution of the formulaLXV iodo-ether acid, mixed isomers (Example 4, 5.0 g.) 100 in 50 ml. of acetone is cooled to about -10° C. and treated with 3.0 ml. of triethylamine and 3.0 ml. oi isobutyl chloroformate. After 5 min. there is added 100 ml. of acetonitrile saturated with ammonia, and the reaction mixture allowed to warm to about 25° C. The mixture is filtered, and the filtrate concentrated. The residue is taken up in ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The residue is subjected to silica gel chromatography, eluting with acetone (25100$)-methylene chloride. There are obtained the formula LXVI iodo-ether, amide, less polar isomer, 0.02 g., having Rf 0.40 (TLC on silica gel in acetone); a fraction of mixed less and more polar isomers, 2.2 g.; and the more polar isomer, 1.5 9., having Rf 0.37 (TLC on silica gel in acetone), infrared absorption at 3250, 3150, l660, l6l0, 1085, 1065, 1050, and 965 cm'1; and NMR peaks at 6.4, 5.5, 3.5-4.7 and 0.9 δ.

II. A mixture of the formula-LXVI 5-iodo-9-deoxy20 6,9a-epoxy-PGFi, amide,mixed isomers (Example 13-1, 0.48 g.) in 15 ml. of ethanol is treated at about 25° C. with about 0.5 ml. of tributyltin chloride and a mixture of sodium borohydride (0.10 g.) in 5 mi. df ethanol. The reaction is followed by TLC (silica gel in acetone). After about 30 min. additional 0.75 ml. of tributyltin chloride is added, and, after further stirring for 45 min., 0.15 g. of sodium borohydride is added. After an additional hour the reaction is complete as shown by Rf = 0.49. The reaction mixture is diluted with ice and water and extracted with ethyl acetate. The organic phase is washed with brine, 101 4S604 dried, and concentrated. The residue is subjected to silica gei chromatography, eluting with acetone (30-100/)-methyleno chloride. There is obtained a fraction consisting of a mixture of the less and more polar isomers, 0.17 g.> and another fraction consisting of the more polar isomer, 0.18 g. The less polar isomer has Rf 0.46 (TLC on silica gel run twice in acetone). The more polar isomer has Rf 0.43 (TLC on silica gel run twice in acetone), and infrared absorption at 3275, 3060, 1680, 1640, l6l0, 1300, 1275, 1225, ll60, 1130, 1080, 1045, 970, 910, and 775 cm'1.

Example 14. 9-Deoxy-6^, 9a-epoxy-PGFr, Methylamide, mixed isomers (Formula LXVII : one Rls is hydrogen and the other Rls is methyl). i. Refer to Chart K. There is first prepared the formu15 la LXVI 5r--iodo-9-deoxy-65,90£-epoxy-PGFi, methylamide, mixed · isomers. A solution of the formula-LXV 5ξ iodo-9-deoxy6g',9a-epoxy-PGFi, mixed isomers (Preparation 4, 4.66 g.) in 50 ml. of acetone is treated with 1.42 mi. of triethylamine and cooled to -5° C. Thereupon 1.3 ml. of isobutyl chloroformate is added, with stirring at 0° C. for 5 min., followed by 25 ml. of 3M methylamine in acetonitrile. The solution is stirred for 20 min. more as it warmed to about 25° C. The mixture is filtered and concentrated.

The oily residue is triturated with methylene chloride, and Filtered to remove a precipitate. The filtrate is subjected to silica gel chromatography, eluting with acetone (50-90/j-methylene chloride, to yield the 55-iodo9-deoxy-6ξ 9a-epoxy-PGF1, methylamide mixed isomers, 3-45 g.., having NMR peaks at 6.3, 5-4-5-7, 3.2-4.7, 2.78, and 0.73° 2.05 ft. 102 46604 II. A solution of the above formula-5£- iodo-9-deoxy6ξ,9a-epoxy-PGFn methylamide mixed isomers (0.67 9·) in 15 mi. of methanol is treated at about 25° C. with 1.5 nil. of tributyltin chloride and thereafter with sodium borohydride (0.35 g. ) added portionwise within 15 min. After one hr. an additional 0.75 ml. of tributyltin chloride is added and stirring continued 16 hr. Then another 0.15 g. of sodium borohydride is added and stirring continued for 15 min. The reaction mixture is diluted with ml. of brine and extracted with ethyl acetate. The organic phase is separated, washed with brine, dried over sodium sulfate, and concentrated. The residue is chromatographed on silica ge),eluting with acetone (25-75$)methylene chloride, to yield the title compound as mixed C-6 isomers, 0.46 g., having mass spectral peaks at 511.3520, and NMR peaks at 6,7, 5.3-5.7, 3.3-4.6, 2.76, and 0.7-2.6 6. Example IS 9-0soxy-6^,9a-epoxy-PGFi, Benzylamide, mixed isomers (Formula LXVII: one Ria is hydrogen and the other RiS is benzyl).

I. Refer to Chart K- Following the procedures of Example 14 there is first prepared the formula-LXVI 5^-iodo9-deoxy-6£ ,9a-epoxy-PGFu benzylamlde, mixed isomers. There is used 4.66 g, of the formula-LXV 5^-i odo-9-deoxy-6^’,9aepoxy-PGFi, mixed isomers, and 1,08 g. of benzylamine instead of methylamine. The crude product is chromatographed on silica gel, eluting with acetone (50-70$)-methylene chloride, to yield the 5£-iodo-9~deoxy-6£,9a-epoxy-PGFi, benzylamide mixed isomers, 4.1 g, having NMR peaks at 7.3, 6.6, 5.3-5.7, and 3.5-4.6 6. il. Following the procedures of Example 14-11, the 103 5604 above formula-LXVI compound is treated with tributyltin chloride and sodium borohydride until the reaction is complete as shown.by TLC. Silica gel chromatography yields the title compound as mixed C-6 isomers, 0.22 g., having mass spectral peaks at 659.4204, 644, 588, 569, 221, and 173.

Example 16 ' 9-0eoxy-6ij_j9a-epoxy-PGFi, Ani1ide, mixed isomers (Formula LXVIi : one R1S is hydrogen and the other RiS is phenyl).

I. Refer to Chart K- Following the procedures of Example 14 there is first prepared the formula-LXVI 5^-iodog-deoxy-e^gu-epoxy-PGFt, anilide, mixed isomers. There is used 4.66 g. of the formula-LXV S^-iodo-g-deoxy-e^g®epoxy-PGFi, mixed isomers, and 0.94 g. of aniline. The crude product is chromatographed on silica gel, eluting with acetone (10-50$)-methylene chloride, to yield the 5iodo-9-deoxy-6^,Qa-epoxy-PGFi, anilide mixed isomer's, 4.0 g., having NMR peaks at 8,4, 6.9-7.7, 5.3-5-7, and 3.4-4.7 6.

II. Following the procedures of Example 14-11, the above formula-LXVI compound is treated with tributyltin chloride and sodium borohydride until the reaction is complete as shown by TLC. Silica gel chromatography yields the title compound as mixed C-6 isomers, 0.29 9·, having mass spectral peaks at 645.4033, 630, 574, 555, 540, and 514. · . \ §-Bromo-9-deoxy-6£,9a-epoxy-PGFi, Methyl Ester, mixed isomers (Formula LXIII) and 9-Deoxy-6?,9a-epoxy-PGFi, Methyl Ester, mixed i somers ., Example 17 104 · '· I. Refer to Chert3· A solution of POF-^,, methy1 ester (1.00 g.) in 25 ml. of methylene chloride is treated at about 0° C. with N-bromosuccinimide (0.50 g.) added in portions within 3 min. After additional stirring for 10 min. the reaction is complete as shown by TLC (on silica gel in ethyl acetate). The solution is washed with aqueous sodium sulfite and water, dried over magnesium sulfate, and concentrated. The colorless oily residue is chromatographed on silica gel, eluting with acetone (2040^)-methylene chloride to yield the mixed isomers of the formula-LXII I 5-bromo title compound, 1.18 g,, a colorless oil, having mass spectral peaks at 575.2203, 559, 519, 511, 510, 500, 469, 429, 403, 199, and 173; and having an NMR spectrum essentially identical to that of the corresponding 5?-iodo compound prepared by the method of Example 10, Viz.: 5.5, *.55, 33-4.2, 3.65, and 0.9 δ.

II. Thereafter, following the procedures of Example 10-11 but replacing the formula-LX111 5-iodo compound of that example with the formula-LX!I I 5-bromo compound above, there is obtained the formula-1 V title compound, Example /8 9,15-Dideoxy-6?,9a-epoxy-13,14 -dihydro-PGFp Methyl Ester and 9-Deoxy-65,9a-epoxy-13,T4-dihydro-PGFp Methyl Ester. 105 A solution of 9-deoxy~6jj,9a-epoxy-PGFi.,; methyl ester (Example 10, estimated 10 mg.) in 3 ml. of methanol is hydrogenated at atmospheric pressure in the presence of platinum oxide until the starting material is no longer evi dent by TLC. There are-obtained the titie compounds : the 15-deoxy compound having Rx 0.60 (TLC on silica gel in acetone-methylene chloride (3:7) and mass spectral peaks at 4-26,-336, 311, and 221; and the 9-deoxy-6j’,9a-epcxy-13,l4-dihydro-PGEj., methylester having Rf 0.24 (TLC on silica gel in acetone-methylene chloride (j:7) and mass spectral peaks at 443, 425, 424, 414, 409, 399, 393/ 353, 334, 309, 267,219, 199, 177, and 173.

Example 19 9-Deoxy-6,9a-epoxy-15(S)-15-methyl-PGF.|, Amide, more polar isomer is II C”jy(R·^^ A solution of 9-deoxy-6,9“-epoxy15(s)-15-methyl-PGFu more polar isomer (Example 23', , 0.50 g.) in 10 ml. of acetone is cooled to about -10° C. and treated with.0.3 ml. of triethylamine and 0.3 ml. of isobutyl chloroformate. After 5 min. there is added 10 ml. of acetonitrile saturated with ammonia, and the reaction mixture allowed to warm to about25° C. within 10 min.

The mixture is filtered, and)'the-fi 1 trate concentrated.

The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. 106 4S00 The residue is subjected to silica gel chromatography, eluting with acetone (40-100#)-methylene chloride, to yield the title compound, a colorless ol1, 0.43 g., having Rf 0.14 (TLC on silica gel in methanol-acetic acidchloroform (5:5:90)), having 4.2, and 0.9 fi, and infrared absorption at 3360, 3220, 1670, 1620, 1460, 1410, 1380, 1225, 1125, 1075, 1060, and 975 cm'1.

Following the procedure of Example 19». but starting with the less polar isomer of 9-deoxy-6,9a-epoxy-15(S)-15methyl-PGFi (Example 2.3), there is obtained the less polar isomer of 9-deoxy-6,9a-epoxy-15(S)-15-methyl-PGFt, amide. Example 20 5-(Ch1oromercuri0)-9-deoxy-6?,9a-epoxy-16,16dimethyl-PGFi, Mixed Isomers (Formula LXIX: G is chlorine, L is -(CH2)s-, Qs is H OH, OH and^ is alpha or beta): and 9-Deoxy-65,9a-epoxy-l6,16-dimethyl - PtSF-j, Mixed Isomers. 107 f. Refer to Chart L. A solution of 16,l6-dimethyl ; PGP2a, 11,15-bis(tetrahydropyran-2-yl· ether} (U.S. Patent Specification No. 3,903,131, Example 17, 1.02 g.) i n 20 ml. of chloroform is treated with a solution of mercuric acetate (1,15 g.) in 4o ml. of acetic acid and left standi ng with 1ight excluded for 5 hr. Thereupon 7θ ml. of toluene is added, and the mixture concentrated. The residue is taken up in 75 mi. of diethyi ether contacted with water and brine, dried, aid concentrated. The residue, an oil, which is largely the bistetrahydropyranyl ether of the formula- LXIX chloromercurio title compound, is treated with 50 ml. of a mixture of acetic acid-water-tetrahydrofuran (20:10:3) at 43*47° C. for 2.5 hr. 'Thereupon 40 ml. of toluene is added and the mixture concentrated to yield the formula-LXIX chloromercurro compound, an oily residue containing the mixed isomers.

II. The residue from 1 above is dissolved in 10 ml. of tetrahydrofuran and diluted with 10 ml. of water. To the mixture, while stirring, is added 10 ml. of aqueous 3M. 108 6604 sodium hydroxide and 10 ml. of aqueous 0.5 M sodium borohydride in 3M. sodium hydroxide. After additional stirring for one min., the mixture is'cooled in an ice bath and diluted with 100 ml. of ethyl acetate and 10 ml. of water. There is then added 12 g. of potassium hydrogen sulfate and solid sodium chloride to saturation. The aqueous phase is extracted with ethyl acetate. The ethyl acetate solution is combined with the organic phase, dried over sodium sulfate, and concentrated. The residue, an oil, is subjected to silica gel chromatography, eluting with methanol (l-ll#)dichloromethane, to yield the formula-IV title compound, mixed isomers, 0.l80 g., having Rf 0.24 (TLC on silica gel in A-IX system); NMR peaks at 0.8-1.1, 1.15-1.85, 2.0-2.5, 3.5-3.9, 4.35-4.6, and 5·5-5·7 δ; and mass spectral peaks (TMS derivative) at 44l, 423, 383, 351, 325, 323, 307, 233 and 201.

Preparation 6 5-(Acetatomercurio)-9-deoxy-6j,9ffl-epoxy-PGFi Mixed Isomers (Formula LXlXi G is acetoxy, L, Q2R36 and are as in Example 20 and R25 is n-pentyl), -(Chloromercurio)-9-deoxy-6^,9a-epoxy-PGFi, 109 48S04 Mixed Isomers (Formula LXIX; as above except G is chlorine; ,I. Refer to Chart L. A solution'of PGFaa, 11,15bi stetrahydropyran-2-yl ether (1.3 g.) in 30 ml. of chioro5 form is treated with a solution of mercuric acetate (1.59 9·) i n 60 ml. of acetic acid and stirred with light excluded for 5 hr. To the resulting clear solution is added 75 ml. of toluene and the mixture is concentrated to yield the bi stetrabydropyranyl ether of the formula-LXIX acetatomercurio title compound. The residue is treated with 50 ml, of a mixture of acetic acid-water-tetrahydrofuran (20:10:3) at about 40° C. for 4 hr. Thereafter 40 ml. of toluene is added and the mixture is concentrated to yield the formulaLXIX acetatomercurio title compound, mixed isomers. il, - The-above bistetrahydropyran-2-yl ether of the formulaLXIX acetatomercurio compound is taken up in a mixture of diethyl· ether-water and contacted with 20 ml. of brine.

The organic phase is dried over anhydrous sodium sulfate - and concentrated to yield mainly the bistetrahydropyrany) ; 20 ether of the formula-LXiX chloromercurio compound,. The residue is treated with 6.6 ml. of a mixture of acetic acid-water-tetrahydrofuran (20:10:3) at about 40° C. for 4 hr, Thereupon 20. nil. of toluene is added and the mixture is concentrated to yield the formuls-LXlX chloromercurio titie compound: 2.0 g,, an oil, soluble in ethyl acetate or diehloromethane. An analytical sample is obtained on subjecting the material to silica gdl chromatography. 110 . eluting with ethyl acetate (50-100%)-hexane. The product, mixed isomers, 0.256 g., an oil, has Cl:Hg atomic ratio 1:1, and infrared absorption spectral peaks at 3360, 2660, 1720, 1705, 1305, 1225, 1185 and 1060 cm”1. An alternative name for this chloromercurio compound is - Carboxy - 1 - (3,3ag, 4,5,6,Sag - hexahydro - 5a - hydroxy - 4g - (lt',3S) - 3 - hydroxy - 1 - octenyfj - 2H - cyclopenta(a]furan 2ξ - yljbutyl ] chloromercury.

Following the procedures of Example 20 and 10 Preparation 6, but replacing those starting materials with the appropriate tetrahydropyran-2-yl ether of PGF„ or a PGF„ analog, there are obtained the 2a aa formula-LXIX mercuric products identified in the table below.

TABLE Mercurio products of formula LXIX R36 is COOP.p L is trimethylene, X is trans CHgCH-, Q2 is Z\ r3 0R4 R4 is hydrogens [R22 ) is I HO 111 TABLE (continued) G = RtR25 phenethyl Ra - chlorine hydrogen hydrogen chlorine methyl n-pentyΪ hydrogen chlorine n-octyl n-pentyl hydrogen chlorine methyl 1,1-dimethyl -penty, hydrogen chlorine hydrogen phenoxy- hydrogen methyl chlorine hydrogen n-pentyl (L and Q are as defined above and is methyl chlorine. hydrogen n-pentyl hydrogen acetoxy. hydrogen n-pentyl methyl Preparation 7 5-(Acetatomercurio)-9-deoxy-6£,9-epoxy I WI 1 Methyl Ester, Mixed Isomers (Formula LXIX: G , L, Qs, (Figs/ Ras, andare as defined in. Preparations, and Rsa is -COOCHa).

A solution of the formula-LXIX acetatomercurio 112 8 6 0 4 compound of Preparation 5 in methanol -diethyl ether (1:1) is treated with a solution of diazomethane in diethyl ether at about 25° C. for 5 min. The reaction mixture is concentrated to yield the methyl ester t'tie compound.

Following the procedure of Preparation.7 but using in place of the diazomethane, diazoethane, diazobutane, and l-diazo-2-ethyIhexane, there are obtained the corresponding ethyl, butyl, and 2-ethylhexyl esters of 5(acetatomercurio)-9-deoxy-6|T,9a-epoxy-PGF1. In the same manner, the methyl, ethyl, butyl, and 2-ethylhexyl esters of 5-(chloromercurio)-9-deoxy-6ij,9a-epoxy-PGFi are prepared. Likewise using each of the acids identified in Examples 39 and 40, hereafter, there are obtained the corresponding methyl, ethyl, butyl, and 2-ethylhexyl esters. Preparation 8 5-(Acetatomercurio)-9-deoxy-6^9a-epoxyPGFi, Methyl Ester, Mixed Isomers (Formulaare as defined in Preparation 7.

Refer to Chart L, a solution of PGF2a, methyl ester (1.75 g.) in 25 ml. of tetrahydrofuran is treated with a solution of mercuric acetate (3.5 g.) in 25 ml. of water and 25 ml. of tetrahydrofuran and stirred at about 25° C. for 2 hr. The reaction mixture is concentrated and extracted with ethyl acetate. The organic phase is washed with water, dried .over magnesium sulfate, and concentrated to the product, mixed isomers, an oil, about 4.0 g,, having NMR peaks at 5.5, 4.7, 3.8-4.6, 3.67, 2.0 and 0.9 δ.

Preparation 9 5-(Chloromercurio)-9-deoxy-6^9a-epoxy-PGFi, Methyl Ester, Less Polar Isomer and More Polar Isomer (Formula LXIX of Chart L; G is chlorine, 113 and L, R25 R36 and are as defined in Preparation 7.

The product is obtained from the acetoxy compound by g exchange of acetoxy with chlorine. A solution of the acetoxy mercurio compound of Preparation 8 (2.8 g.) in 50 mT. methanol is contacted with 25 ml. of brine at about 25° C. for 2 hr.

The mixture is concentrated to half volume and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and concentrated to a residue, 2.2 g. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (5O-lOO#)-8kellysolve B to yield two fractions, one less polar and the other more polar.

The less polar consists of the less-polar isomer of the titie compound, waxy crystals, 0.33 g., recrystallized from ethyl acetate-hexane as colorless needles m, 60-1° C. (softening at 56° C.), having Rf 0.4-7 (TLC on silica gel in A-IX system); Ci :Hg atomic ratio 1:1; and infrared absorption bands at 3400, 1735, 1470, 1370, 1245, 1065, 970 and. 890 cm l. The more-polar isomer is an oil, 1.00 g., having Rf 0.41 (TLC on si 1ica gel in A-IX system); Cl:Hg atomic ratio 1:1; NMR peaks at 5.5, 3,8-4,7, 3.65, 3.2, , 2.75, and 0.9 δ; [a}D+l4° (¢=0.9015 in CH‘Cl3)j ®ss spectral 114 4S604 peaks (TMS derivative) at 746, 675.1727, 656, 535, 511, 421, 199, and 173; and infrared absorption bands at 3450, 1740, 1435, 1370, 1240, 1045, 970 and 875 cm'1. .

Example 21 9-3eoxy-6,9«~epoxy-PGFi, Methyl Ester, less5 polar isomer and more-polar isomer.

Refer to ChartL. A solution of PGFsa, methyl ester (0.73 g.in 10 ml. of tetrahydrofuran is treated with a suspension prepared by mixing mercuric acetate (0.95 9·) in ml. of water with 10 ml. of tetrahydrofuran. The mixture is stirred at about 25° C. for 2 hr. to yield the formula-LXIX : S-acetoxyraercurio) - 9-deoxy-6^,9«-epoxy-PGFi, methyl ester. Thereafter a solution of sodium borohydride (0.200 g.) in 10 mi. of 1 N potassium hydroxide is added in portions within 3 min. Stirring is continued for 20 min. and diethyl ether and brine are added. The organic phase is separated, washed with brine, dried over magnesium sulfate and concentrated. The oily residue (0.66 g.) is subjected to siiica gel chromatography, eluting with ethyl acetate (40-100$)-Skellysol ve B. There is first obtained the less-polar isomer, 0.070 g., then a fraction of mixed isomers, 0.112 g., and finally the more-polar isomer, 0.250 g. The mixed-isomer fraction is again chromatographed to yield approximately one part of the iess-polar isomer for every 2 parts of the more polar isomer. The combined title compound less-polar isomer is crystallized from ethyl acetate as needles, m.p, 77-7° C., having [«Jq-+13° (C -0.8245 in chloroform); NMR peaks at 5.55, 3.7-4.5. 3.7, 4.5. 3.1, 2.1-2.5. and 0.9 δ; and Rf 0.40 (TLC on silica gel in acetone-methylene 115 ΰ-6θf / , \ \ ' - - . - ’ chloride 1:1).

The combined fractions containing the more-polar isomer yield the .title compound more-polar isomer which is crystallized from diethyl ether-hexane, m.p. approximately 26° C., -5 having [a}0=-»23° (C. = 0.9815 in chloroform); NMR peaks essentially as. for the less-polar isomer above; Rf 0.37 ' (TLC on silica gel in acetone-methy Iene chloride l:l); and mass spectral peaks at. 512.3356, 497, 48l, 441,.391, and : 173. .

Example 22 , 9-Deoxy-6.9g-epoxv-PGF,, less-polar isomer and more-polar isomer.

Refer to Chart L. A solution of PGFac (2.0 g.) in 40 ml. of tetrahydrofuran is treated with a mixture of mercuric acetate (3.7 g.), 30 ml. water, and 20 ml. of tetrahydroftrran for 2 hr., with stirring. Thereafter a solution of sodium borohydride (0.75 g.) in 30 ml. of 1 N sodium hydroxide is added in portions within’3 min. After 15 min. the mixture is. cooled and cautiously acidified with di lute hydrochloric acid. Diethyl .ether and salt (sodium chloride) are added. The organic phase is separated, washed with brine, dried, and concentrated to an oil, 2.5 g. The oil is subjected to high pressure liquid chromatography on acetic acid-washed silica gel, eluting with acetone (20-65$)-methylene chloride at approximately 50 pounds 2'?. per square inch (350 g./cm2)» There are obtained four main fractions: (l) the less-polar isomer of the title compound, 0.26 g,, (2) mixed isomers, 0,4l g., (3) the more-polar isomer, 1.01 g. and (4) recovered unreacted PGFsu, 0.2 g. The pure Isomers are crystallized from ethyl acetate-hexane. The less-polar'Isomer has Rf 0.50 116 48604 (TLC on silica gel in A-iX system), m.p. 97-9° 0., and faId=+13° (C - 1.061 in ethanol). The more-polar isomer has Rf 0.45 (TLC on silica gel in A-IX system), m.p. 78-80° C, and L«JD=+51° (C * 1.031 in ethanol).

From each of the above isomers, by esterification with diazomethane, there is obtained the corresponding methyl ester having the same properties as that of the corresponding less-polar or more-polar methyl ester of Example 21· Example 23 9-Deoxy-6,9a-epoxy-15(s)-15-methyl-PGFi, less polar isomer and more polar isomer, Refer to Chart L, A solution of 15(S)-15-methy1-PGFgct (U.S. Pat.

No. 3,728,382) (2.94 g.) in 60 ml. of tetrahydrofuran is added in portions within 3 min. to a stirred mixture of mercuric acetate (52 g. ) in 45 mi. of water and 30 mi. of tetrahydrofuran. After 3 hr. stirring, a solution of sodium borohydride (l.1 g.) ϊn 45 ml. of 1 N sodium hydroxide is added in portions. After 15 min. the mixture is cooled and treated with an aqueous solution of potassium hydrogen sulfate to pH 6. Sodium chloride and diethyl ether are added, with stirring for 5 min. The organic phase is separated. The aqueous phase is further acidified to pH 3 and again extracted. The ether extracts are combined, washed with brine, dried, and concentrated to an oil, 3.5 g. The oil is subjected to high pressure liquid chromatography on acid-washed silica gel, eluting with acetone (4θ-6θ#)methylene chloride. There are obtained three main fractions: (1) the less-polar isomer of the title compound, 0,29 g., (2) mixed isomers, 1.10 g,, and (3) the more-polar isomer, 117 45604 ; . . ' .-..1.71 g. Further chromatography of the mixed-isomer fraction yields more of the less- and more-polar title compound.

There is obtained the less-polar isomer of the title compound, 0.43 g., having Rf 0.43 (TLC on silica gel using the A-iX system 2 times ); [ο]θ=49° (C = 1.036 in chloroform); NMR peaks at 5.77, .5.53,. 4.42, 3.5-4.1, and 0.9 δ; infrared absorption at 3380, 2670, 1710, 1455, 1375, 1235,..1080 and 974 cm1; and mass spectral peaks at 584..3748,7 569, 513, 494, 479, 423, 378, 213, 203, and 187.

Likewise, there is obtained the more-polar isomer of the titie compound, 2.35 g., having Rf 0.40 (TLC as above); [a]j-,=+20° (C = 0.8130 in chloroform); infrared absorption at 3400,2650, 1710, 1365, 1220, 1085, 1055, and 975 cm'1; with NMR and mass spectral data similar to those of the less-polar isomer above.

Example 34 9-Deoxy-6g,9a-epoxy-2,2-dif1uoro-PGFi, Methyl Ester, less polar isomer and more. - / polar: isomer.

Following the procedures of Example21 but replacing the PGFaa, methyl ester starting materia] with 2,2-difluoro. PGFga, methyl ester, there are obtained the title compounds.

Example 25 9-Deoxy-6§,9a-epoXy-2,2-difluoro-16,16dimethyl -PGFi, Methyl Ester, less-polar isomer and more-polar isomer. , Following the procedures of Example 21 but replacing the PGF2a, methyl ester starting material with 2,2-difluoro16, 16-dimethyl-PGF2a, methyl ester (U.S. Patent No. 4,001,300, Example 2l) there are obtained the title compounds, Example 26 9-Deoxy-6s,9a-epoxy-2,2-difluoro-17-phenyl ?0 18,19,20-trinor-PGFi, Methyl Ester, less 118 6 0 4 polar isomer and more polar isomer.

Following the procedures of Example 21 but replacing the PGF2 2,2-dif1uoro-17,phenyl-18,19-,20-trinor-PGF2a, methyl ester (U.S. Patent Specification No. 3,987,087) there are obtained the title compounds.

Example 27 g-Deoxy-e^a-epoxy-PGF^, THAM Salt.

A solution of the more polar isomer of 9-deoxy-6s,9a10 epoxy-PGF^ (Example 22, 0.088 g.) in 10 ml. of warm acetonitrile is treated while stirring, with a solution of tris(hydroxymethylJaminomethane (THAM) (0.027 g.) in 1 ml. of dimethyl sulfoxide. The supernatant solution is decanted to yield the title compound, a gummy solid, 0.10 g., having the same in the A-IX system as the starting material.

Preparation 10 9-Deoxy-5c,9ci-epoxy-trinor-PGF.|, Bis(tetrahydropyran-2-yl Ether), Mixed Isomers.

A solution of the formula-XXXIX 9-deoxy-6<,9a-epoxy20 2,3,4-trinor-PGFp ethyl ester, bis(tetrahydropyran-2-yl ether) (Example 1, 3.7 g.) in 30 ml. of methanol is treated with potassium carbonate (1.0 g.) in 12 ml. of water for 16 hours at about 25°C., with stirring. An additional 0.2 g. 119 5604 of potassium carbonate is added and stirring continued for 4 hr. Ice chips are added and the mixture shaken with ? diethyl ether-methylene chloride (3:l) and excess cold dilute hydrochloric acid. The organic phase is separated, -5 washed, with bri ne, dried, and concentrated fo the title compound- 3.5 g. .- ...- ·.

. ., . Example 28 9-Deoxy-6,go-epoxy-PGF:, Methyl. Ester, 11,15Diacetate, More Polar Isomer.

-Acetic anhydride (5 ml.) and pyridine (5 mi.) are mixed 10 wi th 9-deoxy-5,9 Following the procedure of Example 28 but replacing ; the acetic anhydride with propionic anhydride, isobutyric anhydride, and hexanoic acid anhydride, there are obtained the correspond!ng digropionate, diisobutyrate and dfhexanoate derivatives of 9-deoxy-S,9®-epoxy-PGFi, methyl ester. Examp 1e 29 9-Deoxy-6,9a-epoxy~2,3-dinor-PGFi, Methyl Ester, less polar isomer. 1.- Refer.to Charts B and E. There is first prepared the formula-XLl hydroxyethyl compound. The less polar isomer of 9-deoxy-6,9a-epoxy-2,3,4-trinor-PGFi, methyl ester, formula XXXIX (Example J, 0.50 g.) is treated with 1.5 ml. of dihydropyran in 5 ml. of methylene chloride .120 4660 together with 0.5 ml. of a saturated pyridine hydrochloride solution in methylene chloride at about 25° C. for l6 hr. There is added 30 ml. of ethyl acetate and the mixture is washed with water and brine. The organic phase is dried over magnesium sulfate and concentrated to yield 9-deoxy6,9a-epoxy-2,3,4-tri nor-PGFj., methyl ester, bis(tetrahydropyran-2-yliether, 0.75 g., having Rf 0.67 (TLC on silica gel in ethyl acetate-hexane (1:1)).

The above compound, in 8 ml. of diethyl ether, is 10 added to a slurry of lithium aluminum hydride (0.20 g, ) in mi. of diethyl ether and the mixture is stirred and heated at reflux for 2 hr. It is cooled, treated with 0.3 ml of water added cautiously, followed by 0,6 ml. of 30$ aqueous1 sodium hydroxide, stirred until gassing stops, then filtered. The filtrate is concentrated to yield the formula-XLI compound, namely 3,3a£,4,5,6,6a(3-hexahydro-5a(tetrahydropyran-2-yloxy)-2a-(2-hydroxyethyl)-4β-[(3S)-3(tetrahydropyran-2-yloxy)-trans-1-octenyl]2H-cyclopenta[b|furan, 0.70 g., having Rf 0.34 (TLC on silica gel in methanol-methylene chloride (5:95))· II. Step (a) of Chart E, to prepare compound LXXXVI.

A mixture of the product of part I (0.70 g.), 5.0 ml. of pyridine, and p-toluenesulfonyl chloride (0.40 g. ) is stirred at about 25° C. for 5 hr. The mixture is diluted with 50 ml. of diethyl ether, washed with cold dilute hydrochloric acid, water, cold dilute potassium carbonate , solution, and brine, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel (Merck 40-63 μ), eluting with ethyl acetate-hexane (4:6) to yield the formula-LXXXVI tosylate, 0.84 g. having 121 -. / :- 7 - 3 :.../ . 7 ·-- Rf ϋ.58 and 0.62 corresponding to tetrahydropyranyl epimers (TLC on si 1ica gel in ethyl acetate-hexane (4:6)).

III. Step (b) of Chart E, to prepare the tosylate free of THPblocking groups. A mixture of the product of part I I (0.84 g. ) in 18 ml. of acetic acid, 9 ml. of water, and 2 ml. of tetrahydrofuran is sti rred at 40° C. for 3.5 hr.

The mixture is cooled, diluted with 125 ml. of cold (-10° C.) ethyl acetate and washed with about 10« w/v sodium peroxide in an ice-water mixture, and brine, dried over magnesium sulfate, and-concentrated. The residue is chromatographed on si 1ica gel (Merck 40-63 μ), eluting with ethyl acetate, to yield the formula-LXXXVl! compound, namely 3,3aP,4,5,6,6.aP-hexahydro-4P-[(3S)-3-hydroxy-trans-l-octenyl ]5a-hydroxy-2«-(2-tosyloxyethy1)2H-cyclopenta[b]furan, 0.43 g., having Rf 0.37 (TLC on silica gel in ethyl acetate); NMR peaks at 7-71-7-85, 7-22-7-36, 5.38-5.52, 3-63-4.23, and 2.38 δ; and mass spectral peaks at 525.2138, 596, 581, 506, 435, 409 , 390, 173, 155, and 91.

IV. Step (c) of Chart E, to prepare the formula20 LXXXVITI nitrile. A mixture of the product of part III (0,43 g.) and sodi urn cyani de (0.100 g.) 1 n 4.3 ml. of hexamethylphosphoramide is stirred at about 25° C. for 20 hr. The mixture is then diluted with 30 ml. of ethyl acetate, washed with water and brine, dried, and con2y centrated. Further washing of the residue redissolved in ether, with brine, removes traces of hexamethy1 phosphor amide. The ether solution is dried and concentrated .to yield the formula-LXXXVl11 nitrije, 0.30 g,, having Rf O.5I (TLC. on silica gel in acetone-methylene chloride (1-.1)); NMR peaks at 5.41-5.53 and 3.72-4.35 δ; and mass 122 4S604 . μι.ι .. ru I peaks al '»·, *. . A^j, D’i'-ι )J., )2+, - Ί. _O“» 199, and 173.

V. Step (d) of Chart E, to prepare the formulaLXXXIX acid. A mixture of the product of part IV (0.30 g. ), 3 mi. of 30# aqueous potassium hydroxide, and 3 ml. of methanol is stirred while heating up to 100° C. in 4 hr., allowing the methanol to escape, then at 100° C. for additional 3 hr. The mixture is cooled, acidified with cold dilute hydrochloric acid, and extracted with 30 ml. of ethyl acetate. The organic phase is washed with brine, dried, and concentrated to yield the formula-LXXXIX acid, namely 9-deoxy-6,9a-epoxy-2,3-dinor-PGFi, 0,24 g,, having Rf 0.39 (TLC on silica gel in acetone-methylene chloride (1:1) containing 1# acetic acid); NMR peaks at 6.48, 5.42-5.55, and 3.63-4,35 δ; and mass spectral peaks at 542.3244, 527, 524, 471, 452, 381, 362, 355, 557, 291, 175, and 173.

VI. Step (e) of Chart E,. to prepare the formula-LU methyl ester. The product of part V (2.5 mg.) is .treated in ether solution with excess diazomethane for 5 min., thereupon removing the ether and excess diazomethane with a stream of nitrogen. The residue is chromatographed on silica gel (Merck 63-200 μ), eluting with acetone-methylene chloride (l:l), to yield the title compound, 1.5 mg., having Rf 0.54 (TLC on silica gel in acetone-methylene chloride (1:1)).

Example 30 9-Deoxy-6,9a-epoxy-2,3-dinor-PGFi, Methyl Ester, more polar isomer.

I. Refer to Charts B and E. Following the procedures of Example 29 but replacing the less polar isomer of the 'jO formula-XXXIX starting material with the more polar isomer 123 -45604 /-. - - - Λ of- 9-deoxy-6,9a-epoxy-2,3,4~trinor-PGFi, methyl ester (Example 3, 0.25 g.) and reducing other quantities proportionally, there is.obtained first the correspond!ng more polar bis-THP ether, 0.37 g., having Rf 0.59 (TLC on silica gel in ethyl acetate-hexane (lsl)), and then the more polar formula-XLI hydroxyethyl compound, 0.34 g., having Rf 0.38 (TLC on silica gelfin ethyl acetate-hexane (3:1)).

II. Tosylate LXXXVI is obtained, 0.43 g., having Rf . 0.57 and 0.6l corresponding to tetrahydropyranyl epimers (TLC on silica gel in ethyl acetate-hexane (4:6)).

III·. Tosylate LXXXVII, free of THP blocking groups, is obtained, as the more polar isomer, 0.29 9·, having Rf 0.33 (TLC on silica gel in ethyl acetate), NMR peaks at 7.73-7,87, 7.26-730, §34-6.57, 3.63-4.54, and 2.42 6; and mass spectral data simi lar to that for the less polar isomer of Example 29-,111.

IV. . Ni tri le LXXXV 1ΪΪ is obtained, as the more polar isomer; 0.21 g,, having Rf 0,50 (TLC on silica.gel in . acetone-methylene chloride 1:1)); NMR peaks at 534-5.57 20 and. 332-4.67 δ; and mass spectral peak at 451.2953, otherwise similar to data for the less polar isomer of Example 29-IV. .

V. . Acid LXXXIX as the more polar isomer, is obtained, 0.l8 g., having Rf 0.32 (TLC on silica gel in acetone25 methylene chloride (lsl) containihg acetic acid; NMR peaks at 6.50, 535-5.58, and 339-4.56 δ; and mass spectral peak at 5*2.3292, otherwise similar to data for the less 1 polar isomer of Example 29-V.

VI. Methyl ester LII (or IV) is obtained, namely the >0 title compound, more polar isomer, 1.5 mg. from 2.0 mg. of 124 4ΰ6 0,Λ the acid, having Rf 0.4-9 (TLC on silica gel in acetonemethylene chloride (1:1)).

- Preferred compounds of the invention other than those exemplified above are the methyl ester, the sodium salt and the amide of each of 2,2-difluoro-9-deoxy-65,9a-epoxy-13,14dihydro-U-phenyl-lSJP-ZO-trinor-PGF^ and the 2,2-difluoro-9deoxy-δς,9a-epoxy-13,-4-di hydroxy-16-phenoxy-17,18,19,20tetranor-PGF^.

Claims (51)

1. A cyclicether of the formula wherein L’ Is (1) a valence bond, 5 (2) - (CHg) g - wherein d is an integer of from one to 5, : (3) -(CHgj^-CFg- wherein t is 2, 3, or 4, (4) -(CH 2 ) p -CH = CH - (CH 2 ) h wherein h is zero, one, 2 or 3 and p is zero or one, or _ 10 (5) -CH 2 -0-(CH 2 ) k - ' wherein k is one, 2 or 4; wherein (i) Q‘ and Q together are oxo, of one to 4 carhon atoms (ii) Q' and Q are both hydrogen, or (iiij one of Q‘ and Q is hydrogen or alkyl and the other is hydroxy; wherein ch 2 126 wherein R 2g is ω - CR 5 R 6- C g H 2g~ CH 3 wherein CgHgg is alkylene of one to 9 carbon atoms, with one to 5 carbon atoms in the chain between -Cf? 5 Rg- and the terminal methyl, 5 and R g and R g are the same or different and are each hydrogen, alkyl of one to 4 carbon atoms or fluorine, with the proviso that -CR g R g is not -CFAlkyl-; wherein Z is -0- or Cjfty wherein CjHgj is a valence bond 10 or alkylene of one to 9 carbon atoms optionally substituted with one to 2 fluorine atoms, with one to 6 carbon atoms in the chain between -CR g Rg- and the phenyl ring; wherein T is alkyl or alkoxy of one to 4 carbon atoms, fluorine, chlorine or tri fl uoromethyl and s is zero, one, 2 or 3 , with 15 the provisos that not more than two T’s are other than alkyl and that when s is 2 or 3 the T’s may be the same or different; and wherein R g and R g are as defined above with the proviso that neither R g nor R g is fluorine when Z is -0-; or (3) -cis-CH 2 —CH = CH ~CH 2 CH 3 ; 127 4.36 0 4 wherein R^g is (1) -COOR-jg wherein R 19 is hydrogen, a-pharmacoTogicaTly acceptable cation, alkyl of one to 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, phenyl substituted with 5 one, 2 or 3 chlorine atoms or alkyl radicals of one to 4 carbon ' atoms, £- (jo 1 -acetamidobenzamido)phenyl, jJ-benzamidophenyl, £-acetamidophenyl, £-0reidophenyl, £-semicarbazonomethylphenyl, 2. -naphthyl or -CHR 3g - C0R 34 wherein R 34 is phenyl·, jj-hrompphenyl, j)-biphenylyl 5 £-nitrophenyl, .10 - p-benzaminophenyl or 2-naphthyl and R 3g is hydrogen or· benzoyl, (2) -CHgOH, (3) -CH 2 N(R 18 ) 2 wherein the P-jg’ s are the same or different and are each hydrogen, alkyl of one to 12 carbon atoms, phenyl or benzyl, . (4) -C0N(R-jg) 2 wherein the R 18 J s are as defined above, or (5) tetrazolyl; wherein X is trans-CH = CH-, cis-CH = CH-, -C» C-, or -CHgCHg-; and wherein *·'-’ indicates attachment in alpha or beta configurations and alkanoates thereof which are derived from alkanoic acids of 2 to 8 carbon atoms; with the overall proviso that, .when L is -CH = CH-(CH 2 )^ - wherein h is as defined above, then R 2g is not cis-CH 2 -CH' B CH-CHpCHg and/or Q 1 and Q together are not oxo.

2. A compound as claimed in claim 1 wherein X is 25 trans-CH = CH-.

3. A compound as claimed in claim 1 wherein X is cis-CH=CH-. 128

4. A compound as claimed in claim 1 wherein X is -0» C-.

5. A compound as claimed in claim 1 wherein X is -CH 2 CH 2 -.

6. A compound as claimed in any preceding claims wherein Q‘ is hydrogen and Q is hydroxy.

7. A compound as clained in any of claims 1 to 5 wherein Q 1 is methyl and Q is hydroxy.

8. A compound as claimed in any of claims 1 to 5 wherein 0' and Q are both hydrogen.

9. A compound as claimed in any preceding claims wherein L 1 is a valence bond or -(CH^- wherein d is as defined in claim 1.

10. A compound as claimed in claim 9 wherein L' is a valence bond. n. A compound as claimed in claim 9 wherein 1? is methylene 12. A compound as claimed in claim 9 wherein L' is ethylene. 13. A compound as claimed in claim 9 wherein L' is trimethylene.

11. 14. A compound as claimed in any of claims 1 to 8 wherein L 1 is -CH = CH-(CH 2 )j 1 ~ wherein h is as defined in claim 1.

12. 15. A compound as claimed in claim 14 wherein L 1 is trans-CH=CH-.

13. 16. A compound as claimed in any of claims 1 to 8 wherein L‘ is -(CHg - 0 -(CHgJfc wherein k is as defined in claim 1.

14. 17. A compound as claimed in any of claims 1 to 8 wherein L' is 1 (CH 2 ) t -CFg wherein t is as defined in claim 1. 129 4 56 G 4 '5

15. 18. A conipound as claimed in any preceding claim wherein R 25 is n-pentyl. _

16. 19. A compound as claimed in any of claims 1 to 17 wherein R 25 is 1,1-dimethylpentyl.

17. 20. A compound as claimed in any of claims! to 17 wherein R 25 is phenethyl.

18. 21. A compound as claimed in any of claims 1 to 17 wherein R 28 is phenoxymethyl.

19. 22. A compound as claimed in any preceding claims wherein K 30 is -COORIjq wherein R^ is as defined in claim 1.

20. 23. A compound as claimed in any of claims 1 to 21 wherein Rg 0 is -C0N(R lg )0 2 wherein each R^ 8 is as defined in claim 1.

21. 24. A compound as claimed in any preceding claims wherein R 2Z is V

22. 25. 9-0eoxy-6?,9tt-epoxy-2,3,4-trinor-PGF^i methyl ester, less or more polar isomer.

23. 26. 9-Deoxy-66,Sa-epoxy-2,3,4-trinor-PGF^, ethyl ester, 20 less or more polar isomer. 130

24. 27. 9-Deoxy-6g,9 a -epxoy-2,3-dinor-PGF^, methyl ester, less or more polar isomer.

25. 28. 9-Deoxy-65,9a-epoxy-2,3-dinor-PGFp less or more polar isomer.

26. 29. 9-Deoxy-65,9oi-epoxy-2-nor-PGFp methyl ester, less or more polar isomer.

27. 30. 9-Deoxy-6S, 9a- epoxy-PGFp methyl ester, less or more polar isomer.

28. 31. 9-0eoxy-6£, θα-epoxy-PGF^, less or more polar isomer.

29. 32. 9-Deoxy-65,9a-epoxy-PGFp ΪΗΑΜ salt, more polar isomer.

30. 33. 9-Deoxy-65,9a-epoxy-PGFp amide, less or more polar isomer.

31. 34. 9-Deoxy-6,9a-epoxy-PGFp methylamide, less or more polar isomer.

32. 35. 9-Deoxy-6,9it-epoxy-PGF^, benzylamide, less or more polar isomer.

33. 36. 9-Deoxy-6,9a-epoxy-PGF^, anilide, less or more polar isomer.

34. 37. 9-0eoxy-65,9a-epoxy-16,16-dimethyl-PGFi,

35. 38. 9-Deoxy-65,9a-epoxy-17-phenyl-18,19,20-trinor-PGF^, methyl ester, less or more polar isomer.

36. 39. 9-Deoxy-3,4-trans-didehydro-6g,9a- epoxy-2-nor-PGF^, ethyl ester, less or more polar isomer.

37. 40. 9-Peoxy-3,4-trans-didehydro“6g,9a-epoxy-17-phenyl2,18,19,20-trinor-PGF^ methyl ester, less or more polar isomer.

38. 41. 9-Deoxy-K .ga-epoxy-S-oxa-PGF^, methyl ester, less or more isomer. 131

39. 42.. 9-Deoxy-5? s 9a-epoxy-l5(5)-15-rcethyl-PG^, less or more polar isomer. _ .,

40. 43. 9-De0xy-5?>9tt-epoxy-15(S)-15-methyl-PGFp amide more polar isomer.

41. 44. 9-Deoxy-6? 5 9 i a-epoxy-13,14-dihydro-PGF|, methyl ester, less or more polar isomer.

42. 45. : ' 2,2 - Difluoro.- 9 - deoxy - 6ξ, 9« -epoxy - 13,14 dihydro - 17 -phenyl .- 18, 19,20 -trinor -..PGFp : methyl-ester.

43. 46.. 2,2 - Oi fluoro - 3 - deoxy - 6ς, 9» - epoxy-I3,14-dihydro-17’ ,---’ . - phenyl18, 19 , 20 - trinor - PGFp sodium salt.

44. 47. 2,2 - Difluoro - deoxy - 6ξ, 9α - epoxy - 13,14 - dihydro -17- phenyl - 18,19,20- trinor - PGFp amide.

45. 48. / 2,2 - Difluoro - 9 - deoxy - 6ξ, 9«- epoxy -13,14 - dihydro16-phertoxy-17,18,19,20-tetranor-PGFp methyl ester,

46. 49. 2,2-Difluoro-9-deoxy-6?,9a-epoxy-l3,14-dihydro-16-phenoxy17.18.19.20- tetranor-PGF.j, sodium Salt,

47. 50. 2,2-Difluoro-9-deoxy-6g,9a-epoxy-13il4-dihydro-16-phenoxy17.18.19.20- tetranor-PGF|, amide.

48. 51. 9,15-Dideoxy-6g,9a-epoxy-13,14-dihydro-PGF 1 , methyl ester.

49. 52. A process for the preparation of a compound as claimed-.in claim 1 substantially as herein described with reference to any of the Examples.

50. 53. A compound as claimed in claim 1 when prepared by a process according to claim 52.

51. 54. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 51 and 53 pharmaceutically acceptable carrier.