IE47284B1 - Prostaglandin amides - Google Patents

Abstract

Pharmaceutically useful compounds are amido derivatives of known prostaglandins having a 6- oxo and a 9 alpha -hydroxy or hydroxymethyl group, and 6,9-lactones thereof, and a 6-hydroxy, 5-halo and 5,6-didehydro analogues of the lactones.

Description

Prostaglandins and their analogues are wellknown organic compounds derived from prostanoic acid.

For background, see for example Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and Pace-Asciak et al·, Biochem. 10, 3657 (1971). 6-0xo-PGFla: is disclosed by Pace-Asciak, J. Am. Chem. Soc. 98, 2348 (1976) and ''PGX (alternatively 6,9a-oxido-9a,15a-dihydroxyprosta-(Z)5,(E)13-dienoic acid) by E. J. Corey et al., J. Am. Chem. Soc. 99, 2006 (1977).

This invention provides, in a first aspect, novel compounds of formula I - 2 Λ.7 2 84· <~Υ'ΟΗ s ί Rao 1---W -C-CHg-L-Ri \—X· X -C-R 4 or a mixture comprising that compound and the enantiomer thereof wherein (Rao) is o'h OH CHgOH wherein, when W is methylene, L is (1) -(CH2)d-CR2R3(2) -CHg-0-CHg-Y- or (3) -CHaCH=CHwherein d is zero to 5, Rg. and R^ are each hydrogen, methyl,or fluorine, with the proviso that -CRgRg- is not -CFMe-, -3and Y is a valence bond, -CH2- or -(CH2)2-, and, when W is ethylene, L is (1) -(CH2)d-CR2R3(2) -O-CH2-Y- or (3) -CH«CH-, wherein Q is II x-X , Η Η , Ra OH , or Ro OH wherein Re is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R1 is 0 (I -c-N(R9)(r18) wherein R3 is hydrogen, methyl, or ethyl, and R1B is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive; wherein R4 is (I) c-c h2 -ch3 ι g g (2) -c-z-c (τ). or (3) -CH2 \ X H C^C.

,CH2CH3 H -441 3 8 4 wherein C H2 is alkylene of one to 9 carbon atoms, 9 inclusive, with one to 5 carbon atoms, inclusive, in the chain between -CRsRe- and terminal methyl, wherein R5 and Ro are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R5 and R6 is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R5 nor Re is fluoro when Z is oxa (-0-); wherein Z represents an oxa atom (-0-) or C.H2, whereJ J in C.H2, is a valence bond or alkylene of one to 9 carJ V bon atoms, inclusive, with one to 6 carbon atoms, inclusive between CRSR6- and the phenyl ring; wherein' T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or -0R7- wherein R7 is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; wherein V is a valence bond or methylene and W is methylene or ethylene; and wherei η X i s (1) trans-CH=CH(2) cis-CH=CH(3) -C=C- or (4) -CHaCHaThere are likewise provided compounds of the formula Q -54728 4 and Q wherein (Rs^, L, Q, Ri, R«, V, W, and X are as defined above 15 for formula I.

In compounds of formula III, R19 is chloro, bromo, or iodo.

In compounds of formula II and III, the wavy line indicates attachment in alpha or beta configuration, In compounds of formula III, Q, is II A /\ /\ Ο , Η H j Rs 0R13 } or Re ORis s -647 2 8 4 CH2ORl3 In formula 111, R13 is (a) hydrogen, (b) tetrahydropyranyl, (c) tetrahydrofuranyl, (d) 1-ethoxyethyl, (e) a group of the formula H I R i4 ”0 _C - C -R17· I I RlS Rl6 wherein R14 is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to carbon atoms, inclusive, yherein R15 and Rie are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alky, of one to 4 carbon atoms, inclusive, or, when Rl5 and R16 are taken together -(CH2)a- or -(CH2)b-0-(CH2)c- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R17 is hydrogen or phenyl, or (f) carboxyacyl including (a') 0 (A)e wherein A is alky, of one to 4 carbon atoms, inclusive, bromo, phenylalkyl of 7 to 10 carbon atoms, inclusive, or -74728 4 nitro, and e is zero to 5, inclusive, provided that not more than two A's are other then alkyl, and that the total number of carbon atoms in the A's does not exceed 10 carbon atoms, (b>) COORao wherein Rao is alky, of one to 4 carbon atoms, inclusive, (A)e wherein A and e are as defined above, or (d·) II -C-R31 wherein R31 is alkyl of one to 7 carbon atoms, inclusive.

In formulas I-IV as used herein, attachment to and corresponds to bonds to the cyclopentane ring at the C-8, C-9, and C-12 positions following prostaglandin nomenclature, thus: /QC Within the scope of the prostaglandin derivatives described herein there are represented (a) PGFcx compounds when (R20) is -847384 OH (b) ΙΙβ-PGFa compounds when (Rao) is OH (c) ll-Deoxy-ll-keto-PGFa compounds when (R20) is (d) 11-Deoxy-ll-methylene-PGFa compounds when (rZo^) CHS (e) ll-[ieoxy-PGFa compounds when M is (f) ll-Deoxy-10,11-Didehydro-PGFa compounds when R2o)i! -947284 (g) ll-Deoxy-ll-hydroxymethyl-PGFa compounds when ι CHaOH For those compounds of formula l-IV wherein Q is i.e. wherein the C-15 hydroxyl group is attached to the side chain in alpha configuration, the configuration at C-15 is identical with that of the naturally occurrng prostaglandins such as PGEi obtained from mammalian tissues.

The 15-epimer compounds are represented by formulas l-IV when Q i s Re OH and are identified variously as 15-epi or 150 or 15R by the appropriate prefix in the name. As is known in the art, R and S designations depend on the neighboring substituents. See R. S. Cahn, J. Chem. Ed. 4l, 116 (1964).

A typical example of the keto compounds of formula I is represented by the formula V -10- 47284 named 6-keto-PGFiu , amide. The compound of species of the formula-1 compounds wherein ( formula V is i Reo) is OH L is Q is II Ri is -C-NHz , R4 is n-pentyl, V is a valence bond, W is methylene and X is trans-CH = CH-. An example of the hemi-ketal compounds of formula il is represented by the formula named 9'deoxy-6^,9a-epoxy-6)j-hydroxy-PGFi , amide.

An exampleof the halo compounds of formula III is represented by the formula -114738 4 and named 5£-iodo-9-deoxy-o£,9u-epoxy-PGFi, amide. An example of the enol ethers of formula IV is represented by the formula 0 c-< (CHs)3-C-NHCH-, VI I I named (5Z)-9-deoxy-6,9li-epoxy-A5-PGF1, methylamide. gee R, A. Johnson et a 1., J. Am. Chem. Soc. 99, 4l82 (1977). Alternatively, the formula-VI11 compound may be referred ]5 to as the methylamide of prostacyclin (PGI2), see R. A. Johnson et al.. Prostaglandins 12, 915 (1976) and Anonymous, ibid., 13, 375 (1977).

As to the Z and E nomenclature for stereoisomerism about a double bond, see for example J. E. Blackwood et al., J. Am. Chem. Soc. 90, 509 (1968).

The formula-I compounds wherein V 1s a valence bond and W is methylene are named as 6-keto-PGF-ia compounds following prostaglandin nomenclature, with appropriate use of homo or nor for variations in chain length as known in the art. Likewise, the corresponding formula-II compounds are identified as 6-hydroxy compounds and the formula-III compounds are 5-halo compounds, regardless of chain length.

Those formula-I compounds wherein V and W are methylene are named as 9-hydroxymethyl analogs. The corresponding formula-II, -III, and -IV compounds are named as 6,9-epoxy-1247284 methano analogs. When Visa valence bond and W is ethylene, the formula-I compounds are named as 5-ketoPGFi(x derivatives. The corresponding formula-II, -III, and -IV compounds are named as 5,9-epoxy-PGF-,a derivatives, the formula-III halo compounds then being named as 4-haio compounds.

The compounds of formulas I, II, and IV, and those of formula III wherein R13 is hydrogen are extremely potent in causing various biological responses. For that reason, these compounds 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 administration of prostaglandin synthetase inhibitors.

Because of these biological responses, these novel 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.

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 condi-1347284 • tions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in v/hich the underlying etiology is associated with lipid imbalance or hyperlipidemia. Other in vivo appli ca5 tions include geriatric patients to prevent cerebral ischemic attacks and long term prophylaxis following myocardial infarcts and strokes. For these purposes, these compounds are administered system!cal 1y, 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 in the range about 0.01 to about 10 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 these 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 platelets is avoided by the presence of these compounds. For this purpose, the compound is ad';- d 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 or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001-1.0 ug./ml. of -144 7 2 8 4 whole blood. These compounds are also useful in preparing platelet-rich concentrates from blood for use in treating thrombocytopenia or in chemotherapy.

These compounds are extremely potent in causing 5 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 ig 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 latter purpose, the compound is administered in intravenous infusion immediately after abortion or delivery at a dose i n the range about 0.01 to about 50 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 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 prostaglandin derivatives 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 gastrointestina] ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this 3q purpose, these compounds are inj'ected or infused intra-154728 4 2871A-1Α-F venously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 pg. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.01 to about 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 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 prostaglandin derivative and the anti-inflammatory prostaglandin synthetase inhibitor.

See Partridge et al., U.S. Pat. No. 3,781,429, for a dis15 closure 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 PGEi, PGEe, PGE3, 13,14dihydro-PGEx, 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 in Partridge et al. as non-steroidal, anti25 inflammatory agents. These are also known to be prostaglandin synthetase inhibitors. The anti-inflammatory synthetase inhibitor, 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 -16• 4 7284routes of systemic administration.

The prostaglandin derivative is administered along with the anti-inflammatory prostaglandin synthetase inhibitor ei liner 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 supposi10 tory or a vaginal device for slow release, for example, as described in U.S. Pat. No. 3,545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the prostaglandin derivative is also administered rectally. Further, the prostaglandin derivative con 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-infiammatory substance and prostaglandin derivative, to combine both into a single dosage form.

The dosage regimen for the prostaglandin derivative in accordance with this treatment will depend upon a variety of factors, including the type, age, weight, sex and medical condition oi the mammal, the nature and dosage regimen of the anti-inflammatory synthetase ι η» i L, 1L or being administered to the mammal, the sensitivity of the particular prostagiandin derivative to be administereu. for example, not every human in need of an anti-inflammatory substance experiences the same adverse gastrointestina] effects when taking the substance. Trie gastrointestinal effects wi i 1 frequently vary substantially in kir.-ί ar.d -1747284 degree. But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflanimatory substance is causing undesirable gastrointestinal effects in tne human or animal subject and to prescribe an effective amount of the prostaglandin derivative tc 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 Ιθ bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antiboJy complex. Thus, these compounds control spasm and facilitate breating 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 adminis2θ tration being preferred in emergency situations-, oy inha la tion in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.01 to 5 mg. per kg. of boay 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 r-*· te of administration. For the above use these prostaglandins can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophy11ine); and corti-1847284 costeroids (ACTH and prednisolone).

These compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalation.

For administration by the oral inhalation route with concentional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute solution, preferably at concentrations of about 1 part of medicament to form about 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 citrate, citric acid, and the like 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 the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichi orotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can also be used a dispersing agent such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technique are described fully in U.S.

Pat. No. 2,868,691 for example.

These compounds are useful in mammals, including man, as nasal decongestants and are used for this purpose in a dose range of about 10 pg. to about 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 peri-1947284 pheral 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 cere5 brovascular disease, artheriovenous fistulas, ischemic leg ulcers, phlebitis, venous insufficiency, gangrene, hepatorenal syndrome, ductus arteriosus, non-obstructive mesenteric ischemia, arteritis lymphangitis and the like. These examples are included to be illustrative and should not be construed as limiting the term peripheral vascular disease. For these conditions the compounds of this invention 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.ΟΧΙ 5 1.0 pg./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, ln the event that sys. temic or side effects are observed the dosage is lowered below the threshold at which such systemic or side effects 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 -204728 4 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. 58,400V. See Elliott, et al., Lancet, January l8, 1975, pp. 140-142.

These 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 weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 ug. per kg. of body weight per minute until or near the termination of the second stage of labor, 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 labor has not yet started. An alternative route of administration is oral.

These compounds are further useful for controlling 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 prostaglandin derivative is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approvimately 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 administra-21/4-728 4 tion. Additionally, expulsion of an etribryo or a fetus is accomplished by similar administration of the compound during the first or second trimester of the normal mammalian gestation period.

These 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 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 system!cally.

The prostaglandin derivative, for example, is administered orally or vaginaily at doses of about 5 to 5θ 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 about 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 abortifacient (especially for feedlot heifers), as art aid to estrus detection, and for regulation or syn-22>4-7284 chronization 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 labor 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 prostaglandin is injected or applied in a feed at doses of 0.1100 mg. per animal and may be combined with other agents such as steroids. Dosing schedules will depend on the species 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.

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. 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 a 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 -2347284 the range 0.05 to 2 mg. per kg. of body weight per day.

These prostaglandin derivatives are useful for treating proliferating skin diseases of man and domesticated animals, including psoriasis, atopic dermatitis, non5 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 in15 completely cleared or completely cleared.

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; constitute from about 0.1$ to about 15/ by weight of the composition, preferably from about 0.5/ to about 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-inflammatory agents for inhibiting chronic inflammation in mammals including the swelling and other unpleasant effects thereof using -2447284 methods of treatment and dosages generally in accord with U.S. pat. No. 5,885/)41, which patent is incorporated herein by reference.

Many of the biological responses known for these 6-keto, iodo-ether, enol-ether, and hemi-ketal prostaglandin derivatives are also known for the older prostaglandin compounds. However, these derivatives are surprisingly more specific with regard to potency in causing prostaglandin]ike biological responses. Each of these novel derivatives is therefore useful in place of the known prostaglandintype compounds for at least one of the above pharmacological purposes and, moreover, is surprisingly and unexpectedly more useful for that purpose because it causes smaller and fewer undesired side effects than the known prostaglandins.

The compounds of formula l-IV wherein R13 is not hydrogen but a blocking group such as tetrahydropyranyl are useful as intermediates in the various processes for preparing other useful compounds as described herein or known in the art.

To obtain the optimum combination of biological response specificity, potency, and duration of activity, certain compounds within the scope of formulas l-IV are preferred. For example it is preferred that Q be wherein it is especially preferred that Ra be hydrogen, methyl, or ethyl. λ / \ When Q is r8 θΗ it is preferred that Re be methyl or ethyl. -2547284 It is especially preferred that at least one of R9 and Ris be hydrogen.

As to variations in L, it is preferred that d be 2, 3, or 4, and especially 2. When both R2's are fluoro, it is preferred that Rs in Q be methyl, or that R4 be OH -CH· or As to var iati ons i n it is preferred that or When R-i in the compounds of formulas I-IV is -C-CgHag-CHa Re -2647284 it is preferred that CgH;,g be alkylene of 2, 3, or Jl carbon atoms, and especially that it be trimethylene.

It is further preferred that R5 and Rc, be hydrogen, methyl, ethyl, or fluoro, being the same or different.

It is further preferred, when Rs and Rc are not hydrogen, that both Rs and Re be methyl or fluoro. It is especially preferred that R4 be n-pentyl, 1,1-dimethylpentyl, or 1,1diI 1uoropenty1.

When R.) in the compounds of formulas I-IV is Rg it is preferred that s be either zero or one. When s is not zero, it is preferred that T be methyl, chloro, fluoro, trifluoromethyl, or methoxy with meta or para attachment to the phenyl ring. When Z is oxa (-0-), it is preferred that Rs and R6 be hydrogen, methyl, or ethyl, being the same or different. It is further preferred, when Rs and RG are not hydrogen, that both R5 and Ro be methyl. When Z is CjH2j, it is preferred that CjHaj be a valence bond, methylene, or ethylene. It is especially preferred that R4 be There are herein provided the various processes for -2747284 preparing the 6-keto compounds of formula 1, the 6-hydroxy (hemi-ketal) compounds of formula II, the 5-halo compounds of formula III, and the PGIa-type (enol ether) compounds of formula IV.

Thus, for the formula-1, -II, and -111 compounds one process comprises the steps of starting with a compound of the formula above, and (a) halogenating and cyclizing to form a compound of the formula 1(1 wherein L, Qi, Ri, R4, Rlg, > V, W,X, and--^< are as defined above, (b) subjecting the product of step a to dehalogenation and hydrolysis to form a keto compound of the formula -2847284 -OH ' Π ( R2, Μ —C-CHe-L-Rj '--Q^X-C-iU Qi and a hemi-ketal compound of the formula XI wherein L, Qi, Ri, R4j ijlsi/. V, W, X, and-—are as defined above, and, when R13 in ^r7^ or Qi is not hydrogen, (c) replacing the blocking groups of Ri3 with hydrogen to yield and and (d) separating the products.

The symbol Θ includes all of the ring systems of the symbol (R20) defined above, together with those in -2947284 which there is a blocking group as defined by and within the scope of R13 at C-ll. The compounds produced, as represented by formulas X and XI, are inclusive of the formula-1 and -11 compounds together with those in which there is a blocking group retained from the formula-IX starting material. The compounds with blocking groups are useful as intermediates in further transformations of the formula-III, -X, and -XI compounds.

An alternate process for the formula-1 and -II compounds is by starting with a formuia-IV compound (to be discussed below) and subjecting it to acid hydrolysis.

If that formula-1 V compound has blocking groups, e.g. if it is a 11,15-bis(tetrahydropyran-2-y1) ether, those blocking groups are replaced with hydrogen by methods known in the art.

For the formula-1 V enol ethers, the process employs dehydrohalogenation of the formula-III halo compounds. Accordingly, the process comprises the steps of starting with a compound of the formula XII wherein L, Q, Rx, R4, . V, W, and X are as defined above, and (a) transforming that compound to a halo compound of the formula -3047384 ίο II Q wherein L, Q, Ru R4, Rie, above.

V, M, and X are as defined (b) subjecting the product of step a to dehydrohalogenation with a tertiary amine or a reagent selected from the group consisting of sodium or potassium superoxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium acetate, sodium or potassium trifluoroacetate, sodium or potassium bicarbonate, silver acetate, and a tetraalkylammonium superoxide of the formula (Ria)4N02 wherein R12 is alkyl of one to 4 carbon atoms, inclusive to form the enol ethers ; and (c) separating the products.

Reference to Chart A, herein, will make clear the steps for preparing the formula-1, -II, and -III compounds dlsclosed herei n.

In Chart A, the terms L, Q, Qx, Ri, R-n R19, (Rao) , ^Rai), V, W, X, andhave t.he same meanings as defined above.

Examples of alkyl of one to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomeric forms thereof. Examples of alkyl of one to 7 carbon atoms, inclusive, are, in addition, pentyl, hexyl, heptyl, and isomeric forms thereof. Examples of alkyl of one to 12 carbon atoms, inclusive, are, in addition, octyl, nonyl, decyl, -3147284 CHART A iRai ^L_Rl —•y<^X-C-R4 (a) v -3247284 undecyl, dodecyl, and isomeric forms thereof. Examples of· alkyl of one to 18 carbon atoms are, in addition, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl octadecyl, and isomeric forms thereof.

Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, which includes alkyl-substituted cycloalkyl, cyclopropyl, 2-methylcyclopropyl, 2.2- di methylcyclopropyl, 2.3- diethylcyclopropyl, 2-butylcyclopropyl cyclobutyl, 2- methylcyclobutyl, 3- propy1cyclobuty 1, 2,3,4-tr iethy1cyclobuty1, cyclopentyl, 2.2- di methyl cyclopentyl, 3-pentylcyclopentyl, 3- tert-butylcyclopentyl, cyclohexyl, 4- tert-butyIcyclohexyl, 3-isopropylcyc!ohexyl, 2.2- dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of phenylalkyl of 7 to 10 carbon atoms, inclusive, are benzyl, are -331- phenylethyl, 2- phenylethyl, 2-phenylpropyl, 4-phenylbutyl, and 3-phenylbutyl.

Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are, in addition 2-(l-naphthylethyl), and l-(2-naphthylmethyl).

Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-tri chiorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-ch1oro-2-methy1pheny1, and 2,4-dichioro-3-methylpheny1.

Examples of alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain, within the scope of CgH2g 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(CH3)2-, -3447284 -ch(ch2ch3)-, -ch2-ch(ch3)-, -ch(ch3)-ch(ch3)-, -CH2-C(CH3)2-, -CH2-CH(CH3)-CH3-, -CHs-CHs-CH (CHsCHsCHa)-, -CH(CH3)-CH(CH3pCH2-CH2-, -CH2-CHs-CH2-C(CHs)2-CHa, and -CH2-CH2-CH2-CH2-CH(CH3)-. Examples of alkylene of one to 9 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, 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 thereof, and including those alkylene groups with one or 2 fluoro substituents on one or 2 carbon atoms thereof, e.g. -CHF-CH2-, -CHF-CHF-, -CHa-CHa-CFa-, -CH2-CHF-CH2-, -CH2-CH2-CF(CHa)-, -CH2-CH2-CF2-CH2-, -CH (CH3) -CH2 -CH2 -CHF -, -CH2 -CH2 -CH2 -CHs -CFa -, -CHF-CH2-CH2-CH2-CH2-CHF-, -CF2-CHa-CH2-CH2-CH2-CHs-, -CH2-CH2-CH2-CF2-CH2-CH2-, and -CH2-CH3-CH2-CH2-CHa-CFa.

Examples of as defined above are phen yb (ο-, m-, or p-)tolyl, (ο-, m-, or p-)ethylpheny1, (ο-, m-, or p-)propylphenyl, (ο-, m-, or p-)butylphenyl, (ο-, m-, or p-)i sobutylpheny1, (ο-, m-, or p-)tert-butylphenyl 2.3- xylyl 2.4- xylyl 2.5- xylyl -3530 2.6- xylyl, . з, 4-xylyl, 2.6- di ethylpheny1, 2-ethyl-p-tolyl, 4-ethyl-o-tolyl, - ethyl-m-toly1, 2- propy1 -(ο-, m-, or p-)tolyl, 4-butyl-m-tolyl, 6- tert-butyl-m-toly1, 4-isopropyl-2,6-xyly1, 3- propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenyl, (ο-, m-, or p-)fluorophenyl, 2-f1uoro-(ο-, m-, or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (ο-, m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5-, or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4- chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dlchlorophenyl, 4-chloro-3-fluorophenyl, (3-, or 4-)chloro-2rfluorophenyl, и, u, ct-tri f1uoro-(o-, m-, or p-)tolyl, (ο-, m-, or p-)methoxyphenyl, (ο-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, and 2,4-dichloro(5- or 6-)methoxyphenyl. -364 7 2 8 4 Referring to Chart A, the starting materials of formula IX are known in the art or are readily available by processes known in the art. For example, see Derwent Farmdoc Abstract No. 46957Y or U.S. Patent No. 4,081,478.

See also Derwent Farmdoc No. 5751 1Y,· As to 4,5-cis-didehydro-PGF1a and its derivatives, see for example U.S.

Patent Nos. 3,933,889, 3954,835, and 4,028,419.

As to ether-bonded blocking groups such as tetrahydropyranyl or ethoxyethyl and others within the scope of Ri3, see for example Corey et al., J. Ain. Chem. Soc. 92, 397 (1970).

When Ri3 is carboxyacyl, for example benzoyl, it is preferred that such groups be introduced on the halo compound III using methods known in the art. Thus benzoyl chloride is reacted with the formula-ΠΙ compound in the presence of a tertiary amine such as pyridine at 20°-60° C. in an inert solvent such as benzene, toluene or chloroform. See U.S. Patent No. 3,778,450. Likewise blocking groups such as tetrahydropyranyl and ethoxyethyl may be intro20 duced on the halo compound III by methods known in the art. For tetrahydropyranyl groups, for example, 2,3-dihydropyran is used in an inert solvent such as methylene chloride at 20°-50° C. in the presence of an acid condensing agent such as p-toluenesulfonic acid. See U.S. Patent No. 3,944,593.

In step a of Chart A, the starting material IX is subjected to halogenation and cyclization to yield the formula-1 halo compounds. For this purpose there are various methods available. For the iodo compounds there may be used an aqueous system containing iodine, potas-3747284 sium iodide, and an alkali carbonate or bicarbonate, or an organic solvent system such as diehloromethane containing iodine in the presence of an alkali metal carbonate. The reaction is carried out at temperatures below 25° C., preferably about 0-5° C. for 10-20 hours. Thereafter the reaction is quenched with sodium sulfite and sodium carbonate and the formula-1 I I compound separated from the reaction mixture.

For the bromo compounds, N-bromosuccinimide or N10 bromoacetamide are useful. See Fieser et al,, Reagents for Organic Synthesis, Vol. 1, pp. 74 and 78, Vol. IV, p. 51j John Wiley and Sons, Inc., N.Y. For the chloro compound various methods are available, for example exchange of bromo with chloro with the silver salt of chiorodif1uoroacetic acid. See I. T. Harrison et al., Compendium of Organic Synthetic Methods, p. 246, 1971, Wiley Interscience, N.Y.

The formula-I halo compounds are obtained as two isomers, one in minor and the other in major quantity, differing in their chromatographic mobility.

These C-5 and C-6 isomers are separable by silica gel chromatography, yielding on elution, e.g. with methylene chloride (i5-50%)-acetone, first the less polar (5S,6S) or (4S.5S) isomer in about 8% of the total, and, second, the more polar (5R,6R) or (4R,5R) isomer.

Normally these isomers need not be separated, as either one yields the desired products in step (b) of Chart A.

In step b of Chart A the halo compound III is converted to an equilibrium mixture of the 6-keto -3847284 compound X and the 6-hydroxy compound XI by contacting with silver carbonate and perchloric acid. The reaction is done in an inert organic medium such as tetrahydrofuran and is followed with TLC to determine com5 pletion, normally in 15-24 hours at about 25° C. The reaction is preferably done in absence of light.

Although the product of step b normally contains compounds X and XI, further equilibration may be accomplished merely by preparing a solution of that product 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.

In optional step c of Chart A, the products of step b are freed of blocking groups within the scope of R13 if present from the initial starting materials of formula IX, to yield the formuia-l and -II compounds. For this purpose methods known in the art are used, for example mild acid hydrolysis for tetrahydropyrany1 and similar ether-bonded groups, using dilute acetic acid, aqueous citric acid, or aqueous phosphoric acid in a mutual solvent such as tetrahydrofuran. For carboxyacylates, mild deacylating agents are used, for example potassium carbonate in methanol at about 25° C.

A preferred method of preparing amides of formulas OH H H , ,, I R20 V -- W—C-CH2-L-C-N (Rg) (Rie --/4''''X-C-R4 XV -3947284 CHART Β (a) XVI I ψ Ri9 0 CH-L-C-N(Rs)(Rle) (b) XVI 11 -w~c-ch2-l-c-n (r9)(r18) x-c-r4 II Q XV and V-O-C-CHs-L-C-N-(Rg)(Rie) XVI X-C-R4 II is by the steps shown in Chart B. In Chart B, the terms L, Q, R4, Rs, Ris, Ris,, V. W. X andx^ have t.he sane meanings as defined above.

Halo acid XVII is converted to amide XVIII, e.g. by way of a mixed anhydride. For this purpose, compound XVII is treated with isobutyl chloroformate in the presence of a tertiary amine such as triethylamine and thereafter with an amine of the formula HN(Rg)(RiS) wherein Rs and Rig are as defined herein. The halo amide XVI I I is then subjected to reductive dehalogenation as disclosed herein to form the mixed formula-XV and -XVI products. Optionally those products are separated, as by silica gel chromatography. 2o Reference to Chart C herein will make clear the steps for preparing the formula-IV enol ethers. In Chart C the terms L, Q, Rn R4, Rt8, are as defined for Chart A.

The starting materials XII are known in the art (see 25 references cited above for Chart A) or are prepared by methods desci'.bed herein or known in the art. They differ from the formula-IX compounds of Chart A in that they do not have blocking groups and thereby yield haio intermediates XII) and enol ethers IV free of blocking groups.

If enol ethers corresponding to formula IV but with -4147284 CHART C -4247284 blocking groups are desired, as for transformation to other useful compounds, they are obtained by replacing compounds XII or XIII with suitably blocked compounds or by simply reacting the formula-IV compounds with suitable reagents. If the blocking groups are to be ultimately removed to yield a formula-IV type product, it is preferred that they be not ether-bonded groups such as tetrahydropyranyl which normally are removed by acid hydrolysis. Contact of a formula-IV type product with acid readily converts it to a 6-keto compound of formula I.

In step a of Chart C, the starting materials XII are subjected to halogenation or otherwise transformed to the halo compounds of formula XIII, as in Chart A, and as described above.

In step b of Chart C the halo compounds XIII is converted to the formula-IV enol ether compound by contacting it with a dehydrohalogenation reagent. For such reagents see, for example, Fieser and Fieser, Reagents for Organic Synthesis p. 1308, John Wiley and Sons, Inc., New York, N.Y. (1967). Preferred for the reaction of step b are tertiary amines and reagents selected from the group consisting of sodium or potassium superoxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium acetate, sodium or pc-assium trif1uoroacetate, sodium or potassium bicarbonate, silver acetate, and a tetraalkylammonium superoxide of the formula (Ri2)4N02 wherein R12 is alkyl of one to 4 carbon atoms, inclusive.

Of the tertiary amines, preferred amines are -4347284 1,5-di azabi cycl o [ 4.3.0 ] no nene -5 (DBN), 1.4- diazabicyclo[2.2.2Joctane (DABCO), and 1.5- di azabi cyclo[5.4.0 iundecene-5 (DBU).

Other preferred reagents are sodium or potassium super5 oxide and tetramethylammonium superoxide. For further information on the superoxides see Johnson and Nidy, J.

Org. Chem. 40, l68O (1975). For larger scale preparation the electrochemical generation of superoxide is recommended. See Dietz et al., J. Chem. Soc. (B), 1970, pp. 816-820.

Iq The dehydrohalogenation 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 (Florisil ) is preferred over silica gel. Decomposition of the product is avoided by pretreating the column with triethylamine.

As discussed above, the compounds of formula 1, 11, and IV are acini ni s tered in various ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, 'intravaginal1y, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action. -4447284 ί* For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceuti cal carriers are used for oral sublingual administration. For rectal or vaginal administration suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.

It should be understood that although the Charts have formulas drawn with a specific configuration for the reactants and products, the procedural steps are intended to apply not only to the other optically active isomers, but also to mixtures, including racemic mixtures or mixtures of enantiomeric forms,, If opticallyactive products are desired, optically active 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.

Compounds within the scope of formula I, II, 111 or IV are transformed from one to another by methods known in the art. Accordingly, the compound of formula V, a compound within the scope of formula I wherein (ίζο) i s -4547284 OH is transformed to another formula-1 compound wherein is another ring within the scope of , for example an 11-deoxy compound, by methods known or described herein. A compound wherein the Ci3-C14 group is trans-CH=CH10 is transformed by known methods to another compound wherein the Ci3-Ci4 group is cis-CH=CH-, -C^C-, or -CH2CH2-. For example, -C-C- is obtained by selective bromination and dehydrobromi nati on.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention is further illustrated by, but not limited to, the following examples.

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a PerkinElmer model 421 infrared spectrophotometer. Except when 20 specified otherwise, undiluted (neat) samples are used.

The NMR spectra are recorded on a Varian A-60, A-6OD, T-60 or XL-1OO spectrophotometer in deuterochloroform solu tions with tetramethylsilane 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 an LKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ev.), and samples are usually run as TMS (trimethylsilyl) derivatives.

Brine, herein, refers to an aqueous saturated sodium -4647284 chloride solution.

DBN, herein, refers to l,5-diazabicyclo[4.3.0]non e.ne-5.

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

DBU, herein, refers to 1,5-diazabicyclo[5.A.O]undecene-5.

E and Z, herein, follow Blackwood et al., cited above.

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.

IS 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 material and impurities.

HPLC,, herein, refers to high pressure liquid chroma20 tography.

Concentrating, as used herein, refers to concentration under reduced pressure, preferably at less than 50 mm. and at temperatures below 35° C.

DIBAL, herein, refers to diisobutyla 1uminum hydride.

Preparation 1 5^-lodo~9-deoxy-6^,9a-epoxy-PGFi, Amide, less polar and more polar isomers (Formula XVIII: L is -(CHjJs-, Q is H OH R4 is n-pentyl, Ru and Ria are hydrogen, and X is trans-CH=CH-).

Refer to Chart B. A solution of the formula-ill or XVII iodo-ether acid, mixed isomers (Example 4, 5.θ g.) in 50 ml. of acetone is cooled to about -10° C. and treated with 3.0 ml. of triethylamine and 3.0 ml. of 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, el ut i hg wi th‘acetone (25-100$)methylene chloride. There are obtained the formula-XVI11 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 g., having Rf 0.37 (TLC on silica gel in acetone), infrared absorption at 3250, 3150, 1660, l6l0, 1085, IO65, 1050, and 965 cm l, and NMR peaks at 6.4, 5.5, 3.5-4.7 and 0.9 δ.

Preparation 2 5jj-1odo-9-deoxy-6£,9a-epoxy-PGFi, Methylamide, mixed isomers (Formula -484 7 2 8 4 XVIII: R9 is hydrogen and RiS is methyl).

Refer to Chart B. A solution of the formula-III or XVII 5j;-iodo-9-deoxy-6|,9a-epoxy-PGFi, mixed isomers (Example 4, 4.66 g.) in 50 ml. of acetone is treated with 1,42 ml. 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 (50-90½)-methylene chloride, to yield the 5j-iodo-9-deoxy-6J,9a-epoxy-PGFi, methylamide mixed isomers, 3.45 g., having NMR peaks at 6.3, 5.4-5.7, 3.2-4.7, 2.78, and 0.7-2.65 δ.

Preparation 3 5^-lodo-9-deoxy-6^,9«-epoxy-PGFi, nButylamide, Mixed Isomers (Formula XVIII: Rg is hydrogen and Rla is n-butyl) Refer to Chart B. A solution of the formula-III or XVII iodo-ether acid, mixed isomers (Example 4, 5.0 g.) in 50 ml. of acetone is cooled to about -10° C. and I treated with 2.0 ml. of triethylamine and 1.9 ml. of isobutyi chloroformate. After 6 min. there is added a solution of 15 mi. of n-butyiamine in 20 ml. of acetone.

After about 15 min. the reaction mixture is allowed to warm to about 25° C. and stirred for 3 hr. The mixture is concentrated and the residue is taken up in ethyl acetate.

The solution is washed with water and brine, dried over -494728 4 magnesium sulfate, and concentrated. The residue is chromatographed on silica gel, eluting with acetone (5-100/)-methylene chloride to yield the title compound, .3 g. The product is rechromatographed to remove color using silica gel and eluting with acetone-methylene chloride (l:3). From 0.48 g. there is obtained the title compounds as a pale yellow oil, 0.35 g., having Rf 0.63 (TLC on silica gel in acetone), and infrared absorption peaks at 3300, 3100, 1735, 1715, 1645, 1555, 1070, 1055, 1020, and 965 cm'1.

Preparat!on 4 5J-1odo-9-deoxy-6£,9“-epoxy-PGF1, Benzylamide, mixed isomers (Formula XVI 11 : Rg is hydrogen and Rls is benzyl).

Refer to Chart B. Following the procedures of Preparation 1, there are used 4.66 g. of the formula-ill or XVII 5^-iodo-9-deoxy-6£,9a-epoxy-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-9deoxy-6jf-9a-epoxy-PGFl, benzylamide mixed isomers, 4.1 g., having NMR peaks at 7.3, 6.6, 5.3-5.7, and 3.5-4.6 δ. Preparation 5 5^-1odo-9-deoxy-6^,ga-epoxy-PGFj, Anilide, mixed isomers (Formula XVIII: Rg is hydrogen, R18 is phenyl).

Refer to Chart B. Following the procedure of Preparation 1, there are used 4.66 g. of the formula-ill or XVII 5^-iodo-9-deoxy-6£',9a-epoxy-PGF1, mixed isomers, and 0.94 g. of ani1 ine. The crude product is chromatographed on silica gel, eluting with acetone (10-50/)-methylene -5047284 chloride, to yield the 5£-iodo-9-deoxy-6£,9a-epoxy-PGFi, anilide mixed isomers, 4.0 g., having NMR peaks at 8.4, 6.9-7.7, 5.3-5.7, and 3.4-4.7 δ.

Example 1 5j-lodo-9-deoxy-6£,9a-epoxy-PGFi, Methyl Ester Mixed Isomers and Separated Isomers (Formula III: L is -(CH2)3-, Qi is /\ H OH Ri is -COOCH3, R4 is n-pentyl, Ris is iodo, OH and X is trans-CH=CH-).

Refer to Chart A,.step a. A suspension of the formula-IX PGF2a, methyl ester as its 11,15-bis(tetrahydropyranyl) ether (2.0 g.) in 23 ml. of water is treated with 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 l6 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 extracted with chloroform. The organic phase is washed with brine, dried over sodium sulfate, and concentrated to yield mainly the bis(tetrahydropyrany1 ) 30 ether of the title compound; 2.2 g., an oil. Hydrolysis of this ether in acetic acid-water-tetrahydrofuran (20:10:3) yields mainly the title compound, which is further purified by silica gel chromatography. Rf 0,20 (TLC on silica gel in acetone-dichloromethane (30:70)). The mass spectral peaks for the formula-111 compound (TMS derivative) are at 638, 623, 607, 567, 548, 511, and 477.

The above mixed isomers are separated by silica gel chromatography, eluting with methylene chloride (15-50$)acetone. From about 4.0 gram of mixed isomers there are IQ obtained a less polar (5S,6S) isomer, 0.29 g. and a more polar (5R,6r) isomer, 3.36 g. The respective Rf‘s are 0.42 and 0.40 (TLC on silica gel in ethyl acetate).

Following the procedures of Example 1, as illustrated in Chart A, but replacing the formula-IX starting material with the following formula-IX compounds or C-ll derivatives within the scope of formula-IX: -Methyl -PGF2(2 - Ethyl-PGF2a l6,l6-Dimethy1-PGF2a 16,l6-Dif1uoro-PGF2a 16- Phenoxy-17,18,19,20-tetranor-PGF2a PGD2 (alternately ll-deoxy-ll-oxo-PGF2a) 11-Deoxy-PGF2cc 2a,2b-Di homo-PGFso 3-0xa-PGF2a 3-0xa-17-phenyl-18,19,20-tri nor-PGF2a there are obtained the corresponding formula-ill iodo compounds. Those iodo compounds obtained from non-blocked formula-IX compounds are identified by formula XII in Chart C herei n. -5217 2 8 4 Example 2 6-Keto-PGFia, Methyl Ester (Formula I: L, Ri, R4, ancl X as defined in Example 1, and Q is H OH and (R2 and OH 9-Deoxy-6^9a-epoxy-6^-hydroxy-PGFi., Methyl Ester (Formula I I ).

Refer to Chart A, step b. A solution of the formula111 iodo compound, methyl ester (Example 1, 0.45 g.) in ml. of tetrahydrofuran is treated with silver carbonate (0.250 g.) and perchloric acid (70#, 0.10 ml.), and stirred at about 25° C. for 24 hr. The mixture is diluted wi'th 25 ml. of ethyl acetate and the organic phase rs washed with saturated sodium carbonate solution and brine, dried, and concentrated to an oil, 0.4l g. Separation by silica gel chromatography eluting with ethyl acetate-Skel1ysolve B (?:l) yields mainly the formula-1 title compound as a more polar material than the formula-1iI starting materia,. The product is an oil, 0.32 g., having R^ 0.38 (TLC on silica gel in M-2 system (upper layer of ethyl acetatemethanol -water (8:2:5)), 0.20 (in ethyl acetate), and 0.26 in acetone-dichloromethane (l:l)); infrared spectral peak at 1740 cm1 for carbonyl; NMR peaks at 5.5, 3.2-4.8, 3.7, 2.1-2.7, and 0.9 δ; and mass spectral lines (TMS 30 derivative) at 6ΟΟ.3669, 585, 569, 529, 510, 495, 485, 420, -5347284 349, 217, and 173. The product is crystallized with difficulty. Crystals from acetone-hexane have m.p. 50-65° C., from ether-hexane, 68-74° C. The formula-1 I 6-hydroxy compound is also present in the product.

The infrared absorption spectrum of a pasty mull shows bands at 3380, 1740, and 1710 cm'1. The spectrum of a melted sample has bands at 339θ, 1740, 1720, 1245, 1200, 1170, 1090, ¢055, 1020, and 970 cm1.

Following the procedures of Example 2, but replacing the formula-ill iodo compound therein with those formulalil iodo compounds described subsequent to Example 1, there are obtained the corresponding formula-1 and -II keto and hydroxy compounds.

Example 3 9-Deoxy-6^,9a-epoxy-6^-methoxy-PGFi, Methyl Ester A solution of the formuia-l 6-keto compound (Example 2, 0.32 g.) in 10 ml. of methanol is left standing at about 25° C, for 2 days. It is then concentrated and subjected to silica gel chromatography eluting with ethyl acetate (50100$)-Skellysolve B to yield the formula- XIV title compound 0.10 g., having Rf 0.45 (TLC on silica gel in acetone-dichloromethane (1:1)); *H NMR peaks at 5.5, 4.35, 4.0, 3.68, 3.12, and 0.9 fi; l3C NMR peaks at 111.48 and 47.79 ppm. referred to tetramethylsilane; and mass spectral peaks (TMS. derivative) at 512.3498, 527, 511, 510, 471, 452, 439, and 427.

Example 4 5j-lodo-9-deoxy-6^,9a-epoxy-PGF!, Mixed Isomers (Formula III) and 9-Deoxy-6j;,9aepoxy-6j’-hydroxy-PGF1 (Formula I l) and 6keto-PGFia (Formula I).

Refer to Chart A, A solution of the formula-III iodo -54· compound methyl ester (Example 1, 1.0 g.) in 30 ml. of methanol is treated with 20 ml. of 3N aqueous potassium hydroxide at about 0° C. for about 5 min., then at about 25° C. for 2 hr. The mixture is acidified with 45 ml. of 2N potassium acid sulfate and 50 ml. 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-dichioromethane (30:70 to 50:5θ) to yield, first the formula-111 free acid compound and later, the mixed formula-1 and -II compounds as a more polar fraction.

The formula-ill compound is an oil, 0,33 g., having Rf 0.33 (TLC on silica gel in acetone-dichloromethane (1:1) plus 2$ acetic acid), [aJo=4fio° (0=-0.992 in chloroform), infrared spectral peaks at 3360, 2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050, 1015, 970, and 730 cm1, and mass spectral peaks (TMS derivative) at 696.2554, 68l, 625, 606, 569, 535, 479, and 173.

The mixture of g-deoxy-e^ga-epoxy-ejf-hydroxy-PGFi and 6-keto-PGFia is a solid 0.113 g., melting at 93-98° C., containing no iodine, having Rf 0.13 (TLC on silica gel in acetone-dichloromethane (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.

Example 5 (52)-9-Deoxy-6,9a-epoxy-As-PGFl, Amide (Formula IV: L is -(CH2)3-, Q is Z\ H OH , -5547284 Ιί Rj is -C-NH2, R4 is n-pentyl, is OH and X is trans-CH=CH-) Refer to Chart C. A solution of the formula-XIII ?-iodo-9-deoxy-6j’,9tx*epoxy-PGF1, amide (Preparation 1 , 2.46 g.) in 125 ml. of benzene is treated with 5 ml. of DBN in 5 ml. of methylene chloride at 40-45° C. for about l6 hr. The mixture is cooled, diluted with ice water, and extracted with benzene and methylene chloride, keeping a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried, and concentrated. The residue is crystallized from ether-chloroform, obtaining 0.13 g. from 0.25 g., having m.p. 103-106° C., Rf 0.42 (TLC on silica gel in acetone), and infrared absorption peaks at 3440, 3360, 3200, 1690, 1645, 1615, 1315, 1285, 1140, 1090, 1050, and 970 cm’1.

Example 6 (5Z)-9-Deoxy-6,9ct-epoxy-As-PGFj, Methylamide (Formula IV: L, Q, R4, (R^ and X are as in Example 5 and Rt is -C(0)NHCH3).

Refer to Chart C. A solution of the formula-XIII ^-1 odo-9-deoxy-6|,9a-epoxy-PGFi, N-methyl amide, mixed isomers (Preparation 2, 1.2 g.) in 75 ml. of benzene is treated with 3 ml. of DBN at 40° C. for 24 hr. and then at reflux for 3 hr. The mixture Is cooled, diluted with 25 ml. of benzene and washed with ice water. The organic phase -5610 47384 is dried over sodium sulfate and concentrated. The residue is crystallized from acetone-hexane to yield the title compound, 0.27 g.j having m.p. 87-94.6° C., and high resolution mass spectrum (TMS derivative) at 581.37-40.

Example 7 (5Z)-9-Deoxy-6,9a-epoxy-A5-PGFi, n-Butylamide (Formula IV: L, Q, R4, (Rao) > and X are as in Example 5 and Rj is -C(0)NHC4Hg).

Refer to Chart C. A solution of 5£-i°do-6t;,9a-epoxyPGFi n-buty,amide (Preparation 3, 3.5 g.) in 100 ml. of benzene is treated with 8 ml. of DBN at 40-45° C. for about l6 hr. The mixture is cooled, diluted with ice water, and extracted with chloroform, keeping a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried and concentrated to an oil, 3.64 g. Of this, 3.1 g. is taken up in warm diethyl ether, and the ether solution when cooled yields 1.5 g., mainly solid. The product is recrystallized from ether, 0.85 g., m.p. 102-104° C.

Example 8 (5Z)-9-Deoxy-6,9“-epoxy-A5-PGF1, Anilide (Formula IV: L, Q, R4, and X are as in Example 5 and Rt is -C(0)NHCeHs).

Refer to Chart C. A solution of 9-deoxy-6^,913epoxy-PGFi, anilide ((Preparation 5, 1.8 g.) in 100 ml. of benzene is treated with 4 ml. of DBN at 4o° C. for 22 hr. Thereafter the mixture is cooled to about 25° C., diluted with 50 ml. of benzene, and washed with ice water. The organic phase is dried over sodium sulfate, treated with 1 ml. of triethylamine, and concentrated. The residue, 1.8 g., is crystallized from ethyl acetate-hexane and recrystallized from acetone-hexane as the title compound, -574728 4 I I I I 0.58 g., having Rf Ο.38 (TLC on silica gel in acetonemethylene chloride (l:l) with l/ triethylamine), mass spectral peaks (TMS derivative) at 643.3876, and infrared absorption peaks (liquid melt) at 3300, 3140, 3060, 1690, 1665, 1620, l600, 1545, 1500, 1310, 1295, 1255, 1130, 1085, 1045, 970, 755, and 695 cm'1.

Example 9 (5Z)-9-Deoxy-6,9a-epoxy-As-PGFi, Benzylamide (Formula IV: L, Q, R4, (R20) and X are as in Example 5 and Rj is -C(0)NHCH2CeHs).

Refer to Chart C. A solution of 5^-ϊοάο-9-αβοχγ-.6/,9αepoxy-PGFi benzylamide (Preparation 4, 1.8 g.) in 100 ml. of benzene is treated with 4 ml. of DBN at about 40° C. for 22 hr. The mixture is cooled, diluted with 50 ml. of benzene and washed with ice water. The organic phase is dried and concentrated to yield the title compound.

Examp 1e 1Q 6-Keto-PGFia, Amide (Formula 1: L is -(CH2)3-, Q is H OH Rx is -C(0)NHs, R4 is n-pentyl, (r2q) is OH and X is trans-CH=CH-), and 9-deoxy-6j;9aepoxy-6£-hydroxy-PGFi, Amide (Formula Il).

A solution of (5Z)-9deoxy-6,9a-epoxy-As-PGFi, amide (Example 5, 2,0 g.) in 50 ml. of tetrahydrofuran is treated with 3 ml. of 10/ potassium hydrogen sulfate. After 10-20 min. the mixture is concentrated. The residue is taken up -584 7284 in water and ethyl acetate. The solution is saturated with sodium chloride and diluted with acetone (equal in volume to one-fifth of the ethyl acetate). The organic phase is separated and the aqueous phase again extracted with ethyl acetate. The combined organic phases are washed with brine, dried, and concentrated. The residue is chromatographed on silica gel, eluting with acetone (75-1θθ$)-methy1ene chloride to yield a mixture of the title compounds, 0.25 g., having Rf 0.31 (TLC on silica gel in acetone), mass spectral peaks (TMS derivative) at 655.3930, 640, 624, 552, 477, 243, 217, and 173, and infrared absorption peaks at 3360, 1705, 1670, 1620, 1455, 1410, 1090, 1050, and 970 cm'1.

Example 11 6-Keto-PGFia, Methylamide (Formula I: L, Q, R4, (^2°) and x are as 'n ExamP'e and Rj is -C(0)NHCH3), and 9-Deoxy-6jf 9aepoxy-6^-hydroxy-PGFi, Methylamide (Formula ID.

A solution of the formula-IV (5Z)-9-deoxy-6,9a-epoxyAs-PGFt, methylamide (Example 6 , 0.29 g.) in 5 ml. of tetrahydrofuran is treated with about 1 ml. of 5$ aqueous hydrochloric acid and stirred at 25° C, for one hour. The mixture Is diluted with 50 ml. of brine and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, dried over sodium chloride, and concentrated. A second lot is prepared in the same way and the two products are combi ned for chromatography on silica gel. Eluting with acetone (50-100$)methylene chloride yields the title compound, 0,17 g., an oil, having a high resolution mass spectral line at 479.3223 for the TMS-methyl boronate derivative, and NMR -594728 4 spectral peaks at 6.7, 5.3-5.7, 3.5-4.9, and 2.78 δ.

Example 12 6-Keto-PGFia, η-Butyl amide (Formula 1 : L, Q, R4, and X are as in Example 10 and Ri is -C (o)NHC4Hg), and 9-Deoxy-6*,ya-epoxy5 6^-hydroxy-PGFi, n-Butyiamide (Formula Il).

A solution of (5Z)-9-deoxy-6,9“-epoxy-A5-PGF1, nbutylamide, (Example 7 , 3.0 g.) in 25 ml. of tetrahydrofuran is treated with sufficient 10# aqueous potassium hydrogen sulfate solution to bring the pH to 5.0. The Ίθ mixture is concentrated to remove tetrahydrofuran and the residue is taken up in water and ethyl acetate. Sodium chloride is added to saturation and the organic phase is separated. The aqueous phase is extracted with acetoneethyl acetate (l:4) and the organic phases are combined. j 5 The organic phases are washed with brine, dried, and concentrated. The residue, 2.10 g., is chromatographed on silica gel, eluting with acetone (33-100#)-methylene chloride to yield a 1:1 mixture of the title compounds, having Rf 0.57 (TLC on silica gel in acetone).

The mixture is dissolved in 10 ml. of tetrahydrofuran and acidified with aqueous potassium hydrogen sulfate, thereby converting the mixture to substantially all 6-keto-PGFia, n-butylamide, having Rf 0.58 (TLC on silica gel in acetone).

The product is recovered by concentrating the solution, portioning between ethyl acetate and water, washing the organic phase with brine, and concentrating to an oil, 1.90 g., having a high resolution mass spectral peak (TMS derivative) at 641.4258.

Examp1e 13 6-Keto-PGFia, Benzylamide (Formula 1: L, Q, R4, (R2ch and X are as in Example 10 and -6047284 Ri is -C(0)NHCH2CeHs), and 9-Deoxy-6£9«epoxy-6£-hydroxy-FGFi, Benzylamide (Formula ll).

I. There is first prepared the formula-III bis(THP) ether. A solution of the formula-III 5|’-iodo-9-deoxy-6fc,9a5 epoxy-PGFi, benzylamide (Preparation 4, 2.0 g.) in 30 ml. of methylene chloride with 2.5 ml. of dihydropyran and 25 mg. of p-toluenesulfonic acid monohydrate is stirred at 25° C. for 25 min. The mixture is diluted with 100 ml. of methylene chloride and washed with 25 ml. of saturated aqueous sodium bicarbonate solution and 25 ml. of brine. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel eluting with acetone (5-25½)-methy1ene chloride to yield the bis(THP) ether, 2.4 g. having Rf 0.73 (TLC on silica gel in acetone15 methylene chloride (l:l)). il. There is next prepared the formula-1 V enol ether, N-benzylamide, bis(THP) ether. A solution of the bis(THP) ether above, 2.4 g. in 100 ml. of benzene is stirred with 4 ml. of DBN at 40-45° C. for 22 hr. The mixture is cooled, diluted with 25 ml. of benzene, and washed with 25 ml. of ice water. The organic phase is dried and concentrated. The residue consists of the enol ether, i.e. (5Z)-9-deoxy6,9“-epoxy-As-PGF!, benzylamide, bis(THP) ether, having Rf 0.73 (TLC on silica gel in acetone-methylene chloride (l:l)).

It is treated with a solution of 45 ml. of tetrahydrofuran and 5 ml. of 5½ aqueous hydrochloric acid at about 25° C. for 15 min. The mixture is diluted with 50 ml. of brine and extracted with ethyl acetate. The organic phase is washed with brine, dried, and concentrated to yield the 3θ bis(THP) ether of the title compound, 2.0 g., an oil, -6147284 having Rf 0.50 (TLC on silica gel in acetone-methylene chloride (1:1)). 111. The title compound is obtained by hydrolytic removal of the THP groups. The product of part II, 1.0 g., is treated with 20 ml. of acetic acid-water-tetrahydrofuran (20:10:3) at 40-45° C. for 3.5 hours. The mixture is diluted with 30 ml. of water and freeze-dried. The residue is dissolved in methylene chloride and chromatographed on Florisil . Elution with acetone (20-70$) Ιθ methylene chloride yields 0.47 g. of impure product which is again chromatographed on silica gel. Elution with acetone-methylene chloride (50-100$) yields the title compound, 0.34 g., having Rf 0.07 (TLC on silica gel in acetone-methylene chloride (1:1)), and NMR peaks at 7.26, 15 6.6-7.0, 5.2-5.6, 4.2-4.5, 3-5-4.2 and 0.7-3.0 δ.

Example 14 (4R,5R)-4-Iodo-9”deoxy-5,9n_epoxy-PGFi, Methyl Ester (Formula III) and (4S,5S)-4-lodo-9-deoxy5,9a_epoxy~PGFi, Methyl Ester (Formula III).

Refer to Chart A. A solution of iodine in methylene 20 chloride (112 ml., 2.5$, 10.9 mmols) is added dropwise (35 min.) at room temperature to a stirred mixture of the formulaIX cis-A4-PGFia, methyl ester (2.01 g., 5-45 mmole) dissolved in methylene chloride (260 ml.) and a saturated aqueous solution of sodium bicarbonate (92 ml.). The reaction is worked up after 2 hr. by first adding methylene chloride (1300 ml.) and then shaking with aqueous 0.2M sodium thiosulfate solution (80 ml.). The layers are separated quickly and the organic layer washed successively with water (360 ml.), pH 2 buffer (l40 ml.), and water (360 ml.). Following drying over magnesium sulfate, the organic layer is concentrated and the -6247Z84 residue chromatographed over three Merck B HPLC columns. Eluting with acetone-hexane (l;3) yields first (4r,5R)-4iodo-9-deoxy-5,9a-epoxy-PGFi, methyl ester (1.215 g.), as a colorless oil, Rf Ο.38 (TLC on silica gel in acetone-hexane (4O.-6o)); and having mass spectral peaks (TMS derivative) at 638.2308, 623, 567, 548, 517, 511, 477, 451, and 173; 'H NMR signals at 5-50, 3-98, 3-67, and 0.88 δ (CDC13); 13C NMR signals at 173.0, 135-3, 132.4, 79-6, 79.0, 78.1, 72.8, 52.5, 51.6, 42.7, 41.3, 37.1, 34.0, 32.2, 31.7, 25.9, 25.2, 22.6, 10 21.7, and 14.0 δ (COCl3).

Eluted from the column second is (4S,5S)-4-iodo-9_ deoxy-5,9a-ep°xy-PGFi, methyl ester, (0.440 g.) as a crystalline material, fine needles from ether-hexane, m.p. 72-74° C,; Rf 0.32 (TLC on silica gel in acetone-hexane (4θ:6θ)); having 15lH NMR signals at 5-49, 4.34, 4.10, 3-67, and 0.88 δ (CDC13); ‘3C NMR signals at 173-0, 135.8, 132.6, 75-9, 73-0, 71-3, 54.4, 51.7, 41.6, 4o.o, 37.0, 34.2, 31.7, 31.2, 25.2, 24.4, 22.6, 20.7, and 14.0 δ (CDCl3).

Example 15 4^-lodo-9-deoxy-5/i9a_epoxy-PGF1, Mixed Iso20 mers (Formula III) and Mixture of 9-Deoxy* £,9a-epoxy-5^-hydroxy-PGFi (Formula ll) and -keto-PGFia (Formula l).

Refer to Chart A. A solution of the formula-ill iodo compound methyl ester (Example 14,1.0 g.) in 30 ml. of methanol is treated with 20 ml. of 3N aqueous potassium hydroxide at about 0° C. for about 5 min., then at about 25° C. for 2 hr.' The mixture is acidified with 45 ml. of 2N potassium acid sulfate and 50 ml. of water to pH 1.0, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with brine, -6347284 dried over sodium sulfate and concentrated to an oil . The oil is subjected to silica gel chromatography, eluting with acetone-dichloromethane to yield, first the formula-ill free acid compound and later, the mixed formula-I and -ii compounds as a more polar fraction.

Example 16 4^-lodo-9-deoxy-5£,9a-ep°xy-PGFi, Amide, less polar and more polar isomers (Formula XVIII: L is (-CH2)3-, Q is R4 is is n-pentyl iodo, (Rao) R9 and RiS are hydrogen, Rig is OH V is a valence bond, W is methylene, and X is trans-CH*CH-).

Refer to Chart B . A solution of the formula-II I or XVII iodo-ether acid, mixed isomers (Example 15 5.0 g.) in 50 ml. of acetone is cooled to about -10° C. and treated with 3-0 ml. of triethylamine and 3-0 ml. of isobutyl chloroformate. After 5 min. there is added 100 ml. of aceto25 nitrile 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 cv· ;*·>· -644728 4 with acetone-methylene chloride. There are obtained the formula-XVI11 iodo-ether, amide, less polar isomer; a fraction of mixed less and more polar isomers; and the more polar isomer.

Example 17 4^-lodo-9-deoxy-5^,9a-epoxy-PGFi, Methylamide, mixed isomers (Formula XVIII: Rg is hydrogen and Rie is methyl).

Refer to Chart B. A solution of the formula-ill or XVII 4£-iodo-9-deoxy-5£,9a_epoxy-PGFi, mixed isomers (Example , 4.66 g.) in 50 ml. of acetone is treated with 1.42 ml, of triethylamine and cooled to -5° C. Thereupon l.J ml. of isobutyl chloroformate is added, with stirring at 0° C. for 5 min., followed by 25 ml. of 3M methy1 amine 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-methylene chloride, to yield the 4^-iodo-9- deoxy-5jf,9a-epoxy-PGFi, methylamide mixed isomers.

Example 18 4^-|odo-5^,9“*epoxy-PGFi, n-Butylamide, Mixed Isomers (Formula XVi11 : Rg is hydrogen and Rie is n-butyl).

Refer to Chart B. A solution of the formula-ill or XVII iodo-ether acid, mixed isomers (Examplel5, 5.0 g.) in 50 ml. of acetone is cooled to about -10° C. and treated with 2.0 ml. of triethylamine and 1.9 ml. of isobutyl chloroformate. After 6 min. there is added a solution of 15 ml. of n-butylamine in 20 ml. of acetone.

After about 15 min, the reaction mixture is allowed to warm -65to about 25° C. and stirred for 3 hr. The mixture is concentrated and the residue is taken up in ethyl acetate.

The solution is washed with water and brine, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel, eluting with acetonemethylene chlo-ide to yield the title compound. The product is rechromatog-aphed to remove color using silica gel and eluting with acetone-methylene chloride.

Example T9 /-lodo-9-deoxy-5$,9“-epoxy-PGFi, Benzylamide, mixed isomers (Formula XVIII.- Rg is hydrogen and Ria is benzyl).

Refer to ihartB·. Following the procedures of Example there are used 4.66 g. of the formula-ill or XVII 4^-iodo9-deoxy-5)j’,9a“epoxy-PGFi, mixed isomers, (Example 15) and 1.08 g. of benzylamine instead of methylamine. The crude product is chromatographed on silica gel, eluting with acetone-methylene chloride, to yield the 4^-iodo-9-deoxy-5^,9aepoxy-PGFi, benzylamide mixed isomers.

Examp 1e 20 (4Z.)-9*Deoxy~5,9a-epoxy-A4-PGFi, Amide (Formula IV: L is -(CH2)3-, Q is H OH Ri is -C-NH2, R4 is n-pentyl, ί Rao) i s OH V is a valence bond, W is methylene, and X is trans-CHsCH-). -664738 4 Refer to Chart C. A solution of the formula-XIII 4^-iodo-9-deoxy-5^,9«-epoxy-PGFj., amide (Example T(j, 2.46 g. ) in 125 ml. of benzene is treated with 5 ml. of DBN in 5 ml . of methylene chloride at 40-45° C. for about l6 hr. The mixture is coded, diluted with ice water, and extracted with benzene end methylene chloride, keeping a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried, and concentrated to give the title compound.

Example 21 (4Z)-9-Deoxy-5,9a-epoxy-A4-PGFi, Methylamide (Formula IV: L, Q, R4, (Rao), V, W, and X are as in Example 20 and Rt is -C(O)NHCH3).

Refer to Chart C. A solution of the formula-XIII 4^-iodo-9-deoxy-5^,9a’eP°xy-PGFi, N-methylamide, mixed isomers (Example 17, 1.2 g. ) i n 75 ml. of benzene is treated with 3 ml. of DBN at 40° C. for 24 hr. and then at reflux for 3 hr. The mixture is cooled, diluted with 25 ml. of benzene and washed with ice water. The organic phase is dried over sodium sulfate and concentrated to yield the title compound.

Example 22 (4Z)-9-Deoxy-5,9a-epoxy-A4-PGFi, n-Butylamide (Formula IV: L, Q, R4, (r7^( y, w, and X are as in Example 20 and Rt is -C(O)NHC4H9).

Refer to Chart C, A solution of 4*^—ι odo-5<7,9^-epoxyPGFi n-butylamide (Example 18, 3.5 g.) in 100 ml. of benzene is treated with 8 mb. of DBN at 40-45° C. for about 16 hr.

The mixture is cooled, diluted with ice water, and extracted with chloroform, keeping a few drops of triethylamine in the organic phase. The combined organic phases are washed -6747284 with ice water, dried and concentrated to the title compound. Example 23 (4Z)-9-Deoxy-5,9a-epoxy-A4-PGFi, Benzylamide (Formula IV: L, Q, R4, ζκΖο), V, W, and X are as in Example 20 and Ri is -C(0)NHCH2CeHs), Refer to Chart C. A solution of 4iodo-5¾9“-epoxyPGFi benzylamide (Example 19, 1.8 g.) in 100 ml. of benzene is treated with 4 ml. of DBN at about 40° C. for 22 hr.

The mixture is cooled, diluted with 50 ml. of benzene and washed with ice water. The organic phase is dried and concentrated to yield the title compound.

Example 24 5-Keto-PGFia, Amide (Formula I: L is -(0112)3-, Q is H OH Ri is -C(o)NH2, R4 is n-pentyl, \ OH V is a valence bond, W is methylene, and X is trans-CH=CH-), and 9-deoxy-5,9a_ epoxy-5^>-hydroxy-PGFi, Amide (Formula 11).

A solution of (4Z)-9-deoxy-5,9a-epoxy-A4-PGFt, amide (Example 20, 2.0 g.) iη 5θ ml. of tetrahydrofuran is treated with 3 ml. of 10$ potassium hydrogen sulfate. After 10-20 min. the mixture is concentrated. The residue is taken up in water and ethyl acetate. The solution is saturated with sodium chloride and diluted with acetone (equal in volume to one-fifth of the ethyl acetate). The organic phase is separated and the aqueous phase again extracted with ethyl -6847284 acetate. The combined organic phases are washed with brine, dried, and concentrated. The residue is chromatographed on silica gel, eluting with acetone-methylene chloride to yield a mixture of the title compounds.

Example 25 5-Keto-PGFia, Methyiamide (Formula I: L, Q, R4, ^25)» V, 17, and X are as in Example 24, and Ri is -C(0)NHCH3), and 9-0eoxy-5,9*epoxy-5^.-hydroxy-PGFi, Methyiamide (Formula II).

A solution of the formula-IV (4Z)-9-deoxy-5,9«-epoxyA4-PGFi, methyiamide (Example 21', 0.29 g. ) in 5 ml. of tetrahydrofuran is treated with about 1 ml. of 5# aqueous hydrochloric acid and stirred at 25° C. for one hour. The mixture is diluted with 50 ml. of brine and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, dried over sodium chloride, and concentrated. A second lot is prepared in the same way and the two products are combined for chromatography on silica gel. Eluting with acetone-methylene chloride yields the title compounds as a mixture.

Examg_le_26_ 5^-lodo-9-deoxy-6^,9a-epoxy-nethano-PGF1, Methyl Ester Mixed Isomers and Separated Isomers (Formula III; L is -(CH2)a-, Qx is H OH Ri is -C00CH3, R4 is η-pentyl, Rls is iodo, Qis -694728 4 OH V and W are methylene, and X is trans-CH=CH-).

Refer to Chart A, step a. A suspension of the formula-IX 9-deoxy-9a-hydroxymethy1-PGF2a, methyl ester as its 11,15-bis(tetrahydropyranyl) ether (2.0 g.) in 23 ml. of water is treated with 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 l6 hr. at about 0° C. Thereafter a solution of sodium sulfite (1.66 g.) and sodium carbonate (Ο.76 g.) in 10 ml. of water is added. After a few minutes the mixture is extracted with chloroform. The organic phase is washed with brine, dried over sodium sulfate, and concentrated to yield mainly the bis(tetrahydropyrany1) ether of the title compound. Hydrolysis of this ether in acetic acid-water-tetrahydrofuran (20:10:3) yields mainly the title compound, which is further purified by silica gel chromatography.

Example 27 5ty-lodo-9-deoxy-6,!y 9a-epoxymethano-PGF!, Mixed Isomers (Formula III) and 9-0eoxy25 6^.,9“-epoxymethano-6^hydroxy-PGFl (Formula II) and 9-0eoxy-9a-hydroxymethyl-6-keto-PGFla (Formula I).

Refer to Chart A. A solution of the formula-ill iodo compound methyl ester (Example 2&, 1.0 g.) in 30 ml. of 2Q methanol is treated with 20 ml, of 3N aqueous potassium -7047284 hydroxide at about 0° C. for about 5 min., then at about 25° C. for 2 hr. The mixture is acidified with 45 ml. of 2N potassium acid sulfate and 50 ml. 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.

The oil is subjected to silica gel chromatography, eiuting with acetone-dichloromethane to yield, first the formula-ill free acid compound and later, the mixed formula-1 and -II compounds as a more polar fraction.

Example 5 lodo-9-deoxy-6^,9a-epoxymethano-PGFj, Amide, less polar and more polar isomers (Formula XVIII: L is -(CHa)a-, Q is R4 is n-pentyi Rig is iodo, Rg and Ria P20) i s are hydrogen, V and W are methylene, and X is trans-CH=CH-).

Refer to Chart B. A solution of the formula-ill or XVII iodo-ether acid, mixed isomers (Example 27, 1.0 g.) in 10 ml. of acetone is cooled to about -10° C. and treated with 0.6 ml. of triethylamine and 0.6 ml. of isobutyl chloroformate. After 5 min. there is added 20 ml. of acetonitrile saturated with ammonia, and the -7147 28 4 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 (25-100$)methylene chloride. There are obtained the formula-XVl11 iodo-ether, amide, less polar isomer; a fraction of mixed less and more polar isomers; and the more polar isomer.

Example 29 5^-lodo-9*deoxy-6^,9a-epoxymethano-PGFi, Methylamide, mixed isomers (Formula XVIII: Rg is hydrogen and RlB is methyl).

Refer to Chart B. A solution of the formula-1 11 or XVII 5^-iodo-9-deoxy-6_^,9a-epoxymethano-PGFi, mixed isomers (Example 27 , 1.0 9·) ΐn 10 ml. of acetone is treated with 0.3 ml. of triethylamine and cooled to -5° C. Thereupon 0.26 ml. of isobutyl chloroformate is added, with stirring at 0° C. for 5 min., followed by 5 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 (5O-9O$)-methylene chloride, to yield the ^-iodo-9-deoxy-6^,9a-epoxymethano-PGFi, methylamide mixed i somers.

Example 3o 5^-lodo-6^,9a-epoxymethano-PGF!, nButylamide, Mixed Isomers (Formula: XVIII: Rg is hydrogen and Ria is n-butyl).

Refer to Chart B. A solution of the formula-111 or -7217 3 8 4 XVII iodo-ether acid, mixed isomers (Example 27, 1.0 g.) in 10 ml. of acetone is cooled to about -10° C. and treated with 2.0 ml. of triethylamine and 0.38 ml. of isobutyi chloroformate. After 6 min. there is added a solution of 3 ml. of n-butylamine in 4 ml. of acetone. After about 15 min. the reaction mixture is allowed to warm to about 25° C. and stirred for 3 hr. The mixture is concentrated and the residue is taken up in ethyl acetate.

The solution is washed with water and brine, dried over magnesium suifate, and concentrated. The residue is chromatographed on silica gel, eluting with acetone (5-100$)-methylene chloride to yield the title compound.

The product is rechromatographed to remove color using silica gel and eluting with acetone-methylene chloride (1:3).

Example 31 5J-1odo-9-deox y-6 £, 9“-epox y me tha no-PGFt, Benzylamide, mixed isomers (Formula XVII I : Rg is hydrogen and Rib is benzyl ).

Refer to Chart B. Following the procedures of Example 29, there are used 1.0 g. of the formuia-lI I or XVII 5^'-iodo-9deoxy-6jf,9«-epoxymethano-PGFi, mixed isomers, and 0.22 g. of benzylamine instead of methylamine. The crude product is chromatographed on silica gel, eluting with acetone (50-704) -methylene chloride, to yield the 5^-iodo-9deoxy-6^-9t£-epoxymethano-PGFi, benzylamide mixed isomers.

Example i? ^-1 odo-9-deoxy-6|’, 9a-epoxymethano-PGF 1, Anilide, mixed isomers (Formula XVIII: Rg is hydrogen, R1S is phenyl). -7347284 Refer to Chart B. Following the procedure of Example 29, there are used 1.0 g. of the formula-III or XVII -i odo-9-deoxy-6^,9a-epoxy methano-PGFi, mixed isomers, and 0.1 g. of aniline. The crude product is chromatographed on silica gel, eluting with acetone (10-50/)-methylene chloride, to yield the 5^*iodo~9-deoxy-6£,9a-epoxymethano-PGFi, anilide mixed isomers.

Example 33 (5Z)-9-Deoxy-6,9«-epoxymethano-As-PGFi, Amide (Formula IV II Ri is -C-NH; L is -(CH2)3-, Q is H OH R-ί is n-pentyl, (R.-q, is OH V and W are methylene, and X is trans-CH=CH-).

Refer to Chart C. A solution of the formula-XIII 5£-iodo-9-deoxy-62f,9a-epoxymethano-PGFi, amide (Example 28, 2,46 g.) in 125 ml. of benzene is treated with 5 ml, of DBN in 5 ml. of methylene chloride at 40-45° C. for about l6 hr. The mixture is cooled, diluted with ice water, and extracted with benzene and methylene chloride, keeping a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried, and concentrated. The residue is purified by chromatography on Florisil to yield the title compound.

Example 34 (5Z)-9-Deoxy-6,9a-epoxymethano-A5-PGFi, -7447284 Methylamide (Formula IV: L, Q, R4, and X are as in Example 33, and Ri is -c(o)nhch3).

Refer to Chart C. A solution of the formula-XIII ^-iodo‘9deoxy-6^,9a-epoxymethano-PGFi, N-methyIamide, mixed isomers (Example 29,1.2 g.) in 75 ml. of benzene is treated with 3 ml. of DBN at 40° C. for 24 hr. and then at reflux for 3 hr. The mixture is cooled, diluted with 25 ml. of benzene and washed with ice water. The organic phase is dried over sodium sulfate and concentrated. The residue is purified by chromatography on Florisil to yield the title compound.

Example 35 (5Z)-9-Deoxy-6,9a-epoxymethano-A5-PGFi, n15 Butylamide (Formula IV: I, Q, R4, and X are as in Example 33 and Ri is -C(O)NHC4H9).

Refer to Chart C. A solution of 5^-iodo-6^9a-epoxymethano-PGFi n-butylamide (Example 30,3.5 g.) in 100 ml. of benzene is treated with 8 ml. of DBN at 40-45° C. for about 16 hr. The mixture is cooled, diluted with ice water, and. extracted with chloroform, keeping a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried and concentrated. The residue is chromatographed on Florisil to yield the title compound.

Example 36 (5Z)-9-Deoxy-6,9a-epoxymethano-A5-PGFi, Anilide (Formula IV: L, Q, R4, and X are as in Example 33 and Ri is -C(O)NHCeHs). Refer to Chart C. A solution of 9-deoxy-6<^,9a-epoxy30 methano-PGFi, anilide (Example 32, 1.8 g.) in 100 ml. of -7547284 benzene is treated with 4 ml. of DBN at 40° C. for 22 hr. Thereafter the mixture is cooled to about 25° C., diluted with 50 ml. of benzene, and washed with ice water. The organic phase is dried over sodium sulfate, treated with 1 ml. of triethylamine, and concentrated. The residue is purified by chromatography on Florisil to yield the title compound.

Example 37 (5Z)-9-Deoxy-6,9ct-epoxymethano-A5-PGFl, Benzylamide (Formula IV: L, Q, R4, (Rao) and X are as in Example 33' and Rt is -C(O)NHCH2CeHs).

Refer to Chart C. A solution of 5^-iodo-6^., 9ra-epoxymethano-PGFi benzylamide (Example 31 , 1.8 g.) in 100 ml. of benzene is treated with 4 ml. of DBN at about 40° C. for 22 hr. The mixture is cooled, diluted with 50 ml. of benzene and washed with ice water. The organic phase is dried and concentrated to yield the title compound.

Example 38 9-De°xy-9a-hydroxymethyl-6-keto-PGFia, Amide (Formula 1: L is -(CH2)3-, Q is H OH Ri is -C(O)NH2, R4 is n-pentyl, s OH V and W are methylene, and X is trans-CH=CH-), and 9-deoxy-6,9a-7647284 •.. epoxymethano-6^-hydroxy-PGFi, Amide (Formula ID.

A solution of (5Z)-9-deoxy-6,9ct-epoxymethano-As-PGFi, amide (Example 33, 2.0 g.) in 5θ nil. of tetrahydrofuran is 5 treated with 3 ml. of 10$ potassium hydrogen sulfate. After -20 min. the mixture is concentrated. The residue is taken up in water and ethyl acetate. The solution is saturated with sodium chloride and diluted with acetone (equal in volume to one-fifth of the ethyl acetate). The organic 10 phase is separated and the aqueous phase again extracted with ethyl acetate. The combined organic phases are washed with brine, dried, and concentrated. The residue is chromatographed on silica gel, eluting with acetone-methylene chloride to yield a mixture of the title compounds.

Example 39 9-Deoxy-9a-hydroxymethyl-6-keto-PGFi ., Methylamide (Formula I : L, Q, R4, and X are as in Example 37 , and Ri is -C(O)NHCHs), and 9-Deoxy-6,9c:-epoxymethano·6^-hydroxy-PGFi, Methylamide (Formula II).

A solution of the formula-lV (5z)-9-deoxy-6,9a-epoxymethano-A5-PGFi, methylamide (Example 34 , 0.29 g.) in 5 ml. of tetrahydrofuran is treated with about 1 ml. of 5$ aqueous hydrochloric acid and stirred at 25° C. for one hour. The mixture is diluted with 50 ml. of brine and extracted with 25 ethy) acetate. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, dried over sodium chloride, and concentrated. A second lot is prepared in the same way and the two products are combined for chromatography on silica gel. Eluting with acetone30 methylene chloride yields the title compound. -774 Example ¢0 9-Deoxy-9a-hydroxymethyl-6-keto-PGFi ., n Butylamide (Formula I: L, Q, R4, and X are as in Example 37 and Rt is -C(O)NHC4H9), and 9-Deoxy-6,9a-epoxy-6-hydroxy-PGFi, nButylamide (Formula I l).

A solution of (5Z)-9-deoxy-6,9a-epoxymethano-As-PGFg, nbutylamide, (Example 35, 3.0 g.) in 25 ml. of tetrahydrofuran is treated with sufficient 10$ aqueous potassium hydrogen sulfate solution to bring the pH to 5.0. The mixture is concentrated to remove tetrahydrofuran and the residue is taken up in water and ethyl acetate. Sodium chloride is added to saturation and the organic phase is separated. The aqueous phase is extracted with acetoneethyl acetate (l:4) and the organic phases are combined.

The organic phases are washed with brine, dried, and concentrated. The residue is chromatographed on silica gel, eluting with acetone-methylene chloride to yield a mixture of the title compounds.

Examp 1e 43 9-Deoxy-9a-hydroxymethyl-6-keto-PGF! , and and 9*Deoxy-6,9ct-epoxymethano-6-hydroxy-PGFi, Benzylamide (Formula 11).

I. There is first prepared the formula-ill bis(THP) ether. A solution of the formula-ill 5^-iodo-9-deoxy-6^,9«epoxy-PGFj, benzylamide (.Example 31, 2.0 g.) in 30 ml. of methylene chloride with 2.5 ml. of dihydropyran and 25 mg. of p-toluenesulfonic acid monohydrate is stirred at 25° C, for 25 min. The mixture is diluted with 100 ml. of methylene chloride and washed with 25 ml. of saturated aqueous -7347384 sodium bicarbonate solution and 25 ml. of brine. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel eluting with acetone-methylene chloride to yield the bis(THP) ether.

II. There is next prepared the formula-IV enol ether, N-benzylamide, bis(THP) ether. A solution of the bis(THP) ether above, 2.4 g. in 100 ml. of benzene is stirred with 4 ml. of DBN at 40-45° C. for 22 hr. The mixture is cooled, diluted with 25 ml. of benzene, and washed with 25 ml. of ice water. The organic phase is dried and concentrated. The residue consists of the enol ether, i.e. (5Z)-9-deoxy6,9a-epoxymethano-A5-PGFi, benzyl amide, bis(THP) ether.

It is treated with a solution of 45 mi. of tetrahydrofuran and 5 ml. of 5$ aqueous hydrochloric acid at about 25° C. for 15 min. The mixture is diluted with 50 ml. of brine and extracted with ethyl acetate. The organic phase is washed with brine, dried, and concentrated to yield the bis(THP) ether of the title compound.

III. The title compound is obtained by hydrolytic removal of the THP groups. The product of part II, 1.0 g., is treated with 20 ml. of acetic acid-water-tetrahydrofuran (20:10:3) at 40-45° C. for 3.5 hours. The mixture is diluted with 30 ml. of water and freeze-dried. The residue is dissolved in methylene chloride and chromato25 graphed on Florisil . Elution with acetone-methylene chloride yields the title compound.

Preferred compounds of the invention other than those exemplified above are the benzylamide and anilide of 6-oxo-PGF1a; 9-deoxy-65,9a-epoxy-65-hydroxy-PGF^, anilide; and the amide and methylamide of 9-deoxy-6g, 9a-epoxy-methane-6?-hydroxy-PGF1. -7947384

Claims (5)

CLAIMS 1. ,1-dimethylpentyl, 1,1-difluoropentyl, phenoxymethyl or phenethyl. of claims 1 , 2 , 4 and of claims 1, 2, 4 and of claims 1, 2, 4 and of claims 1, 2, 4 add of claims 1, 2, 4 and of claims 1, 2, 4 and of claims 1, 2, 4 and L is 16. 6-Oxo-PGFj^,amide. 17. 6-Oxo-PGF| a ,methylamide. 18. 6-Oxo-PGF·^,benzylamide. 19. 6-Oxo-PCF^ a ,anilide. 20. 5-Oxo-PGF^ a ,amide. 21. 5-Oxo-PGF la ,methylamide. 22. 9-Deoxy-9-hydroxymethyl-6-oxo-PGF^ a , amide. 23. 9-Deoxy-9-hydroxymethyl-6-oxo-PGF^ w ,methylamide. 24. 9-neoxy-9-hydroxymethyl-6-oxo-PGF| a ,benzylamide. 25. 9-neoxy-9-hydroxymethyl-6-oxo-PGF^ a ,butylamide. 26. 9-Deoxy-6C,9α-epoxy-6ξ-hydroxy-PGF 1 , amide. 27. 9-Deoxy-6E,9a-epoxy-6E-hydroxy-PGFpmethyIamide. 28. 9-Deoxy-65,9a-epoxy-6E-hydroxy-PGF 1 .benzylamide. 29. 9-Deoxy-6£,9a~epoxy-65-hydroxy-PGFpanilidc. -845 30. 9-Deoxy-5?,9a-epoxy-5E-hydroxy-PGFj, amide. 31. 9-Deoxy-5?,9a-epoxy-SC-hydroxy-PGFj,methylamide. 32. 9-Deoxy-6£,9a-epoxymethano-66-hydroxy-PGFj, amide. 33. g-Deoxy-GE.Oa-epoxymethano-OC-hydroxy-PGFj, methylamide. 34. 9-Deoxy-6?,9a-epoxymethano-65-hydroxy-PGFj, benzylamide. 35. 9-Deoxy-6?,9a-epoxymethano-6E-hydroxy~PGFj, butylamide. 36. 5E-Iodo-9-deoxy-6ξ,9a-epoxy-PGFj, amide 37. SE-Iodo-9-deoxy-6£,9oc-epoxy-PGFj,methylamide. 38. 5E-Iodo-9-deoxy-6E,9a-epoxy-PGFj,n-butylamide. 39. 5E-Iodo-9-deoxy-6C,9a-epoxy-PGFj.benzylamide. 40. 5C-Iodo-9-deoxy-6E,9a-epoxy-PGF .anilide. 41. 4g-;Iodo-9-deoxy-SE ,9a-epoxy-PGFj .amide. 4Z. 45-Xodo-9-deoxy-55,9a-epoxy-PGFj.methylamide. 43. 4E-Iodo-9-deoxy-5C,9a-epoxy-PGFj,n-butylamide. 44. 4£-Iodo-9-deoxy-5E,9a-epoxy-PGFj.benzylamide. .45. 5?-Iodo-9-deoxy-6£,9a-epoxymethano-PGFj.amide. 46. 5?-Iodo-9-deoxy-6E,9a-epoxymethano-PGFj, methylamide. 47. 5E-Iodo-9-deoxy-6E,9a-epoxymethano-PGFj,n-butylamide. 48. 5C-Iodo-9-deoxy-6C,9a-epoxymethano-PGFj, benzylamide. 49. (5Z)-9-Deoxy-6,9a-epoxy-A 5 -PGFj, ami de. 50. (5Z)-9-Deoxy-6,9a-epoxy-A 5 -PGFj.methylamide. 51. (5Z)-9-Deoxy-6,9a-epoxy-A 5 -PGFj,n-butylamide. 5Z. (5Z)-9-Deoxy-6,9a-epoxy-A 5 -PGFj.anilide . 53. (5Z) -9-l)eoxy-6,9a-epoxy-A 5 -PGF.benzylamide. 54. (4 Z)-9-Dcoxy-5 , Sa-epoxy-A 1 * -PGFj .amide. 55 . (4Z) -9-Deoxy-5,9a-epoxy-A'' -PGFj .methylamide. 56. (4Z)-9-Deoxy-5,9a-epoxy-a-PGFj,n-butylamide. 57. (5Z)-9-Deoxy-6,9a-epoxy-inethano-a 5 -PGFj.amide. 58. (5Z)-9-Deoxy-6,9a-epoxy-methano-A 5 -PGFj.methylamide. 59. (5Z)-9-Deoxy-6,9a-epoxy-methano-d 5 -PGFj,n-butylamide 60. (5Z)-9-Deoxy-6,9a-epoxy-methano-Δ 5 -PGFj,benzylamide. -8547284 61. A compound as claimed in any of claims 1, 2, 3 and 7 substantially as described in any of the Examples. 62. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with 5 a pharmaceutically acceptable excipient. 63. A composition according to claim 62 in which the compound is as claimed in any of claims 1,2,4 and 7 to 60. Dated this 27th day of July 1978. BY: TOMKINS CO., Applicants Agents, (Signed) (1) Qj andQ2 are both hydrogen, (2) Qj and Q 2 together are oxo, or (3) one of Qj and Q 2 is hydrogen or alkyl of one to 4 carbon atoms and the other is -8047284 hydroxy; R 4 is (1) each hydrogen, alkyl of one to 4 carbon atoms or fluorine with the proviso that and alkylene of one to 9 carbon atoms with one to 5 carbon toms in the chain between terminal met yl, (2) _ CR R _ z _ -CRgRg-CgH 2 g-CIi2 wherein Rg and Rg are CRjRg- is not -CFAlkylCR c R,- and the 5 6 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 -CRgRg- and the benzene ring, Rg and Rg are as defined above with the proviso that neither Rg nor Rg is fluorine when Z is an oxygen atom, T is hydroxy, alkyl or alkoxy of one to 4 carbon atoms, flu'orine, 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.,-cis-CH=CII-C 2 llg; X is trans-CH°CH-. cis-CH=CH-, -C=C- or -C1I 2 -CH 2 -; Rg is hydrogen, methyl or ethyl; and Rjg is hydrogen, alkyl of one to 4 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl or (C^alkyl) phenyl.

1. An optically active compound of the formula or a mixture of enantiomers thereof, wherein either A is a- or β-hydroxy, oxo, 5 methylene ,hydrogen or a-hydroxymethyl, in which case the dotted carbon-carbon double bond is absent, or A is absent and the dotted carbon-carbon double bond is present; n is zero or one and h is one or 2; L is (1) 10 -(Clipj-CR^j- wherein d is an integer of from one to S and R 2 and R, are each hydrogen, methyl or fluorine with the proviso that -CR^^- is not -CFMe-, (2) -(Clip -O-(CH 2 ) k - or (3) -(CH 2 ) e ~CH=CH- wherein k is one, 2 or 3 and e is zero or one, provided that e plus h 15 is 2;

2. An optically active compound of the formula -8147284 or a mixture of the enantiomers thereof, wherein Λ, n, h, L, Qp Q 2 , Rp X, R g and R lg are as defined in claim 1.

3. An optically active compound of the formula .0 or a mixture of the enantiomers thereof, wherein either B is a* or 8-0Rp, oxo, methylene, hydrogen or a-CH 2 0Rp, in which case the dotted carbon-carbon double bond is absent, or B is absent and the dotted carbon-carbon double bond is present; Rp is (a) hydrogen, (b) 2-tetrahydropyranyl, (c) 2-tetrabydrofuranyl, (d) a group of the formula 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 by one, 2 or 3 alkyl radicals of one to 4 carbon atoms, either R. r and R,, are the same or different and are each 15 16 hydrogen, alkyl of one to 4 carbon atoms, phenyl or phenyl substituted by one, 2 or 3 alkyl radicals of one to 4 carbon atoms, or Rp and Rp are taken together and are - (CH 2 ) a - or -(CH 2 )0-(CH 2 ) c ~ wherein a is 3, 4 or 5, b is one, 2 or 3 and c. is one, 2 or 3, with the proviso that b plus c is 2, 3 or 4, and Rp -8247284 is hydrogen or phenyl; (f) benzoyl optionally substituted by one to 5 substituents selected from alkyl of one to 4 carbon atoms, phenylalkyl of 7 to 10 carbon atoms, and nitro, 5 the substituents being the same or different when there are 2 or more, provided that not more than 2 substituents are other than alkyl; (g) benzoyl substituted by a (Cj^alkoxy) carbonyl group; 10 (h) naphthoyl optionally substituted by one to 9 substituents selected from alkyl of one to 4 carbon atoms, phenylalkyl of 7 to 10 carbon atoms and nitro, the substituents being the same or different when there are 2 or more, provided that not more than 2 10 substituents on each ring are other than alkyl , or (i) (Cj_yalkyl)carbonyl; R ig is chlorine, bromine or iodine; and n, h, L, Q 3 , Q 2 , R4, X, Rg and R^g are as defined in claim 1. 20

4. A compound as claimed in claim 3 wherein B is Λ as defined in claim 1. 5. A compound as claimed in claim 3 wherein R 13’ if present, is 2-tetrahydropyranyl. 6. A compound as claimed in claim 3 wherein R 13 , 25 if present, is optionally substituted benzoyl, optionally substituted naphthoyl or (C. 1 _ 7 alkyl) carbonyl, as defined in claim 1. 7. An optically active compound of the formula -834738 4 or a mixture of the enantiomers thereof, wherein A, n, h, L, Qp Q 2 , Rp X, Rg and R lg are as defined in claim 1. 8. A compound as claimed in any of claims 7 wherein A is 8-hydroxy. 9. A compound as claimed in ί 7 wherein A is oxo. 10. A compound as claimed in ; wherein A is methylene. 11. A compound as claimed in ί wherein A is hydrogen. 12. A compound as claimed in ι wherein A is absent. 13. A compound as claimed in ; wherein A is α-hydroxymethyl. 14. A compound as claimed in ι wherein A is a-hydroxy. 15. A compound as claimed in claim 14 wherein •-(CH 2 ) 3 -, -CCII 2 ) 4 ~ or -(CII 2 ) 5 -, either Q x and together are oxo or one of and Q 2 is hydrogen, methyl or ethyl and the other is hydroxy, and R^ is n-pentyl,

5. , Dartmouth Road, DUBLIN 6.