IE45266B1 - Prostaglandins - Google Patents

Description

This invention relates to prostaglandin derivatives and to their preparation.

According to a first aspect of the present invention there are provided novel optically active compounds of the formula and mixtures of the enantiomers thereof, whereir either A is a or c-hydroxy, oxo, methylene, hydrogen or α-hydroxymethyl, in which case the dotted carboncarbon double bond is absent, or A is absent and the dotted carbon-carbon double rend is present; L is (1) -(CHp) wherein a is zero or an integer of from one to 5 snd P? and Rg are each hydrogen, methyl or fluorine with the proviso that -CR,Rg- is not -CFMe-, (2) -CHg-O-fCHg)wherein k is one, 2 or 3, or (3) -CHg-CH -CH-; Q, and q2 are butti hydrogen or Q- and Og together are oxo or one of ζ. and Qg is hydrogen or alkyl of one to 4 caroon atoms -md the other is hydroxy; Rj is (1) -CH-CH, (2) -CRgfiRgRjQ wherein Rg and Rj0 are each hydrogen or alkyl of one to 4 carbon atoms, (3) 5-tetrazolyl, of (4) CGilRg wherein Rg is hydrogen, alkyl of one to 12 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; aralkyl of 7 to 12 carbon atoms; phenyl; phenyl substituted one, 2 or 3 times by chlorine atoms or alkyl radicals of one to 4 carbon atoms; * 'ί:;· -D-NH-CO-D-NH-COCHj, -D-NH-COPh, -D-NH-COCHg, -D-NH-CONHZ or -D-CH»N~NH-CONH2 wherein D is 1,4-phenylene; 2-naphthyl; -CHR-^-COR-jg wherein is phenyl, £-bromophenyl, j>-biphenylyl, j>-nitrophenyl, £-benzamidophenyl or 2-naphthyl and is hydrogen or benzoyl;· or a pharmacologically acceptable cation; R^ is (1) -CRgRg-CgUzg-CHg wherein Rg and Rg are each hydrogen, alkyl of one to 4 carbon atoms or fluorine with the proviso that -CRgRg- Is not -CFAlkyl- and CgHgg is alkylene of’one to .9 carbon atoms with one to 5 carbon atoms in the chain between -CRcRfi- and the terminal methyl, ZTTtx-COg (2) -CRgRg-Z-/' wherein .2 is an oxygen atom, a valence bond or alkylene of one to 9 carbon atoms with one to 6 carbon atoms in the chain between -CRgRg- and the benzene ring, Rg and Rg are as defined above with the proviso that neither Rg nor Rg is fluorine when 2 is an oxygen atom, T is hydroxy, alkyl or alkoxy of one to 4 carbon atoms, fluorine, chlorine or trifluoromethyl and s is zero, one, 2 or 3 provided that when s is 2 or 3 not more than two T's are other than alkyl and the T's are the same or different when s is 2. or 3, or (3) -CH,'-cis-CH=CH-C3Hg; n is zero or one and h is one or 2; X is' trans-CH=CH-, cis-CH=CH-,-C=C- or -CHg-CHg-j and a? Indicates attachment in cis or trans configuration.

According to a second aspect of the present invention, there are provided novel optically active compounds of the formula and mixturso of the enantiomers thereof, wherein either E is a- or g-CR^j, oxo, methylene, hydrogen or u-CHgOR^-, in which case the dotted carbon-carbon double bond is absent, or B is absent and the dotted carbon-carbon double bdnd is present, wherein is hydrogen, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or a group or the formula H ’ J i ί r> . - c ... r> . ... ... - C Λ-, R1S IS wherein is alkyl of one to 18 carbon atoms, cyeloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl or phenyl sebstit: ted one, 2 or 3 times by alkyl radicals of one to 4 carbon atoms; either and are each hydrogen, alkyl of one so 4 carbon atoms, phenyl or phenyl substituted cne, 2 or 3 times by alkyl radicals of cne to 4 carbon atoms or R15 and P<16 are taken together and are -(CH-j..- wherein a is 3, 4 or 5 or - (CHg) ^-0-(CHg) c~ wherein b and c are each one, 2 or 3 with the proviso that b ~ c is 2, 3 or 4;and R,? is hydrogen or phenyl; and L, QpQg’ Ri» P4’ h» n and x ara as defined above.

According to s third aspect of the present invention, there are provided novel optically active compounds of the formula *4 I and mixtures of the enantiomers thereof, wherein B, L, Q·^, Q2, Rj, R^, h, η, X and are as defined above. ' According to a fourth aspect of the present invention, there are provided novel optically active compounds of the formula -5and mixtures of the enantiomers thereof, •jθ wherein B, L, Qp Q2s R^, h, n and X are as defined above.

The compounds of the invention are (a) PGF^ compounds when A/B is α-hydroxy, (b) Ιΐβ-PGF^ compounds when A/B is B-hydroxy, (c) ll-deoxy-ll-oxo-PGFK compounds when A/B li is oxo, (d) ll-deoxy-ll“methylene-PGFK compounds when A/B is methylene, (e) 11-deoxy-PGF compounds when A/B is hydrogen, < - 45263 (£) 11-deoxy- 10,ll-didehydro-PGFK compounds when A/B is absent and the dotted carbon-carbon bond is present, and (g) ll-deoxy-ll-hydroxymethyl-PGFa compounds when A/B is hydroxymethyl.

An example of the compounds of formula I a is 9-deoxy-6,9-epoxy-5-iodo~BGFln , viz. when B is ot-hydroxy, L is is hydrogen, Q2 is hydroxy, Rj is COOH, R4 is n-pentyl, h is one, n is zero and X is trans-CHaCH-. The analogous compounds of formulae!!!, Ilia and IVa are 9-deoxy-6,9-epoxy-i 5-PGFjffl,9-deoxy-6,9-epoxy-6-hydroxyPGFja and 6-oxo-PGFja ,respectively.

In the compounds of formula II, the wavy line indicates attachment in cis or trans configuration relative to the (CH-J^-C bond. In the above formulae, IS is bonded to the cyclcpentane ring at the C-8 position, (CH2)n at the C-9 position and X at the G-12 position.

In compounds of formula Ilia,indicates attachment of -OH in alpha or beta configuration.

The formula II enol ethers are named as derivatives of PGF2a,regardless of the variations in either of the side chains, h and n in the heterocyclic ring, or the nature of A, following the conventions known and used in the prostaglandin art. The formula Ilia 6-hydroxy compounds (hemi-ketals) and the formula IVa 6-keto compounds are named 2ς as derivatives of PGFja· -64$ Examples of alkyl of one to 12 carbon atoms, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and isomeric forms thereof. Examples of cycloalkyl of J to 10 carbon atoms, which includes alkyl-substituted cycioalkyl, are cyclopropyl, 2-methylcyclopropyl, · 2.2- dlmethylcyclopropyl, · ‘ 2.3- diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2- methy1cycl obuty 1, \ 5-propyl cyclobutyl, 2,3,4-tr1ethy1 cyclobutyl, cyclopentyl, 2,2-di methyl cyclopentyl, 3- pentyl cyclopentyl, 3“tert-buty1 eyelopenty1, cyclohexyl, I 4-tert-butyIcyclohexyi, 3-lsopropyIcyclohexyi, 2,2-di methylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, . and cyclodecyl. -7ν- ά2ββ Examples of araIk/1 of 7 to 12 carbon atoms benzyl, phenethyl, 1- phenylethyl, 2-phenyIpropy 1, 4-phenylbutyl, 3- pheny!butyl, 2- (l-n3phthylJethyl and (2-nsphthy’Jmefhyi.

Examples of phenyl substituted by one to 3 times &y chlorine atoms or alkyl radicals of one to 4 carbon atoms p-chlorophenyl, m-chlorophenyl, o-ch1orophenyl, 2,4-dichlorophenyl, 2,4,6-tri chlorophenyl, p-tolyl, m-tolyl, o-tolyl, 2C p-ethylphenyi, p-tert -butyIpheny 1. 2,5'dimethylphenyl, 4- ch1oro »2-methy i pheny1, and 2,4-dichloro-3-methylpheny1.

L8G The products of formula II and the onhlocked products of formulae lAs Ilia and IVa (i.e. when B is equivalent to A’as defined above 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, systemic blood pressure Towering, inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systemic administration of prostaglandin synthetase inhibitors.

Because of these biological responses, the known prostaglandins are useful to study, prevent, control, or alleviate a.wide variety of diseases and undesirable physiological conditions in mammals, including humans, use15 ful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys. 'These compounds are useful whenever it is desired to inhibit platelet aggregation, 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 post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as - atherosclerosis, 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 ·. ϊ32Έ(ί 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 IG 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 admin10 istrati on.

The addition of these compounds to whole blood provides in vitro applications such as, storage of whole blood to be used >n heart-lung machines. Additionally whole blood containing these compounds can be circulated through organs, e.g. heart and kidneys; which have been removed from a donor and prior to transplant. Also useful in preparing platlet rich concentrates for use in treating thrombocytopenia, cbemotherapv, and radiation therapy. In vitro applications utilize a dose of 0,001-1.0 ug/ml of whole blood. 2q These compounds are extremely potent in causing stimula tion of smooth muscle, and are also highly active in potentiating other known smooth muscie stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alka· loids including derivatives and analogs thereof. Therefore. £5 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 or the placenta, and during the puerperium. For the latter purpose, the compound is ζ?'** Λ S ί/ ο- V u administered by intravenous infusion immediately after abortion or delivery at a dose of 0.01 to 5θ U9· per kg. °f body weight per minute until the desired effect is obtained. Subsequent does are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range, of 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.

These compounds are useful as hypotensive agents to 10 reduce blood pressure in mammals, including man. Fpr this purpose, the compounds are administered by intravenous infusion at the rate of 0.01 to 50 pg. per kg. of body weight per minute or in single or multiple doses of .25 to 500 pg. per kg. of body weight total per day.

These prostaglandin derivatives are as 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 purpose, these compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range of 0.1 pg. to 20 pg. 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.

These compound are also useful in reducing the un30 desirable gastrointestinal effects resulting from systemic i S 2 ΰ· 6 administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the prostagiandin derivative and the antiinflammatory prostaglandin synthetase inhibitor. U.S.

Patent Specification No. 3,781,429 discloses that the ulcerogenic effect induced by certain non-steroida, anti -i nHammatory agents in rats is inhibited by concomitant oraiadiministrati on of certain prostaglandins of the E and A series, including PGEi, PGE2, PGEa, 15,l4-dihydro-PGEi, and the corresponding 11-deoxy-PGE and PGA compounds. Prostaglandins are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned iri U.S. Patent Specification No. 3,781,429 as nnn-steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.

The ant’-inf lammatory synthetase i nhi bi tor, for example indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known r.outes of systemic administration.

The prostaglandin derivative 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 anti-inflammatory substance is being administered orally, the prostaglandin derivative 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. 3.545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the prostaglandin 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 prostaglandin derivative, to combine both into a single dosage form.

The dosage regimen for the prostaglandin derivative 10 in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex 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 prostaglandin derivative to be administered, for example, not every human in-need of an 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 administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of the prostaglandin derivative to reduce and then substantially to eliminate those undesirable effects.

These 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 act!50 vated by an antigen-antibody complex. Thus, these comΛ w 2 ί> Ο pounds 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 ug . per kg. o'f 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 these prostaglandins can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine and ephedrine); xanthine derivatives (theophylline and aminophy11ine); and corticosteroids (ACTH and prednisolone).

These compounds are effectively administered to human asthma patients by oral inhalation cr by aerosol i nhalation.

For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute solution, preferably at concentrations of 1 Part of medicament to form 100 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 ο citrate, citric acid and/or sodium bisulfite can be employed · For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suita5 ble for inhalation therapy the composition can comprise the active ingredient suspended, in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can a-lso be used d dispersing agent such as oleyl alcohol. Suitable meads to employ the aerosol inhalation, therapy technique are described fullyr for'example, in U.S. Patent Specification No. 2,868,691 These compounds are useful in mammals, including man, as nasal decongestants and are used for this purpose in a dose range of 10 pg. to 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

These 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, artheriovenous fistulas, ischemic leg ulcers, phlebitis, venous insufficiency, gangrene, hepatorenal syndrome, ductus arteriosus, non-obstructive mesenteric ischemia and arteritis lymphangitis. For these conditions the compounds of this -_.ίί263 invention are administered orally or parenterally via injection or infusion directly into a vein or artery, intra-venous or intra-arterial injections being preferred. The dosages of these compounds are in the range of 0.01-1.0 ug./kg. 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 affects are observed.

These compounds are 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 No. 74/0149 referenced as Derwent Farmdoc No. 58,4001/.

See Elliott- et ai.. Lancet, January 18, 1975, pp. 140-142.

These compounds are useful in place of oxytocin to induce labour 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 20 weeks to term. For this purpose, the compound is in16 fused intravenously at a dose of 0.01 to 50 ug. pe.r 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 labour 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.

These compounds are further useful for regulating the reproductive cycle in menstruating female domestic animals and livestock 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 ihe prostaglandin derivative is administered systemically at a dose level of 0.01 mg. to mg. per kg. of body weight of the 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 alternative methods of administration. .

These compounds are further useful In causing cervi cal dilation in pregnant and nonpregnant female mannals 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 com3ΰ2«<: pounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostaglandins 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 prostaglandin derivative is administered locally or systemically.

The prostaglandin derivative, for example, is administered orally or vaginally at a dose 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 a dose of one to 25 mg. per treatment. The exact dosages for these purposes depend on the age, weight, and condition of the patient or animal.

These compounds are further useful in domestic animals as an abort!facient (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 mors efficient management of both concepti'on and labor by enabling the herdsman to breed all his femals in short, pre-defined intervals. This synchronization results in a higher percentage of .live births than the percentage achieved by natural control. The prostaglandin is injected or applied in a feed at doses of 0,1-100 mg. per animal and may be combined with other agents such as steroids. Dosing schedules will depend on the species -IS- ί* ,S 3 6 6 treated. For example, mares are given the prostaglandin derivative 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. g These 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. Illus10 tratively, 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 a dose of 10 to 1000 pg. per kq. of body weight or by intravenous infusion at a dose of 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 2Q 2 mg. per kg. of body weight per day.

These prostaglandin derivatives are useful for treating proliferating skin diseases of man and domesticated animala, 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 -0 animals. These compounds alleviate the symptoms of these _iqλ ΰ 2 G 3 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. b For these purposes, these compounds are applied topically as compositions including a suitable pharmaceutical carrier, for example as an ointment, lotion, paste, jelly, spray, or aerosol, using topical bases such as petrolatum, lanolin, polyethylene glycols, and alcohols. These compounds, as the active ingredients preferably constitute from 0.1% to 15% by weight of the composition, more preferably from 0.5% to 2%.

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

These compounds are useful as anti-flammatory agents for inhibiting chronic inflammation in mammals including the swelling and other unpleasant effects thereof using methods of treatment and dosages generally in accord with U.S. Patent Specification No. 3,885,041. 4326S A pharmaceutical composition according to the invention comprises a compound of formula I, II, III or IV in association with a pharmaceutically acceptable Carrier.

Methods for the preparation of compounds of the 5 invention will now be described.

The formula I compounds (those of formula la in which B = A) may he prepared by iodinating and cyclising a compound of the formula XIII wherein A, L, Qj, Q2, Rp R^, n, h and X are as defined above. The starting materials of formula XIII are known in the art or are readily available by processes known in the art. For example, as to PGF2a , see U.S. Patent Specification (hereinafter abbreviated to USPS) No. 3,706,789; as to -methyl- and 15-ethyl-PGF2ot, see USPS 3,728,382; as to 16,16dimethyl-PGF2a, see USPS 3,903,131; as to 16,16-21* ΰ 2 6 J difluoro-PGFga compounds, see U.S. Patent Specifications Nos. 3,962,293 and 3,969,380; as to 16-phenoxy-17-18,19,20tetranor-PGF2fl(, see Derwent Farmdoc No. 73279U; as to 17-phenyl-18,19,20-trinor-PGF2a, see Derwent Farmdoc 5 No. 31279T; as to 11-deoxy-PGF2a> see Derwent Farmdoc No. 10695V; as to PGDg, see U.S. Patent Specification No. 3,767,813: as to 2a,2b-dihomo -PGFgjj» see Derwent Farmdoc No. 61412S and U.S. Patent Specifications Nos. 3,852,316 and 3,974,195; as to 3-oxa-PGFga, see U.S. Patent Specification No. 3,923,861; as to 3-oxa-17-phenyl-18,19,20-trinor-PGF2a, see U.S. Patent Specification No. 3,931,289; as to substituted phenacyl esters, see Derwent Farmdoc No. 16828X; as to substituted phenyl esters, see U.S. Patent Specification No. 3,890,372; as to C-l alcohols, i.e. 2-decarboxy-2-hydroxymethyl compounds, see U.S. Patent Specification No. 3,636,120; as to C-2 tetrazolyl derivatives, see U.S. Patent Specifications Nos. 3,883,513 and 3,932,389; as to A2-PGF2u( see Derwent Farmdoc No. 46497W and German Offenlegungsschrift 2,450,285; as to 2,2-dimethylPGF2a ana^°9s» see Derwent Farmdoc No. 59.033T and German Offenlegungsschrift No. 2,209,039; as to 9-deoxy-9-hydroxymethyl-PGF2a, see U.S. Patent Specification No. 3,950,363; as to 11f?-PGF2a compounds, see U.S.

Patent Specification No, 3,890,371; as to 11-deoxy-PGF2a> see Derwent Farmdoc No. 10695V; as to 11-deoxy-11-hydroxymethyl -PGFga’ see U-S. Patent Specifications Nos. 3,931^82 and 3,950,363; as to 16-methylene-PGF2a, see Derwent Farmdoc No. 19594W and German Offenlegungsschrift No, 2,440,919; as to 17,18-didehydro-PGF2a compounds, see U.S. Patent Specification No. 3,920,725; as to 3-(or 4-) oxa-17,18-didehydro-PGF2a compounds, see U.S. Patent Specification No. 3,920,723; as to T5-oxo-PGF2c(, see U.S. Patent Specification No. 3,728,382 as to 15-deoxy-PGF2a, see Derwent Farmdoc No. 9239W; as to 13,14-cis compounds, see U.S. Patent Specification No. 3,932,479; as to 11-deoxy-15-deoxy-PGF2a see Derwent Farmdoc No. 5694U; as to ui-homo-PGFg^ compounds, see Derwent Farmdoc No. 4728W; and as to 2,2-difluoro10 PGF2a compounds, see Derwent Farmdoc No. 67438R.

As to 2-decarboxy-2-amino-PGF2a compounds, see British Patent Specification No. 1,554,041, For the iodination and cyclization reaction, either an aqueous system containing iodine, potassium iodide, and an alkali metal carbonate or bicarbonate, or an organic solvent system such as dichloromethane containing iodine in the presence of an alkali metal carbonate, is used. The reaction is carried out at temperatures below 25°C., and preferably 0-5°C. for 10-20 hours. Thereafter 20 the reaction is quenched with sodium sulfite and sodium carbonate and the formula I compound^separated from the reaction mixture.

The 6-oxa-compounds of formula IV (equivalent to formula IVa when B = A) may be prepared by contacting a formula I compound with silver carbonate and perchloric acid. The reaction is carried out in an inert organic medium such as tetrahydrofuran and is followed with TLC to determine completion, normally in 15-24 hours at about 25°C. The reaction is preferably carried out in absence 30 of light.

The 5-oxo compounds IV may then be equilibrated in solution to a mixture of the formula HI a°d formula IV compounds. This is accomplished merely by preparing a solution of the formula IV compound in an organic solvent, e.g. acetone or dichloromethane, and letting it stand for several days. The resulting mixture is concentrated and separated, for example by silica gel chromatography, to yield the formula III hemi-ketal.

In an alternative route to the formula III hemiketal, the formula I iodo compound is treated in alcoholic solution, e.g. methanol, with aqueous alkali metal hydroxide, e.g. potassium hydroxide, at a temperature in the range of 0° to 30°C. for several hours. After acidification there is obtained a mixture of the acid form of the formula I compound and the formula III hemi-ketal together with some of the formula IV compound; these are separated, for example, by silica gel chromatography or by fractional crystallization.

The novel compounds of formulae 1,111 and IV wherein Rl is other than -COOH, e.g., the esters wherein Rj of -COOR3 is as defined above, are prepared from the corresponding acids of formulae I,III and IV, i.e., wherein R- is -COOH, by methods known in the art. For example, the alkyl, cycloalkyl, and aralkyl esters are prepared by interaction of said acids with the appropriate diazohydrocarbon. For Example, when diazomethane is used', the methyl esters are produced. Similar use of diazoethane, diazobutane, l-diazo-2-ethylhexane, diazocyclohexane, and phenyldiazomethane, for example, gives the ethyl, butyl, 2-ethylhexyl, cyclohexyl, and benzyl esters, respectively.

Of these esters, the methyl or ethyl is preferred. 2-63 Esterification with diazohydrocarbons is carried out by mixing a solution of the di azohydrocarbon 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 di azohydrocarbon be no longer-than Ιθ necessary to effect the desired esterification, preferablv 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)..

An alternative method for esterification of the carboxyl group of the compounds of formulae I, III and IV comprises transformations of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl, cyeloalkyl or aralkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tertbutyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide and phenethyl iodide. The silver salts * * are prepared by conventional methods, for example, by dis25 solving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding Lhe stoichiometric amount of silver nitrate. ί ΰ G The phenyl and substituted pheny] esters of the formulae I, ΠΙ and IV compounds are prepared by silylating tne acid to protect the hydroxy groups, for example, replacing each -OH with -0-Si-(CHg)3· Doing that may b also change -COOH to -CO0-5i-(CH3}3. A brief treatment of the silylated compound with water will change -COO-Si(CH3)3 back to -COOH. Procedures for this silylation are known 4r· the art and are discussed below. Then, treatment of the silylated compound witn oxalyl chloride gives the acid chloride which is reacted with phenol or the appropriate substituted phenol to give a silylated phenyl or substituted phenyl ester. Then the silyl groups, e.g., -0-Si-(Ch'3)3 are changed back to -OH by treatment with dilute acetic acid. Procedures for these transformat15 ions are known in the art.

The enol ethers of formula II may be prepared by contacting a formula I compound with a dehydroiodination reagent. For such reagents see, for example, Fieser and Fieser, Reagents for Organic Synthesis p. 1308, John Wiley and Sens, Inc., Hew York., N.Y. (1967).

Preferred dehydroiodination reagents in this invention are tertiary amines and reagents selected from sodium or potassium superoxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium 492θδ benzoate, · sodium or potassium acetate, sodium or potassium tri fluoroacetate, sodium or potassium bicarbonate, silver acetate, and a tetraalkylammonium superoxide of the formula (Ria^NOs wherein R12 is alkyl of one to 4 carbon J atoms.

Of the tertiary amines, preferred amines are l,5-diazabicyc1o[4.3.0]nonene-5 (DBN'’), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,5-diazabicyclo[5.4.0)undecene-5 (DBU).

Other preferred reagents are sodium or potassium superoxide and tetramethylammonium superoxide. For further information on the superoxides see Johnson an*1 Nidy, J. Org. Chem. 40, 1680 (1975). For larger scale preparation the electro15 chemical generation of superoxide is recommended. See Dietz ejt aj., J. Chem. Soc. (B), 1970, pp. 8l6-820, The dehydroiodination step is carried out in an inert Organic medium such as dimethylformamide and is followed by TLC to show the disappearance of starting material.

The reaction proceeds at 25° C. and can be accelerated at 40-50° C.

In working up the reaction mixture it is advantageous to maintain basic conditions, e.g. with triethylamine, to avoid acidic decomposition or structural changes of the product. Purification is achieved by crystallization and consequent separation from impurities or starting material left in the mother liquor, or by column chromatography. For chromatographic separation a column of magnesium silicate is preferred over silica gel. Decomposition of the product·is avoided by pretreating the column with triethylamine. j ΰ 3 o -J Ester groups such as the £-phenylphenacyl group on the C-l carboxyl are unchanged by the reactions involved in preparing the enol ethers, and, if present on the formula XIII starting material, are also present on the formula II product. For the final products of formula II which are esters the preferred method of preparation is from formula I iodo compounds which are corresponding esters.

Especially useful for administration because of their form as free-flowing powders and their ease of dissolving are sodium salts. They are obtained from the formula II esters by saponification with equivalent amounts of sodium hydroxide in a solvent, preferably an alcohol-water solution, thereafter lyophilizing (freezedrying) the mixture to obtain the powdered product. The starting esters are preferably alkyl esters, of which methyl or ethyl are especially preferred.

The preparation of the formula II enol ethers from the compounds of formula XIII via those of formula I followed by a separation step, using the conditions described above, constitutes a further aspect of this invention.

Another aspect of this invention lies in the preparation c of 9-deoxy-5,S-epoxy-A -PGF, , sodium salt, in free-flowing Itl powder form from the corresponding methyl ester using the method described in the preceding paragraph, i.e. removing solvent and water from the product of the reaction between a solution of the ester and an equivalent amount of sodium hydroxide.

In those instances where the blocked compounds of formulae Ila, Ilia and IVa are desired rather than the unblocked compounds of formulae II, III and IV, respectively, the latter may be suitably blocked with an R13 blocking group.

It should be understood that the procedural steps described above are intended to apply not only to all optically active isomers and cis/trans geometric isomers, but also to mixtures, including racemic mixtures or mixtures of enantiomeric forms.

If optically active products are desired, optically active 10 starting materials or intermediates are employed or, if racemic starting materials or intermediates are used, the products are resolved by methods known in the art for prostaglandins.

The products formed from each step of the reaction are often mixtures and, as known to one skilled in the art, may be used as such for a succeeding step or, optionally, separated by conventional methods of fractionation, column chromatography, liquid-liquid extraction, and the like, before proceeding.

To obtain the optimum combination of biological response specificity, potency, and duration of activity, certain compounds within the scope of formulae I-IV are preferred. For example it is preferred that Q-| is hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, and most preferably hydrogen, while Qg is hydroxy.

Another preference, for the compounds of formulas I, III, and IV, is that R^ is COORgj Rg is preferably either hydrogen or alkyl of one to 12 carbon atoms, e.g. hydrogen or methyl. It is further preferred that Rg is alkyl of one to 4 carbon atoms, especially methyl or ethyl, for optimum absorption on administration. For the compounds of formula II, it is preferred that Rg 1S not hydrogen but rather an alkyl ester or a salt of a pharmacologically acceptable cation.

For purposes of stability on long storage, it is also preferred that R3 is amido-substituted phenyl or substituted phenacyl, as illustrated herein.

A is preferably α-hydroxy, oxo or hydrogen. B is preferably oxo, hydrogen or a- 0R-j3 wherein R-j3 is as defined above, and more preferably α-hydroxy. R^ is preferably n-pentyl, 1,1-dimethylpentyl, 1,1-difluoropentyl, phenoxymethyl or phenethyl. L is preferably - (CH2)3-, - (CH2)4-, or - (CH2)5~, especially ~ (CH2)3-. h is preferably one. n is preferably zero.

The invention is further illustrated by, but not limited to, the following Examples.

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 A60, A-60D, or T-60 spectrophotometer in deuterochloroform solutions with tetramethylsilane as an internal standard. *Varian is a Registered Trade Mark.

Mass spectra are recorded on a Varian Model MAT CH7 Mass Spectrometer, A CEC Model Π0Β Double Focusing High Resolution Mass Spectrometer, or an LKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ev.). 263 All solvent proportions are by volume.

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

Skellysolve B, herein, refers to mixed isomeric hexanes.

DBN11, herein, refers to 1,5-diazabicyclo [4.3.0] nonene-5. DABCO, herein, refers to 1,4-diazabicyclo [2.2.2]octane.

“DBU, herein, refers to 1,5-diazabicyclo[5.4.0]undecene-5. DIBAL. herein, refers to diisobutylaluminium hydride.

*Florisil, herein, is a chromatographic magnesium silicate produced by the Floridin Co. See Fieser et al. Reagents for Organic Synthesis p. 393 John Wiley and Sons, Inc., New York, N.Y. (1967).

TLC, herein, refers to thin layer chromatography.

Silica gel chromatography, as used herein, is understood to include elution, collection of fractions, and combinations of those fractions shown by TLC to contain the desired product free of starting materials and impurities.

Concentrating, as used herein, refers to concentration under reduced pressure, preferably at less than 50 mm, and at temperatures below 25°C.

*Florisil is a trade mark. «*ϊ 6 6 Preparation 1 ll-Deoxy-10,ll-didehyo’ro-PGF2a, Methyl Ester and its 90-epimer; and 11-Oeoxy10,11-didehydro-PGF2Q and its 93-epimer.

A mixture of PGA2, methyl ester (1.74 g.) and 12 ml. of tetrahydrofuran is treated at -78° C. with 24 ml. of 10$ DIBAL in toluene. After one hour's stirring at -78° C, the mixture is quenched with 100 ml. of tetrahydrofuransaturated aqueous ammonium chloride (1:1) and warmed to about 25° C. The mixture is acidified with sodium bisulfate and extracted with ethyl acetate. The organic phase is washed with sodium bisulfate, sodium carbonate, and brine, dried over sodium sulfate, and concentrated to yield 1.8 g.

The crude product is subjected to column chromatography to separate the title compounds, in the order: ll-deoxy-10,11-didehydro-PGFsa, methyl ester· 11-deoxy-10,11-didehydro-PGFgg, methyl ester; ll-deoxy-10,11-didehydro-PGF2a, and 11-deoxy-10,11-didehydro· -pgf^· Example 1 9-Deoxy-6,9-epoxy-5-iodo-PGFia, Methyl Ester (Formula I: L is -(CHg)j-, R·, is -COOCHg, Rd is n-phenyl, A is a α-hydroxy, n is zero, h is one, X is trans-CH=CH-, Q, is hydrogen Q? hydroxy).

A suspension of the formula XIII PGF2a, ester as its 11,15-bis(tetrahydropyranyl)ether (2.0 g.) in 23 ml. of v/ater is treated v/ith sodium bicarbonate (0.7 g.) and cooled in an ice bath. To the resulting solution is added potassium iodide (1.93 g.) and iodine (2.82 g.) and stirring continued for 16 hours at about 0°C. Thereafter a solution of sodium sulfite (1.66 g.) and sodium carbonate (0.76g.) in 10 ml. of water is added. After a few minutes the mixture is extracted v/ith chloroform. The organic phase is washed with brine, dried over sodium sulfate, and concentrated to yield mainly the bis(tetrahydropyranyl)ether of the title compound, 2.2 g., an oil. Hydrolysis of this ether in acetic acid-watertetrahydrofuran (20.-10:3) yields mainly the title compound, which is further purified by silica gel chnomatography, Rf 0.20 (TLC on silica gel in acetone-dichloromethane (30:70)). The mass spectral peaks for the formula I compound (THS derivative ) are at 638, 623, 607, 567, 548, 511 and 477. 2Q . Following the procedures of Example 1, but replacing the formula XIII starting material with the following formula XIII compounds or their C-11 ethers, there are obtained the corresponding formula I iodo compounds: ·» υ 3 ϋ U -Methyl-PGF2(i 15-Ethyl-PGF2a 16.16- Dimethyl-PGF2ct 16.16- Dif1uoro-PGF2a $ 16-Phenoxy-17,18,19,20-tetranor-PGF2a 7-Phenyl-18,19,20-trinor-PGF2a 11-Deoxy-PGF2a 2a,2b-Dihomo-PGF2a 3-0xa-PGF2a 3-0xa-17-phenyl-18,19,20-trinor-PGF2c{.

Example 2 6-0xo-PGF|a, Methyl Ester (Formula IV: A, L, Qj, Q2> R4> n> and X are as defined in Example 1).

Ij A solution of the formula I iodo compound, methyl ester (Example 1, 0.45 g.) in 20 ml. of tetrahydrofuran is treated with silver carbonate (0.250 g.) and perchloric acid (907·, 0.10 ml.), and stirred at about 25°C. for 24 hours. The mixture is diluted with 25 ml of ethyl acetate and tO the organic phase is washed with saturated sodium carbonate solution and brine, dried, and concentrated to an oil, 0.41 g. Separation by silica gel chromatography eluting with ethyl acetate-Skellysolve B (3:1) yields the formula IV title compound as a more polar material than the formula I starting material. The product is an oil, 0.32 g., having Rf 0.38 (TLC on silica gel in acetone-dichloromethane (1:1)); infrared spectral peak at 1740 cm”^ for carbonyl; NMR peaks at 5.5 , 3.2-4.8, 3:7, 2.1-2.7 4.

• Cl Example 3 9-Deoxy-6,9-epoxy-6-hydroxy-PGF-|a, Methyl Ester (Formula III: A, L3 Qi, Q2j R], R4, h, n and X as defined in Example 1, andindicates attachment in alpha or beta configuration).

A solution of the formula IV 6-oxo-compound (Example 2, 0.2g.) in 10 ml. of acetone is left standing at about 25°C. for 2 days. It is then concentrated and subjected to Silica gel chromatography to yield the formula III title compound having R^ 0.50 (TLC on silica gel in lb acetone-dichloromethane (1:1)).

Example 4 9-Deoxy-5,9-epoxy-5-iodo-PGF^a (Formula I) and 9-Deoxy-6,9-epoxy-6-hydroxy-PGF^a (Formula III: A, L, Q-j > Q2, R4> h, n and X are as defined in Example 1 and R1 is COOH) A solution of the formula I iodo compound (Example 1, 1.0 g.) in 30 ml. of methanol is treated with 20 ml. of 3 N aqueous potassium hydroxide at about 0°C. for about 5 minutes, then at about 25°C for 2 hours. The mixture is acidified with 45 ml. of 2 N potassium acid sulfate and m!. of water to pH 1.0, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and' concentrated to an oil, 1.3 g. The oil is subjected to silica gel chromatography, eluting with acetone-dichloromethane (30:70 to 50:50) to yield, first the formula I compound and later, the formula III compound as a more polar fraction.

The formula I compound is an oil, 0.33 g., having .

Rf 0.33 (TLC on silica gel in acetone-dichloromethane (1:1) plus 22 by volume acetic acid); infrared spectral peaks at 3360, 2920, 2860, 2540, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050, 1015, 970, and 730 cm1; and mass spectral peaks (TMS derivative) at 681, 525, 606, 569, 535, 479 and 173.

The formula III compound is a solid 0.113 g., melting 93-98°C., recrystallized from acetone-Skellysolve B and melting at 95-105.2°C.; containing no iodine; having Rf 0.13 (TLC on silica gel in acetone-dichioromethane (1:1) plus 2% acetic acid) and having mass spectral peaks (TMS derivative) at 587, 568, 553, 497, 485, 478, 407, 395, 388 and 173.

The formula III compound, above, is esterified with diazomethane to form the methyl ester, having identical properties with the product of Example 3 herein.

Following the procedues of Examples 2 and 4, but replacing the formula I iodo compound therein with those formula I iodo compounds described subsequent to Example 1, there are obtained the corresponding formula IV and III compounds. Further, following the procedures of Example 3, but utilizing the thus-obtained formula IV compounds there are also obtained the corresponding formula III compounds by that method.

Example 5 9-Deoxy-6,9-epoxy-A^-PGFla, Methyl Ester (Formula II: L is -(CH2)3-, Q1 is hydrogen, Q2 is hydroxy, R1 is -C00CH3, is n-pentyl, X is trans-CH = CH-, h is one and n is zero).

A mixture of the formula I iodo compound (Example 1, 0.25 g.), 0.25 ml. of 1,5-diazabicyclolj.3.Qj nonene-5 (DBN), and 15 ml. of benzene is left standing at about 25°C. for 72 hours, and then warmed to 45°C. for 4 hours. The resulting mixture is then cooled, mixed with ice water and a small amount of diethyl ether, and the layers separated. The organic phase is dried over magnesium sulfate and concentrated to the title compound, an oil, 0.20 g. The product is crystallized from cold (-10°C.) hexane to yield 0.14 g., softening at about 25°C., having Rf 0.51 (TLC on silica gel in ethyl acetate); NMR peaks at 5.5, 4.57, 3.8-4.3, 3.62, 3.53 and 0.96; infrared absorption at 1755 and 1720 cm ; and mass spectral peaks (TMS derivative) at 495, 479, 439, 423.2724, 349, 199 and 173.

Following the procedure of the above Example but replacing DBN with DBU, using 0.75 ml. DBU with 0.5 g. iodo compound,·there is obtained 0.44 g. of product. 36a 'ϊ 5' 2 ΰ; Example 6 9-Deoxy-6,9-i5-PGF^a, Methyl Ester A mixture of the formula I iodo compound (Example 1, 1.0 g.), 1.0 ml. of DBN, and 60 ml. of benzene is heated at about. 42°C. for 20 hours. Thereupon 0.5 ml. of DBN is added and the heating continued for 6 hours more. The mixture is left stirring at about 25°C. for 60 hours, then heated again for 8 hours at 40-50°C. The reaction mixture is cooled, washed with ice water mixed with a few drops of triethylamine, and dried over magnesium sulfate, to yield the title compound, an oil, 0.9 g. The product is dissolved in 8 ml. of diethyl ether and crystallized from cold (-10°C.) hexane containing a trace of triethylamine to yield crystals 0.46 g., mushy at 25°C. Additional fractions of crystals, 0.33 g., are combined and subjected to chromatographic purification on a Florisil column pretreated with triethylamine, using hexane-ethyl acetate-triethylamine (75:25:0.5), eluting with ethyl acetate (50c75%)-hexane containing 0.25% by weight triethylamine to yield 0.21 g. of the title compound which crystallizes on chilling.

Example 7 9-0eoxy-6,9-epoxy-A5-PGFia, Methyl Ester (Formula II).

A mixture of the formula I 9-deoxy-6,9-epoxy-5-iodo-PGF^a> methyl ester (Example 1, 0.213 g.) in 3 ml. of dimethylformamide is treated with a fresh solution of potassium superoxide (0.45 g.) in 10 ml. of dimethylformamide containing dicyclohexyl-18-crown-6 (0.75 g.) in an ice bath.

After about 30 minutes the reaction mixture is quenched in ice water, thereafter extracted with diethyl ether. The organic phase is dried Over magnesium sulfate and concentrated to yield the title compound, having the same Rf by TLC as the product of Example 5.

The above product is subjected to column chromatography on Florisil pre treated with triethylamine (5% w/w)-dichloromethane. The product is eluted with ethyl acetate-hexane-triethylamine (50:50:0.1) to give the title compound, 0.076 g., having Rf 0.45 (TLC on silica gel in acetate37 , ef ο Κ 6 4 ο *? υ ’· dichloromethane (3:7) using plates pretreated with triethylamine (5%-dichloromethane).

Following the procedure of Example 7, but replacing potassium superoxide with each of the following reagents, the title compound is likewise obtained: sodium superoxide tetramethy!ammonium superoxide sodium carbonate potassium carbonate sodium hydroxide 1q potassiurn hydroxide sodium benzoate potassium benzoate sodium acetate potassium acetate sodium trifluoroacetate potassium tri fluoroacetate sodium bicarbonate potassium bicarbonate ' and 2Q silver acetate.

Example 8 9-Deoxy-6,9-epoxy-5-iodo-PGFia, p-Phenylphenacyl Ester (Formula I ) and c 9-Deoxy-b,g-epoxy-A -PGFia, £-Phenylphenacyl Ester (Formula II).

A. A mixture of the formula i iodo acid compound (Example 4, Formula I, 0.20 g.) , p-phenylphenacyl bromide (0.50 g.), 0.4 ml. of diisopropylethylamine, and 10 ml. of acetonitrile is stirred at about 25° G. for 40 min. It is mixed with dilute aqueous citric acid and brine and 3Q extracted with ethyl acetate. The organic phase is dried and concentrated. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (25-100#)Skellysolve B to yield the title 5-iodo compound as a colorless oi1, 0,20 g. 38' li A* C O B. The product of Part A above (0.20 g.) is treated with 0.4 ml. of DBN in 15 ml. of benzene at 42°C. for 22 hours. The reaction mixture is cooled, washed with ice-water containing sodium chloride, dried over magnesium sulfate and concentrated to the second title compound, an oil, 0.12 g. The oil is crystallized from benzenehexane. All fractions are combined and subjected to chromatographic separation on a Florsil column pretreated with hexane-ethyl acetate-triethylamine (80:20:0.5), eluting with ethyl acetate to yield the formula II compound, an oil. Crystallization from diethyl ether-hexane yields crystals, 0.015 g., m. 71-2°C. (sintering at 65-7°C). 2 6-6 Example 9 9-Deoxy-6,9repoxy-A5-PGFlctj Sodium Salt.

A mixture of 9-deoxy-6,9-epoxy“AS-PGFia, methyl ester (Example 5/ 0-.030 g.) in 5 ml. of methanol is treated with 9 mi. of 0.01 NNaOH and stirred at about 25° C. for 72 hr.

The solution is then diluted with 5 ml. of water, frozen at about -75° C. and lyophilized overnight. The title compound is obtained as a white free-flowing powder.

The procedure above is repeated using larger quantities.

From 0.150 g. of the enol ether methyl ester there is obtained 0.155 g. of the title compound as a white free-flowing powder. A sample of the material dissolved in methanolwater shows practically no mobility by TLC on silica gel plates in acetone-dichloromethane (3:7), compared with the I5 starting material which has Rf 0.45 (TLC an silica gel in acetone-dichloromethane (3:7) using plates pretreated ί n triethylami ne-(5$)-dichloromethane).

Following the procedures of Examples 1, 2, 3, 5 and 7, but employing corresponding starting materials as described above, there ere prepared the formula I,1 Π, ΙΓΙ and IV compounds, namely, ι„?6ΰ 9-deoxy-6,9-epoxy-5-iodo-PGFia-, 9-deoxy-6,9*epoxy-ώ3-PGP ία-, 9-deoxy-6,9*epoxy*6*hydroxy-PGFia-, and 6-oxo-PGFj-type compounds in methyl ester Form wherein Ri is -COOCH3, having the following structural features: 16- Methyl-; 16.16- D imethy1 -; IG-Fluoro-; 16.16- Dlfluoro-; 17- Pheny1-18,19,20-trinor-; 17*(nj“trlfluoromethylphenyl)-l8,l9,20-trinor-; 17*(o-chlorophenyl)-18,19,20-trinor-j 17*(p-fluorophenyl )-18,19,20-trinor-; 16-Methyl-17*pheny1-18,19,20-tri nor-; 16.16- D imethyl-17*phenyl-18,19,20-trinor-; l6-Fluoro-l7-phenyl-18,19,20-trinor-; 16.16- 01fluoro-17*pheny1-18,19,20-t ri nor-; l6-Phenoxy-17,18,l9,20-tetranor-; 16- (m_-t r i f luoromethyl phenoxy )-17, l8,19,20-tet ranor- ; 16-(m.-ch!orophenoxy)-l7,18,19,20-tetranor-; l6-(p-fiuorophenoxy)-l7,18,19,20-tetranor-; l6-Phenoxy-l8,19,20-tri nor-; 16-Methyl-16-phenoxy-18,19,20-tri nor-; 13,14-Di dehydro -: 16-Hethyl -15,14-di dehydro- ; 16.16- Dimethyl-13,14-di dehydro-; 16- Fluoro-15,14-d i dehyd ro16.16- Di fluor0-15,14-didehyd ro-; 17- Pheny1-18,19,20-trinor-l>,l4-didehydro-; I7- (m_-tr; fluoromethy lphenyl )-18,19,20-t rinor-15,14dl dehydro-; ···'· <ϊ52ϋ3 ' r' ’ 17- (m-chlorophenyl )-18,19,20-trinor-13,l4-didehydro·;; 17“ (p-“ fluoropheny 1) -18,19,20-1 r i nor-13, 14-d idehydro-; * 16-Methyl-17-pheny1-18,19,20-trinor-13,14-didehydro-; 16.16- Dimethy1-17-pheny1-18,19,20-trinor-13,14-dide5 hydro-; l6-Fluoro-17-pheny1-18,19,20-trinor-13,14-didehydro-; 16.16- Di fluoro-17-pheny1-18,19,20-trinor-lj,14-didehydro-; 16-Phenoxy-17,18,19,20-tetranor-13,14-didehydro-; 16-(m-tri fluoromethylphenoxy)-17,18,19,20-tetranor15,14-didehydro-; 16-(«.-chi orophenoxy )-17,18,19,20-tetranor-15,l4-di dehydro-; 16-Phenoxy-18,19,20-trinor-13,14-didehydro-; 16-MethyI-l6-phenoxy-l8,19,20-trinor-13,l4-didehydro-; ,14-Dihydfo-; Ιό-Methy1-13,14-dihydro-; 16.16- Dimethyl-15,l4-dihydro-; 16- Fluoro-15,14-d ίhydro-; I6,l6-0ifluaro-13jl4-dihydro-; 17- Pheny1-18,19,20-tri nor-13,14-dihydro-; 17-(m-tri fluoromethylphenyl)-l8,19,20-trinor-13,14dihydro-; 17- (ηχ-ch loropheny 1)-18,19,20-1 ri nor-13,14-d i hydro-; 17“(jarfluorophenyl )-18,19,20-trinor-13,l4-dihydro-j 16-Methyl-17-phenyl-l8,19,20-trinor-13,14-dihydro-; 16.16- 0 imethy1-17-pheny1-18,19,20-trinor-13,14dI hydro-; l6-Fluoro-17-phenyl-l8,19,20-trinor-13,14-dihydro-; 16,16-Di fluoro-17-phenyI-18,19,20-trinor-13,14-di hydro-; ί Μ .» Ο Ο l6-Phenoxy-17,l8,19,2Q-tetranor-13,l4-dihydro16-(m-trifluoromethylphenoxy}-17,18,19,20-tetranor13,14-dihydro-; l6-(avchlorophenoxy)-17,18,19,20-tetranor-13,145 djhydro-; 16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14dihydro-; l6-Phenoxy-l8,l9,20-trinor-13,l4-dihydro-; l6-Methyl-l6-phenoxy~l8,19,20-trinor-15,14-dihydro-; 2,2-Difluoro-; 2.2- Di fluoro-l6-methyl-; 2.2- 0 ί fIuoro-l6,l6-dimethy1-; 2,2,1G-Tri f 1 uoro-; '2,2,16,1G-Tetrafluoro-; 2,2-Di fluoro-17-phenyl-18,19,20-trinor-; 2.2- Di fluoro-l?-(nr-tri fluoromethylphenyl)-18,19,20tri nor-; 2,2-Di rluoro-17-(m-chlorophenyl)-18,19,20-trinor-; 2,2-Di fluoro-17-(g-fluorophenyl)-18,19,20-trinor-; 2,2-D:fluoro-l6-methy1-17-pheny1-18,19,20-trinor-; 2,2-Di fluoro-l6,l6-dimethyl-17-phenyl-l8,19,20-trinor2,2,Ιό-Trifluoro-l7-phenyl-13,19,20-trinor-; 2,2,16,16-7etrafluoro-17-phenyl-18.15,20-trinor-: 2.2- Di fluoro-l 6 -phenoxy-l7,l8,l9,20-tetranor-; 2,2-Di fluoro-16- (m-tri f luorometbylphenoxy)-17,l8,ig,20 tetranor-; 2.2- D i fluoro-16-(m-chlo;ophenoxy)-l7,18,19,20tetranor-; 2,2-D i fluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor 2.2- 0ΐfluoro-l6-phenoxy-l8,19,20-trinor-; 2.2- 01 fluoro-16-methyl-l6-phenoxy-l8,19,20-tri nor-; 2.2- DifIuoro-l6-methyl-l6-phenoxy-l8,19,20-t.rinor-; 2.2- Di fluoro-l6-methyl-13,14-didehydro-; 2,2-Difluoro-l6,l6-dlmethyl-13,14-didehydro-; g., 2,1.δ-Trifl uoro-13,14-di dehydro-: 2.2.16.16- Tetraf 1 iiono-1.3,14-di dehydro-; 2.2- 0ifluor(3-17-pheny 1-18,19,20-trinor-13,14didehydro-; 2,2-0ί fluoro-17-(m-tri fluoromethylpheny1)-18,19,20trinor-13,14-didehydro-; 2.2- DIFluoro-17- (nrchl.orophenyl )-18,19,20-trinor-13,14 ' didehydro-; 2.2- Di fluoro-17-(jj-fluorophenyl )-18,19,20-trinor-13,14 Ιό didehydro-; 2.2- Difluoro-l6-methyl-17-phenyl-18,19,20-tri norXj,14-didehydro-; 2.2- 0i fluoro-16,l6-dimethyl-17-phenyI-18,19,20-trinor13.14- dldehydro-; 2,2,l6“Trifluoro-17-phenyl-18,19,20-trinor13.14- didehydro-; 2.2.16.16- Tetrafluoro-17-phenyl-18,19,20-trinor13,14-didehydro-; 2.2- 0ifluoro-16-phenoxy-17,18,19,20-tetranor-13,1425 dlde'nydro-; 2.2- 0 i f luoro-16-JiH.-tr i fluoromethyl phenoxy )-17,18,19,20 tetranor-13,14-di dehyd ro-; 2.2- 0ifluoro-16-(nr chlorophenoxy)-17,18,19,20-tetranor-13,l4-didehydro-; '44 2.2- Di fluoro-l6-phenoxy-l8,19,20-trinor-13,l4-didehydro-; 2.2- 0i f luoro-16-rnethyl-l6-phenoxy-l8,l9,20-trinor13,14-didehydro-; 2.2- Di fluoro-13,14-dihydro-; 2.2- Di fluoro-l6-methyl-13,14-dihydro-; 2.2- D1fluoro-16,16-dimethyl-13,14-dihydro-; 2.2.16- Trifluoro-13,14-dihydro-; 2.2.16.16- Tetrafluoro-13,14-dihydro-; 2.2- Di fluoro-17-pheny1-18,19,20-trinor-13,14dihydro-; 2.2- Difluoro-17-(m-tri fluoromethylphenyl)-18,19,20tri nor-13,14-dihydro-; 2.2- Di fluoro-17-(m-chlorophenyl)-18,19,20-trinor13.14- dthydro-; 2,2-Di fluoro-17-(p-fluorophenyl)-18,19,20-trinor13.14- dihydro-; 2.2- Di fluoro-16-methyl-17-phenyl-18,19,20-tri nor13,14-dihydro-; 2.2- Difluoro-l6,l6-dimethyl-l7-phenyl-l8,19,2Qtrlnor-13,14-dihydro-; 2.2.16- Tri fluoro-17-pheny1-18,19,20-trinor-13,14“ dihydro-; 2.2.16.16- Tetrafluoro-17-phenyl-18,19,20-trinor* 13,14-dihydro-; 2.2- Di fIuoro-l6-phenox.y-l7,l8,19,20-tetranor-13,14dihydro-; 2,2-Di fluoro-16- (m-tri fluorcmethylphenoxy)17,l8,19,20-tetranor-13,14-dihydro-; 2,2-Di fluoro-16-(m-chlorophenoxy)-17,18,19,2045 te£ranor-13?<l4-dihydro-; 2.,2-D-i fluoro-16- (ji-f luorophenoxy )-17,18,19,20tetranor-13,l4*d!hydro-; 2,2 -D i f1uoro-l6-phenoxy-l8,19,20-1 rInor-13,145 di hydro-; · 2.2- DifIuoro-l6-methyl-l6-phenoxy-18,19,20-trίnor13,U-dihydro-; 16- Methy 1 -cis.-13 j 16.16- Dimethyl-cis-13·; l6-Fluoro-c?s-13-; 16.16- D i f1u6ro-cis-l3-; 17- Pheny1-18.19.20-trinor-cis-13-; 17- (m_tri fiuorcmethylphenyl)-l8,19,20-trinor-cls-13“;· 17-fm-chlorophenyl)-18.19.20-trinor-cis-13-; 17“(£-fluorophenyl)-18,19*20-trinor-teis-13”; 16-Methyl-l7~pheny1-18,19,20-trinor-cts-13~; 16.16- D imethyl-17-pheny1-18,19,20-tr i nor-cis-13; 16-Fluoro-l7-phenyl-l8,19,20-trinor-£jLsxi'3“; 16.16- Dl fiunro-17-phenyl-l8,19,20-trinor-cis-13-; l6-Phenoxy-17,l8,19,20-tetranor-£iail3·! 16-(nrtri fluoromethylphenoxy)-17,18,19,20-tetranorcis-13-; l6-fa°chlorophenoxv)-17.l8.l9.20-tetranor-els-13-; l6-(p;fluorophenoxy)-17>18.19»20-tetranor-cis-13-t l6-Phenoxy-l8,19,20-trinor-cis-13-; l6“Methyi-l6-phenoxy-l8.19,20-trlnor-cis-13-; 2.2- DSfluoro-cis-13-; 2.2- Dif luoro-l6-methyl“cis.-13-; 2.2- DIfluoro-l6.l6-dimethyl-cis-13- ; . 2,2,1o-Trifluoro-cis-13-; 2,2,16,1 ύ-Te t raf 1 uoro-cis,-13 -; 2.2- Difluorc-l7-pheny1-18,19,20trinor-c£sjl3-; 2.2- Di fluoru-ly-(m-trifluoromethylphenyl)-18,19,20t r i nor-cis-13-; 2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinorcis-13-; 2.2- Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-c£s-13 2,2“01fluoro-l6-methyl-l7-phenyl-18,3.9,20-trinor-cis13“; 1° 2,2-Di fluoro-l6,l6-dimethyl-17-phenyl-18,19,20trinor-cis-13-; 2.2- Di fluoro*l6-fluoro-l7-pheny1-18,19,20-trinorcis-13-; 2.2- Di fluoro-l6,l6-dif luoro-^-phenyl-lSjig^Q-trinorlii cis-13~: 2.2- Difluoro-l6-phenoxy-17,13,19,20-tetranor-cis-13-; 2.2- Di fluoro-16-(m-tri fluoromethylphenoxy)-17,18,19,20tetranor-cis-15-; 2,2-Di fluoro-16-(m-ehlorophenoxy)-17,18,19,2020 tetranor-cis-13: 2,2-Di fluoro-Ιβ-(p-fluorophenoxy)-17,18,19,20tetranor-cis-13~; 2.2- Di fIuoro-l6-phenoxy-l8,l9,20-trinor-cis-15-; 2.2- Difluoro-lS-met1/l-l6-phenoxy-l8,19,20-trinor23 cis-13-; 2.2- Di fIuoro-l6-methyl-l6-phenoxy-l8,19,20-trinorjeisrli-; -Oxa-; 3-0xa-l6-methyl-; 3-0xa-l6,l6-dimethyI -; 4SS66 3-Qxa-l6-fluoro-; 3-0xa-l6,l6-difluoro-; 3-0xa-17phenyt-l8,19,20-tr inor-; -0x3-17“(m-trifluoromethylphenyl)-18,19,20-trinor-; 5^0x3-17“(m-chlorophenyl)-l8,19,20-trinor-; 3-0x3-17“ (p.-f luorophenyl )-18,19,20-trinor-; 3-0xa-l6-methy1-17-pheny1-18,19,20-1 r1 nor-,3-0xa-l6,l6-d?msthyl-17-pheny1-18,19,20-trinor-j 3-Oxa-16-fluoro-17-pheny1-18,19,20-trinor-; -Oxa-16,Ιβ-di fluoro-rf-pheny1-18,19,20-trinor-; 3-0xa-l6-phenoxy-l7,18,19,20-tetranor-; -0xa-l6- (m-tri f luoromethylphenoxy)-17,18,19,20tetranor-; 3-0xa-l6-(m-chlorophertoxy)-17,18,19,20-tetranor-; 5-0xa-l6-(£-fluorophenoxy)-17,18,19,20-tetranor-; 3-0xa-l6-phenoxy-l8,19,20-trinor-; 3-0xa-l6-methyl-l6-phenoxy-l8,l9,20-trinor-; 3-0xa-13,l4-didehydro-; -.Qxa-lS-methy 1-13,14-d i dehyd ro-ζ 3-0xa-l6',l6-difnethyl-13,14-d.idehydro- j 5-0xa-lS-fluoro-l3,14-didehydro-; 3“0xa-l6,16-di fluo.ro-13,14-didehydro-; 3-0xa-l?-pheny1-18,19,20-trinor-13,14-didehydro-; 3“0xa-17-(nrtrifluoromethylphenyl)-18,19,20-trinor13,14-didehydro-; 3-OX3-I7-(nrch1oropheny1)-18,lg,20-t ri nor-13,14didehydro-; >0xa-17“.(p“f luorophenyl )-18,19,20-trinor-13,14dfdehydro-; 3-0xa-lo-methyl-17“phenyl-l8,19,2o-trinor-13,l448 » · ·* ο *· •λ U U ‘J> di dehydro-; 3-0xa-l6,l6-dimethyl-17-pheny1-18,19,20-trinor13.14- didehydro- ; 3-Oxa-ΐβ-fluoro-17-pheny1-18,19,20-trinor-13,145 didehydro-; 3-Oxa-16,16-di fluoro-17-pheny1-18,19,20-trinor15.14- didehydro-; 3-0xa-lo-phenoxy-l7,l8,l9,20-tetranor-13,14didehydro-; 3-0xa-l6-(m-tri fluoromethylphenoxy)-17,18,19,20tetranor-13,14-didehydro-; 3-0xa*l6-(m-chlorophenoxy)-17,18,19,20-tetranor13.14- didehydro-; 3-0xa-l6-pbenoxy-l8,19,20-tri nor-l>,14-didehydro-; 15 3-Oxa-l6-methyl-l6-phenoxy-18,19,20-trinor-13,14didehydro-; 3-0xa-13,14-dihydro-; 3-0xa-10-methy1-13,14-dihydro-; 3-0xa-l6,l6-dimethyl-13,14-dihydro-; 3-0xa-l6-fluoro-13,14-dihydro-; 3· Oxa-16,16-di fluoro-13,14-dihydro-; 3-Oxa-17-pheny1-18,19,20-tri nor-13,14-dihydro-; 3-0xa-17 Qn-tri fluoromethylphenyl)-18,19,20-tri nor13,14-dihydrO-; 3-Oxa-17-(m-chlorophenyl)-!8,19,20-trinor-l3,14dihydro-; 3-0xa-17(p-fluorophenyl )-18,19,20-trinor-13,14dihydro-; 3-0xa-l6-methy1-17-pheny1-18,19,20-trinor-13,1430 dihydro-; 4g?^s 3-0xa-l6,l6-Dimethyl-l7-phertyl“l8,19,20-trinor15.14- dihydrο-; -0xa-l6-fluoro-17-pheny1-18,19,20-tr?nor-13,14dihydro-; 3-0xa-l6,16-di fluoro-17-pheny1-18,19,20-trinor13,14rdihydro-;. 3-0xa-l6-phenoxy-l7,l8,19,20-tetranor-13,l4dfhydro-; 3-0xa-l6-(m-tri fluoromethylphenoxy)-17,18,19,20tetranor-15,14-dihydro-; -0xa-l6-(m“chlorophenoxy)-17,18,19,2O“tex:ranor13.14- dihydro-j 3-Oxa-l6-(p-fluorophenoxy)-17,18,19,20-tetranor13.14- dihydro-; . 3-0xa-l6-phenoxy-l8,19,20-trinor-13,14-dihydro-5 3-0xa-l6-methyl-l6-phenoxy-l8,19,20-trinor13,14-dihydro-; -0xa-cSs-‘l3-; -0xa-l6-methy1-cis-l3-; 3-OXa-l6,l6-dimethyl-cis-13“5 3-0xa-16-fluoro-£isrl3-; ~0xa-l6,l6-di fiuoro-cis-15“; 3-Oxa-17-pheny1-18.19,20-t r i nor-c i s-13-; 3“0xa-l7-(m-trifluoromethylpheny1)-18,19,20-trinorcis-13- ; 3“Oxa-17-(m-chlorophenyl)-18,19,20-trinor-cis-13-; 3-0xa-17-(p-fluorophenyl)-18.19.20-trinor-cis-13-; 3-0xa-l6-methy1-17-phenvl-18.19.20-trinor-cis-13-; 5-0Xa-l6.16-dimethy1-17-pheny1-18,19,20-trinor-cis13-5 3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-cis-13-; 3-0xa-l6,16-di. fluoro-17-phenyl-18,19-20-tri nor-cis-13-; 3-0xa-l6-phenoxy-l7,18,19,20-tetranor-ci s-13-; 3-0xa-l 6-(m-trif 1 uoromethy!phenoxy)-17,18,19,20-tetranor ci s-13-; 3-0xa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-l3-; 3-Oxa-(p-fluorophenoxy)-17,18,19,20-tetranor-cis-13-; 3-0xa-l6-phenoxy-l8,19,20-trinor-ci s-13-; 3-0xa-16-methy1-16-phenoxy-l8,19,20-tri nor-cis-13-; Likewise, following the procedures of Examples 1, 2, 3, 5 and 7, but employing corresponding starting materials as described above, there are obtained the formulae I, II, III and IV compounds, namely, 9-deoxy-6,9-epoxy-5-iodo-PGF1a-, 9-deoxy-6,9-epoxy-A^-PGF^a-, 9-deoxy-6,9-eppxy-6-hydroxy-PGFla-, and 6-oxo-PuFja-type compounds, in methyl ester form wherein R-j is -COOCHg, having the following structural features: 2,3-Didehydro-; 2,2-Dimethyl-; 2a,2b-Dihomo-; 4-0xa-4a-homo-; 7a-Homo~; 2a 11-Deoxy-10,!1-aidehydro-; . £-; 11-Deoxy-11-oxo-; 11-Deoxy-; 11-Deoxy-11-methyl ene-; 11-Deoxy-Π-hydroxymethyl; 15β-; -Deoxy-i5-oxo-; -Deoxv-; -Methyl-15{S)-; -Methyl-15{R)-; and 5 C7s-17ST8-Didehydrog The compound 9-deoxy-6,9-epoxy-A ,-PGF^a is known. We make no claim herein to that compound as a compound per se.

Claims (15)

1. An optically active enol ether of the formula ύ or a mixture of the enantiomers thereof,

2. A compound as claimed in claim 1 wherein A is α-hydroxy, L is trimethylene, is hydrogen, Q 2 is hydroxy, R^ is -COOCH,., R^ is n-pentyl, n is zero, h is one and X is trans-CH=CH- i.e. 2-naphthyl; · CHR^-COR^ wherein R^ 2 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenvl. p^bgnzamido- phenyl or 2-naphthyl ana R^ is hydrogen or benzoyl; or a pharmacologically acceptable cation; R^ is fi) -CR^Rg-CgHgg-Cii^ wherein R^ and Rg are each hydrogen, alkyl of one to 4 carbon atoms or fluorine with the proviso that -CR^Rg- is not -CRAlkyland C gH2g i s alkylene of one to 9 carbon atoms with one to 5 carbon atoms in the chain between -CRcRc- and the terminal methyl, (2) -CR^Rg-Z —ν -γ & wherein Z is an oxygen atom, a valence bond or alkylene of one to 9 carbon atoms with one to 6 carbon atoms in the chain between -GR^Rg· and the benzene ring, R^ and Rg are as defined above with the proviso that neither R^ nor Rg is fluorine when Z is an oxygen atom, T is hydroxy, alkyl or alkoxy of one to 4 carbon atoms, fluorine, chlorine or trifluoromethyl and s is zero, one, 2 or 3 provided that when s is 2 or 3 not more than two T’s are other than alkyl and the T’s are the same or different, or (3) -CH 2 -cis-CH=CH-C 2 H 5 ; n is zero or one and b is one or 2; X is trans-CH = CH-, cis-CH =CH- S -C = G- or -CH 2 - CHg· and czi indicates attachment in cis or trans configuration

3. The p-phenylphenacyl ester of 9-deoxy-6,9-epoxy-

4. A compound as claimed in claim j. wherein A is α-hydroxy, L is trimethylene, is hydrogen, Q 2 is hydroxy, R^ is -COONa, is n-pentyl, n is zero, h is one and X is trans-CH=CH~, in free5 flowing powder form. 5. If 24. A process for preparing a compound as claimed in Claim 9 substantially as described in Example 3 or Example 4. 25. A process for preparing a compound as claimed in Claim 12 substantially as described in Example 1 or 5 hydrogen or a-CH 2 0R^, in which case the dotted carboncarbon double bond is absent, or B is absent and the dotted carbon-carbon double bond is present, wherein R^ is hydrogen, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, or a group of the formula R 14° “ θ - C - Ri? R 15 R 16 wherein Rp is alkyl of one to 18 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl or phenyl substituted one, 2 or 3 times by alkyl radicals of one to 4 carbon atoms; either R. g and Rp are each hydrogen, alkyl of one to 4 carbon atoms, phenyl or phenyl substituted one, 2 or 3 times by alkyl radicals of one to 4 carbon atoms or Rp and Rp are taken together and are -(CH 2 ) a - wherein a is 3, 4 or 5 or -(CH 2 ) b - 0 -(CH 2 ) c - wherein b and c are each one, 2 or 3 with the proviso that b+c is’2, 3 or 4; and Rp is hydrogen or phenyl; and L, Q-p £) 2 , Rp Rp h, n and X are as defined in Claim 1,

5. An optically active compound of the formula or a mixture of the enantiomers thereof, wherein either B is ct- or β-OR^, oxo, methylene, 5 9-deoxy-6,9-epoxy- Δ^-pgf methyl ester. 5 wherein either A is a- or β-hydroxy, oxo, methylene, hydrogen or a-hydroxymethyl, in which case the dotted, carboncarbon double bond is absent,or A is absent and the dotted, carbon-carbon double bond is present; L is (1) -(C&Pd-CRgRj- wherein d. is zero or an IQ integer of from one to 5 and R 9 and R^ are eaca hydrogen, methyl or fluorine with the proviso that -CRgRy is h· 0 ^ -CFMe-, (2) -CHg-O-CCHg)^- wherein k is one, 2 or 3, or (3) -CH 2 -CH=CH-; Q., and. Q 2 are both hydrogen or and Q 2 together 15 are oxo or one of and Q 2 is hydrogen or alkyl of one to 4 carbon atoms and the other is hydroxy; is (1) -CH 2 0H, (2) -CHgNRg^Q wherein Rg and R 10 are each hydrogen or alkyl of one to 4 carbon atoms, (3) 5-tetrazolyl, or (4) 000¾. wherein R^ is hydrogen; 20 alkyl of one to 12 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; aralkyl of 7 to 12 carbon atoms; phenyl; phenyl substituted one, 2 or 3 times by chlorine atoms or alkyl radicals of one to 4 carbon atoms; -D-NH-CO-D-NH-COCH 3 , -D-NH-COPh, -D-NH-COCHj, $5363 -D-NH-C0NH 2 or -D-CH=N-NH-C0NH 2 wherein L is 1,4-phenylene;

6. A compound as claimed in Claim 5, wherein B is oxo, hydrogen ora-ORp and Rp is as defined in Claim 5; L is -{CK 2 ) 3 -, -(CH 2 ) 4 - or -(CH 2 ) 5 -; Q 1 is hydrogen, methyl or ethyl; Q 2 hydroxy R^ is COORg and Rg is as defined in Claim 1; is n-pentyl, 1,1-dimethylpentyl, 1,1-difluoropentyl, phenoxymethyl or phenethyl; h is one, n is zero; and X is trans - CH = CH-.

7. A compound as claimed in Claim 5, wherein B is a-hydroxy, is hydrogen, Q 2 is hydroxy, L is trimethylene, R 1 is -COORg, wherein Rg is hydrogen or methyl, and is n-pentyl, 8. Amine is 1,4-diazabicyclo / 2.2.2_/ octane. 18. A process according to Claim 15, wherein the tertiary amine is 1,5- diazabicyclo / 5.4.0_7 undecene-5. 19. A process according to any of Claims 15 to 18, wherein the dehydroiodination reagent is potassium superoxide. 10 20. A process according to any of Claims 15 to 18, wherein the dehydroiodination reagent is potassium carbonate. 21. A process for preparing the compound claimed in Claim 4, in free-flowing powder form, which comprises (a) contacting a solution of 9-deoxy-6, 9-epoxy - δ 5 - PGFj 15 methyl ester, with an equivalent amount of aqueous sodium hydroxide; and (b) removing solvent and water from the product of step (a). ώϊτέ· 3 6 22. A process for preparing a compound as claimed in Claim 1 substantially as described in any of Examples 5 to 8. 23. A process for preparing a compound as claimed in Claim 5 substantially as described in Example 2.

8. A compound as claimed in Claim 6, wherein B, L, Qp Q 2 , and R^ are as defined in claim 7,

9. An optically active compound .of the formula OH or a mixture of the enantiomers thereof, wherein B is as defined in Claim 5 and L, , Qg, Rp R^, h, η, X and -'are as defined in Claim 1. 10. 9t -7 .Example 8. 26. A process according to Claim 21 substantially as described in Example 9. 27. Tbe product of a process according to any of Claims 15 to 26. 10 in Claim 12, wherein R 13 is hydrogen; (b) subjecting the product of step (a) to dehydroiodination with a tertiary amine or a reagent selected from sodium or potassium superoxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium 15 or potassium acetate, sodium or potassium trifluoroacetate, sodium or potassium bicarbonate, silver acetate, and a tetraalkyl ammonium superoxide of the formula (Rj 2 )^N0 2 wherein Rj 2 is alkyl of one to 4 carbon atoms, to form the enol ethers; and (c) separating the products. 16. A process according to Claim 15, wherein the tertiary amine is 1,5-diazabicyclo 4.3.0_/ nonene-5. 17. A process according to Claim 15, wherein the tertiary

10. A compound as claimed in Claim 9, wherein B, L, Qj, Q 2> Rj, R^, h, n and X are as defined in Claim 6,

11. A compound as claimed in Claim 10, wherein B, L, Qj, Q 2 , Rj and R^ are as defined in Claim 7.

12. An optically active compound of the formula or a mixture of the enantiomers thereof, wherein B is as defined in Claim 5 and L, Qj, Q 2> Rj, R^, h, n and X are as defined in Claim 1.

13. A compound as claimed in Claim 12, wherein B, L, Qj, Q 2 , Rj, R^, h, n and X are as defined in Claim 5.

14. A compound as claimed in Claim 13, wherein B, L, Qj, Q 2 , Rj and R^ are as defined in Claim 7. 15. A process for the preparation of a compound as claimed in Claim 1 which comprises the steps of (a) iodinating and cyclising a compound of the formula wherein A, L, Qp Q 2 , Rp R^, n, h and X are as defined in 5 Claim 1, by reaction either with an aqueous system comprising iodine, potassium iodide and an alkali metal carbonate or bicarbonate, or with an organic solvent system containing iodine in the presence of an alkali metal carbonate, at a temperature below 25°C., to form an iodo compound as claimed

15. ( j 28. A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 14 and 27 in which, where appropriate, R^g is hydrogen, in association with a pharmaceutically acceptable carrier.