CA1179335A - 5Z-9-DEOXY-6,9-EPOXY-5-IODO-PGF 1N/.alpha. XX - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Prostaglandin (PG1) derivatives having (1) a 9-deoxy-6,9- epoxy feature as well as 5-iodo, 5,6- didehydro, or 6-hemiketal or (2) a 6-keto feature are disclosed; including processes for preparing them and the appropriate inter-mediates; said derivatives having pharmacological activity, A typical 5-iodo compound is 9-deoxy-6,9-epoxy-5-iodo-PGF2.alpha. represented by the formula:

Description

~ is application is a division o~ copending Canadian ~pplica-tion Serial No. 270,416, filed ;ranuary 25, 1977.

BACKGROUND OF THE INV~NTION
This invention rela-tes to pros-taglandin deriva-tives and to a process for preparing -them.
The prostaglandins and analogs are will known organic compounds derived from pros-tanoic acid which has the ~ollowing struc-ture and atom numbering:

7\~z~; C~)o~
~o As drawn hereinafter the formulas repres2nt a particular optically active isomer having -the same ab-solute con-Eiguration as PGEl obtained from mammalian tissues.
In the formulas, broken line attachments to the cyclopentane ri~g or side chain indica-te su~situents in alpha confiquration, i.e. belo~ the plane of the ring or side chain. Heavy solid line attachments indicate sub-s-tituents in beta configura-tion, i.e. above the plane.

For background, see Eor example Bergstrom et cl:L.~ Pharmocol. Rev. 20, 1 (1968) and Pace-~sciak et al., Biochem. 10, 3657 tl971).

SUMMARY OF THE INVENI':~ON
__ __ ._ It is the purpose of this invention to provide novel products having pharmacological activity. It is a further purpose to provide a process for preparing these products and their intermediates.

Accordingly, there is provided a compound oE the formula ~ - 2 -~ 3 ~3~ 2871~

.

,V-O-C-Ctl-L-R~
~ ,W/

X-C-R~
Q

wherein D iS

oh OH O CH2 ~ , `

, ~ , or ~H20H

wherein ~ is (1) -(CH2)d-C(R2)2-

(2) -CH2-O-CH2-Y- or ~ 5) -CH2CH=CH-whelein d is zero to 5; R2 is hydrogen, methyl, Ot' ~luoro~ bcing the s~me or different with the proviso that one R2 is not methyl when the other is fluoro;
and Y is a valence bond or -(CH2)k-wherein k is one or 2;
wherein Q is Il /\ ~" ~'\

3 O, H H ~ R~ OH, or R8 OH

9;~3 ~ 2871A

wherein R8 is hydrogen or alkyl of one to 4 carbon atoms~
inclusive;
wherein R~ is ~ COOR3 (2) -CH20H
(3) -CH2N(Rg)2 or

(4) NH-N
~N - N
wherein R3 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;
...
O O
(f) ~ -NH-C ~ NH-C -CH3, (9) ~ NH-C-O
~h) ~ NH-C-CH3, (i) 4/ ~ NH-C-NH2 ~ CH=N-Ntl-C-Nt-t2, or 3o (k) (1) -IH-C-Rlo Rl, wherein Rlo is phenyl, p-bromophenyl, p-biphenylyl, p-nitropheny1, p-benzamidophenyl, or 2-naphthyl;
wherein R " is hydrogen or benzoyl;
(m) hydrogen; or (n) a pharmacologically acceptable cation; and wherein Rg is hydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same or different;
wherein R~ is - C g~2 g -CH3 R~
Rs (2) -C-Z ~ (T)s or ( ~ ) -C~J2~ C C ~C~lzc1-~3 H ~ H

wherein C9Hz9 is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms~ inclusive, in the chain be~ween -CRsRG- and terminal methyl, wherein R5 and R~ are hydrogen, all<yl of one ~o 4 ~ 3 ~ 2871A
.

carbon atoms, inc~uslve, or fluoro, being the same or different, with ~he proviso that one of R5 and R~
is f~uoro only when the other is hydrogen or fluoro and the fur$her proviso that neither R5 nor Ra is fluoro when Z is oxa (-0-); wherein Z represents an oxa atom (-O-) or CjH2~ wherein CJH2; is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atomS, inclusive between CR5R6- and the phenyl ring;
wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or -OR7- wherein R7 is hydrogen or alky1 of one to 4 carbon atoms~ inclu-sive, 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 dif-ferent whercin V is a valence bond or -CH2-; wherein W is -(CH2) wherein h is one or 2; and wherein X is (1) trans-CH-CH-(2) cis-CH=CH-(3) -C-C- or ~ C~12CH2-.
Within ~he scope oF the prostaglandin derivatives described herein there are represented (a) PGF~ compounds when ~ is ~' .
~ .
OH
3o ~ ~7 ~ ~ 3 5 ~871 (b) ll~-P~F~l compounds w~en ~ is ¢l 0~ i (c) ll-Deoxy-ll-keto-PGF~ cornpounds when ~ i s (d) ll-Deoxy-ll-meihylene-PGFa compounds when ~ is (e) ll-Deoxy-PGF~ compounds when Dis ~ ' ~ (f) ll-Deoxy-10,11-Didehydro-PGFa compounds when ~ ; and (9) ll-Deoxy-ll-hydroxymethyl-PGF~ compounds when 7 ~ 2~7~

A typical example of the compounds of formula i is represented by ~he ~ormulaO

_ CH-CH-(CH2)3-COO~l ~H

/ ~
H OH

and named as a derivative of PGF1a: 9-deoxy-6J9-epoxy-5-iodo-PGF1a. The compound of formula V is a species of the formula-l 5-iodo compounds wherein ~ is ~ .
~, '.
OH

L is -(CH2)3-, Q is H OH, R1 is -COOH, R~ is n-pentyl, ` V is a valence bond, W is -CH2 -J and X is ~rans-CH=CH-.
There are likewise provided compounds oF the formula _ ~V-O-C-CH~L-R~
~-w/

_ X-C-R~

~7'~3~ 2871~

.
OH
,V-O-C-CH2-L-RI
-~-W ~ 511 X-C-R~ and ~H
V~ O
~ ~ W-C-CH2-L-R~
) lV

--~X-C-R4 Q
~ . I
wherein ~ , LJ 0~ R1, R4, V, W, and X are as defined broadly above for formula 1, with the proviso thatJ in the enol ether compounds of formula 11, R1 is not-COOH
when -D is bH

~"
20 Q iS ~ OHg L is -(CH2)3-, R~L is n-pen-tyl, V is a valence bondJ W is -CH2-, and X is trans-CH-CH-.
In compounds of formula 11, the wavy line ~ indicates at~achment in cis ot- tr-ans configuration relative to the W-C bond. In Formulas l-IV as used herein, W is bon~ed to 25 the cyclopentane ring at the C-8 position, V at the C-9 position, ancl X at the C-12 position. In compounds of formula 111, ~ indicates attachment of -OH in alpha or beta configura-tion.
The form~la-ll enol ethers are named as derivatives oF
3o PGF2~, regardless of the variations in either of the side ~L~7~3S

chains~ V and W in the heterocyclic ring, or the cyclo-pentan~ ringsystem represented by D ~ followincJ the conven-tions known and used in the prostaqlandin art. The formula-III 6-hydroxy compounds (hemi-ketals) and the Eorm-ula-IV 6-keto compound~ are named as derivaties ~f PGF~.
Typical examples of the compounds of formula II, III, and IV, when ~ , L, o, R~, RL,, V, W, and X are as illustrated above for the compound of formula V are:
O _C~-C~-(CHz )3 -~0 lQ
~C -C
HO H \C-C5 H OH

named 9-deoxy-6,9-epoxy-~s-PGFI~;
OH

~-(CH2)4-COOH

~ C=C ~ H

H OH
named 9-deoxy-6,9-epoxy-6-hydroxy-PGF~x; and OH O
' C~2 -C - (C~2 ) ~-COOI-I
~C -C ~ H V I I I

o~,~ f,C~- C 5 H
H OH

named 6-keto-PGFItx.

rlc~ ~

3 ~ 2871~

The products of thi~ inven~;on~ represen~ed here;n by formulas ig Il) Ill, and IV, are extremely poten~ in causing various biological responses. For that reason, these c5m-pounds are useful for pharmacolo~1cal purposes. A few o~
those bioloyical responses are: inhibition of blood plate1et aggregat;on, stimulation of smooth muscle, system;c blood pressure l~wering, inhibitTng gastric secretion and reducing undesir~ble gastrointestinal effects from systemic administration of pros taglandin synthetase inhibitors.
Because of these biological r-esponses~ the known prostaglandins are usefu7 to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in mamm~ls, including humans, use-ful domest;c animals, pets, and zoological spec imens, and in laboratory anima1s~ for example, mice, rats> rabbitsJ
and monkeys.
These compounds are useful whenever it is desired to :inhibit platelet aggregat;on, to reduce the adhesi~e character of platelets, and to remove or prevent the forma-tion of thrombi in mammals, including man, rabbitsJ and rats.For example, these compounds are useF~Il in the treatment ancJ prevention of myocardia1 infarcts, to treat and pr~vent pos~-opetative throrrlbosis, to promote patency of vascular cJI-afts followiny surgery, and to ~reat conditions such as ~5 atherosclel-osis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia Other in vlvo applications include geriatric patients to prevent cerebral ischemic attacks and long term prophylaxis following myocardial infarcts ~ ~7~3 ~ ~

and strokes. For these purposes, these compounds are ad-ministered systemically~ e.g., intravenously, subcutane-ously, intramuscularlyJ and in the form of sterile imp~ants for prolonyed action~ For rapid response, especially in emergency situations9 the intravenous route of adminis~ra-tion is preferred. Doses in the range abou~ O.Q1 to abo~t 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 admin-istration.
The addition of these compounds to whole blood providesin vitro applications such as, storage of whole blood to be used in heart-lung machines. Additionally whole blood con-ta;ning these compounds can be circulated through organs, e.g. heart and kidneys, which have been removed from a donor and prior to transplant. Also useful in preparing platlet rich concentrates for use in treating thrombocytopenia, chemotherapy, and radiatlon therapy. In vitro applications utilize a dose of 0.001-1.0 ~g/ml of ~hole b100d.
These compounds are extremely potent in causing stimula-tion of smooth muscle, and are also highly active in poten-tiating other known smooth muscle stimulators, for example, c~xytocic agents, e.g., oxytocin, and the various ergot alka-loids including derivatives and ancllogs thereof. Therefore, ~5 they are useful in placc of or in combination with less than wsual arr~ounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ïleus, or to contIol or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placentaJ and during ~ the puerpe~rium. For the latter purpose, the compound is .

~ ~t7~

admjnistered by intravenous in~usion irnmediatcly after abortion or delivery at a dose in the range about 0.31 to about 50 ~ ~er kg. o~ body weight per minute unt; ~ the desired effect is obta!ned. Subsequent doses are ~iven by intravenous, subcutaneousJ or intramuscular injection or i~usion d~r; n~ puerperium in the range 0.01 to 2 mg. per kg ~ b~dy wei ght per day, the exac~ dose depending on the age/ weight~ and co~dition of the patient or animalO
These compounds are useful as hypotensive agents to reduce blood pressure in mammals, including man For this purpose, the compounds are administered by intravenous in-fusion at the rate about 0.01 to about 50 ~g. per kg. ofbody weight per minute or in single or multiple doses of about 25 to 500 ~9. per kg. o-f body weight total per day.
These prostaglandin derivatives are as useful in mam-mals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reduce or avoid gastrointes-tinal ulcer f~rmation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this purpose, these compounds are inJected or in~us~d intravenously~ sub-c-Jt~neously, or intr-al-nuscularly in an infusion dose range about 0.1 ~CJ, to about 20 ug. per kg. of body weight per minute, or in a total daily dosc by injection or infusion in the range about 0~01 to about 10 mg. per kg of body wei~ht per day, the exact dose depending on the age, weightJ
and condi tion of the patient or anirnalJ and on the fre-quer)cy and route of adminis tr-ation.
Thcse compoun~ are also useful in reducin~ the un-desirable gastrointestinal effects resultin~ from systemic 3~

ndmlnlstrntlon of ant~ lnflumm~tory pro~tD~lnndln 8yn~he~nBe inhlbitors, ~nd are used for that purpose by ConComi~an~
administrcitlon of ~he pros~nglandin derlvative and tlle Enei~
inflamma~ory prost~]nndin synthetase inhibi~or. See Paltridge et al, U.S. Pat. No. 3,781,429 issued Derember ~5, 1973, for dlsclosurc that theiulcerogelllc effec~ induced by certain noa~
steroldal anti-lnflammatory agents in rats ls inhibited by cDr~comitant oral admlnlstratlon of cert~in prostag~andins of the E and A serie~, including PGE~, PG~2, PGE3, 13,14-dihy~ro-PGEl, and the correspondlng ll-deoxy-PGE and PGA compounds.
Prostaglandins are useful, for example, in reducing the undesirab]e gastrointestinal effects resulting from syste~ic administration of indomethacin, phenylbutazone, and Aspirin.
These are substances specifically mentioned in Partridge et al as non-steroidal, anti-inflammato~y agents~ These are also ~nown to be prostaglandin synthetase inhibitors.
The anti-inflammatory synthetase inhibitor, for example, indomethacin, A~pirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammator~
condition, for example, in any dosage regimen and by any af the known routes of systemic administration.
The prostaglandin derivative ls administered along wlth the anti-inflammatory prostaglandin synthetase inhibi~or elther by the same route of administratlon or by a different route. For example, if the anti-inflammatory substance is being admlnistered orally, the prostaglandin derivative is also administered orally, or, alternatively, is administered rect~lly in the form of a supposltory or, in the case of women, ~a~inally ln ehe form of a suppository or a vaginal device for slow release, for example as described in U.S. Pnt~

* Trademark Jl/ ~ -14 , . . .
~ ~ ,j ~9~3~
No. 3~545,439 ~Dec. 8, 1970, The Up~ohn Company~. Alternatively9 if the anti-inflammatory substance is beln~ administered rectally, the prosta~landin derivative ~ 5 al.so administered rectally. Further 9 the prostaglandin derivative can be conven-iently administered orally or, in the case of women, vaginallyO
It is espec~ally convenient when ehe administration route i~ ~o be the same for both anti-inflammatory substance and prostaglandin derivative, to combine both into a single dosage form.
The dosagc regimen for the prostagland~n derivative in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular prostaglandin derivative to be administered. For example, not every human in need of an anti-inflammatory substance experiences the same adverse gastro-intestinal effects when ta~ing the substance. The gastro-intestinal effects will frequently vary substantially in kind and degree. But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastro-intestinal effects in the human or animal subject and to pre-scribe an effective amount of the prostaglandin derivative to reduce and then substantially to elimlnate those undesirable efectsO
These compounds are also useful in the treatment of asthma. For example, these compounds are useful as broncho-dilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex~ Thus, these com-~ 15-L79~35 287lA-1 pounds control spasm and facilitate breathing in condi~
tions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these com-pounds are administered in a variety of dosa~e forrns, e.~., orally in the form of tablets, capsules, or liquids; rec-tally in the form of s~ppositories; parentera1lyJ sub-cuta~e~usly, or i ntramuscu~ar~y, wi th 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 ~imes a day, the exact dose depending on the age, weight, and condition of the patient and on the fre-quency and route 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 am7nophylline); and cortico-steroids (ACTH a~ prednlsolone).
These compounds are effectively administered to human asthma patients by oral inhalation or by aerosol i nhalation.
For administration by the oral ir-halation route with conventional nebulizers o~ by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute solution, preFerably at concéntrations oF about 1 part oF medicament to form about 100 to 200 parts by weiyht oF total solution. Entirely conventional additives may be employed to stabilize these solutions or to pro-vide isotonic med;a, for example, sodium chlorideJ sodium citrate, citrlc acid, sodium bisulfite, and the li~e can be employedO
For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suita-ble for inhalation therapy the composition can comprisethe active ingredient suspended 1n an inert propellant tsuch as a mixture of dich7Orodifluoromethane and di-chloratetraf7uoroethane) together with a co-solvent3 such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can also be used a dispersing agent such as oleyl alohol. Suitable means to employ the aerosol inhalation therapy technique are described fully in U.S, 2J868,691 (Jan. 13/59, Riker Laboratories, Inc.) for exalrE>le.
These compounds are useful in mammals, inciuding m~n, as nasal deconyestants and are used for this purpose in a dose range of about 10 ~9. to about 10 mg. per ml. of a pharmacolo~ically suitable liquid vehicle or as an aerosol spray, both for topical application.
These compounds are also useful in treatin~ peripheral vascular disease in humans. The term peripheral vascular disease as used herein means di sease oF any of the blood vessels outside of the heart and to disease of the lymph vessels~ for example, Frostbite, ischemic cerebrovascu1ar clisease, artherioveno(ls flstulas, ischemic leg ulcers~
~5 phlebitis, venous insu$ficiency, gangrene, hepatorenal syn~
drome, ductus arteriosus, non-obstructive mesenteric ischemia, arteritis l~mphangitis and the like~ These examples are included to be illustrative and should not be construed as limiting the term peripheral vascular 3~ disease. For these conditions the compounds of this -lf-Lnvention are administered orall~ or parenterally Vi8 inJection or infuslon directl.y into a vein or artery9 lntra-~enous or in~ra-arterial in~ections being preferredO The dosages of these compounds are in the range of 0.01-1.0 ~g/kg admlnistered by infusion at an hourly rate or by inJection on a dally basis i.e. 1-4 times a day9 ~he exact dose depending on the a~e9 weight, and condition of the patient and on the frequency and route of admlnis~rationO Trea~ment is continued for one to five days, altho~gh three dayq is ordinarily sufflcient to assure long-lasting therapeutic action. In the event that systemic o~ side effects are observed the dosage is lowered below the threshold a~ ~hich such systemic or side effects are observed.
These compounds are accordingly useful for treating peripheral vascular diseases in the extremities of humans who have circulatory insufficiencies in said extremities, such treatment affording relief of rest pain and induction of healing of ulcers.
For a complete discussion of the nature of and clinical manifestations of human peripheral ~ascular disease and the method previously known of its treatment with prostaglandins see South African Patent No. 74/0149 (March 7, 1975, L.A. Carlson), or corresponding U.S. Patent 4,103,026 (July 25, 1978). See ~lliott, et al, Lancet, January 18, 1975, pp. 140-142.
These compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and plgs, at or near term, or in pregnant animals with intra-uterine death of the fetus from about 20 weeks to term. For this purposel the compound is in-~ 18-3L~ 7$~3~ 2871A-l-F

fused intravenously at a dose of 0.01 to 50 ~9. per kg.
of body weight per minute un~il or near the terminatlon 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 mem branes have ruptured and natural labor has not yet started.
An alterna~ive route of administration is oral.
These compounds are further useful for controllin~
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 approximately at the time of ovulation and endin~ approximately at the tirne of menses or just prior to menses. Intravaginal and intrauterine routes are laternate methods of administra-tion. Additionally, expulsion of an embryo or a fetus is accomplished by siIllilar aclministration of the compound ciuring the ~irst or second trimester of the normal mam-maIian gestation period.
These cornpounds are Fur~her useful in causing cervi-cal dilation in pre~nant and nonpregnant female-r~ k~
~or purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases ~0 of infertility, cervical dilation produced by these com-~ ~7 9 ~ 3 5 2871A-1~F

pounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostaglandins is also use-f~l 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 prosta~landin derivative is administered locally or systemically.
The prostaglandin derivative, for example, is admin-istered orally or vaginally at doses of about 5 to 50 mg.
per treatment of an adult female human, with From one to five treatments per 24 hour period. Alternatively the compound is administered intramuscularly or subcutaneously at doses of 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 an aid to estrus detection, and -For regulation or synchroniza-tion of estrus. Domestic animals include horsesJ cattle, sheep, and swinc. The reyulation or synchronization of estI-us allows for more efficient management o~ both con-ception ancI 1abor by enabling the herdsman to breed all his Femals in short pre-deFinecl intervals. This synchroniza-tion results in a higher percentage oF live births than the percentaye achieved by natural control. The prostaglandin i 5 i njected or applied in a feed at doses of 0.l-100 mg.
per animal an~J may be combined with other agents such as steroids. Dosing schedules will depend on the species 3 3 ~ -287lA-l-F

treated. For example, mares are given the prostaglandin derivative 5 to 8 days after ovulation and return to estrus.
Cattle are treated at regular in~ervals over a 3 week per;od to advantageously bring all into estrus at ~he same time.
These compounds increase the flow of blood in the mammal;an kidney~ thereby ;ncreasin~ volume and electr~-lyte content o~ the urine For tha~ reason, these compo~nds are useful in managing cases of renal dysfunc~ion, especial7y those involving blockage of the renal vascular bed. Illus-tratively, these compounds are useful to alleviate and cor-rect cases o-f edema resulting, for exa~ple, From massive surface burns, and in the management of shock. For these purposes, these compounds are pre~erably ~irst admin;stered by intravenous injection at a dose in the range 10 to 1000 ~9 per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 ~g. per Icg. of body weight per minute until the desired effect is obtained. Subse-quent doses are ~iven by T ntravenous~ in~ramuscular, or subcutaneous injectlon or infusion in the range 0.05 to 2 mg. per k9~ of body weight per day.
rllese prostaglandirl derivatives are use~ul for treating proliferatin~ sl<in diseases oF man and domesti-c~ted animala, including psoriasis, atopic clermatitis, non-5pecific dermatitis, primary irritant contact dermatitis;
G~5 allergic contact dermatitis, basal and squamous cell carcinomas o~ the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premaliynant sun-induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in domesticated animals. These compQurlds alleviate the symptoms of ~hese -2~-3~
proliferativc ~kin diseases: psori~sis, for example, belng alleviated when a scale~free psoriasis lesion is noticeably decreased in thickness or noticeably but incompletely cleared or completely cleared, For these purposes~ these compounds are applied topically as compositions including a suieable pharmace~ical carrier, for example as an ointment9 lotion, paste, jelly, spray, or aerosol, using topical bases such as petrolatum, lanolin, poly-ethylene glycols, and alcoholsO These cDmpounds, as the active ingredientsj constitute from about D.1% to about 15% by weight of the composition, preferably from about 0.5% ~o about 2%.
In addition to topical administration, injection may be employed, as intradermally, intra- or peri-lesionally, or subcutaneously, using appropriate sterile saline compositions.
These compounds are useful as antiflammatory agents for inhlbiting chronic inflammation in mammals including the swelling and other unpleasant effects thereof using methods of treatment and dosages generally in accord with U S Patent Number 3,885,041, issued to G.D. Searle and Co.~ May 20, 1975.
These 6-keto, iodo ether~ enol-ether, and hemi-ketal compounds of this invention cause many of the biological responses known for the older prostaglandin compounds. For examp.l.e, they are surprisingly more specific with regard to potency and have a substantially longer duration of b:lological activity~ They have the further advantage that they may be adllllnistered effeceively orally, subli.ngually, intravaginally, ~7 ~ ~ 3 5 -287lA

buccally, or rectally as well as by the u~ual methods.
Each of these novel analogs is ~herefore useful in place of the known prostaglandin F~ -~type compounds for at least one of the pharmacological p~rposes known for ~hem, and is surprisingly and unexpectedly more useful for that purpose because ;t has a different and narrower spectrum of blolog-ical acti~i~y than the known prostaglandin, and therefore is more specific in it5 activity and causes smaller and ~ewer undesired side effects than the known prostag~andin.
MoreoverJ because of its prolonged activity, fewer and smaller doses of these novel compounds can frequently be used to attaln the desired result.
There are further provided the various processes for preparing the 5-iodo compounds of formula 1, the enol ethers of formula 11, the hemi-ketals of formula 111, and the 6-keto compounds of formula IV.
Thus, for the ~ormula-l, -111 J and -IV compounds, the process comprises the steps of starting with a compound of the formula OH

~ ~ ,W-C~=cH-L-R1 ~ ~ X-C-R4 IX

wherein L~ J R4, and X are as ~ fined above, includ-ing -COOH for R1J and wherein ~ is ~0 ... .. .. _ 9 ~[~J j~J<~J~

7 ~ ~ or ~

' 10 wherein R13 is hydrogen, tetrahydropyranyl, tetra-hydrofuranyl, 1-ethoxyethyl, or a group of the formula i-i Rl~-O-C - C-R ~7 Rl5 P~

wherein Rl~ is alkyl of one to 1~ carbon atoms, in-clusive, cycloalky1 of 3 to 10 carbon atoms, inclu-sive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2J or ~ alkyl of one to 4 carbon atoms, inclusive, wherein Ft15 and and R1~ are the same or different, being hydrogen, alkyl o~ one to 4 carbon atoms, inclusive, phenyl or pheny1 substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, in~lusive, orl when R13 and Rl~ are taken together, -(CH2 )a~ or -(CH2)b-O-(CH2)c- w~erein a is 3, 1~, 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 ~, and wherein Rl7 i5 hydrogen or phenyl; and (a) lodinating and cyc1izin~ to form a compound of the formula 33~ ~ 2871~
.

- - V-O--CII-CH-L -R I
~ , ~

~ X -R"

where;n~), Ll, ~, Rl, R4, V, W, and X are as deflned above, (b) subjecting the product of step 1'a" to dehalogen-ation and hydroly5;5 to form a keto compound of the formula OH

~ W-C-CH2-L-R~
~ 'XII

~~' X -C -R 4 and a hemi-ketal compound o~ the formula OH
, V -OjC -CHz -L -R
.I ~-W Xl X -C -R ~
, WhCre;r) J~ LJ Q; RIJ R4~ VJ W~ X~ and ~, are as defined 25 a bove, a nd (c ) separati ng ~he products~
I n this disclosure of the process3for the formula-l, -I I I J and -IV compounds, the symbol p i nclude:s al l of the ri ng systems of the symbol 'D def i ned a~ove, together wlth those in whlcl~ there i s a blocki ng group wi thi n the -2~-~L7~ ~3 287 lA

ssope of Rl3 at C^ll. The compounds producedl as repre-sented by formulas X, Xi, and Xll, are inclusive of the formula~ 111, and -IV compounds together with those in which there is ~he blocking group from the formula-lX
starting material O The compounds with blocking groups are useful as ineermediates in further trans~ormations of the Formula-X, ~XIg and -Xll products.
For the formula-ll enol ethers, the process employ~
dehydroiodination of formula-l iodo compounds. Accordingly, the process comprises the steps of starting with a compound of the formula H

W -CH=CH-L -R
) Xlll : 15 ~

wherein ~ , L, Q, Rl, R4, V, W, and X are as defined a~ove, including -ÇOOH for Rl, and.
(a) iodinating and cyclizing to form an iodo compound of the formula y-0-CH-~H-L-R

-C-R~
Il .

wherein ~,L, Q, R " R~, V, W, and X are as defincd above;
(b) subjecting the product of step "a" to dehydro-. -~6~

~ 3 5 2871A

iodination with a tertiary amine or a reagent seleceed from the group consistlng of sodium or potassium superoxide, sodi-um or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium acetate, sodium or potassium trif1uoroacetate, sodium or potassium bicarbonate, silver acetate, and a tetraa1ky1ammonium super-oxide of the ~ormula (Rl2)4NO2 wherein Rl2 is a1kyl 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 formu1a-l, -Ill, and -IV products of this invention.
In Chart A, the terms are defined as follows:
~D i5 h , or C'H20H
For those instances in wh1ch the formula-X, -Xl9 and -Xll compounds are desired, corresponding to the formula-l~ lll, and IV products, the C-ll hydroxyls of Xlll are suitably protected with blocking groups within t~e scope of R19 as de~ine~ above and D then becomes ~ as defined abov~.
L is (1) -(C~2)d-C(R2)2-~3~7~35 2871~

CHARr A

~,W -Cl l=CH-L -R 1 3 Xlll X - C - R ~

`¦, (a ) V -O -CH-~H -L -R

0 ~ ,(b) OH O
f~ ,W -e-CH2 -L -R 1 (d ) ~ X ~S -R ~., Q ~ `(c) ~H l .
/V-O -C -CHz -L -R I
~'_W 1"

X -C -R
~0 . Q

~2) -CH2~0-CH2-Y- or (3) -CHzCH=CH-wherein d ;s zero to 5; R2 is hydrogen, methyl~ or fluoro, being the same or different with the proviso that one R2 is not methyl when the other is fluoro;
and Y is a valence bond or -(CHz)k-wherein k ;s one or 2i Q is O, H H , Ra OH, or R8 OH

wherein Ra is hydrogen or alky1 of one to 4 carbon a~oms, inclusive;
R~ is (1) -COOR3 (2) -CH20H
(3) -CH2N(R9)2 or (1~) ~NH-N
~N -N
wherein R3 is (a) alkyl of one to 12 carbon atoms, inclusive, (b) cycloallcyl of 3 to 10 carbon atoms, inclusive, (c) arallcyl of 7 to 12 carbon atoms, in-clusive, (d) phenylJ (e) phenyl substituted with ~5 one, 2, or 3 chlor~ or alkyl of one to 4 carbon atoms~
inclusive;

O O
(b) ~ -NH-C ~ NH-C-CH3, .
3o O
g) ~ NH-C~, ( h ~ H-C -C1~3, O ' .
( j ~ ~NH-C-NH2 ) ~ ~ CH~ NH-C-NH2, or (k) \~ J

( " fi H C-R Io R
wherein R1o is pheny~, p-bromophenyl, p-biphenylylJ p-nitrophenyl, p-benzamidophenyl, or 2~naphthyl;
wherein Rll is hydrogen or benzoyl;

(m) hydrogen; or (n) a pharmacologically acceptabl e cat i on; and wherein R9 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same or different;
wherein R~ is C ~H2 g -CH3.
3 Ro ~ 3 ~ ~ 2871 (2) -C-Z ~ (T)s or R~

(3) -CH2 ,,CH2CH3 H ~ `~

wherein C~H29 is al~ylene of one to 9 car~on atoms~
inclusive, with one to 5 carbon atoms, inc1usive, in the chain between -CR5R6- and terminal methyl, wherein R5 and R6 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoroJ being the same or different, with the proviso that one of R5 and R~
is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R5 nor R~ is - fluoro when ~ is oxa (-0-); wherein Z represents an oxa atom (-0-) or CjH2; wherein C,,H2J is a valence bond or alkylene of one to 9 carbon atoms~
inclusive, w;th one to 6 carbon atoms, inclusive between CR5R6- and the phenyl ring;
wherein T i5 alkyl of one to 4 carbon atoms, inclusive~
fluoro, chloro, triflooromethylJ or -OR-r- wherein ~7 is hy(lroyerl or alkyl of one to IJ carbon atoms7 inc1u-sive, and s is ~ero, one, 2 or 3, with the proviso tllat 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 dif-ferent;
where;n ~ is a va1ence bond or -CHz-; wherein W is ~(CH2)h-wherein h is one or 2; and where7n X is .

~ 33 ~ 2871A

(1) trans-CH=CH-(2) cis-CH=CH-(3) -C-C- or (4) -CH2CH2-u Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl~ ethyl, propyl, butyl~ pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and isomeric f~rms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms5 inclusiveJ which includes alkyl-substituted cycloalkylJ are 10 . cyclopropyl, 2-methylcyclopropylJ
2,2-dimethylcyclopropyl, 2,3-diethylcyclopropylg 2-butylcyclopropy1, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2~3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentylJ
3-pc~ntylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tcrt-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl~
cyclooctyl, cyclononyl, 3 and cyclodecyl~

-3~-~7~33~
Examples of aralkyl of 7 tu 12 carbon atoms, lnclusive, are benzyl, phenethyl~
l-phenylethyl9 2-phenylpropyi 9 4-phenylbutyl 9 3-phenylbutyl 9 2-(1-naphthylethyl) 9 and 1-(2-naphthylmethyl).
Examples of phenyl substi~uted by one to 3 chloro or alkyl o~
one to 4 czrbon atoms, inclusive are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-t~lyl, m-tolyl, o-tolyl, p-ethylphe~yl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichl.oro-3-methylphengl.
Referring to Chart A the startlng materials of formula XIII
are known in the art or are readily available by processes known in the art. For example, as to PGF2a see U.S. Pat. No.
3,706,789 (S. Bergstrom et al, December 19, 1972); a~ to 15-methyl- and 15-ethyl-PGF2a, see U.S. Patent No. 3,728,382 ~he Upjohn Company~ April 173 1973); as to 16,16-dimethyl-PGF2a, see V.S. Patent No. 3,903,131 (The Vp~ohn Company, September 29 1975) 9 as to 16,16-g~ 33~
dif~urO-pG~a compounds, ~ee The Up~ohn Company's U.S. Pa~ent Nos. 3,962,293 (June 89 1976) and 3,969,380 (July 13, 1976);
as to 16-phenoxy-17,18,19,20-tetranor-PGF2a, see Netherlands Patent 7306462 (November 139 19739 The Upjohn Company); as to 17-phenyl-18,19,20-trlnor-PGFaa9 see UOS~ Patent No. 3,987,087 (October 19, 1976, The Up~ohn Gompany); as to ll~deoxy-PGF~a, see Netherlands Patent 7309856 (January 28, 1974, The Up~ohn Company); as to PGD2, see UOSO Patent No. 3,767,813 (October 23, 1973, B. Samuelsson), as to 2a92b-dihomo-PGF2a, see Derwent Farmdoc No. 61412S and U.SO Pa~ent NoO 3,852,316 (December 3, 1974, The Upjohn Company) and 3,974,195 (August 10, 1976, The Upjohn Company); as to 3-oxa-PGF2a, see U.S. Patent No.
3,923,861 (December 2, 1975, The Upjohn Company); as to 3-oxa-17-phenyl-18,19~20-trinor-PGF2a9 sPe UOS. Patent No. 3,931,289 (January 6, 1976, The ~pjohn Company); as to substituted phenacyl Psters, see The Upjohn Company's Belgian Patent No.
832,459, February 16, 1976; as to substituted phenyl esters, see U.S. Patent No. 3,890,372 (June 17, 1975, The Upjohn Company); as to C-l alcohols, i.e 2-decarboxy-2-hydroxymethyl compounds, see U.S. Patent No. 3,636,120 (January 18, 1972, The Upjohn Company); as to C-2 tetrazolyl derivati~es, see Pfizer, Inc.'s U.S. Patent Nos. 3,883,513 (May 13, 1975) and 3,932,389 (January 13, 1976); as to Q2-PGF2a see Derwent Farmdoc No. 46497W and German 0ffen. 2,460,285 (July 3, 1975, Ono Pharmaceutlcal Co.); as to 2,2-dimethyl-PGF2a analogs~ see BelgLan P~tent 779898 (Au~ust 25, 1972, Imperial Chemicals, Inc.);
as to 9-deoxy-9-hydroxymethyl-PGF2a, see U.S. Patent No.
3,950,363 (April 13, 1976, The Upjohn Company); as to llB-PGF2a compo~nds, ~ee U.S. Patent ~o. 3,890,371 (June 17, 197S, The UpJohn Company); as to ll-deoxy PCF2a, see Derwent Farmdoc No.
10795V; as to ll-deoxy-ll-hydroxy-methyl-PGF2a, see U.S. Patent No. 3,931,282 (January 6, 1976, Syntex (IJ.S.A.) Inc.) and the ~ -34-~333~
aforementioned U.S. Patent No. 3,950,3G3; as to 16-methylene-PGF~, see Derwent Farmdoc ~o. 19594W and ~er. Offen. 2,440,919 (March 13, 19759 Ono Pharmaceutical Co.), as ~o 17,18-didehydro-PGF~a compoundsj see U.S. Patent No. 3,920,726 (November 18, 1975, The ~p~ohn Company); as to 3-(or 4-) oxa-17,18-didehydro-PGF2a compounds~ see U.S. Patent 3,92~,723 (November 1~, 1975, The Up~ohn Company); as to 15-oxo-PGF~, see V.S. Patent No.
3,728,382 (Aprll 179 1973, The Vpjohn Company); as ~o 15-deoxy-PGF2~, see Canadian Patent 961,489 issued to American Cyanamid Co., January 21, 1975; as to 13,14-cis compounds, see U.S.
Patent No. 3,932,479 (American Cyanamid Co., January 13, 1976);
as-to ll-deoxy-15-deoxy PGF2a see Netherlands Patent 7208576 (American Cyanamid Company, January 16, 197~); as to ~-homo-PGF2~ compounds, see Japanese Patent 91026/47 (Ono Pharmaceutical Co., September 27, 1974); and as to 2,2-difluoro-PGF2a compounds see U.S. Patent 3,987,083 issued October 19, ]976 to The Upjohn Company.
As to 2-decarboxy-2-amino-PGF2~ compounds, sèe U.S. Patent NoO 4,085,1399 issued April 18, 1978 to the Upjohn CotnpanyO
In step "a" of Chart A, the starting material XIII is sub-jected to iodination and cyclization to yield the formula-l iodo compounds. For this purpose there is used either an aqueous system containing iodine, potassium iodide, and an allcali carbonate or bicarbonate~ or an organic solvent system such as dichloro-methane contalning iodine in the presence of an alkali metal carbonate~ The reaction is carried out at temperatures below 25C, preferably about 0 5C for 10-20 hr. Thereafter the reaction is quenched with sodium slllfite and sodium carbonate and the formula-l compound separated from the reaction mixture.
In step "b" of Chart A the lodo compound 1 is converted to the 6-keto compound by contacting with silver carbonate and perchloric acldO The reaction is done in an inert organic medium such as tetrahydrofuran and i8 followed wlth TLC to 7~

determlne completion, normally in -15-24 hr. at about 25C.
The reaction ~s preferably done in absence of light.
In step "c" of Chart A the 6-keto compound IV ls equilibrated ln solution to a mixture of the for~ula-lll and formula~lV compounds. This is accomplished merely by preparing a solution of the formula-lV compound in an Jl/~ ~ -35a-7 ~ 3 3 ~

organic solven~, e.g. ac~tone or dichlorome~hane, anb let-ting it stand for several days. Thc resulting mixture is concentrated and separated, for example by silica gel chroma-tography~ to yield the ~ormula-lll hemi-ketal.
Step "d" of Chart A provides an alternate route to the formula~l~hemi-ketal. The formula-l iodo compound is treated in alcoholic solution, e.g. rnethano1) with a~ueous alkali metal hydroxide, e.g. potassium hydroxide, at ~
temperature in the range of 0 to 30 C. for several hours.
After acidification there is obtained a m;xture of the acid form of the formula-l compound and the formula-lll hemi-keta1 toyether with sorne of the formula-lV compouncl, which are separated, for example, by silica gel chroma-tography or by fractional crystallization.
The novel compounds of formulas 1, Ill, and IV wherein R1 is other than -COOHg e.g.g tne esters wherein R3 of -COOR3 is alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms~ inclusive, aralkyl o~ 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are prepared From the corresponding acids of Formulas 1, lll J
and IV, i.e., wherein R1 is -COOH, by methods known in the ~rt For example, the allcyl~ cycloalkyl, and aralkyl esters are prepal-c!d by interactivn of said acids ~ith the appro-priate diazohy~rocarborl. For example, when diazomethane is uscd~ the methyl! esters are produced. Similar use of diazoethane~ di'azobutane, 1-diazo-2-ethylhexane, d;azocyc10 hcxane, and phenyldiazorl-ethane, for example, gives the ethyl, butyl, 2-ethylhexyl, cyclohexyl, and benzy1 esters, respectively. Of these esters, the methy1 or ether are 9 ~3 preferred D
Esteri~ication with diazohydrocarbons is carried out ~y mixing a solution of the diazohydrocarbon in a sui~a~le inert solven~, preferably diethyl ether, with the acid

5 reactant, advantageously in the same or a different inert diluent. After the esterification reac t i on i s comp 1 e t e , the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferab1y by chromatography~ It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification3 preFerablY
about one to about ten minu~es, eo avoid undesirecl molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art~ See, for example Organ;c Reactions, John Wiley & Sons, Inc.J New York, N.Y., Vol. ~, pp. 3~9-394 (195~1).
An alternative method for esterification of_the car-boxyl moiety of the novel compounds of formulas l; 1l1, and IV comprises transformations of the ~ree acid to the cor-responding silver sal~t, followed by interaction of that saltwith an alkyl iodide. Examples of suitable iod;des are methyl, iodide, ethyl ioclide, butyl iodide, isobutyl iodide, tert-buty1 ioclide, cyclopropyl iodideJ cyclopentyl iodide, benzyl iodid~J phenethy1 iodide, and the like~ The silver salts ~5 are prepared by conventional methods, for example, by dis-solving the acid in cold dilute aqueous ammonia, evaporating the excess amrnonia at reduced pressureJ and then addin~
lhe stoichiolrletric amount o~ silver nitrate.
The phenyl and substituted pheny1 esters of the ~ ~ormula 1, lll~ an~ IV compounds are prepared by s;ly~ating ~37-the ac i d to protect the hydroxy groups, for ex~3rrple, re-placi ng each -OH w; th -~-Si -~CH3~3. I~oi ng that may also change -COOH to -CGO-Si-~CH3)3. A brief treatment of the si lylated compound w; th water wi 11 change -COO-Si -(CIH3)3 back to -COOH. Proced~res for this silyla~ivn are known in the a~t and are disc~ssed hereinafter. Then, treatmen~ of the si lylated compound with oxalyl chloride gives the acid chloride which is reacted with phenol or the appropria~e s~bstituted phenoi to g i ve a s i I y I a ted phenyi or substituted .phenyl ester. Then ~he s i I y I groups, e . 9., -0-S i - (CH3 ~3 are changed back to -OH by treatment with dilute acetic acid. Procedures for these transformations are known in the art.
Reference to Chart B, herein will make clear the steps for prepari ng the form~la-ll products of this Tn-vention~
In Chart B the terms ~ , L, Q, R1, R4, V, W, and X are as defined above for Chart A, In step "a" of Chart B, as in Chart A, the starti ng materials XIII are subjected to iodination and cyclization to yield the formula-l iodo compounds~
In step "b" of Chart ~ the iodo compound I is con-verted to the formula-II enol ether compound by contacti ng i t wi th a dehydroiodination reagent. For such reagents s~e, for example, Fieser and Fieser, "Reagents for Organic Synthesis" p. 1~08, John Wiley and Sons, Inc.,New York, N Y. (1967). Preferred for the reaction of step "b" are tertiary amines ancl reagents selected from the group con-sisting of sodium or potassium superoxide, sodium or potas-~ sium carbonate, sodium or pot2ssium hydroxide, sodium or potas-3~ 2871 Cha rt ~0 ~W-C~CH~L-R~

Q X l l I

(a) `~
~J .

(b ) V-O-C=CH-L-R

X-5-R~

3o ~39 -~ s3 ~ 2871A

sium benzoate~ sodium or potassium acetate, sodium or potassium ~rifluoroacetate, sodium or potassium bicarbonate9 silver acetate, and a tetraalkylammonium superoxide of the formula (Rl2~NO2 wherein R12 is alkyl of one to 4 carbon atoms,inclusive~
Of the tert;ary amines, pre~erred amines are 1,5-diazabicyc~o~4.~.03nonene-5 ("DBN"), 1 ) 4 -d i azabi cyc l o [2 . 2 . 2 ]oc tane ("DABCO")~
and . 1,5-di azabi cyclo[5.4.0lundecene-5 ("DBU")~
Other preferred reagents are sodium or potassium superoxide and tetramethylammon7um superoxide. For further informa-t~on on the superoxides see Johnson and Nidy, ~. Org. Chem.
40, 1680 (1975). For larger scale preparation the electro-chemical generation of superoxide is recommended. See Dietz et al., J. Chem. Soc. (~), 1970, pp. 816-820.
The dehydroiodination step is carried out in an inert organic medium such as dimethylformamide and is followed by TLC to show the disappearance of starting material.
The reaction proceeds at 25 C. and can be accelerated at 40-50 C.
In working up the reaction mixture it is advantageous to mailltain basic conditions~ e.g. with triethylamine, to avoid acidic decomposition or structural chanyes of the product. Purification is achieved by crystallization and consequent separation from impurities or starting mater-ial left ~n the mother liquor, or by column chromatography.
For chromatographic separation a column of magnesium sili-cate ("Florisil~") is preferred over silica gel. Decompos-ition of the product is avoided by pretreating the column 3~
.
with triethylamine.
Ester groups such as the p-phenylphenacyl group on the C-l car~oxyl or 4-bromobenzoate on C-ll and C-15 hydroxyls are unchanged by the transformations of Chart B, and, if present on the formula-Xlll stcrting material, are also present on the formula-ll product. For the final products of formula 11 which are esters the preferred method of preparation is from formula-l iodo compounds which are corresponding estersO
Especially useful for administration because of their form as free-flowing powders and their ease of dissolving are sodium salts. They are obtained from the formula-ll esters by saponification with equivalent amounts of sodium hydroxide in a solvent, preferably an alcohol-water solution, thereafter lyophilizing (freeze-drying) -the mixture to obtain the powdered product. The starting esters are preferably alkyl esters, of which methyl or ethyl are especially preferred.
This invention also includes the 1,15-lactones obtained from the formula-l, -11, -111, and -lV compounds wherein R

is -COOH and Q is 1- 0~1, for example 9-deoxy-~,9~epoxy-5-iodo-PGF1~ 1,15-lactone and 9-d~oxy-6l9-epoxy- Q -PGF~ 5-lactone.

For theix preparation, analogous methods are used to those disclosed in U.S. Patent No. 4,067,991 issued January 10, 1978, .

3~i to The Upjohn Company.
It should be understood that althou~h the Charts have formulas drown with a specific configuration Eor the reactants and products, the procedural steps are intended to apply not only to the other optically active isomers and cis/tra~s geometric isomers, but also to mixtures, including racemic mixtures or mixtures of enantiomeric forms.
If optically active 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 ar~, may be used as such for a succeeding step or, optionally, separated by conventional methods of fractionation, column chromatography, liquid-liquid extraction, and the like, before proceeding.
To obtain the optimum combina-tion of biological response specificity, potency, and duration of activity, certain compounds within the scope of formulas l-lV are pre:eerred. For example it is preferred that Q be wherein :i.t is especially preferred that R8 be hydrogen or me thy 1 .
~no-ther preeerence, for the compounds of Eormulas 1, 111, and lV as to Rl, is that R3 in -COOR3 be either hydro-- 42 - - ~

3~3~

gen or alkyl of one to 12 carbon atoms~ inclusi~e. it is further preferred that R3 be alkyl of one to 4 carbon atoms~
inclusive, especially methyl or ethyl, for optimum absorption on administration~ For the compounds of formula-II, it is preferred that R3 not be hydrogen but rather an alkyl ester or a salt of a pharmacologically acceptab1e cation.
For purposes of stability on long storageJ it is also preferred that R3 be amido-subst~tuted phenyl or substituted phenacyl, as illustrated herein.
As to variations in D it is preferred that ~ be ~ ~ I or ~
oh o As to variations in P4, it is preferred that R4 be n-pentyl 1,1-dimethylpentyl 1J 1-difluoropentyl -CH2-O- ~ or -C2~

As ~o variations in L, it is preferred that L be -(CH2)3-, -(CH2)~-, or -(~H2)5 -J especially -(CH2 )3-DESCRIPTION OF THE PREFERRED EM _ DIMENTS
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 Perkin-. .

-4~

~7~3;3~

Elmer*model 421 infrared spectrophotometer. Except when specified otherwise~ undiluted (neat) samples are used, ~he NMR spectra are recorded on a Varian~A-60, A-60D, or T-~O spectrophotometer ;n deuterochloroform solutions with tetramethylsilane as an internal standard~
Mass spectra are recorded on a Varian*Model MAT CH7 Mass Spectrometer3 a CEC Model 110B Double Focusin~ High ~esolut70n Mass Spectrometer, or an LKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ev.).
"Brine", herein, refers to an aqueous saturated sodium chloride solution.
"Skellysol~e*B';, herein, refers to mixed isomPric hexanes.
"DBN", herein, refers to 1,5-diazabicyclo[4.~.0~nonene-5.
"DABCO", herein, refers to 11,4-diazabicyco[2.2 2]octane.
"DBU", herein, reFers to 1,5-diazabicyclo[5.4.0]un-decene-5.
"DIBALi', herein, refers to diisobutylaluminum hydride.
"Florisil*", herein, is a chromatographic magnesium silicate produced by the Floridin Co. See Fieser et al.
"Reagents For Orc3anic Synthesis" p. 39~ John Wiley and Sons, Inc., New York, N.'Y. (1967).
"TLC", herein, reFers to ~hin layer chromatography.
Silica gel chromatography, as used herein, Is under-s~ood to include elution, collection of fractions, and combin-ations of those fractions shown by TLC to contain the desired product Free of starting material and impurities.
~0 "Concentrating", as ~sed herein, refers to concentration * - Trademarks ~ ~7~3~ ~o71A

under reduced pressure, preferably at less than 50 mm~ and at temperatures below 35 C
Preparation 1 11-Deoxy-10,11-didehydro-PGF2a, Methyl Ester and its 9~-epimer; and 11-Deoxy-10, ll-di dehydro-PGFza and its 9~-epimer.
A mixture o~ PGA2, methyl ester (1.74 9.) and 12 ml.
of tetrahydroFuran is treated at -78 C. wlth 2~ ml. of 10~ DIBAL in to~uene A~ter one hourts stirring at -78 C~
the mixture is quenched with 100 ml. of tetrahydrofuran-saturated aqueous ammonium chloride (1:1) and warmed to about 25 C. The m7xture is acidified with sodium bi-sulfate and extracted with ethyl acetate. The organic phase is washed with sodium bisulfate, sodium carbonate, and brlne~
dried over sodium sulfate, and concentrated to yield 1c8 g.
The cr~dc product is subjected to column chromatography to separate the tit1e compounds, in the order:
11-deoxy-10,11-didehydro-PGF2a, methyl ester~
ll-deoxy-lOJ ll-di dehydro-9~-PGF2c,,, methyl esterJ
ll-deoxy-10, 11-didehydro-PGF2a, and ll-deoxy-10, ll-di dehydro-913 ~PGF2a.
Exam~le 1 9-Deoxy-6,9-epoxy-5-iodo-PGFl~, MethyI Ester (Formula I: L is (CH2)3-, Rl is -COOCH9, R~ is n-pentylJ V is a valence bond, W is -CH2-, X is trans-CH-CH-, ~ is ~' .
~1 ~ 7 ~ ~ 3 ~ 2871A
;

and Q 1s ~ j.
H OH

Refer to Chart A, step l'a". A suspens;on of the formula-Xlll PGF2a~ meth~l ester as i~s 11,15-bis(~etrahydropyrany~) ether (2.0 9.) Tn 23 ml. of water is treated with sodium bi-carbonate (0.7 9.) and cooled 1n an ice bath. To the re-sulting solution is added potassium iodide (1.93 9.) and iodine (2.82 9.) and stirring continued for 16 hr. at about 0 C. Thereafter a solution of s-odium sulfite (1.66 9.) and sodium carbonate (o.76 9.) in 10 ml~ of water is added.
After a few minutes the mixture is extracted with chloroform.
The organic phase is washed wlth brine, dried over sodium sulfate, and concentrated to yield mainly the bis~te~ra hydropyranyl) ether of the title compound; 2.2 9., 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 (~0:70)). The mass spectral peaks for the formula-l compound (TMS derivative) are at 638, 623, 607, 567, 548, 511, and 477.
Following the procedures of Example 1~ but replacing the formula-XIII starting material with the following formula-Xlll compounds or their C-ll ethers, there are obtained the corresponding formula-l i~odo compounds:
15-Mettlyl-pGF
15-Ethyl PGF2a 16~l6-Dirnethyl-pGF2a 16~l6-Difluoro-pGF2a 16-Phenoxy-17, 18J 19,20-tetranor-PGF

~7~933~ 2~371A

;

17-Phenyl-18,19~20-trinor-PGF2a 11-Deoxy~PGF2a 2a,2b-Dihomo-P~F
3-Oxa-PGF2a 3-Oxa-17-phenyl-18,19l20-trinor-PGF2a.

Example 2 6-Keto-PGF~a, Methyl Ester (Figure IV:
~ ~ LJ Q J R1J R~ VJ W~ and X as de-fined in Example 1).
Refer to Chart A, step "b". A soluti~n of ~he formula-I iodo compound, methyl ester (Example l, 0.45 9.) in 20 ml. of tetrahydrofuran is treated with silver carbonate (0.250 90) and perchloric acid (90~, 0.10 ml.)3 and sti rred at about 25 C. for 24 hr. The mixture is diluted wi~h ~5 ml.
of ethyl acetate and the organic phase~is was~ed with saturated sodium carbonate solution and brine, dried, and concentrated to an oil, 0.41 g. Separation by silica gel chromatography eluting with ethyl acetate-Skellysolve B
(~:1) yields the formula-lV title compound as a more polar material than the formula- I starting material. The pro-duct is an oil, 0.32 9., having Rf o.~8 (TLC on silica gelin acetone-dichloromethane (1 1)); infrared specl:ral peak at 1'71~0 cm 1 for carbonyl; N~R peaks at 5.5J 3.2-4.8, 3.7, 2.1-2.7 ~, Example 3 9-Deoxy-6,9-epoxy-6-hydroxy-PGFIa, Methyl Ester (Formula lll: D~ ~ Q~ R1, R~, V, W, and X as defined in Example 1, and ~ indicates attachment in alpha or beta confi~uration).
3o Refer to Chart A, step "c". A solution of the form~la -47 ~

~L~t79 ~3 ~ 287 lA

IV 6-keto compound (Example 21 0.2 9. ) i n lo ml ~ of ac~tone is left s~anding at about 25 C. for 2 days. It is then concentrated and subjected to silica gel chromatography to yield the formula-illtitle compound having Rf 0.50 (~LC on silica gel in acetone-dichloromethane (1 1)~a Example 4 9-Deoxy-6,9-epoxy-5-iodo-PGF~a (Formula 13 and 9-Deoxy-6,9-epoxy-6-hydroxy-PGF~a (Formula I I I, 3 . Q R1, R4, V, W, and X as defined in Example 1.
Refer to Chart A, step "d". A solution of the formula-I iodo compound (Example 1, 1.0 9.) in 30 ml. ~f methanol is treated with 20 ml. of 3N aqueous potassium hydroxtde at about 0 C. for about 5 min., then at about 25~ C. for 2 hr. The mixture is acidifled with 45 ml. of 2~ potassium acid sulfate and 50 ml. o~ water to pH 1.0, saturated with sodium chloride and extracted with ethyl acetate. The or~anic phase is ~ashed with brine, dried over sodlum sul-fate and concentrated to an oil, 1.3 9. The oil is subjected to si lica gel chromatography, eluting with acetone dich1Oro-methane (30:70 to 50:50) to yield,first the formula-l compound and later, the formula-lllcompound as a more polar frac~ion.
The formwla- l co~pound is an oil, 0.33 9., having Rf 0.3~ (TLC on silica gel in acetone-dichloromethane (1:1) plus 2~ acetic acid); infra recl spectral peaks at 3360, 2920, 2~60, 26~oJ 1730, 171OJ 11~55, ~ o, 1380, 1235, 1185, 1075, 1050, 1015, 970, and 730 ~m~ ~; and mass spectral peaks (r~lS derivative) at 681, 625, 606, 569, 535, 479, and 173.
The formula~ cornpound is a solid 0.113 9., melting 3 93-98 C., recrystallized from acetone-Skellysolve B and ~ 79~`3~

melting at 95-1~5.2 C.; containing no iodine; having R~
0.13 (TLC on silica gel in acetone-dichloromethane (1:1) plus 2~ acetic acid) and having mass s~ectral peaks (TMS
derivative) at 587, 568J 553, 497~ 435, 478~ 4073 395~ 388, and 17~.
The formula1llcompound, above, ;s methylated with diazomethane to form the methyl ester~ havin~ iden~ial properties with the product of Example 3 herein~
Following the procedures of Examples 2 and 4J but replacing the ~ormula- I iodo compound therein with those formula-l iodo compounds described subsequent to Example 1, there are obtained the corresponding formula-lV and -iii compounds. Further following the procedures of Example 3 but utilizing the thus-obtained formula-lV cQmpounds there are also obtained the corresponding formula~llcompounds by tha~ method.
9-Deoxy-6J9-epoXy-~5 pGFl~, Methyl Ester (For~Jla ll: L is -(CH2)3-, Q is ~"
~ OH , Ri is -COOCH3, R~ is n-pentyl, X is trans -CH-CH-, V is a valence bond, and W is methylene) Refer to Chart B. A mixture of the formula-l iodo compound (Example 1, 0.25 ~.) 0 25 ml. of 1,5-diazabicyclo-~4.~.0)nonene-5 (DBN), and 15 rnl. of benzene is left standing at about 25 C. for 72 hr. ancl then warmed to ~5 c. for 4 hr. The resulting mixture is then cooled, mixed with ice water and a small amount of diethyl ether, ~49-3~ 2871A

and the layers separa~:ed. The organic phase is dried over magnesium sulfate and concentrated to the title compound, an oil, 0.20 9O The product is crystallized frorn cold (-10 C.) hexane to yield 0.14 9., softening at about 25 C., havlng Rf 0~51 (TLC on silica gel in ethyl acetate);
NMR peaks at 505, 4,575 ~.8-4.~, ~.62, ~.5~, and 0.9 ~;
infrared absorption at 1755 and 1720 cm 1; and mass spectral peaks (TMS derivat7ve) at 495~ 479, 439, 423.2724, 349, 199, and 17~.
Following the procedure of the above Example but re-placing DBN with DBU, using 0.75 ml. DBU with 0.5 g iodo compound, there is obtained 0.44 9. product.
Example 6 9-Deoxy-6,9-epoxy-~5-pGFl~ Methyl Ester (Form~Jla ll: L is -(CH2)3-, Q is f~
H OH, R~ is -COOCH3, R~ is n-pentyl, X is trans-CH=CH-, V is a valence bond, and W is methylene).
Refer to Chart B. A mixture of the formula-l iodo compound (Example 1, 1.0 9.), 1.0 ml. of DBN~
and 60 ml. of benzene is heated at about 42 C. for 20 hr.
Thereupon 0.5 ml. of DBN Ts added and the heating continued for 6 hr. more~ The mixture is left stirring at about 25 C.
for 60 hr , then heated aga;n ~or 8 hr. at 40-50 C. The reaction mixture is cooled, washed w;th ice water mixed with a few drops of triethylamineJ and dried over magnesium sul-fate, to yield the title compound, an oi ;J 0.9 9, The product is dlssolved in 8 ml. of diethyl ether and crystal-llzed From cold (-10 C.) hexane containing a trace of tri--50~

~ ~7 ~ 2871A
.

ethylamine~to yield crystals o.46 y,, mushy at 25 C. Addi tional fractions of crystals3 0.33 g., are combined and sub-jected to chromatographic purification on a Florisil column pretreated with triethylamine9 using hexane-ethyl acetate-triethylamine (75:25:0.5)9 eluting with ethyl acetate (~0-75~) hexane containing 0.25~ trtethylamîne to yield 0.21 9. o~
the title compound which crystallizes on chilling.
Example 7 9-Deoxy-6~9-epoxy- ~s-PGFI~, Methyl Ester (Formula ll).
Refer to Chart B, A mixture of the formula-l 9-deoxy-6J9-epoxy-5-iodo-PGF1~, methyl ester (Example 1~
0.213 g.) in 3 ml. of dimethylformamide is treated with a -fresh solution of potassium superoxide (0.45 g.) ;n 10 ml. of d7methylformamide containing dicyclohexyl-18-crown-

6 (0.75 9.) in an ice bathO After about 30 min. the .. . :.. .... . .. .
reaction mixture is quenched in ice water, thereafter extracted witll diethyl ether. The organic phase is dried over magnesium sulfate and concentrated to yield the title compoundl having the same Rf by TLC as the product of Example 5.
The above product is subjected to column chromatography on Florisil~ pretreated with triethylamine (5~)-dichloro-methane. Thc product is eluted with ethyl acetate-hexane-triethylamine (50:50,0.1) to give the title compound, 0.076 g.~ having R~ 0.45 (TLC on silica gel in acetate dichlorornethane (~:7) using plates pretreated with tri-ethylamine (5~)-dichloromethane).
Following the procedure of Example 7, but replacing potassium superoxide with each of the following reagents, ~0 the title Fompound is likewise obtained:

3~-j 2871A

sodium superoxide tetramethylammonium superoxide sodium carbonate potassium carbonate sodium hydroxide potassium hydroxide sodium benzoate potassium benzoate sodium acetate potassium acetate sodium trifluoroacetate potassium trifluoroacetate sodium bicarbonate potassium bicarbonate ~nd silver acetate.
Fxample 8 9-Deoxy-6,9-epoxy-5-iodo-PGFla, p-Phenyl-phenacyl Ester (Formula 1) and 9-Deoxy-6~9-epoxy-PGF2a, p-Phenylphenacyl Ester (Formula ll).
A, A rni,Yture o~ ~he formula-l iodo acid compound (Exarnple 4, Formula l/ 0.20 9.) ~ p-phenylphenacyl bromide (.5 (l-)~ 0.~ ml. oF diisopropylethylamine, and 10 rnl.
of acetorlitrile is stirred at about 25 C. for l~o min~ It iS mixed with dilute aqueous citric acid and brine and extracted with ethyl acetate, The organic phase is dried and conccntrated. The residue is subjected to silica gel chrorl1atography, eluting with ethyl acetate (25-100~)-Skellysolve B to yield the title 5-iodo compound ,as a 3o colorless oil, 0.20 9, ~ 2~71A

B The product of Part A above (0.20 9.3 is treated with 0.4 ml. of DBN in 15 ml. of benzene at 42 C. for 2~ hr.
The reaction mixture is cooied, washed with ice-water con-taining sodium chioride, dried over magnesium sulfate and concentrated to the second t;tle compound, an oil, 0.12 9.
The o;l is crystalli~ed frc~ benzene-hexane. All ~ractions are combin ~ and subjected to chromatographic separation on a Florisil column pretreated with hexane-ethyl acetate-triethylamine (80:20:0.5)~ eluting with ethyl acetate to yield the formula-ll compound, an oil. Crystallizat;on from ether-hexane yields crystals, 0.016 9., m. 71-2 C.
(sintering at 65-7 C.).
Examp~ 9-Deoxy-6,9-epoxy-5-iodo-PGFla, Methyl Es~er 11,1~-bis(4-Bromobenzoate) and 9-Deoxy-6J9-epoxy -~5 -pGFlaJ Methyi Ester, 11 15-bis(4-Bromobenzoate).
A. A mixture of the formula-l iodo compo~nd (Example 1, 0.494 y.) in 5 ml. pyridine cooled in an ice bath~
is treated with 0.657 g. of ~-bromob~nzoyl chloride with stirring. The mixture is left stirring 16 hr., then powred into cold 10% sulfuric acid alld extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution and brine, drie~, and concentrated. The residue is subjected to silica gel chromatography to yield the5-iodo ti~le compound, 0.70 g., a colorless oil, having NMR peaks at 7.~-8.oJ 5.65, ~.8-5.5, 3.65, and 0.9 ~.
~ . The product of Part A above (0.20 9.) is treated wi~h 0.4 ml. of i)BN in 15 ml. of benzene at 42 C. for 22 hr. The react;on mixture is cooled, washed with ice water, dried, and concentrated to the second title compound~

~7 9 33 ~ 2871A

an oil, 0.18 9.
The preparation is repea~ed with 0.50 g. of the iodo compo~nd, 1 ml. of DBN and 25 ml. o~ benzene.
The combi ned products are subjected to chromatograph;c separation on a Florisi ~column pre~reated with he~ane-ethyl acetat~-triethylamine (90:10:1), eluting with hexane-ethyl ace~ate triethylamine (90:10 0.25) to yield the second title compound 00~7 g. a colorless oil~ having NMR peaks at 7.2-7.8 5 6 4.9-5.~ 4.6 l~ o 3.6 and 0.9 ~.
Example 10 9-Deoxy-6 9-epoxy-~5-PGFIa Sodium Salt.
A mixture of 9-deoxy-6~9-epoxy-~-PGF~a methyl ester (Example 5 0.030 9.) in 5 ml~ of methanol is treated with 9 ml. of 0.01 N NaOH and stirred at about 25 C. for 72 hr.
The solution is then diluted with 5 ~l. of water~ frozen at about -75 C. and lyophilized overnight. The title compound is obtained as a white free-flowing powder.
The procedure above is repeated using larger quantities.
From 0.150 g. of the enol ether methyl ester there is ob-tained 0.155 g. of the title compound as a white free-flow-ing powder. A sample o~ ~he material disso1ved in methanol-water shows practically no mobility by TLC on silica gel plates in acetone-dichloromethane (3:7) compared with the starting rnaterial which has R~ 0.45 (TLC on silica gel in acetone-dichloromethane (3:7) using plates pretreated in triethylamine-(5~)-dichloromethane).
Following the procedures of Examples l) 2, 3, 5, and 7, but employin~ corresponding starting materials as described above, there are prepared the ~ormula ~ Ill, and -IV compoundsg namely ~0 9-deoxy-6J9-epoxy 5-iodo-PGF~

2871A-~-F

7~ 3 9-deoxy-6~9~epoXy~~g-pGF~
9-deoxy-6~9-epoxy-6-hydroxy-PGF~-, and 9-deoxy-6,9-epoxy-6-keto-pGF~-type compounds, in methyl ester form wherein Rl is -COOCH3, having the following structural fea~ures:
16-Methy l -;
16,16-Dimethyl-;
16-Fluoro-;
16,16-Difluoro-;
17-Phenyl-18,19,20-trinor-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-;
17-(m-chlorophenyl)-18,19,20-trinvr-;
17 (p~fluorophenyl)-18,19~20-trinor ;
16-Methyl-17-phenyl-18,19,20-trinor-;
16,16-Dimethyl-17-phenyl-18,19~20-trinor-;
16-Fluoro-17-phenyl-18,19,20-trinor-;
16,16-Difluoro-17-phenyl-1~,19,20-trinor-;
16-phenoxy-~ gJ2o-tetranor-i 16-~m-trifluoromethylphenoxy)-17,18,19,20-tetlanor-;
16-(m-ch~orophenoxy)~17,18,19,20-tetranor~;
16-(p-fluorophenoxy)-17,18,19,20-tetranor~;
16-Phenoxy-18, 19J20- trinor-;
16-Methyl~16-~henoxy 18~19,20-trinor-;
13,14-~idehyd~o-: 16~ethyl-13,14-didehydro-;
16~16 ~imethyl~13,14-didehydro-;
16-Fluor,o~13,14-didehydro-3.6,16-Difluoro-13,14-didehydro-;
17-Phenyl-1~,19,20-trinor-13,14-didehydro-;
17-(m-trifluorome~hylphenyl~-18,19,20-trinor-1~,14-~0 dldehydro~;

5, 2871A~

17-(m-chlorophenyl)-18,19320-tr;nor-13,14-didehydro~;
17-(p-fluorophenyl)-18,19,20-~r;nor-13,14-didehydro-;
16-Methyl-17-phenyl-18,19,20-trinor-13,14-didehydro~;
16,16~Dimethyl-17-phenyl~18,19,20~trinor~1~14~dide~
hydro-;
16-Fluoro-17-phenyl-1~,19,20~trirlor-13,14-didehydro-;
16,16-Di fluoro-17~phenyl-:~8,19,20-~ri~or-13,14-didehy-dro-;
16-Phenoxy-17/18,19,20-tetranor-13,14-didehydro-;
16-(m-trif~uorcmethylphenoxy)-17J18,19,20-tetranor-13,14-didehydro-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-13~14-dide~
hydro ;
16-Phenoxy-18,19/20-trinor-13,14-didehydro-;
16-Methyl-16-phenoxy-18,19,20-trinor-13,14-didehy~ro-;
13,14-Dihydro-;
16-Methyl-13,14-dihydro-;
16,16-Dimethyl-13,14-dihydro-;
16-Fluoro~1~,14~dihydro-;
16,16-~ifluoro-13,14-dihydro-;
17-Phenyl-18,19J20-trinor-13,14-dihydro ;
17-(rn tri~luoromethylphenyl)-18,19,20-trinor-13,14-dlhydl-o ;
17-(m-chlorophenyl)-18,19,20~trinor-13,14-dihydro-;
17-(p ~luorophenyl)-18,19,20-trinor 13,14-dihydro-;
16-Methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16,16-Dimethyl-17-phenyl 18,19,20-trinor-13,14-dthydro~;
16-Fll~oro-17-phenyl-18,19,20-trinor-13,14-dihydro~;
16,16-Difluoro-17-phenyl-18,19~20-trinor-13,14-~56- -~, 2871A -1 -F

.

dihydro ;
16-Pheno~y l7~l8Jlg~2o-tetranor~l3~l4-dihydr 16-(m-tri~luoromethylphenoxy)-l7~l8~l9~2o-tetranor~
1~,14-dihydro-, 16-(m-chlorophenoxy)-17,18,19,20-tetranor-1~314~
dihydro-;
16-(p-fluorophenoxy)-17,18,19,20-tetranor-1~,14 d;hydro-;
16-Phenoxy-18,19~20-trinor-13,14-dihydro-;
16-Methyl-16-phenoxy-18,19,20-trinor-13314-dihydro-;
2,2-Difluoro-;
2,2-Di~luoro-16-methyl-;
2,2-Difluoro-16,16-dimethyl-;
` 2,2-Di~luoro-16-~luoro-~
2,2-Di~luoro-16,16-difluoro-;
2,2-Difluoro-17-phenyl-18,19,20-trinor-;
2~2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-~rinor-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-;
2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-;
2,2-Difluoro-16-methyl-17-phenyl-18,19J20-trinor~;
2~2-Difluoro-15,16-dimethyl-17-phenyl-18,19,20-trinor-;
2,2-Difluoro-16~fluoro-17-phenyl-18~19,20-trinor-, 2,2-Difluoro-16,16 diFluoro-17-phenyl~18,19,20-trinor-;
2,2-Difluoro~16-pheno~y-17,18,19,20-tetranor-;
2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-t~tranor~;
2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-.
tetranor-;
2,2-Difluoro-16-(p-fluorophenoxy)-17,18, 19J2O-287 lA
'7 ~etranor-;
2,2-Dl~lu~ro 16-pheno~y-18,19,20-trinoro;
2,2-Difluoro-16-me~hyl-16-phenoxy-18~1gJ20-~rinor~;
2J2-Di f1uoro-16-methyl-16-phenoxy-18,19,20-trinor-;
2,2-Difluoro-16-methyl 13,14-didehydro ;
2,2-DiFluoro-16,16-d~methyl-13gl4-didehydro-;
2,2-Difluor~-16-~luorG-13,i4-didehydro-;
2,2-Difluoro-16~16 difluoro-13,14-didehydro-;
2~2-Difluoro-17-phenyl-18,19,20-trinor-13~14-dide-hydro-;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19~20 trinor-13,14-didehydro-;
~ ,2-Difluoro-17-(m-chlorophenyl)-18,19,20 trinor-13,14-didehydro-;
2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;
2,2-Difluoro-16-methyl-17-phenyl-18,19920-trinor--didehydro~;
2,2-Difluoro-16,16 dimethyl-17-phenyl 18,19~20-trinor-13,14-didehydro-;
2,2~16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;
2,2,16,16-Tetrafluoro-17-phenyl-18J19,20-trinor-1~,14-didehydro-, 2,2~Difluoro-16-phencxy-17,18,19,20-tetranor-13,14 didehydro-;
2/2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-1~,14^didehydro-;
2,2-DIfluoro-16-(m-chlorophenoxy)-17,18,19,20-te~ra-nor-13,14-didehydro-;

~L~Lr7~3~ 287 lA -1 -F

2,2-Di fluoro-16-phenoxy~18,19,20-trinor-13,14 dide~
hyd ro-;
2,2-Difluoro-16--methyl-16-phenoxy-18,19,20-trinor-1~14-didehydro ;
2,2-Dlfluoro-13914-dihydro~;
2,2-D i ~1uoro-16 methy1 ~13$14-dihyd~o-;
2,2-D; fluoro-16,16-d;methyl 13,1~-dihydro~;
2J2,16-~rifluoro-1~,14-dihydro-;
2,2,16,16-Tetrafluoro-13,14-dihydro-;
2,2-Difluoro-17-pheny1-18,19,20-tr;nor-l SJl40 dihydro-;
2,2-~ifluoro-17-(m-trifluoro~ethylphenyl) 18,19,20-~rinor-13,14-dihydro-;
2J2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-13J 14-dihydro-;
2,2-Difluoro-17-~p-fluorophenyl)-18~19,20-trinor-1~,14-dihydro-;
2,2-D; ~luoro-16-methyl-17-phenyl -18,19,20-trinor-1~,14-dihydro-;
2,2~Difluoro-16,16-~imethyl-17-phenyl-18l19,20-trlnor-13,14-dihydro-;
2,2,16-Trifluoro-17-phenyl-18J19J20-trinor-13 dihydro-;
~,2,16,.l6-Tetraf1u~ o 17 phenyl -18,19,20-trinor-1~J ll~-d7hydro~;
2,2 Difluoro-16-phenox.y-li,18,19,20-~etranor-13,14-dihydro-;
2,2~Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-1~,14-dihydro-;
~o 2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20 -59~

2871~ -1 -F
33~

.
tetranor-13,14 dihydro-;
2,2-D i f luoro-16- (p f luorophenoxy)^l7~18 ,19,20-tetranor-l~/14-dlhydro~;
2,2-DTfluoro-16-phenoxy-18,19,20-trinor-13,14-5 dthydro-;
2,2-Difluoro-16-methyl-16-phenoxy~18,19,20-trinor-13,14-d1 hydro~;
16-Methy1 cis~13;
16,16-D imethy 1 -r i s -13-;
16-Fluoro-cis-13-;
16,16-D i fluoro cis-13-;
17-Phenyl-18319,20-trtnor-cisol3-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-1~-;
17-(m chlorophenyl)-18319,20-trinGr-cis-13-;
17-(p fluorophenyl)-18,19,20-trinor-cis-13-;
16-Methyl-17 phenyl-18~19,20-trinor-cis-13-;
16,16-Dimethyl-17-phenyl-18,19J20-trinor-cis~
16-Fluoro-17 phenyl-18,19~20-trinor-cis-13-;
16,16-Difluoro-17-phenyl-18,19,20-trinor-cis-13-;
16-Phenoxy-17,18J19,20-tetranor-c7s-1~-;
16-(m-trifluor~nethylphenoxy)-17,18,19,20-tetranor-cis-13-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-13-;
16~(p-~1uorophenoxy)-17,18,19,20-tetranor-cis-13-;
16~Phenoxy-18J19,20-~rinor-cis-13-;
16-Methyl-16-phenoxy-18,19,20-trinor-cis-13-:
2,2-Di~luoro-cis-13-;
2,2-Otfluoro-16-methyl-cis-13-;
2,2-Difluoro-16,t6-dimethyl-cis~13-;
~,2-Dtfluoro-16-fluoro-cis-13-;

~'7~3~
, . . _ .......
2,2-Difluoro-16~16-difluoro-c;s~
2~2-Difluor~ 7-phenyl-l83l9~2o-erinor-cis-l3-;
2,2-Difluor~-17~(m-trifluoromethylphenyl~-18,19J20-trinor-cis~
2,2-Difluoro-~7~(m-chlorophenyl)-18,19,20-trinor~
cis~
2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor~cis 13~;
2,2-Difluoro-16-methyl-17-phenyl :18,19,20-trinor-cis-13-, 2~2-Difluoro-l6/l6-dimethyl-l7-D~enyl-l8~lg~2o .... .
trinor-cis-13-; -2,2-Difluoro-16-fluoro-17-phenyl-18~19,20-trinor-cis-13-;
2,2-Difluoro~16,16-difluoro-17-phenyl-18,19,20-trinor-c~s-13-;
2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-;
2,2-Di~luoro-16-~m-trifluoromethylphenoxy)-17gl8~19~20-~etranor-cis-13-;
2,2-Difluoro-16-(m-chlorophenoxy~-17,~8,19,20-~etranor-cis-13-;
2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-cis 13-;
2,2-Difluoro-16-phenoxy-18,19,20-trinor-cis-13-;
2,2-Difluoro-16-rnethyl-16-phenoxy-18,19,20-trinor-cis~
2,2-Difluoro-16-lnethyl-16-phenoxy-18,19~20~trinor-cls-13~;
3-Oxa-;

~-Oxa-16-methyl~;
3 3~0xa~16,16-dimethyl~;

3`~ 2871A ~ 1 -F

.

~-Oxa-16-fluoro-, ~~--3-Oxa-16316-difluoro-~
3-Oxa-17~phenyl-18,19,20~trinor-;
~-Oxa-17-(m-trifluoromethylphenyl)-18,19920-trinor-, 3~0xa-17~(m-chloropheny~)-18,19,20 trinor-, 3^0xa-17-(p fluorophenyl)-18,19,20-trinor-;
3-Oxa-16-methyl-17-phenyl-18,19~20 trinor-;
~-Oxa-16,16-dimethyl~17-phenyl-18,19920-trinor-;
3-Oxa-16-fluoro-17-pheny1-18,19,20-trinor-;
3-Oxa-16~16-difluoro-17-phenyl-18,19,20-trinor-;
~-Oxa-16-phenoxy-17,18,19,20-tetranor-;
~-Oxa-16-(m-trifluor~lethylphenoxy)-17,18~19,20-tetra-nor-;
~-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-;
3~0xa-16-(p-fluorophenoxy)-17,18~19~20-tetranor-;
3-Oxa-16-phenoxy-18,19,20-trlnor-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-;
~Oxa-13,14-didehydro-;
3-Oxa-16-methyl-13,14-didehydro-;
3-Oxa-16,16-dimethyl 13,14-didehydro-;
3-Oxa-16-fluoro-13,1~--dîdehydro-;
3-Oxa-16,16 difluoro-1~,14 didehydro-;
~-Oxa-17-phenyl 18,19,20-trinor 13,14-didehydro-;
3-Oxa 17-(m-trifluoromethylphenyl)-18,19~20-trinor-13,1l~-didehydro-;
3~0xa-17-(m~chlorophenyl)-18,19,20-trinor~13,14 didehydro-;
~-Oxa-17~(p~fluorophenyl)-18,19,20-trinor-1~,14-dtdehydro~;
~-Oxa-16~methyl-17-phenyl-18,19,20-trinor~ 14-.

2871A -l -F
3i didehydro-;
3-Oxa-16,16~dimethyl-17-phenyl-18J19,20-tr;nor-13,14-didehydro 3-oxa~l6-flu~ro-l7-phenyl-l8Jlg~2o-trinor~ 4 d~dehydro~;
3-Oxa~16,16 difluoro-17-phenyl-18,19,20~trlnor-13,14-didehydro-;
3-Oxa-16-phenoxy 17,18,19,20-tetranor-13914 didehydro ;
3-Oxa-16-(m-trifluoromethylphenoxy)-17918,19,20-tetranor-13,14-didehydro-;
3-oxa-l6-(m~chlorophenoxy)-l7~l8~l9~2o-te~ranor 13,14-didehydro-;
3-Oxa-16-phenoxy-18Jl9/20-trinor-13,14 didehydro-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor 13,14 didehydro~, ~-Oxa-1~,14-dihydro-;
3-Oxa-16-methyl-13,14-dihydro-;
3-Oxa-16,16-dimethyl-1 5,14-dihydro-;
3-Oxa-16-fluQro-13,14-dihydro-;
~Oxa~16~16-difluoro-13,14-dihydro-; -~-Oxa-17-phenyl-18919,20-trinor-13Jl4-dihydro~;
3-Oxa-17-(m-trTfluoromethylphenyl)-18,19,20-trinor-13 J 1 1~ - dihydro-;
3-Oxa-17~(m ch~orophenyl)-18,19,20-trinor-13~14 dlhydro~; `
~-O>~a-17-(p~fluorophenyl)-18,19,20-~rinor--13,14-dlhydro-;
~-Oxa~16-methylw17 phenyl-18, 19J20-t rinor-13, 1 3o dihydro-;

~33~5 2871A-l-F

~-Oxa-16,16 Dime~hyl-17 phenyl-18J19,20-trinor-1~,14-dihydro~, 3 Oxa-16~ fluoro-17=phenyl-18,19"~0-~rinor 13 jl4 dihydro~, 3~oxa-l69l6-d;fluoro~l7-pheny~ 9~2o-er;nor 13,14-dihydro~;
3 -Oxa-16 -phenoxy-17, 18,19,20-tet ranor l3,14-dihydro-;
~-Oxa-16-(m-tri Fluoromethylphenoxy)-17~18,19,20-tetranor;13,14-dihydro-;
3- Oxa-16- (m-ch 1 orophenoxy ) -17, 18J 19~20-tetranc)r~ ~~~ ~~ -1~,14-dihydro~;
3-oxa-l6-(p-fluorophenoxy~-l7~l8~lg~2o-~etranor 13,14-dihydro-;
~-Oxa-16-phenoxy-18, 19,20-t r i nor-13, 14-dihydro-;
3-Oxa-16-methyl-16 ~phenoxy-18,19,20-trinor-13,14-dihydro~;
3-Oxa-cis-13-;.
~-Oxa~16-methyl-cis-13-;
3-Oxa-16,16-d imethyl-cis 13-;
3-Oxa-16-fluoro-cis-13-;
~Oxa-16316-difluoro~cis-l-~ ;
~-Oxa-17-phenyl 18,19,20-trinor-cis-13-;
~-Oxa-17 (m-trifluor~methylphenyl)-18,19,20-trinor-cls-l3 ;
3-Oxa-17 (m-chlorophenyl)-18,19,20-trinor-c;s-13-;
~-Ox~-17~(p~fluorophenyl)-18,19,20-trinor cis-l~-;
3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-cis~
3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-~rfnor-cis ~3~;

3~

.

.. . _ . . .. .
3-Oxa 16-fluoro~17~phenyl-18,19,20-~rinor-c;s-13-;
3-oxa-l6~l6-difluoro-l7-phenyl-l8~lg~2o~tr;nor 3-Oxa-16-phenoxy-17"18gl9,20-tetranor~cis-13~;
3-oxa-l6-(m-triFluoromethylphenoxy)-l7~l8~lg~2 5 ~etranorocis ~ ~
3-Oxa-16-(m-ch 10rophenoxy)-17,18319920-tetranor-cls-13-;
~-Oxa-(p~fluoropheno~y)-17,18,19j20~tetranor-cis~
3-Oxa-16-phenoxy-18,19,20-trinorAcis-13-;
3~0xa-16~methyl~16-phenoxy-18,19,20-trlnor-cis-13-;
3 Oxa-13,14-dihydro-trans-14,15-didehydro-;
3-Oxa-16-methyl-1~,14-dihydro-trans-14J15-didehydro-;
3-Oxa-16,16-dimethyl-13,14-dihydro-trans-14,15 didehydro-;
~5 ~-Oxa-16-fluoro-13,14-d;hydro-trans-14,15-didehydro-;
3-Oxa-16J16-difluoro-13,14-dihydro-trans-14~15-didehydro-; -~-Oxa~17-phenyl-18,19,20-trinor-13,14~dihydro trans-14,15-didehydro-; .
3-Oxa-17-(m-trtfluoromethylphenyl) 18J19,20-trinor-13,14-dihydro-trans-14,15-didehydro~;
3-Oxa-17-(m-chlorophenyl)-18,19J20-trinor-13,14-dihydro-trans-14,15-didehydro-;
3-Oxa-17-(p-Fluoroplenyl)-18,19,20-trinor-13,14-25 dihydro-trans-14J15-didehydro-;
3-Oxa-16-methyl-17-phenyl-18,19J20 trinor-1~i,14 dthydro-trans-14,15-didehydro~
3-Oxa-L6,16-Dimethyl-17-phenyl-18,19,20-~rinor-13,14-dthydro-trans-14,15-didehydro-;

3 Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13J14 . -65 ~.

3~ Z871A-l-f dihydro-trans-14,15-didehydro-;
~ -oxa-l6~l6-difluoro-l7-phenyl-l8~lg~2o-trinor 13,14-dihydro trans-14,15-didehydro~;
~ -Oxa-16-phenoxy-17918,19~20-tetranor~ 14-dihydro-trans l~J15-didehydro-, 3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-~etranor-13,1~-dihydro-trans-14,15-dihydro-;
3-Oxa-~6-(m-chlorophenoxy)-17~18J19J20-tetranor-13,14-dihydro-trans-14,15-didehydro-;
3-oxa-l6-(p-fluorophenoxy)-l7~l89lg~2o~etranor _ _ 13,14-dihydro-trans-14J15-didehydro-;
- ~-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-~rans-1~,15-~idehydro-;
3-Oxa-16-methyl 16-phenoxy-18,19,20-trînor~
1~,14-dihydro-trans-14J15-didehydro-.
Likewise ~ollowing the procedures of Examples 1, 2, 3J
59 and 7, but employing corresponding starting materials as described ~bove/ there are obtained the formula ~I, -Il, -Ill, and -IV compounds 3 namely 9-deoxy-6Jg-epoxy-5-iodo-PeF
9-deoxy-6J9-epoxy- Q5-PGF1a-, .
g-d~o~y-6J9-epoxy-6-~lydroxy-pGFla-~ and 9-deoxy-6J9-epoxy-6-keto-PGFla-type compounds, in methyl ester Form wherairl Rl is -COOCH~, having the following s~ructural features:
2,3-Didehydro ;
2,2-Dimethyl-;
2a,2b-Dihomo~;
4-Oxa-4a-homO-;
3 7a- Homo ;

~.7933~ 2871A-~-F

.. _. . .
... . _ . ...
ll-Deoxy-103 ll -d i dehydro-;

ll-Keto- 9 ll-Deoxy~, 11-Deoxy;-ll methylene-;
ll-Deoxy ll-hydroxymethyl-;
15~-;
15~Keto~;
15-Deoxy-;
15-Methyl-15(S)-;
15-Methyl-15(R)-, and 17,18-Didehydro--,-67-Appendix 1. 2-Decarboxy-2-amino PGF Compounds Char~ G, below, shows the steps for prepari.ng start-ing materials of formula Xlll for Chart A wherein Rl is CH2N(Rg)2o Accordingly in Chart G, the formula Cl PGF
or 11 deoxy-PGF2~-~ype ~ree acid i5 transformed to the various 2-decarboxy-2-aminomethyl or 2--decarboxy-~-(sub--stituted amino)methyl-PGF~- or ll-deoxy-PGFa-type compounds of formulas ClV CVl, CVll~ CVlll, ClX, or CX.

By the procedure of Chart G the formula Cl compound is transformed ~o a foxmula Cll mixed acid anhydride. These mixed anhydrides are conveniently prepared from the corres-ponding alkyl, aralkyl, phenyl, or substituted phenyl chloroformate in the presence of an organic base ~e.g., cb~

3L~7~

Chart G

~0 ~ , C~12 -Z 1 -COOH

'~
Re Y I -F -- -6-R7 M ~

t) O
,CH2 - Z 1 -C -O - C -R
10 ' ~ Cll ~a Ml Ll lS ~, ,c H~ - Z a ^C -NH2 ~y ' Cl~l ~ 11 h l M, Ll J ~ , , HQ, . ~ ~, CHz -ZI -CH2NH2 ~ CIV
, Y I - C ~ C - R7 Ml L

~5 \ H0 B ~
Hz ~ C -N =N --~; C V

~e Ml i ~
;~0 i~7~3~

.
Cha r t G ~ c ~n t I nue d ~

t~o CH2 -Z I -NH-COOR ~
>~
~ ~VI
`~ ~ fi-R7 Re Ml L~

HO

Y a - ~--I R7 . CVI I

HO
CH2-z~ L2 ~J~ , CVII~

Ra I t 1 1, HO~
,C~12 -Z I -NL2COOR ~
CIX
~ ~Y,-C--C-R7 R~3 Ml L

t~O ' ~ , , CH2-ZI-NL2L~, ~ CX
~ Y 1 -~ 7 R~ Ml l-a ... . .. .. . .. .... .. , ~

~ ~7~

triethy~amine)~ Reaction diluents include water in com-bination with water miscible organic so1vents (e.g.) teera-hydrofuran)O This mixed anhydride is then transformed to either the formula Clll PG-type, amide or formula C~ PG-type, azTde~
For preparation of the PGF2a-type, amide (formula C113) the formula Cll mixed acid anhydride is reacted wi th 1 iquid ammOnia or ammonium hydroxide, Alterna~ively, the formula Clll compound i 5 prepared ~rom the formula Cl free acid by methods known in the 3rt for transformation of carboxy acids to corresponding car-boxyamides~ For example, the free acid is transformed to a corresponding methyl ester (employing methods known in the art; e.g., excess etheral diazomethane), and a methyl 1~ ester thus prepared is transformed to the ~ormula C111 amide employi n~ the methods described for the transformation of the formula Cll mixed acid anhydride to the formula Clll amide.
Thereafter the formula CIV 2-decarboxy-2-aminomethy~-PGF~a- or 11-deoxy-PGF2a-type compound is prepared from the formula Clll compound by carbonyl reduc~ion. Methods known in the art art are employed in this trans~ormation.
For example, lithium aluminum hydricle is conveniently employed.
The formula Cll compound is alternatively used to pre-par~ the formula ~V azicie. This reaction is conveniently carried out employing sodium azide by methods Icnown ;n the art. See for ~xample, Ficser and Fieser, Reagents for Organlc Synthe~is vo1. 1, pgs. 1041-1043, whereln reagents 3~ and reactton condittclns for the azide formation are dis 3,3~

cussed.
Flnaliy, ~he formula CYI urethane is prepared from the formula CV az;de reaction with an alkanol, aralkanol, phenol, or substituted phenol. ~or example, when ~ethanol is em-ployed the formula CVI cvmpound is prepared wherein R~ ismethyl. Th;s formula CVI PG~type product is then emplvyed in ~he preparation of either the formula CVII or CV!II pro-duct.
In the preparation of the formul3 CVII primary amine from the forrnula CVI urethane, methods known in the art are emp10yed. ~hus, for example, treatment of thIe formula CVII urethane wi th strong base at temperatures above 50 C0 are employed. For exarnple, sodium potassium ~r lithiurn hydroxide is employed~
Alternatively, the formula CVI compound is employed Tn the preparation of the ~ormula CVII~ compound. Thus, when Ll is alkyl the Formula CV1II compound is prepared by reduction of the formula CVI urethane wherein Rl is al~yl. For this purpose, lithium aluminum hydride is the conveniently employed reduciny agent.
Thereafter, the formula CViII procluct is used to prepare the corresponcling CIX urethane by reaction of the formula CVIII secondary amine (wherein L2 is alkyl3 ~Jith an alkyl chloroformate. The reaction thus proceeds by methods known in the ar~ for the preparation of carbarnates from corresponding secondard amines, Finally, the formula CX
product wherein L2 and L9 are both alkyl is prepared by reduction of the forml-la CIX car~amide. Accordinglv, methods hereindbove descrlbed for the preparat;on of the ~0 formula CVIII compound from the formula CVI cornpound are used. Thus, Char~ A provides a meth~d whereby ~ach ~f the var;ous PGF~ or 11-deoxy-PGF2a-type products o~ this inven~ion is prepared. Opt;onaliy, the vartous reaction steps here;n may be proceeded by the employment of block-ing groups according to R1o, thus necessitating their sub-seq~ent hydrolysis in preparing each of the various product~
above. Methods described hereinabove For the introduction and hydrolysis of blocking groups according to Rlo are em-ployed.
Finally, the processes described above for converting the formula Cll compound to the formula CY compound ~nd the various compounds thereafter, result in shortening the 8a-side chain of the formwla Cl compound by one carbon atom. Accordingly, the formula Cl starting material should 15 be selected so as to compensate for the methylene group which is consumed in the steps of the above synthesis.
Thus, where a 2a-homo-product is desired a corresponding formula Cl ?a,~b-dihomo starting material must be employed.

7~
.

I n Chart ~, Y~ i s t rans -C~ C)l- j - C-C- ~ or -CH2CH~-;
whe re i n Ml i s or wherein R5 is hydrogen or methyl;
wherein Ll is R3 R4, or a mixture 3f R3 R~

and f R3 R.~, ~

25 wh2re~n R3 and R~ are hydrogen; methyl, or fluoro, being the same or different, with the proviso that one of R3 and R~ is fluoro only ~hen the other Is hydrogen or fluoro;
wherein Z1 Is (1) cis-Cl~H-CH2-(CH2)9-CH2~, ~ (2 ) c 1 s - C~ CH -CHz - (CH2 )9 CF2~, .

.L~.7~33 (3 ) c i s - CH2 C~ CH- ( C1~2 ) 9 - CH2 -, (4 ) - ( CH2 )3 ~ ( CH2 ) 9 - C1-12 - ~
(5 ) - (~He )3'' (CH2 )g-CF2-D
(6) -CH2~0-CH2- (CH2)9-CH2-(7 ~ ~ C- C - CH2 ~ ( CHz ) g CH2 ~, (8 ) - CHz - C- C- ( CH2 J 9- CH~ - g ~9) g~ ~H2 - ( CH2 ) -, or ' 10 (10) ~0-(CH2~9-3 wherein g i s one, 2, or ~i;
where i n R, i s (1 ) - ~ CH2 )m~ CH3 ~

( T ) (2) ~~ s, or ~ 3 ) - CH2 ~ / ( r ) s ~vherein m is one to 5J inclusive, T is chloro, fluoro, tri f luc)rornethyl, al kyl o~ one to 3 carbon atoms, inclu-slve, or alkoxy o~ one to 3 carbon atomsJ inclusive., and s is zero, Pne, 2, or ;~, the various T's being the san~e c:)r di fFerent, wTth the provlso that not more than two ~ 7~3'~

T's are other than alkyl; with the further proviso ltha~c R7 is ~ ~r ) wherein ~ and s are as defeind above, only when R3 and R4 are hydrog~n or methyl, belng the sarne or dif~eren~; and where;n Xs is -CHzNL2L3, whereln L2 and L9 are hydrogen, alkyl of one to 4 carbon atorns, inclusive, or -C00~, wherein R
i s as def i ned above 3t3 .
-7~ -~ ~7933~

Preparation 2. 2-Decarboxy-2-azidomethyl-PGF , or 2-nor~
2a PGF2a, azide (Formula CV Zl is CH=CEJ-(CH2~3 or CH=CH-(CH2)2, respectively, RB is hydr~xy~ Yl is trans-CH=CH-, R3 and R~
of the Ll moiety and R5 of the Ml moie~y are all hydrogen, and R7 is n-butyl~O

A. To a cold solution (0C.~ of PGF~ ~7.1 g.~, 125 ml. of acetone, 10 ml~ oE water, and 2.2 g. of triethyl-amine is added with stirring 3.01 g. of isobutylchloxo~--formate. The mixture is stirred at 0C. for about 30 min.
at which time a cold solution of 7 g. of sodium azide on 35 ml. of water is added. The mixture is then stirred at 0VC. for one hr. at whlch time it is diluted with 300 ml.
of water and extracted with diethyl ether. The organic layers are then combined; washed with water, dilute carbonate solution, saturated saline, dried; and concentrated under reduced pressure, maintaining bath temperature helow 30C.
to yield 2-nor-PGF2a~ azide~

B. 2-Decarboxy-2-azidomethyl-PGF2a, is prepared by the following reaction sequence;

cb/ ~ 77 ~

7~3~

(1) A soluti~n of t-butyldime~hylsi)yl chloride ~10 9.3, imidazole (9.14 90), and PGFZa (3 9.) in 12 ml. of dimethyl~
formamide are ~agnetically st;rred under nitrogen atmosphere for 24 hr The resultin~ mixture is then cooled in an ice bath and ~he reaction quenched by addition of ice water~
The resulting m;xture is then diluted with 150 ml of water and extrac~ed with diethyl ether. The ccmbined ethereal extrac~s are then washed with water, saturated ammonium chloride~ a sodium chlnride solution, and there a~er dried over sodium sulfate. Solvent is remc~ved under vacuum yielding PGF2,~, t-butyldimethylsilyl ester, 9,11,15-tris-(t-butyldi~ethylsilyl ether~ NMR absorptions are observed at0.20, 0.~0~ o.83, o.87, G.89, 1.07-Z.50, 3.10-4.21, and 5 38 ~ Characteristic infrared absorptions are observed at 970, 1000, 1060, 1250, 1355, 1460, 1720, and 2950 cm.~~.
(2) To a magnet;cally stirred suspension of lith;um aluminum hydride (7.75 9.) in 18 ml. of diethyl ether is added dropwise at room temperature over a period of 12 min

8.71 9 of the reaction product of part (1) above in ~0 ml.
of diethyl ether. After stirring at ambient temperature for one hr., the resulting p!aduct ;s cooled in an lce water bath arld saturated sodium sulfate is added dropwise until the a~pearance or a milky suspension. The resulting pro-duct is coagulated with sodium sulfateJ triturated with ~lethyl ~ther, and the so1vent is removed by suc~ion fil-tration. Concentration of the diethyl ether under vacuum ylelds 7,014 g. of 2-decalboxy-2-hydroxymethy1-pGF2~
gJ~ 5-tris-(t-butyldimethylsilyl ether), NMR absorp-tions are observed at 0.0~, 0.82, o.87, 1.10-2 60, 3O~0-.

~ 33 ~

.
~.30~ and 5.37 ~. Charac~eristic ;nfrared absorpt;ons are observed at 775 3 840~ g70 J 1065, 1250, 1460, 2895, 2995 and 3350 cmO
(~) p-Toluenesulfonyl chloride (3.514 9.)~ pyridine ~44 ml.)~ and the reaction product of subpart (233 70014 9., are placed in a freezer at -20 C. f~r 3 days. Thereafter~
7.200 g. of 2-decarboxy-2-p-toluenesul~onyloxymethyl-PGt

9,11,15-tris (t-butyld;methylsilyl ether), is recovered.
NMR absorptions are observed at 0.10, 0.94, 0.97, 1.10, 2.50, 2.50, 4.03~ 3~80-4.80, 5.45, 7.357 and 7.80 ~. InFra-red absorptions are observed at 775, 970y 1180, 11903 1250, 1~60, 1470 J 2900, and 2995 cm.~ 2, (4) The reaction product o~ subpart (~) (2~13 9 3 i~
placed in 42 ml. of acetic acid, ~etrahydrofuran, and water (~ 1) containing 0.25 ml. of 10 pereent aqueous hy-drochloric acid The reac~ion mixture beco~es homogeneous after vigorous stirring ~or 16 hr at room tempelature. The resulting solution is then diluted with 500 ml. of ethyl acetate; washed with saturated sod;um chlor;de and ethyl acetate; dr.ied over sodium sulfate; and evaporated under reduced pressure, yielding 1,~01 9. of an oil. Crud~ pr~-duct is chrG~atographed on 150 9. of silica gel packed with ethyl acetate Eluting with ethyl acetate yields o 953 9 of 2-decarboxy-2 p-toluenesui~onyloxym ethyl-PGF2~.
(5) The reaction product of subpart (4)J (0.500 g.~
in 5.0 ml. of dimethylformamide was added to a stirred sus-pension of sociium azide (1 5 9.) in 20 ml. of dimethylfor-mamide. Stirring is contlnued at ambient tempera~ure for 3 hr. The reactTon mixture is then di1uted with water (75 ml.), extracted with dTethyl ether (500 ~ and the ~79~

, gL3~7~3~ , .

the etheral extracts washedsuccessively withwater, satu-rated sodiu~,chloride~ and dried cversodium sulfate. Re~ov~l ofthe diethyl etherunder reduced pressure yields 0.~64 ~. of 2-decarboxy 2-azid~nethyl-PGF2~. A c17aracteristic azido infrared absorpeion is observed a~ 2110 cm.~l.
- . ' . ! ,`"
; ! j -~30 ^

3~

Preparation 30 2-Decarboxy-2-aminomethyl PGF2~ (Formula CXXV: Zl is cis-CH=CH-(CH2)3-, R8 is hydroxy, Yl is trans-CH--CH-, R3 and R4 of the Ll moiety and R5 of the Ml moiety are all hydrogen, and R~ is n-butyl~.
Crude 2-decarboxy-2-azidomethyl-PGF2~ (Example 2~
0.364 g.) in 12 ml. of diethyl ether is added to a magnetically !
stirred suspension of lithium aluminum hydride ~0.380 g.) in ~0 ml. of diethyl ether. Reaction temperature is maintained at about 0C. and addition of lithium aluminum hydride proceeds dropwise over a 4 min. period. After addition is complete, the resulting mixture is stirred at ambient temperature for 1.5 hr. and thereafter placed in an ice bath (0-5C.).
Excess reducing agent is then destroyed by addition of saturated sodium sulfate. After cessation of gas evolu-tion, the resulting product is coagulated with sodium sul-fate, triturated with diethyl ether, and solid salts removed by filtration. The filtrate is then dried with sodium sul-Ch/ - 81 --fate, and evaporated under reduced pressure to yield 0.3C~4 9.
of a s l; ght 1 y ye 1 1 ow oi 1 . Th i s oi 1 (100 mg . ) i s then pur-if ied by preparative thin layer chr~nato~raphyl yielding 42 9. of ~itle product, NMR absorptions are observed at O.go, 1.10-2~80, 30289 ~.65-4.25, and 5045 ~. Character;s-tic in~rared absorptions a~e observed at 970, 1060, 1460, 2995, and 3400 cm.~l. The m3Ss spectrum shows parent peak at 699.4786 and ~ther peaks at 62~3, 684, 59~, 217, and -274.
i0 ~0 .

33~
11. 1,15-Lactones As discussed above~ the 1,15-lactones of the formula~l, -11, -111, and -lV compounds are prepared by analogous methods to those disclosed below.

As will be particularly evident to those skilled in the art, the preparation of a 1,9- 1,11-, or 1,15-lactone will be relatively uncomplicated when the 9-, 11-, or 15-hydroxy group is the only free hydroxy group with which the carboxy function can lactonize. Thus, when more than one hydroxy group is present, as for example in PGF2~, those hydroxyl groups not required for lactone function are optionally derivatized prior to lactonization to xequire formation of the desired lactone. Selecti~e methods for selective derivatiæation of all but one hydroxy of a prostaglandin or prostaglandin analog which contains two or ~ore hydrox~s are kno~n in the art. Suitable derivatives ~re the ~,11 cyclic phenyl-- or butyl-boronates of 9,11-cb/ ~ 83 -L 79 A~3 5jl or 9~ 3-dihydroxylated prostaglandins and prostagladin analogs, acyla-tes sueh as acetate, silyl ethers sueh as -tri-methylsilyl-, -t-butyldimethylsi'yl-, and triphenylsilyl and the :Like. Such func-tional derivatives are known in the pro-staglanclin art and are used with stereoseleetivity or where stereoseleetivity is not aehievable, with careful purifiea-tion the mixtures produced, to obtain the deslre Æuetional7y protected prostaglandLns and prostaglandin analoc3s as ex-emplified further in the examples. Op-tionally, if desired, one or more hydroxy groups are protected by oxidia-tion to a ketone be-Fore or after laetoni~ation. AEter laetoniza-tionl the ketone is redueed again -to produce a free hydroxy grotlp of the same eonfiguration or of opposite confiquration to that oric3inally present.
However, it is not essential in all eases -to proteet hydroxy groups whieh may be present but are not desired to partieipate in the laetone formation. Lactone formation oeeurs at diLEerent rela-ti~e rates wi-th different hydroxy groups depending on the stereoehemistry, sterie bulk in the vicinity of the hydroxy group, and ring size. Moreover it i.s possible -to separa-te 1,9-, 1,11- and 1,15-lactones as exempliE:ied below Eor PGr~'z~ :L,9-, 1,1L-, and 1,15-lactones.
Tllus 15-methyl-:lS~hydroxy- and 16,J6,-clime-thy:L-:L5-hydroxy prostaglclndin analocJs are sterieally hindered in -the viein-:ity oE C-lS ancl laetone Eunetlon at 15 wil:L no-t eornpete with :lacto~e Euetion with a 9- or ll-hyclroxy group. As a eorol-lary, in order to make a lac-tone with a hindred hydroxy grollp such as 15-methyl-15-hydroxy or 16,16-dirnethyl-15-hydroxy-, it is essent:ial that -the other hydroxy qroups whieh may be present be protected. It is also necessary rL-t~ ~-33~
to extend -the duration of the reac-tion until analysis of ~he reactiol~ mix-ture inclica-tes -that some desLred procluc-t is :Eormecl .
Prostaglanclins known in the art as thelr lower al.~yl (e.cJ. methyl, ethyl) es-ter but not as their Free acid may be conver-ted to the free acid for use in lactone fuction by chemical. hydrolysis by known methods. -If -the involved prostaglandin is unstable -toward chemical hydrolysis, as with PGE 2 me-thyl ester, PGD2 methyl ester, and the like, it ïo is pre:Eerred to obtain the free acid by enzymatic hydrolysis, ~or example by using the process of U.S. patent No.
3,761,356, issued September 25, 1973 -to The Upjohn CompaLIy.
With these limita-tions, and options for pro-tectirlg concommitant by presen-t hydroxy groups, selectivel.y, hydroly-zing -the :Eunctionally proteeted hydroxy groups without hydrolizing the desired lactone, separating undesired products Erom those desired, and modifying the lactones by subsequent chemistry obvious to tilose s]cilled in the art, such as oxi-diation, reduction, alkylation and the like, it is possible ko prepare the l,9- 1,11-, and l,15-lactones of prostagland-ins and of prostaglandin analogs of bio:Lo~ical importanee.
The pre.~erred method for lactone func-tion between the carboxy~ roup and the 9~ , or 15-hyclroxyl group :is the method de~c:ri.becl by Corey et al., J. Am. Chem. Soe.
96, 5614 (197~), as :further desc.ribe(l by Corey et a].., J. ~m. Chem. Soc.97, 653 (].975~ and as exemplifiecl further hereln. Op-tionally other rne-thods may be used, i:f clesirec:l r such as those o:E Masamure et al., J. Am Chem. Soc. 97, 3515 (1975) and Cer:Loch et al., Helv Chem. Acta 57, 2661 (1974) - 85_ ~r rlt/

33~

Preparation 4~ PGF ~, 1,15-lactone A solution of 5.5 g of PGF~ and 1.79 ~ of l-butane-boronic acid in 150 ml of methylene chloride was heated at reflux for 15 minO Then about half of the methylene chloride 5 was removed by distillation at atmospheric pressure. Addi-tional methylene chloride was added to bring the volume back to the original 150 mlO This cycle-distil1ation of methylene chloride followed by replacemen~ with fresh methylene chloride-was repeated three times, after which all the solvent was removed in vacuo to produce the 9,11-cyclic boronate o PGF2~ as a residue.

The residue was dissolved in 180 ml of anhydrous, oxygen-free xylene and treated with 5.128 g of 2,2'-dipyxidyl disulfide followed by 6.27 g of ~riphenylphosphine. After 18 hours at 25 under a nitrogen atmosphere, thin layer chromatographic analysis of an aliquot (solvent: 10 acetic acid/10 methanol/80 chloroform) showed complete conversion to the pyridinethiol ester.

The xylene solution was diluted with 300 ml of oxygen-free xylene and was added dropwise over 10 hours to 3.2 litersof vigorously stirred, refluxing xylene under a nitrogen atmosphereO ~fter the addition was complete, 100 ml of xylene was distilled oEf and the cb/ - 86 -~'7~3~i solution was heated and re:Elu~ for 24 hours. The reac-tion mixture was then cooled and -the xylene was removed i~ V~cuo ~35 bath temperature) to give a residue~ The residue was taken up in 500 ml 0l -tetrahydro-furan and treated with 10 ml of 30~ hydrogen peroxide and 100 ~1 of saturated aqueous scclium bicarbona-te. The three-phase muxture ~7as stirred vigorou~ly for 30 min. at 25, then concentrated i-f~ v~uo to give a residue. The residue was taken up in brine/e-thyl acetate ancl extracted thoroughly with ethyl acetate. I~he c~mbination organic la~er was washed with three portions of lN aqueous potassium bisulfate, and once with water, aqueous sodium bicarbonate and brine. ~Eter ~rying over sodium sulEate, the solvent was removed to afford a viscous yellow oil which was chromatographed on 500g o~E Mallinckrodt acidwashed CC-4 sil;.ca. The colu~r wa~ packed with 25~ et~yl ac~t~te/hexane and eluted (100 mLfraction~ with 50% ethyl acetatehexane. Fractions 26-40, containing the product and no prostaglandin-related ~mpurites, were combined. The desired product was crystallized from 40 m~ of 1:1 ether/hexc~ne, thereby affording pure lacton, M.P. 110-111.
The lactone exhibited infarred absorption a-t 3500, 3370, 3290, 3010, 1700, 1320, 1310, 1290, 1260, 1105, 1080, 1055, 970, and 730 cm~l and NMR peaks a-t 6.00-S.75 (vinyl; multiplet; 2H), 5.75-4.95 (vtnyl and C-15H; mNltiplet: 3H), 4.30-3.85 (~-IOH; multiplet: 2H) and 2.65 p.p.m. (OH; broad siylet; shifted downEield on cooling; 2H). The mc~ss spectrum o:~ the bistrimcthylsi.lyl derivative e~l.ib.tted -~:ra~len-ts at ~80 (M~), 465 (M-C~13~, ~36 (M-CO2), 409 (M-C3HI,), 390, 380, 36~, 23~, 217.
Anal. Calc'd. for C20EI32O": C, 7:L.39; E~, 9.59.
Found: C, 70.73; EI, 9.31 In like manner, but substi-tuting ethy aceta-te hexane :Eor e-ther/hexane Eor recrystallization, PGF2~ :l, 15-lac-tone was obtained: m.p. 110.0-111 7,; [~]Et~l _ 71 -v7-L~

33~

Preparation 5: 17-Phenyl-18,19,20-trinor-P~F2~,1,15-lactone A solution of 17-phenyl-18,19,20-trinor-~G~ 76 mg) and l-butaneboronic acid (225 mg) in 25 ml of methylene chloride was heated at reflux. After 15 min. the methylene chloride was allowed to distill off slowly. Fresh methylene chloride was added when the total volume was reduced to about one-hal~
of the original volume. A~ter 90 minutes, all of the methylene chloride was removed in vacuo to afford cycli boronate of the starting prostaglandin.
The cyclic boronate was dissolved in 5 ml of anhydrous, oxygen-free xylene and was treated with 2,2'-dipyridyl di-sulfide (660 mg) and triphenylphosphine (786 mg~. After four hours at 2~ the reaction mixture was diluted with 500 ml of anhydrous, oxygen-free xylene and was heated at reflux for 18 hr. The xylene was removed in vacuo to give a residue~ The residue was taken up in 50 ml of tetrahydrofuran con~aining 1 ml of 30~ aqueous hydrogen peroxide (11.6 mmoles) and treated at 25 with a solution of sodium bicarbonate (1.68 g) in 10 ml of wa~er. This mixture was stirred vigorously ~or 30 min.
then concentrated under reduced pressure to give a residue.
The residue was taken up in brine/ethyl acetate and extracted thoroughl~ with eth~l acetate. The combined extracts were washed with aqueous sodium bisulfate, water, aqueous sodium bicarhonate and brine, then dried over sodium sulfate and concentrated to af~ord a residue of crude 17-phenyl-18,19, 20-trinor PGF2~, l,lS-lactone.
The crude lactone was purified by chromatography on 400 g of neutral silica packed and eluted (22 ml fractions) with ethyl acetate. The fractions which contained the product, based on TLC, were combined yielding purified 17-phenyl-18,19,20-trinor-PGF2~, 1,15-lactoneO The lactone crystallized upon trituration and after two recrystalli~ations from ethyl acetate/hexane exhibited m.p. 116-117.
cb/ ~ 88 -~7~33~
The in~rared spectrum exhibited peak~ at 3460, 3400 sh, 3020, 1705, 1650, 1605, 1495, 1325, 1300, 1265, 1150, 1100, 1040, 1020, 1000, 970 and 700 cm 1 and the mass spectr D
showed fragments at m/e 370 (M-18), 352, 334, 308, 298, 2~19 243, 225. ~No ~ peak was apparent.) AnalO Calc'd. for C~3H3~04: C~ 74.56; ~ 6-Found : C, 74.27; H, 7.97 Preparation 6; 17-PheDyl-18,19,20-trinor-PGE2, l,lS-lac~o~e A solution of 17-phenyl-18,19,20-trinor-PGE2 ~735 mg), 2,2' dipyridyldisulfide (628 mg~ and triphenylphosphine (748 mg) in 10 ml of anhydrous, oxygen-free xylene was stirred at 25 in an atmosphere vf nitrogen for 2 hr. The mixture was then diluted with 400 ml of anhydrous, oxy~en free xylene, heated at reflux for 2.5 hrs, and evaporated under vacuum at 30~ to give a residue. The residue was chromatographed on 100 g of neutral silica, packed and eluted (8 ml fractions) with 80%
ether/hexane. The fractions containing homogeneous product by TLC were combined to afford purified 17-phenyl-18,19,20-trinor-PGE2, 1,15-lactone. Two recrystallizations from ether/hexane afforded pure product, m.p. 81-83. The infra~
rea spectrum exhibited peaks at 3440, 3000, 1725, 1605, 1500, 1330, 1240, 1160, 1145, 1085, 1045, 975, 745, 725 and 700 cm 1 and the mass spectrum showed fragments at m/e 368 (M-18), 350, 332, 297, 296~27~, 264, 259, 241 ~no M+ apparent).
Prepar_tion 7: 16-Phenoxy-17,18,19,20-tetranor-PGF2~,1,15-lactorle Following the procedure of Example 1 but substituting 16-phenoxy-17,18,19,20-tetranor PGF2a for PGF2a there was pro-duced a crude product of 16-phenoxy-17,18,19,20-tetranor-PGF2a, 1,15-lactone as a viscous yellow oil.
3~ The crude product was purified by chromatography o~er neutral silica packed in 50% ethyl acetate/hexane and eluted with 50~ ethyl acetate/hexane followed by 70-~ ethyl acetate ~b/ - ag -333~

hexane. Those fractions containing homogeneous product a~
judged by TLC were combined to afford crystalline 16-phenoxy~17, 18,19,20-tetranor-PGF2~ 1,15-lactone. The lactone thus obtained was recrystallized from ethyl acetate/hexane to S afford pure product, m.p. 185-186. The mass spectrum of the trimethylsilyl derivative exhibited a peak at M~ 516.273Y
(theory for C28~44Si2O5~ 516.2727) and fragments at m/e 501, 426, 423, 409, 400, 333, 307, 217 and 131.
Preparation 8: PGFl~, 1,15-lactone and 15-epi-PGFl~, 1,15-lactone Following the procedure of Example 1 but substituting PGFl~ for PGF2~ there was obtained a crude product containing PGFla, 1,15-lactone as a viscous yellow oil.
The crude product was purified by chromatography on 780 g of neutral silica, packed and eluted with 50% ethyl acetate/
hexane. The first 2 liters of eluate were discarded, after which 100 ml fractions were collected.
A minor product eluted first from the column (fractions 14-19) which was homogeneous by TLC was combined to give 15-epi-PGFl~, 1,15-lactone [~15R)-PGF2a, 1,15-lactone~. The infrared spectrum exhibited peaks at 3450, 1730, 1585, 1250, 1-00, 970 and 735 cm 1 and the NMR spectrum showed peaks (~CMs 3) at 5.85-5.05 ~vinyl and C-15; multiplet; 3H;, 4.25-3.85 ~CHOH;
multiplet; 2H) and 3.30 ppm (singlet, shifts downfield when sample is cooled; OH; 2H).
The major product, eluted later from the column (fractions ~1-28), were combined to afford purified PGFla, 1,15-lactone.
The purified PGFl~t l,lS-lactone crystallized upon trituration with ether, and recrystallization (ethyl acetate/hexane) afforded a pure sample, m.p. 105-106. The infrared spectrum exhibited peaks at vmax 3520, 3480, 3380, 1710, 1300, 1290, 1265, 1250, 1235, 11~0, 1110, 1075, 1055, 1000 and 965 cm 1 The NMR

spectrum showed peaks (~CMcl3) at 6.0-5.75 (vinyl; multiplet;

cb/ ~ ~ ~

93~

2H; 5.60-S.00 (C-15H; multiplet, 1~), 4.25-3.80 ~CHOH; multiplet;
2~) and 3.08 ppm (OH; singlet)O
Preparation 9: 13,14-Didehydro~8~/9~ 12a PGF2~ 1,15-lacto~e and 13,14-didehydro PGF2~ 1,15-lactone Following the pxocedure o Example 1 but substituting 13, 14-didehydro-8~, 9~ , 12~ PGF~a~also known as ent-13~
dehydro-15-epi-prostaglandin F2a (compound 2 of J. Fried and C.
H.Lin. J. Med. ChemO 16, 429 (1973)] and 13,14-didehydro PGF2a for PGF2a, there are produced 13,14-didehydro-8~,9~ ,12a-PGF2~ 1,15-lactone, and 13~l4-didehydro-pGF2a 1,15-lactone, respectivelyO
Preparation_10: 13,14-didehydro-8~ ,12~-PGE~ 1,15-lactone and 13,14-didehydro-PGE2 1,15-lactone Following the procedure of Example 2 but substituting 13,14-didehydro-8~ ,12~-PGE2 [also known as ent-13-dehydro-lS-epi-PGE~ (from 2a of J. Fried and C. H. Li.n. J. Med. Chem.
16, 429 (1973)~ and 13,14-didehydro PGE2 for PGE2 there are produced 13,14-didehydro~8~ ,12a-PGE2 1,15-lactone and 13,14-didehydro PGE2 1,15-lactone, respectively.
Preparation 11: 13,14-dihydro PGF a 1,15-lactone Fcllowing the procedure of Example 1 but substituting 13,14-dihydro PGF2~ for PGF2~, there i5 produced 13,1~-d.ihydro PGF2a 1,15-lac~one.
Preparatio.n 12: (lSS)-15-methyl PGF2~ 1,15-lactone Following the procedure of Example 1 but substituting ~15S) 15-methyl PGF2~ for PGF2~ and extending the reaction time in refluxing xylene from 24 hours to 48 hours there is produced crude ~15S)-15-methyl PGF2a, 1,15-lactone. The crude lactone is purified by repeated chromatography and, urther, if desiredl by TLC purification to afford in low yield (15S)-15-methyl-PGF2~ t 1l15-lactone in essential.ly pure form.
Preparation_13: 16,16-dimethyl PGF2a 1,15-lactone ~/ ~ gl -Followinc~ the procedure of Example 15 but substituting 16,16-dimethyl PGF2~ for (15S) 15~methyl PGF2~ there is produced 16~16-dimethyl PGF2~, 1,15-lactone.
Preparation 14:
~ollowin~ the procedure o~ Example 8 but substi~uting 16-m~trifluoromethylphenoxy-17,18,19,20-tetranor PGF2~, 16-m chlorophenoxy-17,1Qtl9,20-tetranor PGF2~, and 16-p-fluoro-phenoxy-17,18,19,20~tetranor PGF2~ for 16-phenoxy-17,18~19,20-tetranor PGF2~ there are obtained ~he corresponding 1,15-lactonesO
Preparation 15:
Following the procedure of Example 2 but substituting ~16S) 16-methyl-, (16R) 16-methyl- and 16-methylene PGE2 for PGE2 there are produced, respectively, the corresponding tl6S~
16-methyl, (16R) 16-methyl-, and 16-methylene PGE2 1,15-lactones.
Preparation 16: 16,16-dimethyl PGE2 1,15-lactone Following the procedure of Example 3 but substituting 16,16-dimethyl PGF2~ 1,15-lactone for PGF2~ 1,15-lactone there is produced-16,16-dimethyl PGE2 1,15-lactone.
Preparation 17: (15S) 15-methyl PGE2 1,15-lactone Following the procedure of Example 3 but substituting ~15S) 15-methyl PGF2~ 1,15-lactone for PGF2~ 1,15-lactone, there is produced ~15S) :L5-methyl PGE~ 1,15-lactone Pre~aration 18: 11-deoxy PGE 1,15-lactone .. ~
Following the procedure of Example 2 bu-t substituting 11~
deoxy PGE2 for PGE2 there is produced ll-deoxy PGE2 1,15-lactone.
In like manner, substituting ll-deoxy PGEl for PGE2 affords PGEl t 1 t 15-lactoneO
Preparation 19: (15S) ll-deoxy-15-methyl PGE2 1,:L5~1actone __ and ll-deoxy-16,16-dimethyl PGE2, l,l5-lactone Following the procedure of Example 2 but substituting (15S) ll~deoxy-15-methyl PGE2 and 11-deoxy-16,16-dimethyl PGE2 for PGE2 and extendiny the reflux period in xylene rom 2 cb~ ~ 9~ ~

` ~'7~5 h~ur~ to 48 hours there are produced the corresponding 1,15-lactones. The crude lactones are purified by repeated chro~a-tography and further, if desired, by TLC purification to affvrd in low yield (15S) ll-deoxy-15-methyl PGE2 1,15-lactone and 11-deoxy-16,~6-dimethyl PGE~ 1,15-lactone, respectively, in essentially pure .form.
reparat~on ~ -de~y PGF2~ 1,15-lactone A solution of ll-deoxy PGE2 l,lS-lactone ~0.5 g3 in methanol (50 ml) is treated at 0~ with sodium borohydride ~500 mg) added in 50 mg portions every 2 minutes. Aqueous sodium bisulfate ~lM) is added until the mixture is acidic and the product is isolated by extraction with ethyl acetate.
The extract is washed, dried, and concentrated to yield a residue containing ll-deoxy PGF2a, 1,15-lactone.
The residue is purified by chromatography over acid-washed silica using 1~ ethyl acetate/hexane increasing to 40%
ethyl acetate/hexane. Those fractions containing homogeneous product as judged by TLC and by saponification t~ the known 11-deoxy PGF2~ are combined to afford ll-deoxy PGF2~ lactone 29 in essentially pure form.
In like manner, substituting ~15S) 11-deoxy-15-methyl PGE'2~ 1,15-lactone, 11-deoxy-16,16-climethyl PGE2 1,15-lactone PGE2, 1,15-lactone, ~15S) 15-methyl PGF~ 1,15-lactonel 16,16-dimethyl PGE2 1,15-lactone and PGEl 1,15-lactone for ll-deoxy PGE2 1,15-lactone there are produced the 1~15-].actones oE (15S) 11 deoxy 15-methyl PGF2a, 11-deox~-16,16-dimethyl PGF2a, PGF2a, ~15S) 15-methyl PGF2~, and PGFla, respectively.

-b~ - 93 -~933~

SUPPLEMENTARY DISCLOSURE

When this application was filed, it was not known which isomer, 5E form or 5Z form, was obtained by the procedures set out in the examples. The structure has now been established for the compounds of the present invention as the 5Z form. "E" and "Z" nomenclature is discussed in the following reference: J.E~ Blackwood et al., J. Am. Chem. Soc. 90,509 (1968).
The 5Z compounds of the present invention were made from 5,6-cls PGF compounds, whereas the 5E isomers require starting with 5,6-trans PGF compounds.
When considering Examples 5 to 7 and 10 of the principal disclosure, it should be noted that the prefix "52-" properly belongs before each title heading, for example, Example 5, line 17 on page 49: 5Z-9-Deoxy-6,9-epoxy-~5-PGF

Methyl Ester.

. - 94 -

Claims (4)

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

1. A process for preparing a compound of the formula or a mixture comprising that compound and the enantiomer thereof wherein L is (1) -(CH2)d(C(R2)2- or (2) -CH2-O-CH2-Y-wherein d is zero to 5; R2 is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R2 is not methyl when the other is fluoro; and Y is a valence bond or -(CH2)k- wherein k is one or 2;
wherein Q is , or wherein R8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive;
or wherein R3 is alkyl of one to 12 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 chloro or alkyl of one to 4 carbon atoms, inclusive;
, , or hydrogen;
or a pharmacologically acceptable cation; wherein R4 is (1) or (2) wherein CgH2g is alkylene of one to 9 carbon atoms, inclusive, 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; and wherein X is (1) trans-CH=CH-(2) cis-CH=CH- or (3) -CH2CH2- ;
which comprises the steps of starting with a compound of the formula wherein L, Q, R3, R4 and X are as defined above, and iodinating and cyclizing to form said compound.

2. A compound of the formula or a mixture comprising that compound and the enantiomer thereof, wherein L, Q, R3, R4 and X 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 compound of the formula:
which comprises starting with a compound of the formula and iodinating and cyclizing to form said compound.

4. 9-Deoxy-6,9-epoxy-5-iodo-PGF1.alpha., methyl ester, whenever prepared or produced by the process defined in claim 3 or by the obvious chemical equivalent.