CA1184906A - 9-deoxy-5,9-epoxy-prostaglandins - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Processes for preparing dihydro-prostacyclin analogs, which are 9-deoxy-5,9-cyclic ethers of prostaglandin F1.alpha.-type compounds, illustrated, for example, by a compound of the formula

Description

~ 511 BAC,KGROUND OF THE INVENTION
This invention relates ~o products having prosta-cyclin-like struc-ture and to processes for preparing them. In particular this invention relates to prosta-cyclin analogsin which the 5-membered heterocyclic ring oF prostacyclin is enlarged to 6-members wi~h an addi-tional methylene group, and in which the bond between the side chain and ~he heterocyclic ring is a saturated bond instead of a double bond.
Prostacyclin is an organic compound r~lat2d ~o prosta-glandins and identified as 9-deoxy 6,9a~epoxy-~5-PGF1~0 It is particularly charac~erized as an enol ether from its chemical properties. See R.A. Johnson et al,, Prostaglandins 12, 91~ (1976).
The prostaylandins and analogs are well-known organic compounds derived from prostanoic acid which has the foi-lowing structure and atom numbering: ' '7\`~8/~\~COO H
~ B ~ O

As drawn hereinaFter ~he formulas represent a partic-ular optically active isomer having the same absolute con-figur~tion as PGF~a obtained from mammalian tissues.
In the Formulas, broken line attachments to the cyclo-pentane ring or side chain indicate substituents in alpha configuration, i.e, below the plane of the ring or side chain.
Heavy solid line attachments indicate substi~uents in beta configuration, i.e. above ~he plane.
omewh~t rei~ted compounds have been reported by C~

-2 ~511 Pace-Asciak et al., in Biochernistry, Vol. 10, pages 3657-~664 (1971), including, For example:

- ~,L02H
L />
~ ~
) ~,~ I '' OH H
Prostacyclin and prostacyclin-type compound, including derivatives and analogs, are extremely potent in causing various biological responses. For that reason, these com pounds are useful for pharmacological purposes. A few of those biological responses are: inhibition of blood platelet aggregation, stimulation of smooth muscle, inhibition of gas-tric secre,ion and reduction of undesirable gastrointestinal effects from systemic administration of prostaglandin syn-~hetase inhibitors.
Because of thesP biological responses, prostaeyclin and prostacyclin-type compounds are useful to s~udy, pre-vent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in mamrnals, including humans, useful domes~ic animals, pets, and z00109ic31 specimensJ and in laboratory animals~ for example, mice, rats, rabbits, and monkeys.
Prostacyclin and prostacyclin-type compounds are useful whenever it is desired to inhibit platelet aggre-gation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabhits, and rats. For example, these compounds are useful in ~he ~reatment and prevention ~0 ~f myoc~rdial infarcts, ~o treat and preven~ post-~ 6 3511 operative surgery, and co ~reat conditions such as a~h~rosclerosis, arteriosclerosis~ blood ciotting defects dl~e to lipemia, and other clinical conditions in which the und~rlying eti~logy is associated with lipid imbalance or hyperlipidemia Other In vivo applications includeger i atric patients lo prevent cerebral ischemic attacks and long term prophylaxis following myocardial in~arcts and strokes, For these purposes, these compounds are ad-ministered systcmically, e.g., intravencusly/ subcutane-ously, intra~uscularly, and in ~he form of s~erile implantsfor prolonge~ action~ For rapid response, especially in emergency situations, the intravenous route of administra-tion is preferred Doses in the range about 0.01 to about 10 mg. per kg of body weight per d3y are used, the exact dose depending on the age, weight, and condit~.on of the patient or animal, and on the frequency and route of admin-lstration.
The addition of prostacyclin and prostacyclin-type compounds to whole blood provides In vitro applications such as storage of whole blood ~o be used in heart-lung machines. Additionally whole blood containing these com-pounds 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 plate-lets is avoided by the presence of these compounds For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to Lhe blood of thè donor person or animal, to the perfused body ~0 por~ion, attached or detached~ to ~he recipient, or to ~ 511 two or all of those at a total steady state dose of about 0.001-1.0 ~g./ml. of whole blood. These compounds ar~ also useful in preparing platelet-rich concentrates from blood Fc,r use in treating thrombocytopenia or in chemotherapy.
Prostacyclin and pr-ostacyclin-type compounds are extremely potent in causiny stirnulation of smooth muscle, and are also highly active in potentia~ing other known smoo~h muscle stirnulators, for example~ oxytocic agents, e g , oxytocin, and the various ergot `alkaloids including derivatives and analogs thereof. Therefore, they are useful in place of or in combination with less than usual amo~nts of these known smooth muscle stimulators, for e~ampl~, to relieve the symptoms of paralytic ileus~ or to con~rol or ~revent atonic uterine bleeding af~er abortion or delivery, to aid in c~.pulsion of ~he placenta, and during the puerpcrium. For the latter purpose, the compound Is adminis~ered by inLravenous in~usion immediately after abortion or delively at a dose in the range about 0.01 ~o about 50 ~g. per ky. of body wcight per minute u~til the desired ef~ect is obt~ined. Subsequentdoses are given by intravenous, s~bcutaneous, or intramuscular i~njection 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, weigh~J and co~dition of the patient or animal.
Prostacyclin.and prostacyclin--type compounds are also ~seful in mammals, i ncludi ng man and certain useful animals, e.g. dogs and pi gs, to reduce and control excessive gastric secretion, thereby reduce or avoid gastrointestinal ulcer formation, and accelerate the healing of such ulcers al-r~ady present in the gastrointestinal tract. For this ~ 6 35~.1 p~lrpose~ these compounds are injected or infused in~ra-venously, subcu~aneously~ or Intramuscularly in an infuslon dose range abou~ 0~1 ~9O per kg of body ~eight per rninute, or in a total daily dose by injec~ion or infusion in the range abou~ 0.01 ~o about 10 mg. per kg of body weight per day, the exact dose depending on the age, weight, a~d condition of the patient or animal, and on the frequency and route of administration.
Prostacyclin and prostacyclin-~ype compounds are also useful in reducing the urldesirable gastrointestinal effects resulting Çrom systemic administration of anti-inflammatory prostaglandin synthetase inhibitors~ and are used for that purpose by concomitant administration of the prostacyclin or prostacyclin-type compound and the anti-inflammatory prostaglandin syn-thetase inhibitor. See Partridge et al.~
U.S. Pat No. ~781,429, for a disclosure that the ulcero-~enic effect induced by certain non-steroidal anti-inflam-matory agents in rats is inhibited by concomitant oral administration of ~er~ain prostaglandins of the E and A
series, including PGE1, PGEz, PGE3, 13,14-dihydro-PGE1~ and the corresponding 11-deoxy-PGE and PGA compounds. Prosta-cyclin and prostacyclin-type compounds are useful, for example, in reducing the undesirable gastrointestinal ef-fects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifical-ly mentioned in Par~ridye e~ alO, as non-steroidal, anti-lnflammatory agents. These are also known to be prosta-glandin synthetase inhibitors.
The anti-inflammatory ~ nthetase inhibitor, for ex-ample indomethaclnJ Pspirin~ or phenylbutazone Is adminis-~ 3511 tered in any of the ways known in the ar~ to alleviate an in~lammatory condition, for example, in any dosage regimen and by any of the known routes of systemic adrninistration.
The prostacyclin or prostacyclin-type connpound is ad-ministered along with the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of adminis-tration or by a different route. For example, if the anti-inflamma~ory substance is being administered orally, the prostacyclin or prostacyclin-type compound is also a~minis-tered orally, or, alternatively, is administered rectallyin the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example as described in U.S. Patent No. 3,545,439, Alternatively; if the anti-inflammatory substance is being administered rectally, the prostacyclin or prostacyclin-type compound is also administered rectally.
Further, the prostacyclin derivative can be conveniently administered orally or, in the case of women, vaginally.
It is especially convenient when the administration route 20 i5 to be the same for both anti-inflammatory substance and prostacyclin or prostacyclin-type compound to combine both into a single dosage fc,rm.
The dosage regimen for the prostacyclin or prostacyclin-type compound in accord with this treatment will depend upon ~5 a variety of factors, including the type, age, weight, sex and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered -to ~he mammal, the sensitivity of the partic-ular prostacyclin or prostacyclin-type compound to be admTnistered For example, not ev~ry h~man in need of an ~ 3511 anti-inflammatory substance experiences ~he same adverse gastrointestinal effects when taking the substance. The gastrointeStina~ effects will frequently vary substantially i rl kind and degree But it is within the skill of the at-tending physician or veterinarian tQ determine that admin-istration of the anti-inflammatory subs~ance is causing undesirable gastrointestinal efFects in the human or animal subject and to prescribe an effective amount of the prosta-cyclin or prostacyclin-~ype compound to reduce and ~hen substantially to eliminate those undesirable effects.
Pros~acyclin or pros~acyclin-~ype compounds are also useful in the treatment of asthma~ For example, these com-pounds are useFul as bronchodila~ors or as inhibitors of mediators, such as SRS-A, and histamine which are released frorn cells actlvated by an antigen-antibody complex. Thus, these cornpounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchi-ectasis, pneumonia and emphysema. For these purposes, these cornpounds are administered in a variety of dosage forms, e g , orally in ~he form oF ~ablets, capsules, or liquids;
rec~ally in the form of suppositories, parenterally , sub-cutaneously, or intramuscularly, with intravenous adminis-tration being preferred in emergency situations; by inhala-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 body weight are used 1 to 4 times a day, the exact dose depending on the age, weight9 and condi~ion of the patient and on the fre-quency and route of administration For the above use the prostacyclin or prostacyclin-type compound can be combined ~ 35~1 advantageoLIsly with other anti-asthmatic agents~ such as syr~pathomimetics ~isoproterenol, phenylephrine, ephedrine, etc ); xanthine derivatives (~heophylline and aminophylline);
and corticosteroids (AC~H and prednisolone)O
Prostacyclin or prostacyclin-type compounds are e-fFec-tively adminis~ered to human asthma patients by oral inhalation or by aerosol inhalation.
For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenien~ to provide the prostacyclin ingredient in dilute solution, preferably at concentrations oF abc,ut 1 part o~ medicament to form about 100 to 200 parts by wciyht of ~otal 501 U ~ i onO En~irely cc,nventional additives rrl~y be employed to stabilize these solutions or ~o pro-vide isotonic media, for example, sodium chloride, sodium citra~e, ci~ric acid, and ~he like can be employed.
For adminiseration as a self propelled dosage unie for adrninIstering the active ingredient in aerosol form suita-ble for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodi~luoromethane and di-chlorotetl-af luoroethane) together wi th a co-solvent, such as ethanol, flavorîng materials and stabilizers Instead of a co-solvent there can a~lso be used a dispensing agent such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technlque are described fully in U~5. 2 J 868,691 -for exampie.
Prostacycllrl or prostacyclI n-type compounds are use-Ful in marnmalsJ including man, as nasal decongestants and ~r~ us~d for this purpose in a dose range of about 10 ~g.

~ 511 to about 10 mg. per ml. of a pharrnacologically suitable liquid vehicle or as an aerosol spray, both ~or topical appl i cation.
Prostacyclin or prostacyclin-type compounds are also useful in treating peripheral vascular disease in humansO
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 cerebI-ovascular disease, arteriovenous fistulas3 ischemic leg ulcers, phlebitis, venous insufficiency, gan-grene~ 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. ~or these conditions the prostacyclin compounds are administered orally or parenterally via Injection or infusion dîrectly into a vein or artery, intra-venous or intra-arterial injections being pre-ferred The dosages of these compounds are in the range of 0.01-1.0 ~g, administered by infusions at an hourly rate or by injection vn 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 o~ administration Treatment is continued for one to five days, 31though three days is ordinarily suFFicient to assure long-lasting therapeutic action. In the event that systemic or slde eFfects are observed the dosage is lowered below the threshold at which such syste~ic or side effects are observed Prostacyclin or prostacyclin-type compounds are ac--10 ~

~ 3511 cordingly useful for treating peripheral vascular diseases in the extremities of humans who have circulatory insuf-ficiencies in said extremities; such tr-eatment affording re-lief oF rest pain and induction of healing of ulcers.
For a complete discussion of the nature of and clinical manifestations of human peripheral vascular disease and the method previously known of its trea~-ment with prostaglandins see South African Patent No.
74/0149 referenced as Derwent Farmdoc No. 58J400V.
See Elliott, et al.~ Lancet, ~anuary 18, 1975~ pp. 140~ 2.
Prostacyclin or pro~tacyclin-type compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep~ and pigs, at or near term, or in pregnant animals wi~h intrauterine death of the fetus from about 20 weeks to term. For this purpose~ the compound is infused intravenously at a dose of 0 01 to 50 ~y.
per kg. of body weight per minute until or near the termin-ation of the second satge 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 mem-branes have ruptured and natural labor has no~ yet started.
An alternative route of administration is oral.
Prostacyclin or prostacyclin-type compounds are further useful for controlling the reproductive cycle in menstruating female mamrnalsJ including humans. By ~he term menstruating female mamrnals is meant animals which are mature enouyh to menstruate, but not so old ~hat regular menstruation has ceased. For that purpose the prostacyclin cornpound is admin-istered sy5temically at a dose le~el in the ranye 0.01 mg. to about 20 mg~ per kg. of body weight of the female mammal,advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time oF menses or just prior to menses. Intravaginal and intrauterine routes are alternate methods of administra-tion. Additionally, expulsion of an embryo or a fetus is accomplished by similar administra-tion of the compound during the first or second trimester of the normal mam-malian gestation perlod.
Prostacyclin or prostacyclin-type compounds are further useful in causing cervical dilation in pregnant and non-pregnant female mammals for purposes of gynecology and obstet-rics. 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 ~o the uterus Cervical dilation by prostacyclin compounds is also useful In operative gynecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause performation of the uterus, cervical tears, or infections. It is also useful for diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the prostacyclin compound is administered locally or systemically.
The prostacyclin compound, for example3 is admin-7stered orally or vaginally at doses of about 5 to 50 mg.
per ~reatment of an adult female human, with from one to five treat~en~s per 24 hour period. Alternatively the compound is administered intramuscularly or subcutaneously at doses of about one to 25 mg. per trea~ment. The exact ~ 3511 dosages for ~hese purposes depond on the aye, weightJ and condition of the patient or animal Prostacyclin and prostacyclin-type compounds are further useful in domes~ic animals as in abortifacients(especially for feedlot heifers), as an aid to estrus detection, and for regulation or synchronization of estrus. Domestic animals include horses, cattle, sheep, and swine. The regulation or synchronization of estrus allows for more efficient management of both conception and labor by enablin the herdsman to breed all his females in short pre-defined intervals. This synchronization results in a higher per-centaye of live births than the percentage achieved by natural control. The prostacyclin compound is injected or applied in a feed at doses of 0.1'-100 mg. per animal and may be combined with other agents such as steroids.
Dosing schedules will depend on the species treated. For example, mares are given the prostacyclin compound 5 to 8 days after ovulation and return to estrus. Cattle are treated at regular intervals over a 3 week period to advantageously hring all into estrus at the same time.
Prostacyclin or prostacyclin-type compounds increase the flow of blood in the mammalian kidney, thereby increas-ing volume and electrolyte content of the urine. For that reason, these compounds are useful in managing cases of renal dysfunction, especially those involving blo~kage of the renal vascular bed. Illustratively, these compounds are useful to alleviate and correct cases of edema result-Tng, for example) from massive surface burns, and in the management of shock. For these purposesJ these compounds are preferably first administered by intravenous injection at ~13-~ 3511 a dose in the ran~e 10 to 1000 ~g. per kg. of body weight or by intravenous infusion a~ a dose in the ranye 0.1 -to 20 ~9.
per kg of body weight per minute until the desired efFect is obtained. Subsequen~ doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 ~o ~mg. per kg. of body weight per day.
These p~ostacyclin or prostacyclin-type compounds are usefu1 for treating proliferating skin diseases of man and domesticated animals, including psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinornas of the skin, lamellar ichthyosls, epidermolytic hyperkeratosis, premalignant sun-induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in dornestlcated animals. These compounds alleviate the symptoms of these proliferative skin diseases: psoriasis~ for example, being alleviated when a scale-free psoriasis lesion is noticeably decreased in thickness or noticeably but incompletely cleared or completely cleared.
For those purposes, these compounds are applied topically as compositions including a sui~able pharma-ceutical carrier, for example as an oin~ment~ lotionJ
paste, elly~ spray, or aerosol~ using topical bases such as petrolatum, lanolin, polye~hylene glycols, and alcohols. These compounds, as the acti~e ingredients;
constitute From about 0.1'~ to about 15~ by weight of the composition~ preferably from about 0.5% to about 2~.
In addi~ion to topical administration, injection may be employed, as intradermally, in~ra- or perilesionally, or ~ J~ 3511 subcutaneously, usiny appropria~e sterile saline composi~ions.
Prostacyclin or prostaeyclin-type compounds ~re useful as ~n~iflammatory agentS f or inhibiting chronic inflammation in mammals including the swelling and other unpleasant ef-fects thereof usin~ methods of treatment and dosages gener-al ~y i n accot-d with U.S. Patent No. 3,885,041.

SUMMARY OF THE I NVENT I ON
It is the purpose of this invention to provide novel products having pharmacological activity. It is a further purpose to provide processes for preparing ~hese pr-oducts and their intermediates.
The presently provided cyclic ethers include compounds olf the fol lowi ng formula:
1.5 O- -- CH ., CH2 -L -R30 /
~22~C~2)Z

wherein L is (1) a va1ence bond, (2) -(CH2~d- wherein d is one to 5 inclusive, (3) -(CH2)t-CF2- wherein t is one, 2, or ~J (41 -CH=GH-A- wherein A is a valenee bond or -(CH?)h- wherein h is one, 2, OIA 3, or (5) -CH2-O CH2-Y-25 wherein Y i6 ~ valence bond or (CHz)k- wherein k is one or 2; wherei n Q2 i s O , H ~ , R~ OR~ , or R3 OR~

~i wllerein R3 is l~ydrogcn or alkyl Or onc to 4 cal-bon atoms, inclusi\/e, ancJ wl~erein R~ is llytlrrJc3en, tetral-yc~rop/ranyl, tetrahydrofuranyl, 1-etlloxyetl7yl ol- a 910Up Or the formula ~a - O - C----C - R
~9 R ~0 ~/herein R~ is alkyl of onc ~o l~3 COIl~OIl atolns, inclusive 10 cycloalkyl or 3 to 10 carbon ato~lls, inc~lusive, ar~lkyl of 7 to 12 carbon atolns, inclusi~Je~ pllcnyl3 or phenyl sub-stit~Jted ~/itl~ one, 2, or 3 alkyl o~ one to 4 carbol atoms, inclusive, Jherei n R~ and Rlo are tl~e same vr di frerent9 bein~ hydroyen, alkyl of one to ~ cal~on atoms, inclusi~Je, 5 phenyl or phenyl substi tuted wi tl~ one, 2, or ~ alkyl of one to 4 carl~on atoms, i nc lus i ve, or, wllen R~ and R lO are taken toge~ller, - ~C~2 )a - or - (C112 )~)-0 - (CH2 )c- wllerei n a i s 3, ~1, or 5, l~ i s one, 2, or 3, and c is one, 2, or 3 h the provi so that b ~lus c i s 2, 3, or 4, and wherei n 20 R l l i s hy(Jrogen or pheny l;
herei n (~j i s <~ ~ ~ or <~
, , CH20R 4 erei n n~ i s as defIned al~ove;
erei n K?5 i s C -C~H29 -Cl-13 ; R6 ~.~helein C9~12g is all~ylerle Or one to 9 carbon atoms, in~lu-Siv~, with one tQ 5 carboll clto~lls, inclusive, in the chaln be ~ween -CRsRfi - a~ld ternli na l mc tl~y l, ~/here i n Rs and P~; are 0 hydrogen, al l<yl of one to l1 cal bon atol-ls, i nclusi ve, or ~1uoro, being the sam~ or cli~r~:rent, ~ith the proviso that une of ~s ~r.d R6 iS rluoro ol-ly wl~cn the otller is hydrogen or f l uoro Rs (2 ) -I Z,~( T )s r~ G

~ ereln 5~; an~J Rc, are as (Jeri~letJ al~ove ~ith tlle proviso ehat nni tllel- Q~; nor R~3 is r luoro wl~cn Z i s oxa ( -0~ herei n Z
represcnts an oxa a~om (-0-) or CjHz; wllerein ~jH2j is a valence bond or alkylene Or one to 9 carl~on atorns, incl~t-sive, subst~tuted with zero, one. or 2 fluoro/ ~ith one to 6 carbon atoms~ inclusive between -CR5R6- and the phenyl i~ing; ~/herein T is alkyl of one to 4 c~rbon atorns, inclu-s i ve, r luoro, CI1101 OJ tri F luorol~etllyl, or -OR, - wherei n R7 is alkyl of one to ~I carl~on ~3tc1ms, inclusive, and s is zcro, one, 2, or ~3! With tlle l~rO\~'iso tl-3t not more than two T ~ s arc oth~r tllan a I ky I .3~l~1 wl~cn s i s 2 or 3 the T ' 5 3o are ~i tl-~r tl-e s~ e ol~ tJi f~erent or ~5:L~

, (~) -C~12 ,CH2CH~
~C=C~

5 wllorei n R30 i s ( 1 ) -COOR l 9 (2 ) -C~20~

(3) C~12N(RI~)2 O
( 4 ) -C -~ 113 )2 or ~H -~1 (5) r~ 1' ~ N

wherein Rlg is (a) alkyl of one ~o 12 carborl atoms, incltJ.~ e, (b) cycloalkyl of 3 to 10 carbon atoms, I nclusivc, (c ) ar~lkyl of 7 to 12 carbon atomsj in-clusi~e, (d) phenyl, (e) F~l~enyl substitueed with .
on~, 2~ or 3 chloro or al kyl of one to 4 carbon a~3ms~
inclusive;

O O
N H - C ~ N H - C - C H 3, ~0 (h ) ~3N1~-C-CI13, 'P'~;if' ~ 511 (I) ~ ~ N~-C-N~z , (~ 'C~-N-M~-C~ z, (k ! `~_"

o herein R 3~ is ph~nyl, p-bromophenyl, p-bipheny1yl, p-nitrophenyl, p-b~nzamidophcnyl, or 2-naphthyl. and wherein R3s i 5 hydrogen or benzoyl J
(m) hydrogen~ or (n) a pharmacological ly acceptable ca~ion; and wherein R18 is hydrogen, alkyl of one to 12 carbon atoms~ inclusive, benzyl, or phenyl, being the same or different;
wherei n X i s ci s - or ~rans-CH=C~-, -C-C-, or -CH2CH2-; and whereinr~J indicates attachment in alpha orbeta configura-~ion; including the lower alkanoates thereof-By way of illus~ra~ion, formula lll represents 9-deoxy-5~J9a epoxy-2,3-dinor-15(S)-15~methyl^PGF1, when L
Ts a valence bond, ~2 i 5 3~ ~ is ,~;

~ 511 t OH

R25 is n pentyl, R30 is -COOH~ and X is trans-CH=CH-, and is a compound represented by the formula:

~ OH2-COOH
CH
~ -CH2 ~2 iV

~H,C--C/
0 1~ C~- C 5 H

Formula lll represents 9-deoxy-5~,9a-epoxy-PGF1, methyl ester, when L is ethylene, Q2 is ,~, H OH, 20 (~ is ~' OH
RZ5 is n-pentylJ R30 is -COOCH3, and X is trans-CH=CH-, and is a compound represented by ~he formula 3o ~CH2-(CH2)2-COCCH3 ~' -CHz ~ 2 ~C/
OH H \C- C5H11 0~1 Included within the scope of ~ in formula lll, and following the 2 bove nomenclature, are 11~ compounds, 1l-deoxy-11-oxo (PGD) compounds, 11 -deoxy ~ methylene com-pounds, 11-deoxy compounds, 11-deoxy-10~ di dehydro com-pounds, and 11 -deoxy -11 -hydroxymethyl compounds.
Considering the scope of R30 in -formula Iîl, there ~re included acicls, esters, salts, 2-decarboxy~2-hydroxymethyl compounds, amides, and 2-decarboxy-2-tetrazolyl compounds.
The carbon atoms in the formulae herein are numbered as for pros~anoic acid (I)~ except that ~he carbon atoms in longer or shorter side chains are named, following the usual convention, as "nor" or l'homo" atorns Thus in com-pound IV above, the -CH=CH- group i s at ~he "13,14" posi-ticn and, in the upper side chain, C-2 and C-3 are "nor" atoms. See N.A. Nelson, J. Medicinal Chem. 17~ 911 (1974)o ~ttachment to the ~ ri ng is always at C 8J
C_9J and C-12.
For those compounds of formula lll ~herein Q2 is o'"

i,e. wherein the C-15 hydroxyl or ether group is attached to th~ side chain in alpha configuration, the configuration at ~511 C-15 is identical to that oF the nat~lrally occurriny prostaglandins such as PGE1 obtained from mammalian tissues.
The 15-epimer compounds are represented by formula l!l when Q2 is and are identified variously as "15-epi", or "15~"
by the approprîate 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. 41, 116 (1964).
Included within these ~ormula-lll compounds are the isomers wherein ~ is in alpha or beta configurationi The nomenclature for these isomers may refer to "a" or "~" sub-stitution at C-6 or, preferably, it may follow the "R" and 1~ "S" usage, for which see R.S. Cahn,and N A, Nelson, both cited above.
Although these formulas represent specific optical isomers, it is intended that the compounds are clalmed not only in their purified form but also in mixtures, including racemic mixtures or mixtures of the enantiomeric forms.
With regard to formula lll, 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 8 carbon atoms, inclusive, are those given above and pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. Examples of alkyl of one to 18 carbon atoms, inclusive,are those given above and nonyl, decyl; undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and isomeric forms thereoF. Examples 3o of cycloalkyl of 3 to 10 carbon atoms, inclusive, which in-cludes alkyl-substituted cycloalkyl, are cyclopropyl, 2 methylcyclopropyl 3 2,,2-dime~hylcyclopropyl, 2,3-diethylcyclopropyl, 2-bu~ylcyclopropyl, cycl,obutyl, 2~methylcyclobutyl, 3-propylcyclobu~yl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert-butylcyclopentyl, 1~ cyclohexyl,

4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-din~thylcyclohexyl, cycloheptyl J
cyclooctyl, cyclononyl~ and cyclodecyl.
Examples of aralkyl of 7 to 12 carbon atoms, inclusiveJ
are ben2yl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, ~ ~ & ~ 3511 2~ naphthylethyl), and 1-(2-naphthylmethyl~.
Examples of phenyl substituted by alkyl of one to 4 carbon atoms, inclusive, are (o-, m-) or p-)tolylJ
p-ethylphenyl J
p-tert-butylphenyl, and 2,5-dimethylphenyl, Examples of alkylene of one to 9 carbon atoms, inclu-sive, with one to 5 carbon atoms, inclusive, in the chain, within the scope of CgH2g as defined aboveJ are methylene, ethylene, trimethylene, tetrame~hylene, 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-, -CH(CH2CH3)-, -CH2-CH(CH3)-, -CH(CH3)-CH(CH3)-, -CHz-C(CH3)2-, -CH2-CH(CH3~CH3-, -CH2-CH2-CH(CH2CH2CH3)-, -ÇH(CH3)-CH (CH3 ) -CH2 -CHz -, -CHz -CH2 -CH2 -C ( CH 3 )2 -Ctl2, and -CH2-CH2-CH2-CH2-CH(CH3)-. Examples of alkylene of one to 9 carbon atoms3 inclusive, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms in the chain, with-~n the scope of CjH2; as defined above, are those given above For CgHzg and hexamethylene, including hexamethylene with one or more alkyl substituents on one or more carbon atoms therebf, and including those alkylene groups with one or 2 fluoro substituents on one or 2 carbon atoms ~hereof, e, 9. -CHF -CH2 -, -CHF-CHF-, -CH2 -CH2 -CF2 -, -CH2 -CHFWCH2 -, -CH2 -CH2 -CF (CH3 ) -, -CH2 CH2 -CF2 -CH2 -, -CH(CH3 ) -CH2 -CH2 -CHF -, -CH2 -CH2 -CH2 -CHz -CF2 -, -CHF -CHz -CH2 -GH2 -CH2 -CHF -, -CF2 -CH2 -CH2-CH2 -CHz -CH2 - , -CH2-CH2-CH2-CF2-CH2-CI12-, and -CH2~CH2-CH2-CH2-CH2-CF2.

~ 6 3511 Examples of ~ ~ (T~s as defined 2bove are plleny 1, (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyi, (o-, m-, or p-)propylphenyl, (o-, m-, or p-)bu~ylphenyl, (-I m-, or p-)isobutylphenyl, (o-, m-, or p-)tert-butylphenylJ
2,3-xylyl, 2,4-xylyl, 2,5-~ylyl, 2,6-xylyl, 3,1~-xylyl, 2,6-diethylphenyl~
2-ethyl-p-tolyl, 4-ethyl-o-tolyl,

5-ethyl-m-tolyl, 2-propyl-(o-, m-, or p-)tolyl, 4-butyl-m-tolyl,

6-ter~-butyl-m-tolyl, 4-isopropyl-236-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(o-, m-, or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-, m-, or p-)chlorophenyl, ~ ~ ~ 4 9 ~1~ 351l 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-)dichlorophenyl, 4-chloro 3-fluorophenyl, (3-, or 4-)chloro-2-fluorophenyl J
a,u,a-trj~1uoro-(o-, m-, or p-)tolyl, (o-, m-, or p-)methoxyphenyl, (o-, m~, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, and 2,4-dichloro(5- or 6-)methoxyphenyl.
Included in this invention are the pharmacologically acceptable salts when R19 in -COOR19 of R30 is hydrogen Pharrnacologically acceptable salts o~ these formula-lll compounds useful for the purposes described above are those wi.th pharmacologically acceptable metal cations, ammonium, amine cations~ or quaternary ammonium cations.
Especially preferred metal cations arè those derived from the alkali metals, e.g., lithiumJ sodium and potas-sium, and from the alkaline earth metals, e.g.~ magnesTum and calcium, although cationiç forms o-f other metals, e.g , ; aluminum, zinc, and iron are within the scope of this inventionO
Pharmacologically acceptable amine cations are those derived from primary, secondary$ or tertiary amines Exampies of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylarnine, decylamine, dodecylamine, allylamineJ

~26-~ 3511 crotyian1ine, cyclopentylamine, dicyclohexylarl1inej benzyl-amine, diben~ylamine, ~-phenylethylamine, f3-phenyleLhyl-amineJ ethylenediamine~ diethylenetr-iarnine~ and like ali-phatic, cycloaliphatic, and aralipha~ic arnines containing up to and including about ~8 carbon atoms, as well as heterocyclic amines, e.g,, piperidine, morpholine, pyrrolidine piperazinel and lower-alkyl derivatives thereof, e.g., 1-methylpiperidine~ 4-ethylmorphoiine, 1-isopropylpyrroli-dine, 2-methylpyrrolidine) 1,4-dimethylpiperazine, 2-methyl-piperidine, and ~he like, as well as amines containingwater-solubilizing or hydrophilic groups, e.gA, mono-, di-, and triethanolamine3 ethyldiethanolamine, N-bu~ylethanol-amine3 2-amino-1-butanol, 2-amino-2-ethyl-1,3-proparlediol~
2-amino-2-methyl-1-propanol J tris(hydroxymethyl)aminomethane, M-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine, N-me~hylglycamine, N~methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.
Examp!es of suitable pharmacologically acceptabl~
20 quaternary ammonium cations are tetramethylammonium, tetra-ethylammonium, benzyltrimethylammonium, phenyltriethyl-ammonium, and the 1ike The novel 4,5 dihydro-prostacyclin-type compounds of formula 111 have qualitatively the same pharmacological properties described abc,ve ~or prostacyclin or prosta-cyclin-type compounds and can be used for the same purposes and in the same manner described above. But~ quite sur prisingly~ these novel 4~5-dihydro-prostacyclin-type com-pounds are substantially more specific with regard to potency in causing prostacyclin-like biological responses.

-2~ -~ 511 Therefore each of these novel prostacyclin analogs is more useful than prostacyclin for at least one of the pharma-cological purposes indicated above. Use oF the novel analc,g for that purpose results in sm3ller undesired side effects than when prostacyclin is used for the same purpose.
Moreover, because of its prolonged activity, Fewer and smaller doses of the novel analog can frequently be used to attain ~he desired result.
These 4,5-dihydro-prostacyclin-type corrlpounds are especially useful for inhibi~ion of platele~

aggregation in blood for either In vlvo or In vitro appli-cations described above~
To obtain the optimum combination of biological response specificityJ potency, and duration of activity3 certain compounds within the scope of ~he formulas lll are preferred. For example it is preferred that Q be ~`

wherein it is especially preferred that R3 be hydrogen or methyl, and that R4 be hydrogen.
Another preference for the compounds of formula 11l is that R1~ in -COOR19 be either hydrogen or alkyl of one to 12 carbon atoms~ inclusive, especially one to 4, and more especially methyl or ethyl, for optirnum absorption on ad-ministration, or a pharmacologically acceptable cation.
For oral administration it is preferred that R30 in compounds of formula 1ll be O

-C-N-(R1s )2 wherein R18 is hydrogen, all<yl of one to 12 carbon atoms, inclusive, benzyl,-or phenyl, especially nydrogen or alkyl of one to 4 carbon atoms, and more especially hydrogen or methylJ both Rl~'s being the sarne or different.
When R25 in the compounds of formula lll is I s ~C~CgH2g~CH

3o ~ 3~ 3511 it is preferred that CgH2y be alkylene of 2~ ~, or 4 carbcn a~omsJ and especially tha~ it be tr-imethylene. It is fur~her preferred that R5 and R~ be hydrogen/ methyl, ethyl, or fluoro, being th~ same or di~ferent. It is further preferred, when R5 and R~ are not hydrogen~ that bo~h R5 and R~ be methyl or fluoro. It is especially preferred that R~5 be n-pentyl, 1,1-dimethylpentyl, or 1,1-difluoropentyl.
When R25 in the compounds of formula III is C - ~ ~ S
R~

lt Is preferred that "s" be either zero or one, When "s"
is not zero~ it Is preferred that T be methylJ chlorog fluoro, trifluoromethyl, or methoxy with meta or para attachment to the phenyl ring. When Z is oxa (-0-), it is preferred that R5 and Re be hydrogen, methyl, or ethyl, being the same or different. It is further preferred, when R5 and R6 are not hydrogen) that both R5 anc! R~ be methyl. When Z is CjH2j, it is preferred that CjH2j be a valence bond, methylene, or ethylene. It is especially preferred that R25 be -C2H4~) As to ~ariations in ~ in the compounds of formulas 3~ III 3 Tt is preFerred ~hat ~ be ~ ~ , or As to vari3tions in L in co~pounds of formula lll, it is preferred that L be -(CH2)3-, -(CH2)4~ or -(CH2)s~
and especially -(CH2)3-.
There are also provi ded mercury compounds of the 10 formula ~g-G
,0 5H~C~-I-R30 (CH2 )2 XXX I V
X-C-R~5 wherein G is nitrato, iodo, chloro, bromo, acetato, ~ri-fluoroacetatol or benzoato;
~nd wherein L, Q2~ ~ , R2~, R30, X, and rJ are as de-fined above.
The novel mercury compounds disclosed herein are use-ful for pharmacological purposes. They have antiprotozoal and antisyphilitic activity and are consequently effective in treating streptococci and staphylococci. ~hey have an~i-microbial acti~ity and are useful for topical antiseptic ~re~ment for animals, including humans, useful domestlc enlmal5, petsJ ~oologlcal specimens, and laboraboty an;mals.
They are further useful in ophthalmiatrics.
For these purposesJ these mercury compounds are pre-30 f~rably adrninis~red ~opical ly, for example in alcohol ic -3o -,511 ~lu~ion at 0.002 ~o 0.01~ concentration wi~h a benza1konium chloride as a preservative, or as a lo~ion~ cream3 or oint-ment in 0.5-500~ concentration In combina~ion with the usual pharmaceutically acceptable diluents. The exact applica~
tion and concentra~ion depends on such factors as the ageJ
weight and condition of the subject.
Certain mercury compounds within the scope of formulaXXXiV
are preferred for optimum biological response specifi-city, potency, and duration of activity. For example it is preferred that Q2 be / ~

wherein R4 is hydrogen; it is further preferred that L be trimethylene. When R3 is alkyl, it is preferred that R3 be methyl. Likewise, as to R30, when R19 in -COOR19 is alkyl, it is preFerred that R1a be alkyI of one to 4 carbon atoms, especially methyl. Another preference is that ~ be chloro or acetatcl.
The cyclic ethers of formula III are produced by reac-tions and procedures described and exemplified hereinafter, as shown schematically in the charts.
Chart A will make clear the steps by which a cyclic ether of formula ViI is prepared by starting with a lactone f formula VIII, (a~ reducing that lactone to a lactoI of formula IX, (b) reacting that lactol wit~ an anion derived from a substituted propionic acid or propionate of the formula 3o 35~1 CHART A

P \ C ~2 Vlll ~C=C~ 5 H" \S--C~CgH29~CH3 _CH~OH
~H2 I X
P't ,.H R5 I H" ~C C-CgU2 -CH3 Q

~ (b) ,,CH2 -COOR ~z o~ CH2 `~ CH2 X

C~ ~ H R 5 H~C ~ ~ _C -CgH29~CH3 Ql R~;

~5 ,_,CH2 -COOR~
--t~H
CH2 Vl I

~ C
3 OR 4 \ C--C -C 9H2 9 -CH3 Q Ra ~511 wherei n R42 i s hydrogen or alkyl of one to 8 carbon atoms, inclusive, and R1~ i5 the group -P(C~H5 )3 or -P(o)(oR~2)2 to produce a compound of f ormu l a X, a nd (c) transforming the product of step (b) to the formula-VII compound by methods known in the art, including optional acid hydroIysis of blocking groups R~o3 saponificat70n of ester groups R42, and reesterification as desired within the scope of R41.
In Chart A, the terms CgH29~ R~, R5, R~, and ^~ have the same meaning as for compound III above. In addition~ Q i5 R3 OR4 or R3 OR4 wherein R3 is as def i ned for compound lli, Q1 is ~" , '~
R3 OR 40 or R3 OR40 wherein R40 is the same as R4 def i ned above except -that it does not include hydrogen but includes only ~he blocking groups such as tetrahydropyran-2-yl, R41 is hydrogen, alkyl of one ~o 12 carbon atoms, inclusive, or a pharmacolo~ically acceptable ca~ion, and wherein R42 is hydrogen or alkyl 25 f one to 8 carbon atoms, inclusive.
The formula-VIiI starti ng materials for Chart A are lactone intermediates known i n the art or readily avail-able by processes known i n the ar~. For example3 when R40 is tetrahydrcpyran-2-yl ("7HP") and ~0 ~ 511 -C -C 9~2 g -Cl-~3 R~

is n-pentyl~ see Corey et al., J. Am. Chern. Soc. 92, 397 (1970). When R5 and R~ are methyl or ethylg see U.S. Pa~ent No. 3,954,833. When R5 and R~ ar~ fluoro, see UOS. Patent No. 3,962,293. When Q is CH~ OH

see U.S. Patent No. 3,864,387 and 3,9~1,279.
The Formula-lX lactol is obtained in step (a) on reduction of lactone Vlll without reducing the ethylenic gro~p. For this purpose~ diisobutylaluminum hydride is used as known in the art. The reduction is preferably done at -60 to -78 C.
lhe formula-X intermediate is obtained from the lactol in step (b) by reaction with an anion derived from either a phosphonopropionate of the formula R420CC-CH2CH2-P(O)(OR42)2 X I

or a carboxye~hylphosphonium compound of th~ formula Hal R4200C-CH2CH2-P(C~H5) 3 X l I

wherein R42 is alkyl of one to 8 carbon atoms~ inclusive, and Hal is chloro9 bromo, or iodo. Alternatively, the phosphonium compound may be referred to by its ylid form~

~4-~ 3511 R4200(:;-CH2CH=P(C~5H5 )3 Xlla The reaction is done in the presence of a base, prefer ably potassium t-butoxide or sodium hydride for Xl, or potas-sium t-butoxide, sodium ethoxide~ benzyltrimethylammonium, hydroxide~ or preferably, an alkali metal hydroxide for Xll, usually at 0-25 C.
The formula-VII product is obtained in step (c) on re-placement of the R40 blocking groups wi~h hydrogen, by acid hydrolysis, for example in dilute acetic acid, aqueous citric acid, or aqueous phosphoric acid-tetrahydrofuran. When R
in the product i5 different than R42, transformation is brought about by methods known in the art~ including sapon-ification to yield the acid~ optionally followed by ester-ification. Esters are conveniently prepared by interactlonof the acid wlth an appropriate diazohydrocarbon. For ex-ample, when diazomethane is used, the methyl esters are pro-duced. Similar use of diazoethane, diazobutane, and 1-diazo-2-ethylhexane for example, gives the ethyl, butyl, and 2-~thylhexyl esters, respectively. Of these esters, it ispreferred ~hat R41 be methyl or ethyl.
Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable iner~ solvent~ preferably diethyl e~her, with the acid reactant~ advantageously in the same or a different iner~
diluent. Af~er the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods~ preferably by chromatography. It is preferred that contact of the acid reactants with ~he diazohydrocarbon be no longer than ~ 3~11 necessary to effect the desired esterification, preferably about one to about ten mi nutes, to avoi d undesi red molecu-lar chanyes. Diazohydrocarbons are known i n the art or can be prepared by methods known i n the art. See~ for example Organic ReactionsJ John Wi ley & Sons, inc., New York~ N.Y., Vol. 8, pp. 389-~9~ (~954).
An alternative method for esterification of the acid compourlds herein comprises transform3tions of the free acid to the corresponding silver salt, followed by interac~ion of ~hat salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodideJ and isobutyl iodide. The silver sal~s are prepared by conven-tional methods, for example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometriç amount of silver nitrate.
As for all of the reactions described herein, the duration of the reaction is readily determined by mor,itor~
ing with TLC (thin layer chromatography).
Chart B shows the steps by which a cyclic ether of formula XiI~ as prepared by s~arting with a 4,5-cis-didehydro-PGF1~ type compound of formula XIV, halogenating and cycliz~
ing that formula-XIV compound to f~rm a compound of formula XV, and subjecting the formula XV compound to reductive dehalogenation.
in Chart B, the terms L, Q2, ~ ~ R25~ X and ~ ar~
d~fined as For compound III above In addition R1~ is (1) -COOR 17 ~2) -CHzOH
~o (~) -C~2M(~lB)2 ~511 CHART B

,0~
(~ (CH2 )2~c C/L Rl~ Xl V
H~ \H

l (a) R3~
0--CH~CH -L -R 16 r~' /
~--- (CH2 )2 XV

~ (b) ,0 --CH~ CH2 -L -R 1 ~
(C~12)2 Xlll X-C~R25 3o ~ ~ 3511 (4) -C~N(R 18 )2 or N~-N
(5) -C \ II
\N N
wherein R17 is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloall<yl of 3 to 10 car-bon atoms, inclusiveJ (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ~9) 2-naph~hyl;
wherein R~ is hydrogen, al~yl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or diff~rent;
and R33 is iodo or bromo The staiting materials of formula XIV are 4,5-cis didehydro-PGF1~ type compounds (alternately "~4-PGF2~ type compounds") known in the art or readily available by process-es known in the art As to 4,5-cis-didehydro-PGF1ag 4,5-cis-dIdehydro-15(S) or (R)-15-methyl-PGF1a, 4,5 cis-17,lo-cis-tetradehydro PGF1~g and thelr methyl esters, see U S. Paten~
No. 3~954,835; as to 4,5-cis-didehydro-16~16-dimethyl-PGF
and other analogs wi~hin the scope of Rs -C-CgH29-CH3 R~

see U.S. Pat. No. 3,933,889; as ~o 4,5-cis-didehydro-17-phenyl-18,19,20~trinor~PGF1~, see ~elgian Patent No. 842~275 or Derwent Farmdoc No. 92410X; as to 11-deoxy-11-oxo analogsg see Pelgian Patent No. 846,340, and as to 13,14-eis-CH=CH--3~

analogs~ see ~elgian Patent No. ~44,105 or Derwent Farmdoc No. 05676Y.
As ~o a general method for prep~r i ng 4,5-cis-didehydro-PGF1~ analogs, see U.S. Pa~ent. No. 3~933~889~ particulaI-ly columns 21-23 and ~6-50. Therein a lactol of formula OH

~, XV~

~ RX
~H H

is transformed to a 4,5-cis-didehydro-PGF~ type produc~
by cond~nsation with a Wittig reagen~ derived from a 3-carboxypropyltriphenylphosphonium halide and sodio m~thyl-sulfinylcarbanide Accordingly that method is useful for preparing 4,5-cis-didehydro-PGF1a compounds within the scope of XlV as to R25, including 16-phenoxy-17,18,19,20-tetranor compounds, by using formula-XVI lactols wherein Rx is replaced by R25.
Likewise that me~hod is useful for preparing 4,5-cis-didehydro-PGFla compounds within the scope of XIV as to L
by using an appropriate Wit~ig reagent. For example, 4,5-cis-didehydro-2-nor-PGF1~ is obtained by using (2-carboxye~hyl)triphenylphosphonium bromide, and 4/5-cis-didehydro-2-homo-PGF1~ is obtained by using (4-carboxy-butyl)triphenylphosphonium bromide.
2,2 -di f l uoro-4,5 -ci s -didehydro-P~Fl~ is obtained using a ~-carboxy-2~2-difluoro-propyltriphenylphosphonium halide. That phosphonium compound is available from the ~ 3511 reaction of ~riphenylphosphine and 4-bromo-2,2-difluoro-bu~anoic acid. This fluoro-acid and others within the scope of Br-CH2-(CH2)t-CF2-COOH XXIV

useful for preparing similar 2,2-difluoro-4,5-cis-didehydro-PGF1a analoys are obtained by the steps of Chart C. In Chart C and in formula XXIV, "t" is 1, 2~ or 3; R45 is alkyl of one to 4 carbon atoms, preferably methyl.
With reference to Chart C, the stra7ght chain ~-bromo alkanoic acids of formula XVII are known in the art or may be prepared by methods known in the art. The formula-XVIII
aldehyde is prepared from the formula-XVII acid by methods known in the art. For example~ the formula-XVII acid may be reduced to its corresponding primary alcohol using lithium aluminum hydride, and the resulting alcohol then oxidized to form the formula-XVlil aldehyde by the Collins reagent (CrO3-pyridine).
The formula-XlX cyanohydrin is then formed by methods known in the art, for example, usîng aqueous sodium cyanide, or by sulfite addition reaction. The formula-XX a-hydroxy alIcanoic acid is then formed by methods known in the art, for example using hydrolysis under acidic conditions in dimethyIsulfoxide solvent at reflux temperature. Thereafter ~he formula-XXI a-keto alkanoic acid is formed by oxidation of the formula-XX compound by methods known in the art. For this purpose the Jones reagent may be advantageously usedO
The formula-XXlI es~er wherein R 45 is alkyl of one to 4 carbon atomsS preferably methyl, is then prepared from the formula-XXI acld by known methods described hereîn.

~511 H RT C

B r -C H2 ~ ( C H2 ) t - COOH X V l I

Br-CH2-(CH2)t-CHû XVI I I
0~1 Br -CH2 ~ ( CH2 ) t -C -CN X I X
~I OH
Br -CH2 - ( CH2 ) t -~ -COOH XX

~ O
Br -CH2 - ( CH2 ) ~ COOH XX i ~/ 1l Br -CH2 - ( CH2 ) t -COOR 45 XX

Br -CH2 - (CH2 ) t -CF2 -COOR 45 XX

Br -CH2 - ( CH2 ) t CF2 -COOH XX I V

~ 5 ~511 The Formula-XXIIi ~`-bromo alpha difluoro alkanoic acid ester is then prepared by fluorin~tion, reacting molybdenum hexafluoride and boron trifluoride wi th the formula~XXII
alpha keto alkanoic acid ester. This reaction is advan~a geously carried out in a methylene chloride solvent with reaction temperatures of below -35~ C. Finally the formuIa-XXIV free acid is prPpared by saponification of the formula-XXIII methyl ester.
Other 4,5-cis-didehydro-PGF1~ type s~arting ma~erials within ~he scop of formula XIV are readily available by methods described above or known in the art, Generally they are prepared from lactols of the formula ~ H
0~
~ _/
V

-11-R:~5 wherein Q1~ (~) 9 R25~ X3 and~ are asdefined herein.
These formula-XXV lactols are avai lable from lactones of the formula ~ /
~5 . ~ - C~2 X~VI

X-C R2s whlch are known in the ar~ or readily available by methods fl~
~5 known in the art.
When ~ is ~ ~ ' these 11~ lactones are obtained by isomerizing a corresponding lactone having the 11~ configuration, with sui~able blockiny at the C-15 position if desir-ed, by methods known in the art, such as by way of the 11~mesylate or 11-tosylate. For application of the 11-benzoate For example, see Mitsunobu et al, J J . Am. Chem. Soc. 94, 679 (1972).
When ~ is ~

and R25 is alkyl~ see U.S. Patent No. 3,931,279 and Derwent Farmdoc Abstract No. 10695V; when R25 is phenyl-substituted~
also see U.S. Patent No. 3J931,279.
When ~ is a suitable starting material is ~CH3 0~
~ ~ ~XVII

See E.J. Corey et al. J Tetrahedron Lett. 107 (1972). After introduc~ion of the Rzs-containing side chain by known methods including the Wi~ig reaction and reduction of the ~ 3511 15-oxo group, ~he methyl e~her is hydrolyzed to the lactone in acid.
When ~ is ~ ' the lactone is available or prepared by processes known in the art, See Ger. OFfen. 2,437,622 and Derwent Farmdoc Abstract No. 12714W. For example a compound of the -formula H XXVIII
C=C/
1 ~/ ~C-R2 5 COO~ ~

is reduced at the -COOH position to ~he corresponding -CH20H compound using diborane.
In st~p "a" of Chart B~ ~he starting material XIV is subjected to halogenation and cyclization to yield the formula-XV halo compounds. For rela~ed cyclizai~ion pro-cedures see Staninets and Shilov, ChemO Abs~ 64, 12625h (1966). For iodination there is used either an aqeuous sys~em containing iodine, po~assium iodide, and an alkali carbonate or bicarbonate~ or an organic solvent system such as dichloromethane containing iodine in ~he presence of an alkali metal carbonate. The reaction is carried out at temperatures below 25G C.~ preferably about 0-5 C. for 10-20 hrs~ Thereaft~r the reaction is quench~d with sodium ~0 sulfi~e and sodium carbonate and the formula-XV compound _4l~_ ~ 3511 separated from the reaction mixture~ For bromination, N-bromosuccir,imide or N-bromoacetamide is used. 5ee Fieser e~ alO~ Reagen~s for Organic Synthesis, Vol. 1, pp 74 and 78J Vol. IV pO 5~.
In step "b" of Chart B the halo compound XV is sub-jected to reductive dehalogenation. Useful reagents in-clude tribu~yltin hydride, triphenyltin hydride, sodium borohydride in ethanol or dimethyl sulfoxide, and zinc in acetic acid. Especially preFerred is tributyltin hydride freshly prepared from tributyltin chloride and lithium aluminum hydride. The reaction is run in a solvent such as benzene a~ about 15-35 C. and monitored by TLC.
Thereafterg any blocking groups are removed by methods known in the art and product Xl I I i solated by methods de-scribed herein or known in the art9 for example by chroma-tography on silica gel.
A product within the scope of formula XIII may be trans-formed by methods known in the art or described herein to a product within the scope of formula Ill. Thus, if Q2 i n formula X I I I i s ~'~
H OH~

it can be transformed to ~"
~H3 OH

by me~hods known in the art See for example U.S. Patent NoO 3,728,382.
As another illustration, if Rl8 is formula XIII is 35~1 -COOCH3J it can be transformed into any one of ~he substi-tuted phenyl ester groups of -COOR19 by first saponifying that me~hyl ester to yielcl the free acid and then reester-ifying the acid t:o yield the substituted phenyl ester using methods known in the ~rt. See for example U.S. Patent No.
3,894,062.
Chart D shows a preferred rou~e to the amides of for-mula XXXI and ~he amines of formula XXXIi.- The halo acid XXIX is transformed to the halo amide XXX which then yields the amide XXXI by reduc~ive dehalogenation. On further reduc-tion of the amide, the amlne XXXII is obtained using well-known methods. I n Chart D, the terms L, Q2, ~ , R2sg R33, X, and -- are as defined above for Chart B, and Rl9 is hydrogen, alkyl of one to 12 carbon atoms, inclusive3 benzyl, or phenyl, being the same or different.
Ano~her method of preparing the cyclic e~hers within the scope of formula III is by reductive mercura~ion of a compound of formula Vl shown in Chart E, wherein the terms G, L, Q2, ~ , R253 R90, X, and are as defined above.
Char~ E shows the steps by which a 4,5-cis-didehydro-PGF1a-type compound of formula XXXIII is (a) converted to a mercury compound of formula Vi and (b) compound VI is subjected to reductive demercuration to form the formula-IiI product.
Reference to Char~ E will make clear the steps of this process. For hackground on thls mercuratlon-demercuration cyclization see, for example, H.C. ~rown et al., Organo-me~al. Chem. Syn. 1J 7 (1970) and Fieser and F7 eser, Rea -gents~ N.Y.3 1972 The formula-XXXlII starti ng materials have been dis-~ 3511 CHART D
?~3 ,O~CH~ CH-L -COOH
~" ~
~- - (CH2)~ XXIX
X -C -R2s l (a) ~33 , O--ÇH~CH -L -C -N ( R 1 B )2 ~- - ( CH2 )2 XXX
X- I-R

,~ (b) ,0 ~CH~CH2 -L -C -N (Rls )2 (~ - (CH2 )2 XXX I
X -C -R2s I (c) .,0 -CH~CH2 -1; -CH2N ( R 18 )2 ~ /
R22~ - (CH2 ~2 X -C -R

~0 CHART E

,OH

Q H~ C C~H XXX I
I I

(a~

g G
~ ,0 ~iCH~ CH-L -R30 ~~ -(CH2 )2 X -C -R2s (b) , O -CH^-CH2 -L -R30 2 )2 1 1 1 X -C -R2s Qz 3o -4~ -cussed above for Chart B. Additionally, as to substituted phenyl esters see U.S. Patent No~ ~,894,o62, as to substi-tuted phenacyl esters see U.S. Patent No. 3,979g440, and as ~o 2-decarboxy-2-tetrazolyl derivatives see U.S. Patent No. 39883,513 and 3,932,~89. In step "a" of Ghart E, the starting material is reacted with an appropriate mercury (iI) salt corresponding to Hy(G)2, for example mercuric nitrate, chloride, or acetate. Preferred i5 either mercuric acetate or trifluoroac~tate~ The reagent is dissolved in either water or acid, e.g. acetic acid, and combined with a solutlon of thP formula-XXXIlI starting materia) in a sol-vent such as chloroform or tetrahydrofuran. The reaction is conveniently done at about 15-35 C.
In step "b" of Chart E the mercurfo campound is sub-jected to rcductive demercuration. Useful reagents for this step include sodium borohydride, sodium amalgam, and hydrazine Especially preferred is sodium borohydride in alkaline solution, e.g aqueous sodium hydroxide. The reaction is carried out in a solvent such as tetrahyd,o-Furan at about 15-35 C. Thereafter the mercury is sepa-rated, blocking groups removed if necessary, and the pro-duct isolated by methods described herein.
The formula-VI mercurio compounds are useful not only as intermediates for preparing the formula-III products but also for their pharmacological applications as set forth here~n. G may be varied, for example, by 5Ui table choice of reagen~ Hg(G )2 or by rep)acemen~, for example of ace-tate by chloro by ion exchange.
The in~ermedia~es of Charts A, B, C, and E~ including those compound represen~ed by Formulas VI, IX, X, XV~

-4g-XXIX, XXX, and XXXI are frequently not isolated but used directly for a subsequent process step. When they are isolated, they are purified by methods known i n the art, for example partition extraction, frac~ional crystalliza-tion, and3 preferably, silica gel column chromatography.
The compounds of Charts A, BJ D, and E wherein Q or Q~
is in ~ither alpha or beta configuration, for example ~" ,'~
H OH or H OH
represent 15-a and 15-~ isomers. The transformations shown herein generally have no effect on ~he stereochemistry at this position and therefore the final products have the same stereo configuration at C-15 as in'the starting ma-t-erials at the corresponding carbon atoms. Shou'id it benecessary to separate 15a and 15~ isomers, this can be done by methods known in the art, for example by chromatography on neutral silica gel.
When an opti'cally active'intermediate or starting ma~-erl~l i5 employed, subsequent steps yield optically active in~ermediates or produc~s~ That optical isomer of a 4,5-cis-didehydro-PGF1a compound XXXIil is preferr~d which will yield product lll, for example, in the confi~uration corres-ponding to that of the natwrally occurring pros~agl~nd~ ns.
25 When the racemic form of the intermediate or starting mate-rial is employed, the subsequent ;n~ermediates or products are ob~ained in their racemic form~ OptJcally active and racemic forms of the intermediates or starting materials are known or available by methods known in the artO
~50 Cc>mpuunds w1thin the scope of formula~ 111, herein, 5o -~ 511 occur in two isomeric forms wherein ~ is in alpha or beta configuration~ i.e. endo or exo relative to the hetero-cyclic ring. These two isomers differ in their mobility on TLC si 1 i ca gel plates or on a si 1 i ca gel column~ The members of each pair of isomers are distinguished herein as "less polar" or "more polar" isomers, considering that mobili~y Blocking groups, R40, on formula-lll com-pounds are readily replaced with hydrogen$ by acid hydro-10 lysi5, for example in dilute acetic acid, aqueous citric acidJ or aqueous phosphoric acid-~etrahydrofuran.
When the free acid form of the formula-lll compounds is desired, transformation is brought about by m~thods known in the art, for example saponification.
Esters are conveniently prepared by interaction of the acid wTth an appropriate diazohydr3carbon, or by inter-actTon of a silver salt of the compound with a alkyl iodide as discussed above Substituted phenyl and naphthyl esters are prepared by methods known in the art. See for example U.S. Paten~
No 3~890~372. Phenacyl-type esters are likewise prepared by methods known in the art. See U.S. Patent No. 3,979,440.
The lower alkanoates of the formula-lll compounds dis-closed herein are prepared from those compounds by replac-ing any blocking groups (R40) with hydrogen, thereafter ~ubjecting the hydroxy compound to a carboxyacylating 3gent/ preferably the anhydride of a lower alkanoic acid~
I,e., an alkanolc acid of one to 8 carbon atoms~ inclusive.
For example~ use of acetic anhydride gives the correspond-3 ing diace~ate. Similar use of propionic anhydride, iso--5~-~u~yrlc anhydride~ and hexan01c acid anhydr-ide gives the corresponding carboxyacylates.
Ihe carboxyacyl at i on is advantageous 1 y car r i ed out by mixing the hydroxy compound and the acid anhydride, pre-ferably in the presence of a tertiary amine such as pyri-dine or ~riethylamine. A substantial excess of the anhy-dride is used, preferably about 2 to about 10 moles of ~nhydride per mole of the hydroxy compound reactant. The excess anhydride serves as a reaction dil~ent and solvent.
An inert organic dilwent, for example dioxane, can also be added It is preferred to use enough of the tertiary amine to neutralize the carboxylic acid produced by the reaction, as well as any free carboxyl groups present in the hydroxy compound reactant The carboxyacylation reaction is preferably carried out in the r3nge about O to abou~ 100 ~. The necess~ry reaction time will depend on such factors as ~he reac-tion temperature, and the nature of the anhydride; with ~cetic anhydride, pyridine, and a 25 C. reaction temper-ature, a 6 to 24-hour reactivn time is used.
The carboxyacylated product is isolated from th~
reaction mixture by conventional methods. For examp1e, the excess anhydride is decomposed wi~h wa~er, and the resultiny mixture acidified and then extrac~ed with a sol-vent such as diethyl ether. The desired carboxylate isrecovered from the diethyl ether extract by evaporation The carboxylate is ~hen purified by conventional methods, ~dv~ntageously by chroma~o~raphy.
Compounds within the scope of $ormula lll are trans-form~d from one to another by methods known in the art.

~ 3511 Accordingly~ a compound wherein ~ is \

OH

is transformed ~o another compo~nd wherein ~ is another ring within the scope of ~ , for example an 11-methylene compound~ by methods known or described herein. A compound wherein the Cl3-Cl~ yroup is trans-CH=CH.- Is transformed to another eompound wherein the C13-C1~ group is cis-CH=CH-, -C3C-, or -CH2CH~-. For example, -~3G- is obtained by selective bromination and dehydrobromination, A eompound wherein the C2 substituent is -COOR19, e.g. a methyl ester, is transformed by known methods to another compound having another C2 substituent within the scope of R30, 35 defined herein, for example -CH20H or -C-N(R 18 )2 ~
Included among the compounds of formula III are the 11-methylene compounds. Alterna~e me~hods for ~heir prep-aration, other than ~hose included within Charts B, D, and E above wherein ~ is , ~' ~
~H2 u~i~ize ~hose processes of Charts B, D and E by replacing starting materials XIV, XXIX, and XXXIII with corresponding 3 compounds wherein ~ is replaced by ~5~a-~J"
CH2-0-Si(CH3 )2 ( t-C4Hg) Such compounds are readily prepared from the hydroxyme~hyl compounds wherein ~ is ~' described herein for the s~arting materials of Chart B, using the procedures of E~J. Corey et a1., J. Am. Chem~ Soc~ 94, 6190 ( 1970 ) .
Thereafter the procedures of Gharts B5 D, and ~ yield compounds bear i ng ~he t -buty 1 di methy l s i 1 y 1 oxymeti-y 1 group at C-11. It is preferred that Rlgbe alkyl. Next the si lyl groups are replaced with hydrogen using ~etrab~tylammonium fluoride, and the resulting hydroxymethyl groups are con-verted to iodomethyl groups by way of tosyl a~i on and iodide exchange. Finally dehydroiodina~ion) as with po~assi~m tert-butoxide in te~rahydrofuran, yields the 11-methylene compounds.

For all of the reac~ions described herein, the dura-tion of ~he reaction i5 re3dily determined by monitoring -52b-~ 511 wi~h TLC ~thin layer chrom~tography)~
DESCRIPTION OF THE P~EFERRED EMBODIMENTS
The invention is further illustra~ed by, but not lim-ited to, the following examples.
All temper3tures are in degrees centigrade~
Infrared absorption spectra are recorded on a Perkin-Elmer model 421 infrarf~d spectrophotometer. Except ~hen specified otherwise, undilu~ecI (neat) samples are used~
The NMR spec~ra are recorded on a Varian A-60, A-60D, T-60, or XL-100 spectrophotometer in deuterochloroform 501 U
tions with tetramethylsilane as an internal standard.
~ass spectra are recorded on a Varian Model MAT CH7 Mass Spectrometer a CEC Model llOB Double Focusing High Resolution Mass Spectrometer, or a LKB Model ~000 Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ev.), and are usual ly run as TMS (trimethylsilyl) deriva-tives.
"Brine", herein, refers to an aqueous saturated sodium chloride solution. ~
"Skellysolve B", herein, refers ~o mixed isomeric hexanes.
"TLC"~ herein, refers to thin layer chromatography.
Silica gel chromaeography, as used herein, is under stood to include elution3 collection of fractionsJ and com-bination of those fractions shown by TLC to contain ~he desired produe~ fre~ of starting material and impurities~
"Concen~ra~ing", as used herein~ refers ~o concentra-tlon under reduced pressure, preferably a~ less than 50 mm.
Hgo and at temperatures bei~/ 35 CO
"Lower alkanoa~e"9 herein, refers ~o an ester of an ~j .

alkanoic acid of one to 8 carbon atoms~ inclusi.ve.
Preparat_on 1 2-Decarboxy-2-amino-PGF Compounds Chart M shows the steps by which the fcrmula Cl, PGF2 - or 11-deoxy-PGF2 -type free acid is transformed to the various 2~decarboxy-2--aminomethyl or 2-decarboxy-2-(substituted amino)methyl -PGF~- or ll-deoxy-~GF~-type compounds of formulas ClV, CVl, CVll, CVlll, ClX, or CX.
In Chart M, Yl is trans-CEI=CH~ C-C-, or -CT12CE12-;
Ml is R ~ \OI
or ,~

wherein R55 is hydrogen or methyl;
Ll is~

R53 54, /~
R53 S4' or a mixture of ~ ~54 and ~
R53 R54, - 5~ -~,' .

i, 35 1 1 CHART M
_ , CHz-Zl-COOH
<~ Cl 'Y 1 -C-- C -R57 Rs~ 11 11 Ml L

O
1~0 ,C H2 - Z 1 - C -O - C - R s ~ ~11 ~ / Y 1 -C--C R57 Ml L
~ .
H0~ R

¢(~CH2-zl-c-NH2 Cl i I
¦ R 5 eICI I I - R s 7 ¦ Ml L

, ,CH2-Zl-CH2NH2 ~IV
--~ Y I -C--C -R57 R5~ ~1 L

~0 11 ~C~
\~ \ CH2-Zl-C-N=N~N
S,L~ CV
Y 1 - C--C; R s ~

CH~RT P~ (continued~
~' , CH2 - Z l -NH -COOR5 1 ¢~ \~ C~l , Y 1 -C ---C-R7 `\ CH2 ~Z 1 ~NH2 <~ CVI 1, R s ~ Y 1 - ~ - R s 7 H0 CH2 ~Z 1 -NHLe <~1 ~/ CVI!I
Y 1 -Cl--I -Rs 7 Rsa Ll Ml ~/

~ ~ CHz -Z 1 -NL:2COORs 1 S~ ~ Y I -C--C -Rs7 C I X
R 5 ~3 M 1 L 1 '.
~5 110 CH2 -Zl -NL2L3 ~' CX

~ 5 a Y ~ C - R 5 7 ~511 wherei n R~3 and Rs4 are hydrogen, meLhyl~ or fluoro~ being the ~ame or diFferent, ~ith the proviso that one of Rs3 and R5~ is fluoro only when the other is hydrogen or fluoro;
Z 1 i s (1) cis-CH-CH-CH2~(CH2 ~ -CH2-, (2) cis-CH=CH-CH2~(CH2 ~ -CF2-, wherein w is one, 2, or 3;
P`s7 i S
( 1 ) - (CH2 )m-C~3J

0 ~ . cr (3) -CH2 ~ (TL)5 wherein m is one to 5, inclusive, T1 is chloro~ fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclu-sive, c~r alkoxy oF one to 3 carbon atoms, inclusive, and s is zero, one) 2, or 3, the various T1's being the same or di~ferent, with the proviso that not more than two Tl's are other than alkyl, with the further proviso that R~ is 1 ) 5 -O ~) ,, .

wherein T1 and s are as de~ined above~ only when Rs3 and R
are hydrogen or methyl~ bein~ the same or different;
R5~ is hydrogen or hydroxy;
L2 and L~ are hydrogen, alkyl of one to 4 carbon atoms, Inclusive~ or -COORgl3 wherein Rsi is hydrogen~ alkyl of one ~o 12 carbon atoms~ inclusive, cycloalkyl of 3 to 10 carbon ~,~' ~511 j ~crns, i nclusî \~e, aral kyl of 7 to 12 carbon atoms, i nc lu-.ive, phenyl, or pherlyl substi tuted one, 2, or 3 ch10ro or alkyl of one to 3 carbon atoms, ir.clusi\/e7 being the same or differentJ with ~he pro~iso that not more than one of L2 and L3 is -COORsl.
By ~he procedure of Chart M the formula ~I compound is trans~ormed to a formula ~11 mixed acid anhydr;de~ These ~ixe~ anhydrides are convenien.tly prepared from the corres-pond;ng alkyl, aralkyl, phenyl5 or substituted phenyl chloroformate i n the presence of an organic base (e.g~J
~riethyl~mine) Reaction diluents include water ir; com bi nation wi th wa~er misci ble organic solvents (e~g., tetra-~ydrofuran). 1iIis mixed anhydride is ~hen transformed to either ~he form~la Clil PG type, ami de or formula CV PG-L5 ~ypeJa7ide, For preparatior- of the PGF2a-type, amide (forrnula Cl l l the Formula Cl I mixed acid anhydride i5 reacted with liquid a~monia or anlmonium hydroxide A I te ~ na t i ve I y, the f c~rmu l a C I I I compound i 5 prepared 2C~ from the formula CI frec acid by methods known in the art for trans~ormation o~ carboxy acids to corresponding car~
boxyamides. For ~xample, the free acid is transformed to a correspondlng methyl ester (employing methods known in the art; e.g., excess etheral dia~c~ethane)J and a methyl 2~ es~er thus prepared is transformed to the Formula Clll amlde employl ng th rnethods descri bed for the transformation o~

the formula Cl I mix~d acld anhydride to the formula Clll ami de.
Ther~aftcr the formula CIV 2-(lecarboxy-2-aminor~thyl-3() P~F~- or 11 -~coxy -pGr2(~- lype co~ ound is prepar~d from -5~3 -,/ ~.Y, the formula Ci i I compound by carbonyl reduction. Methods 4nown in th~ art ar~ are employed i n this trans~ormat~on.
For ~x~mp I eJ 1 i th i um a 1 unli num hydr i de i s conven i ent 1 y t~mp I oyed.
~he formula Cl I corn~ound is altcrnatively used to-pre-par~ the formula CV ~zideO This reaction is conveniently earrle~ out ~m~lc)yilly sodium a~ide t~y meth~ds known in ~he arc, 5cc for cxamp!e, Ficser ar--~ Fiescr, Rea~cnts for Qr~anl c Syn~i~es I s vol 0 1, pgs . 10)~1-10~ , wherei n r~agents 1.0 and rcact i on cor~di tl ons ~or the azi de formation are di s -cus sed, Flnally, th~ ~orm~la CVI ure~hane is prepared From the rornlula CV a~i~e react:on with an alkanol, ara!kanol, pheno'~
or su~stituted phenol. For example, when methanol ;s em-15 ployed the formula CV1 compound is prepared wherein Rl is ~ethyl. This rormula CVI PG-type product is then employed in the prcparation of either the formula CYIl or CVIII pro-duct .
In the preparation of tlle ~ormula CVII prlmary amine from the form~îa CYI ure~hane, n~et~ods known in the art are employed. ~hus, ~or example, ~reatment of the formul~
CVI I urctil~ne wi th strong base at temperatures above 50 C.
~re e~ployed. For example1 sodium,Potassium,or lithium hydrpxide i5 employed.
a i terna t I ve 1 y, the formu I a CV I compound i s emp I oyed in the prep~ration of the formula CVIII eompound. Thus3 when ~ is alkyl the formula CVIIl compound is prepared by reduction o~ the form~ia C\/l urethane wherein R~ is a1 kyI, ~or thi s purpose, 1 i t!~ m alumi num hydr;de i s `;'C the corl~eniently employed reJucing agent:

~59- 1 !

~511 ~ ilereafter, tbe r~rIn~l~ CYlli procluct Is used to p,epare the corrcspon-~ing CIX ur~thane by reactTon of the forrnula C~IIi seconclary a~nine (w~lerein Lz is alkyl~ with an ~Ikyl chlor~formate. The reaction thu5 proceeds by methods known in ~he art for the preparation of carba~ates frorn corresponding secondard amines. Finally, the formula CX
product ~hercin ~ and L3 are both alkyl is prepare~ by reduction of the Formula CIX carbamide. Accordingly~
methods herei nabove descri bed for the prepar3tion of the formu~a CVIii compound from the formula C~I compound are used.
Preparation lA 2-Decarboxy-2-azidomethyl-PClF2a.
solution of t-butyl~irn~thylsilyl chToride ~10 g.), irnidazole (9 ~4 ~,J,t~nd PGF2n (:~ 9.) in ~2 ml. of dimethyl~
Formarnide are n~a~netically stirred under nitrogen atmosphere for 24 hr Tl-e resultin~J mixt.urc is lhen cooled in an iCE
batl~ and the reaction qucncllecl by addi tion of ice ~ater.
~he re~ulting mixtur~ is tl-en di luted w;th 150 rnl. of ~r~er and ~Xtl'tlCt~ with (IielIlyl ether. The co~bined thcrctll e~tracts are tl-en wasllcd ~lth ~ater, saturated amn~onium clllori~e, a sodiunl cl-l~ricl~ sollItion, and there-aft~r dried over sodiu~n sulra~e. Solvent is re~oved under v~cuu~ yiel~in(~ PG~z~, t-i~utylr~ 7e~lylsilyi ester, r3,1~,l5-tris~t-~utyl~irnel~ylsily1 ether), N~R absorpLions ~?5 arc observed at ~.c~O, V.~V, n.~ 3~, v.~g~ 1.07-2~50, 3,10-4,21~ an~ 5.~ 6. Characteristic inFrared absorpt;ons are observe~l at g70, lO00, 1060, 125(1, 1355, 1460, l-T2~), ancl 2 g5 0 c~
(2) To ~ rn~(Jnetically stirre~ suspension of lithiutn ~c ~lulnir~lltn /~ydride (7.75 ~3. ) irl 1~3 ml . or diethy1 ether is -~0 -,~511 a(.decJ ~Jr~pwise al ro~1~ tctllpCI-3tLlre cvcr 3 per10d Or 12 rn~n~
.71 J. Or ll-e react ion pro~lue.t of part (1) above in 40 rnl .
of diet11yl ~th~l . After stirri~-g at ambient ten1perature for onc ~r,, the resulting procluct i~ cooled in an ice wate~
5 bath and saturated socJiurn s~l rate is added ,dropwise unti I
tlle appcarance of a mi Iky susF~ension." The resulting pro-duc~ is coacJulated ~ith sodiurn sulf.7te, tr~tur~3ted with dieti7yl ether, and tl-l~ solvent i~ rernoved by suction fil-tration. l-,vrlcerllr~tiorl Or ,the diel:t~yl ether under vacuum 10 yie l~s 7 o~ Or 2-dccart~t~x~ -2-l-ytlrclxylnetllyi-PC;F;?~l, ',;~, 1 1, 1~ - ~ r i s - ( l - b u l y 1 d i lll c t i l y I s i I y I e L h c r ~ lR ~ s o r p -tion5 are observed ~lt t~,03, 0.82, ().87, 1.10-2.60, 3.30 4 .30, and ~..37 ~ . Characterist ic infrared absorpt;ons are ob 5 erved at 775, 840, 970, 1()55, 1250, 1460, 2895,, 2995"
:L5 and 3350 crn~ ~, (3) p-Toluencsulfonyl c~)loride (3.514 9.~,, pyridine (4l! m1.), and the reaction product vf subpart (2),, 7.014 ~., arc placed in a freezer ~t -20 C0 ~or 3 days. . Thereafter,

7.200 9. o~ 2-~cearboxy-2-p-to1uencsu1fonyloxyrnethyl-pGF
9,11,15 trIs-(t-butyI~JinletI~ylsi Iyl ether~J is recover^e~i.
N~lR absorptions ~re oL7serve(J at 0.10, 0.94.~ 0.97, 1.10~
2.50, Z.50~ ~Ø~, 3.80-4.80, 5.45, 7.35, and 7.80 ~. infra-red absorptions are observed at 775, 970, 1180~ 1190, 1250, 1360, 1470, 2900, and 299~ cmO~~.
(II) The reaction product or subpal t (3~ (2.13 9.~ is placcd in ~I2 ml. Or ~ncet ic: acid. tclIaIlycJrofur2n, and ~Jater (3:1 :13 conta ining 0.25 n11 . vr lo percent aqueou5 hy-droch 1 or i c ac i d . The reaction ~i~tur-e becomes h~71ogeneous aftcr vigorous stirring ror IG hr. at roo~ temperat~re. ~1e resulting solutior) is thcn diluted with 500 ml. of ~thyi ~51 l ac~tat~ )shecl ~litl- saturatecl socJiu~ll chlorid~ and th~1 ac~tatc; cJricd over sodiu~n sulrt-~tc; t~nd evaporated under reduced prcssure, yielding 1.~01 9~ Or an oi 1 . Crude ~ro-cJ~ct is c~-r~a~o~Jral~heci on 150 c~. Or silica qel l~aeked wilh cthyl acetalc Elutin~j witll r7thyl tacetate yields 0,f353 g. Or 2-dr.~carb~xy-2-p-toluen~ulfonyloxymethyl~PGF
(5) Th~ r~actioll ~roduct of subpart (~ (0.500 9.) ir~ ml. Or di,metllylrorn~tl,nide \~as aclded t~ a stirr~d sus-l~r~sion Or ~ocJium a~i~le (1 5 () ) in ~() nll. o~ din~ethylfor-L0 manlide Slirrin-J i~ continur~d at arnbient temperature ~or hr, Thc re;3ction ~nixture is tl~en di lutecl ~ith wat~r (7S rnl.)~ extracted ~/ith c~ir~ti~yl ether t500 n~ , and the the eth~ral cY.tracts~/tl~h~dsucc~ssively~ith~ater3 5a~u-rated sodi~,ch~oride! ~nd dried oversodiu~ su~fate. R~moval 1~ ofthe die~hyl etherunder r~duced pressure y;elds 0.~5~ y. of Z-decarboxy~2-azicJc)lle~l-yl-PGF2cl~ A character~stic az;do infrarrd absorption i5 obs~rved at 211(1 cm.~~.
P_ep_t i on 1B 2 -Decarboxy -2 -ami nomethyl -PGF2a (F~rmu-1 a CXX V ) Crude 2-decarboxy -2 -az i domethyl -PGF2a ( PrepO 1A9 o. ~s6 g, ) i n 12 rnl . of diethyl ether is added ~o a magnetical ly stirred suspension of lithiurn alumir-um hydride (0~38(~ g.) in 20 ml of di ethyl ether . React i on temperature; s mai n~ai rled at about 0 C. and addi tion of 1 i thium aluminum hydride pro-~5 ceed~ dropwise over a 4 mi n, period. After addi tion i ~ com-plete~ the resulting mixture is stirred at ambient tempera-ture for 1.5 hr, and thereafter placed i n an ice both ~Q-5C.
Excess reducing .~lenl is lllcl~ clcstroyed by addition fc)f ~;atura~d so~lio~n sO1r~tc J~rter cess~lticn Or gas ~v~lu-3o tionJ ti~c rcsultin~J r~rodlJct is co~gulatcd with sodiu~ sul-~; -62 -~511 f~it~, tti lur~ted witl~ hyl ~ er, ~n~l solid sal~s r~moved by fl Iltra~lon~ ~he ~I Itr~e is tllen c3ri~d wlth sodtunl sut-Fa~ and evaporc~ed under redl~cccl prcssure to yield 0.~04 y.
of a slightly yellow oil. This oil (100 mg.) is then pur~
5 I Fied by preparative thin l~yer chron,:lto3raplly, yieldi-ng 42 9 . or t i t le produc~ absorpt i 0'15 are c)bserved at 0,go, 1.1C-2,~0~ ~.28, ~65-4.25~ and 5,45 6. Ch~racteris~
tic infrared absQrptions are observed at 970, 1060, ~ iO, 2g95~ an~ 3400 Cn1. ~ he m355 5pCCt ruT~ sho~/s parent peak at 69~.47f~6 and other pe~lks a~ 628, 684, 59;, 2~7~ and ~74 .
Exarnple 1 9-Deoxy 5~9a epoxy-2J3 dinor-15(RS) 15-metllyl.PGFl, Methyl Esterg less polar Isomer and 1L-) 9 -Deoxy -5~, 9a-epoxy -2, 3-di nor -15 (RS ) -15 -methyl-PGF1, Methyl Ester, more polar isomer~
(Formula Vi I ) A. Refer to Chart A. The formula-lX lac~ol is fTrs~
prepared. A solution of the 15(RS)-15-methyl lactone, bis-(tetrahydropyran~2-yl) ether of formula VI I I (U.S.
3,9319279, 4.24 9. ) in 85 mlO of toluene ;5 treated a~ -~0 to 75 C. w7 th di i sobutylalumi num hydri de (39 ml . of o.56 M.
toluene solution) and stirred for 40 min. Thereafter the reacti on mixture i s quenched wi th a satura~ed aqueous 25 solution of sodium sulfate, mixed with diethyl ether, and f i 1 tered. The organi c phase i s concentrated to an ot 1 containing 13ctol IX~ 4.3 9", having P~f 0.45 (TLC on silTca gel in ethyl acetate-Skellysol\/e B (2~
B, A solution of lactol IX (part A above, 4.25 g. ) and 2-carboxye~hyltriphenylphosphonium chloride (D.B. Denney ~ 63-~ 3511 et al., J. Org. Chem. 27, 3404 (1962)), 10.42 9.) in 120 ml.
of dimethylsulfoxide-tetrahydrofuran (1:1) is added dropwise ~o a suspension of sodium hydride (56.28 mmol.) in 20 ml. of the same sc,lven~, cooled in an ice bath. The mixture is stirred at about 25 C. for 66 hr., cooled to about O C., quenched with ice water, and acidified to pH ~ with 2N
po~assium hydrogen sulfate solution. Water and diethyl ether are added and the organic phase is separated3 washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue is chroma~ographed on silica gel, eluting with e~hyl acetatP~Skellysolve B (1:2) to yield the formula~X compound, as an acid, 3.01 g.
C. The methyl es~er of X is obtained by esterification of the above acid with diazomethane in ether-methanol. The resulting product is chromatographed on silica gel, eluting with ethyl acetate-Skellysolve B (1:3) to yield the formula-X mixed isomer bis(tetrahydropyran-2-yl) ether, 2~410 9.
having Rf 0.53 (TLC on silica gel in ethyl acetate-Skelly-solve B-acetic acid (49 49 2).
D. The formula-VII tttle compounds are ob~ained by subjec~ing ~he product of part C to acid hydrolysis in 66 mlO oF acetic acid~water~tetrahydrofuran (20:10:3) at 40-45 C~ for 4 hr. The solvents are removed by azeotroping with benzene at 40 C./1 mm. The crude product is chromato-graphed on sllica gel, eluting with methylene chloride-acetone (9:1) to yield the formula Vll title compounds:
~5(RS) less polar isomers, 0.130 9., having Rf OD46 (TLC
on silica gel in ace-tone-methylene chloride (3:7~); and 15(RS) more polar isomers~ 0.160 9,, having R~ 0.~7 (TLC
on si lica gel in acetone-methylene chloride (3:7)). The ~ 3511 l~ss polar isorners have NMR peaks at 5.55, 3.92, 3.67, 2090-1023, 2048, 1.25, and 0.90 ~; infrared absorption at 3400, 3000, 1750, 1440, 1340, 1295, 1205, 1120, 1055, and 975 cm ; and high resolution mass spectral peak at 29~.3179.
The more polar isomers have substantially the same values for NMR~ infrared, and mass spectral data.
~e 2 9-Deoxy-5~,9~-epoxy~PGFl, Methyl Ester, less polar isomer and more polar isomer (Formula i I I ) Refer to Chart E. A solution of mercuric acetate (0 95 g ) in 10 mlO of water is mixed with 10 ml. of tetra-hydrofuran~ To ~he resulting suspension is added a solu-tion of formula XXXIII cis-4,5-didehydro-PGF1a~ methyl ester (0.735 g ) in 10 ml. of tetrahydrofuran dropwise.
Stirring is continued at about 25 C. for 4.25 hr. A solu-tion of sodium borohydride (0 200 g.) in 10 ml. of 1 N
sodium hydroxide is added dropwise with stirring. After 20 min. brine is added, toge~her with diethyl ether. The organic phase is separated~ washed with water, dried over magnesium sulfate, and concentrated to oily productJ 0.429 g.
The aqueous phase is acidified with dilute hydrochloric acid and extracted with diethyl ether. The organic phase is worked up as above to yield an oil, 0.192 g. which is esterified with diazomethane and combined with the 0.429 g.
above. The total produc~ is chromatographed on silica gel, using a high pressure column, and eluted with acetone-(20-30~)-hexane to yield the title compounds: less polar isomer, 0.349 g., having R~ o.38 (TLC on silica gel in acetone-me~hylene chloride (3:73), and more polar isomel-, 0 144 g., having Rf 0.33 (TLC on silic gel in acetone ~ 511 methylene chloride (3:7)). The less polar isomer has NMR
peaks at 5.4g, 3.65, and o.88 ~, and mass spec~ral peaks at 512.~320~ 497, 441, 422, 412, 391, 351g 325~ 235, and 17~.
The more polar isomer h3s NMR peaks at 5.50, 3.66, and 0.88 ~, and mass spectral peaks at 512.3331, other peaks as for isomer above.
Example 3 9 Deoxy-5~,9~-epoxy-PGFl, less polar isomer (Formula I I I ) A solution of 9-deoxy-5~,9~-epoxy-PGF1J methyl ester, less polar isomer (Example 2 , 0.410 g.) in 15 ml. of methanol is treated with 12 ml. of 0.1 N sodium hydroxide and stirred at about 25 C. for 2 hr~, then treated with additional 1 ml. 0.1 N. sodium hydroxide for 3.5 hr~ and finally another 2 mlO of 0.1 N. sodium hydroxide for 2.5 hr.
The solvent is removed under reduced pressure and the resi-due acidified to pH<2 with 10~ aqueous potassium hydrogen sulfate. The mixture i5 extracted with ethyl acetate and the combined extracts are washed with water and brin~, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel, eluting with ethyl acetate (50-65~)-hexane to yield the title compound, 0.285 9.~ having Rf 0.53 (TLC on silica gel in ethyl acetate-acetic acid ~95.5)); mass spectral peaks at 570.3575, 555, 5993 4809 465, 409~ 390, 383, 3649 and 173; NMR peaks a~ 5.53, 4.27-3.60, 1.33, and o.88 ~; and infrared absorption at 3300 and 1705 cm~1.
9-Deoxy-5~,9~-epoxy-PGFl, more polar isomer (Formula lll) Following ~he procedure of Example 3 but replacin~
3 ~he methyl es~er of that example with the more polar isomer -~6-(Example 2 , 0.207 g.) ~here is obtained the title com-pound, 0.115 gO, having Rf 0.40 (TLC on silica yel in ethyl ace~a~e-acetic acid (95:5)); ma~s spectral peaks at 570.,598, 555, 4999 480, 465, 409, 390, 38~, 364, and 173; and NMR
5 and infrared values substantially the same as those for the less .polar isomer oF Example 3.
Following the procedures of Examples 2-4 but replacing the formula-XXXill cis 3,4-didehydro-PGF1c~ starting ma-terial wi~h the appropriate cis-~,5-didehydro-PGF,a type compound 10 or analog, there are obtai ned the foliowing 9-deoxy-5~,9a-epoxy-PGP1 type compo~nds withi n the ~cope of formula lll, as the respective less polar isomer and more polar isomer cf each pair of C-5 isomers:
9-deoxy-5~g9a-epoxy 15(5)-15-methyl-PGF1, methyl ester g-deoxy-5~,9a-epoxy-l5(s)-l5-methyl-pGFl 9-deoxy-5~,9~-epoxy-15(R)-15-methyl-PGF1, methyl ester g-deoxy-5~9a-epoxy-l5(R)-l5-methyl-pGF
~0 9-deoxy-5~,9a-epoxy-17-phenyl-18,19,20-trinor-PGF1, methy1 ester g-deoxy-5~,9a-epoxy-17-phenyl-18,19~20-trinor-P~Fl 9-deoxy-5~,9a-epoxy 16-phenoxy-17,18,19,20-tetranor-PGF1, me~hyl ester g-deoxy-5~9a^epoxy-l6-phenoxy-l7/l8~l9~2o~tetranor PGF

~ 51~

9-deoxy-5~39a-epoxy-16,16-dîmethyl-PGFl, methyl ester 9-deoxy-5~9a-epoxy-16,16-dimethyl-PGFl 9 -deoxy -5~ 9a-epoxy 11 -deoxy ~ oxo-15(S)-15-methyl-PGFl~ methyl ester 9-deoxy-5 ~ 9a-epoxy -11 -deoxy -11. -oxo -15 (S ) -15-methyl-PGFl 9 -deoxy -5~, 9~-epoxy -13,14-dihydro-PGF 1 J methyl ester 9-deoxy-5~,9a-epoxy-13,14-dihydro-PGF

9-deoxy -5~3 9a-epoxy -PGF 1 3 amideO

-6~-

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a cyclic ether of the formula wherein L is (1) a valence bond, (2) -(CH2)d- wherein d is one to 5 inclusive, (3) -(CH2)t-CF2- wherein t is one, 2, or 3, (4) -CH=CH-A- wherein A is a valence bond or -(CH2)h- wherein h is one, 2 or 3, or (5) -CH2-O-CH2-Y- wherein Y is a valence bond or -(CH2)k- wherein k is one or 2; wherein Q2 is wherein R3 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein R4 is hydrogen, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or a group of the formula wherein R8 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 sub-stituted with one, 2, or 3 alkyl of one to 4 carbon atoms inclusive, wherein R8 and R10 are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R9 and R10 are taken together, -(CH2)a- or -(CH2)b-O-(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 R11 is hydrogen or phenyl;
wherein is wherein R4 is as defined above;
wherein R25 is (1) wherein CgH2g is alkylene of one to 9 carbon atoms, inclu-sive, with one to 5 carbon atoms, inclusive, in the chain between -CR5R6- and terminal methyl, wherein R5 and R6 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;
(2) wherein R5 and R6 are as defined above with the proviso that neither R5 nor R6 is fluoro when Z is oxa (-O-); wherein Z
represents an oxa atom (-O-) or CjH2j wherein CjH2j is a valence bond or alkylene of one to 9 carbon atoms, inclu-sive, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms, inclusive between -CR5R6- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclu-sive, fluoro, chloro, trifluoromethyl, or -OR7- 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; or (3) wherein R30 is (1) -COOR37 (2) -CH2OH
(3) -CH2N(R18)2 (4) (5) wherein R37 is (a) alkyl of one to 12 carbon atoms, inclusive, (b) cycloalkyl of 3 to 10 carbon atoms, inclusive, (c) aralkyl of 7 to 12 carbon atoms, in-clusive, (d) phenyl, (e) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, (f) (y) (h) (i) (j) (k) (l) wherein R34 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R35 is hydrogen or benzoyl, or (m) hydrogen; and wherein R18 is hydrogen, alkyl of one to 12 carbon atoms, benzyl, or phenyl, being the same or dif-ferent;

wherein X is trans-CH=CH-, cis-CH=CH-, -C?C-, or -CH2CH2-;
and wherein ~ indicates attachment in alpha or beta con-figuration; which comprises the steps of starting with a compound of the formula wherein L, Q2, , R25, R36, X, and ~ are as defined above; and (a) forming a mercury compound of the formula wherein G is nitrato, iodo, chloro, bromo, acetato, tri-fluoroacetato, or benzoato; and wherein L, Q2, , R25, R30, X, and ~ are as defined above;
(b) subjecting the product of step (a) to reductive demercuration to form the desired cyclic ether; and, optionally, (c) separating the product.

A cyclic ether of the formula wherein L, Q2, X, , R25, R30 and ~ are as defined in claim 1, whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.

3. A process for preparing a cyclic ether of formula (I) (I) wherein R is a member selected from the group consisting of (a) COORc, (b) -CH2OH, (c) -CON(Ra)2 or (d) wherein Rc is alkyl of 1 to 12 carbon atoms or hydrogen and Ra is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl;
p is zero or an integer of 1 to 5;
R1 is hydrogen or hydroxy;
X is trans -CH=CH-, cis-CH=CH-, -C?C- or -CH2CH2-one of R2 and R3 is hydrogen or alkyl of 1 to 4 carbon atoms and the other is hydroxy or R2 and R3, taken together, form an oxo group;
R4 is (1) wherein g is an integer of 1 to 9 and R5 and R6 are hydrogen, alkyl of 1 to 4 carbon atoms 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; or (2) wherein R5 and R6 are as defined above with the proviso that neither R5 nor R6 is fluoro when Y is -O-, Y represents -O- or -(CH2)j-wherein j is zero or an integer of 1 to 9, T is alkyl of 1 to 4 carbon atoms, halogen, trifluoromethyl, or alkoxy of 1 to 4 carbon atoms, and s is zero, one, 2 or 3 with the proviso that no more than two T's are other than alkyl when s is3;
which comprises subjecting a compound of formula III to reductive demercuration (III) wherein Z(-) is I(-), Cl(-), Br(-), CH3COO(-), CF3COO(-) or and R, p, R1, X, R2, R3 and R4 are as defined above to form the desired cyclic ether, and optionally, separating the product.

4. A process for preparing a cyclic ether of formula (I) (I) wherein R is a member selected from the group consisting of (a) COORc, (b) -CH2OH, (c) -CON(Ra)2 or (d) wherein Rc is alkyl of 1 to 12 carbon atoms or hydrogen and Ra is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl;
p is zero or an integer of 1 to 5;
R1 is hydrogen or hydroxy;
x is trans -CH=CH-, cis-CH=CH-, -C?C- or -CH2CH2-;
one of R2 and R3 is hydrogen or alkyl of 1 to 4 carbon atoms and the R4 is (1) wherein g is an integer of 1 to 9 and R5 and R6 are hydrogen, alkyl of 1 to 4 carbon atoms 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; or (2) wherein R5 and R6 are as defined above with the proviso that neither R5 nor R6 is fluoro when Y is -O-, Y represents -O- or -(CH2)j-wherein j is zero or an integer of 1 to 9, T is alkyl of 1 to 4 carbon atoms, halogen, trifluoromethyl, or alkoxy of 1 to 4 carbon atoms, and s is zero, one, 2 or 3 with the proviso that no more than two T's are other than alkyl when s is 3;
which comprises the steps of starting with a compound of formula (II) (II) wherein r, p, R1, X, R2, R3 and R4 are as defined above; and (a) forming a mercury compound of the formula III

(III) wherein Z(-) is I(-), Cl(-), Br(-), CH3COO(-), CF3COO(-) or and R, p, R1, X, R2, R3 and R4 are as defined above;
(b) subjecting the compound of formula (III) to reductive demercuration to form the desired cyclic ether; and, optionally, (c) separating the product.

5. A compound of formula (I) as defined in claim 3 or 4 when prepared by a process according to claim 3 or 4 or an obvious chemical equivalent thereof.