CA1160628A - 6-KETO AND 5-HEMIKETAL-PGF IN1.alpha. XX, METHYL ESTERS - 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-hemi-ketal or (2) a 6-keto feature are disclosed; including processes for preparing them and the appropriate intermediates; said derivatives having pharmacological activity.
Typical 6-keto and 6-hemiketal compounds are represented respectively, by the formulae:

and

Description

This application is a division of copending Canadian application Serial No. 270,416, filed January 25, lg77.
BACKGROUND OF THE INVENTION
This invention relates to prostaglandin deriva-; tives and to a process for preparing them.
The prostaglandins and analogs are well-known organic compounds derived from prostanoic acid which has the following structure and atom numbering:

~ 7~\6/5~/3~ COOH

~1~`~20 As drawn hereinafter the formulas represented a particular optically active isomer having the same abso-lute configuration as PGEl obtained from mammalian tissues.
In the formulas, broken line attachments to the cyclopentane ring or side chain indicate substituents`in alpha configuration, i.e. below the plane of the ring or side chain. Heavy solid line attachments indicate sub-stituents in beta configuration, i.e. above the plane.
For background, see for example Bergstrom et al., ~ Pharmacol. Rev, 20, 1 (1968) and Pace-Asciak et al., ¦ Biochem. 10, 3657 (1971).
SUMMARY OF THE INVENTION
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 of-~e formula:

- 2 -mab/~

.

~V-O-C-CH-L-R~
~ ~, "W/

~

Q
: 10 wherein D is oh OH CH2 ~ , `

, or C'H20H

wherein L is (1) -(CH2)d-C(R2)2-(2) -CH2-O-CH2-Y- or . (3) ~CH2CH=CH-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 0~ H H , Ra OH, or R8 OH

287lA

wherein R8 is hydrogen or alkyl of one to 4 carbon atoms~
i~clusive;
wherein Rl is (1 )-COOR3 (2 )-CH20H
( S )-CH2N (Rg )2 or (4) NH -N
~N--N
wherei n R3 is (a) alkyl of one to 12 carbon atoms, 10 . inclusive, (b) cycloalkyl of 3 to 10 carbon atoms, inclusiveJ (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 ) ~9-NH -C ~NH -C -CH3, (9) ~NH-C~9, O
(h ) ~=~NH-C -CH3, ;) ~ N H-C-NH2 CH=N-NH-C-NH2, or (k) ~
o (1) -CH-C-Rlo R l l wherein R1o is pheny1, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl;
wherein R11 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 R4 is Rs ~ F c gH29-CH3 R~

(2) -C-Z ~ (T)s or

(3) -CH2_ C C ~CH2CH3 H' H

wherein CgH29 is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between -CR5R~- and terminal methyl, wherein R5 and R~ are hydrogen, alkyl of one to 4 .

.

., 287 lA

carbon atoms, inclusi~e, or fluoro, being the same or different, with the proviso that one of R5 and R~
is fluoro only when the other is hydrogen or fluo~ro and the further proviso that neither R5 nor R~ is --fluoro when Z is oxa (-0-); wherein Z represents an oxa atom (-O-) or CjH2, wherein ClH2j 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 alkyl 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 -(CHz)h-wherein h is one or 2; and wherein X is (1) trans-CH=CH-(2) cis-CH=CH-(3) -C--C- or

(4) -CH2CH2-~
Within the scope of the prostaglandin derivatives described heretn there are represented (a) PGFa compounds when ~ is <~X' OH
~0 (b) ll~-PGF,~ compounds when D is <~
OH
(c) ll-Deoxy-ll-keto-PGF~ compounds when ~ is <~ , 10 (d) 11-Deoxy-11-methylene-PGFa compounds when ~i5 15(e ) 11 -Deoxy -PGFa compounds when Di s .. ~

20~D(f ) ll-Deoxy-10,11-Didehydro-PGFa compounds when ~ ; and (9~ 11-Deoxy~ hydroxymethyl PGFa compounds when ~ '' ¢~ ' . ~i6~6 ~ 8 2871A

A typical example of the compounds of formula I is : represented by the formula:

_CH-CH-(CH2)3-COOH
/~' V
~C =C
HO H \ C~-C5H
H OH

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

L is -(CH2)3-, Q is H OH, R1 is -COOH, R4 is n-pentyl, V is a valence bond, W is -CH2-, and X is trans-CH=CH-.
There are likewise provided compounds of the formula : ` ' ~ /V-O-C=CH~L-R
., ~
:~ 25 ~ Il ~ X-C-R4 ~ , ' ' .

., .
_O_ 287 lA
6~

OH
~, V-o -C -CH2 -L -R I
-) -W / I ~ I

~_- ~ X-C-R 4 and Q
V~OHo - ~ W-C-CH2-L-R
) lV

wherein ~ ~ L, O, R1J R4J VJ W, and X are as defined broadly above for formula I, with the proviso that, in the enol ether compounds of formula II, R1 jS not-COOH
when D iS ~-~ .
bH

Q is H OH, L is -(CH2)3-, R4 jS n-pentyl, V is a valence bond, W is -CH2-, and X is trans-CH=CH-.
In compounds of formula II, the wavy line ~ indicates attachment in cis or trans configuration relative to the W-C bond. In formulas l-IV as used herein, W is bonded to the cyclopentane ring at the C-8 position, V at the C-9 position, and X at the C-12 position. In compounds of formula III, ~ indicates attachment of -OH in alpha or beta configuration.
The formula-II enol ethers are named as derivatives of PGF2~J regardless of the variations in either of the side ., g :, .

chains, V and W in the heterocyclic ring, or the cyclo-pentane ring system represented by ~ , following the conventions known and used in the prostaglandin art. The formula-tll 6-hydroxy compounds (hemi-ketals) and the formula-lV 6-keto compounds are named as derivatives of PGF~.
Typical examples of the compounds of formula ll, Ill, and IV, when ~ , L, O, R1, R4, V, W, and X are as illustrated above for the compound of formula V are:
O _C~-CH-(CH2)3 -COOH

¢~=C~ Vl H~ \C-CsH
H OH
named 9-deoxy-6,9-epoxy- ~s-PGF la;
~H
_~H-(CH2)4-COOH
O ~

~ C=C ~ Vll HO C~-C5H
H / OH

.
named 9-deoxy-6,9-epox~-6-hydroxy-PGF~a; and .: 25 , . .
: OH O
~CH2-C-(CH2)~-COOH

, ~C-C' Vlll ' H \C-CsH
OH ~ ~
H OH
named 6-keto-pGF~aD

The products of this invention, represented herein by formulas 1, Il, Ill, and IV, are extremely potent in causing various biological responses. For that reason, these com-pounds are useful for pharmacological purposes. A few of those biological responses are: inhibition o~ blood platelet aggregation, stimulation of smooth muscle, systemic blood pressure lowering, inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systemic i administration of prostaglandin synthetase inhibitors.
Because of these bio10gical responses, the known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in mammals, including humans, use-ful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbitsJ
and monkeys.
These compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the forma-tion of thrc;mbi in mammals, including man, rabbits~ and rats.For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular ~rafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks ~0 and long term prophylaxis following myocardial infarcts and strokesO For these purposes, these compounds are ad-ministered systemically, e.g., intravenously, subcutane-ously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations3 the intravenous route of administra-tion is preferred. Doses in the range about 0.01 to about 10 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight~ and condition of the patient or animalJ and on the frequency and route of admin-istration.
The addition of these compounds to whole blood provides în vitro applications such as, storage of whole blood to be used in heart-lung machines. Additionally whole blood con-taining 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 radiation therapy. In vitro applications utilize a dose of 0.001-1.0 ~g/ml of ~hole blood.
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, oxytocic agents~ e.g., oxytocin, and the various er~ot alka-loids including derivatives and analogs thereof. Therefore, they are useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus~ or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and durfng 3 the puerperium. For the latter purpose, the compound is .

6;;~

. _ . .. .
administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 ~y. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneousJ or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or anima~
These compounds are useful as hypotensive agents to reduce blood pressure in mammals~ including man. For this purpose, the compounds are admi ni stered by intravenous in-fusion at the rate about 0.01 to about 50 ~g. per ~9. of body weight per minute or in sing1e or multiple doses of about 25 to 500 ~9. per kg. of 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 gastrointestinal ulcer formation, - and accelerate the healing of such u 1 cers already present ... .. . . . .
in the gastrointestinal tract. For this purpose~ these compounds are injected or infused intravenously, sub-cutaneously, or intramuscularly in an i nfusion dose ranyeabout 0.1 ~9. to about 20 ~g. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.01 to abou~ 10 mg. per kg. of body weight per day, the exact dose depending on the age, we; ght, and condition of the patient or animalJ and on the fre-quency and route of adm;nistration.
These compound;are a1so useful i n reducing the un-desirable gastrointestinal effects resulting from systemic .

6~ .
admillis~:ra~lon of an~ fl,~mDIn~:ory prost~glandill Rynthe~se inllibitor~, ~nd are used for that purpoAe by concomitant admlnl~ration of the prostaglandin derivative and the anti~
inflammatory prostaglandin syn~hetase inhibitor. See Par~ridga et al, U.S. Pat. No. 3,781,429 issued December 25, 1973, for a disclosure ~hat ~heiulcerogenic effect i~lduced by certaln no~-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E and A series, including PGE,, PG~2, PGES, 13,14-dihydro-PGEl, and the corresponding ll-deoxy-PGE and ~GA compounds.
Prostaglandins are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and Aspirin.
These are substances specifically mentioned in Partridge et al as non-steroidal, anti-inflammatory agents. Tnese are also kno~7n to be prostaglandin synthetase inhibitors.
The anti-inflammatory synthetase inhibitor, f or example, indomethacin, Aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflamma.ory condition, for example, in any dosage regimen and by any of the known routes of systemic administration.
The prostaglandin derivative is administered along wlth the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different ; route. For example, if the anti-inflammatory substance is being administered orally, the prostaglandin derivative is also administered orally, or, alternatively, is administered rectally in the form of a suppository or9 in the case of women, vaginally in the form of a suppository or a vaginai device for slow release, for example às described in U.S. Pat.
. .
~' . .
Jl/ ~ -14-* Trademark .

No. 3,545,439 (Dec. 89 1970, The Up~ohn Company). Altern~tively, if the an~i-inflammstory substance is being administered rectally, the pro~taglandin derlvative is also administere~
rectally. Furtner9 the prostaglandin derivative can be con~en -iently administered orally or, in the case of women, vaginally.
It is especially convenient when the administration route is to be the same for both anti-inflammatory sub~tance and prostagland~n derivative, to combine both into a single dosage form.
The dosage regimen for the prostaglandin derivative i~
accord with this treatment will depend upon a variety of factors9 - including the type9 age9 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 a~ti-inflammatory substance experiences the same adverse gastro-intestinal effects when taking 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 cau~sing 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 eliminate those undesirable effec-ts.
These compounds are also useful in the treatment of - asthma. For example9 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-.

6;28 287 lA -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 dosage ~orms, e g., orally in the form o~ tablets, capsules, or liquids; rec-tally in the form of suppositories; parenterally, sub-cutaneously, or intramuscularly, with intravenous adminis-tration being preferred in emergency situations; by inhala-tion in the form of aerosols or solutions for nebulizers;
or by insufftation in the form of powder. Doses in the range of about 0.01 to 5 mg. per kg. of body weight are used 1 to 4 times a day, the exact dose depending on the age, 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 (isoproteren~l J phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophylline); and cortico-steroids (ACTH and prednisolone~.
These compounds are ef~ectively administered to human asthma patients by oral inhalation or by aerosol inhalation.
For administration by the oral inhalation route with conventional nebulizers ol 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 weight of total solution. Fntirely conventional additives may be employed to stabilize these solutions or to pro-vide isotonic media, for example, sodium chloride, sodium ~ 6 ~ ~

citrate, citric acid, sodium blsulf;te, and the like can be employed 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 in an inert propellant (such as a mixture of dich10rodifluoromethane and di-chlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can a~lso be used a dispersing agent such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technique are described fully in U.S. 2,868,691(Jan. 13/59, Riker Laboratories, Inc.) ~or exa~ple.
These compounds are useful in mammals, including man, as nasal decongestants and are used for this purpose in a dose range of about 10 ~g. to about 10 mg. per mlO of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.
These compounds are also useful in treating peripherai vascular disease in humans. The term peripheral vascular disease as used herein means disease of any of the blood vessels outside of the heart and to disease of the lymph vessels~ for example, frostbite, ischemic cerebrovascular disease, artheriovenous flstulas, ischemic leg ulcers, phlebitis, venous insufficiency, gangrene, hepatorenal syn-drome, ductus arteriosus, non-obstructive mesenteric ischemia, arteritis ly,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 .
- -17- , "

~6~
invention are administered orally or parenterally vi~ in~ection or infusion directly into a vein or artery, intra-venous or intra-arterial in~ections being preferred. The dosages of these compounds are in the range of 0.01-1.0 ~g/kg administered by infusion at an hourly rate or by injection on a daily basis i.e. 1-4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of admlnistration. Treatment is continued for one to five days, although three days is ordinarily sufficient to assure long-lasting therapeutic action. In the event that systemic or side effects are observed the dosage is lowered below the threshold at which such systemic or side effects are observed.
These compounds are accordingly useful for treating peripheral vascular diseases in the extremities of humans ~ho have circulatory insufficiencies in said extremities, such treatment affording relief of rest pain and induction of healing of ulcers.
- For a complete discussion of the nature of and clinical manifestations of human peripheral vascular disease and the method previously known of its treatment with prostaglandins see South African Patent No. 74/0149 (March 7, 1975, L.A. Carlson~ 9 or corresponding U.S. Patent 4,103,026 (July 25, 197~). See Elliott, 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 pigs, at or near term, or in pregnant animals with intra-uterine death of the fetus from about 20 weeks to term. For this purpose, the compound is in-~ -18-62~ 2871A-l-F

fused intravenously at a dose of 0.01 to 50 ~g. per kg.
of body weight per minute until or near the termination of the second stage of tabor, i.e.J expulsion of the fetus. These compounds are especially useful when the female is one or more weeks pos~-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 alternative route of administration is oral.
These compounds are further useful for controlling the reproductive cycle in menstruating female mammals, including humans. By the term menstruating female mammals is meant animals which are mature enough to menstruate, but not so oJd 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 approxirnately at the time of ovulation and ending approximately at the time 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 similar administration of the compound during the first or second trimester of the normal mam-malian gestation period.
These compounds are further useful in causing cervi-A cal dilation in pregnant and nonpregnant female = /s for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compoundsJ cervical dilation is also observed In cases ~0 of infertilityJ cervical dilation produced by these com-6~ ~871A~

pounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostag1andins is also use-ful in operative gynecology such as D and C (CerYical Dilation and Uterine Curettage) where mechanical dilation may cause performation of the uterus, cervical tears, or infections. It is also useful for diagnostic procedures where dilation is necessary for tissue examination. For these purposes~ the prostaglandin derivative is administered locally or systemically.
- 10 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 anirnals as an abortifacient (especially for feedlot heifers), as an aid to estrus detection, and for regulation or synchroniza-tion of estrus. Domestic animals include horses, cattle, sheep, and swine. The regulation or synchronization of estrus allows for more efficient management of both con-ception and labor by enabling the herdsman to breed all his femals in short pre-deFined interva1s. This synchroniza-tion results in a higher percentage of live births than the percentagé achieved by natural control. The prostaglandin is injected or applied in a feed at doses of 0.~-100 mg.
per anirnal and may be combined with other agents such as steroids. Dosing schedules wi71 depend on the species .

. .

2~ 287lA-1-F

treated. For examp1e, mares are gi ven the prostaglandi n derivative 5 to 8 days after ovulation and return to estrus.
Cattle are treated at regular i ntervals over a 3 week period to advantageously bring all into estrus at the same time.
These compounds i ncrease the f low of blood i n the mammalian kidney, thereby increasing volume and electro-1 yte content of the ur i ne . For that reason, these compounds are useful in managi ng cases of renal dysfunction, especial ly those i nvolvi ng blockage of the renal vascular bed. I l lus-tratively, these compounds are useful to al leviate and cor-rect cases of edema resulting, for example, from massive surface burns, and i n the rnanagement of shocl<. For these purposes, these compounds are preferabl y f i rst admi ni stered by i ntravenous i nj ecti on at a dose i n the range 10 to 1000 ug. per kg. of body weight or by intravenous infusion at a dose i n the range 0.1 to 20 ug. per kg. of body wei ght per minute until the desired effect is obtained. Subse-quent doses are gi ven by i ntravenous, i ntramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body we i ght per day.
These prostaglandin derivatives are useful for treating proliferating skin diseases of man and domesti-cated animala, including psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun-induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and a top 7 c dermat i t i s and mange i n domes t i cated animals. These ~:ompounds al leviate the symptoms of these - -2~ -proliferative skin-diseases: psoriasis, for example, beiDg alleviated when ~ scale-free psoriasis lesion is noticeably decreased in thickness or noticenbly but incompletely cleared or completely clea~ed.
For these purpose~, these compounds are applied topically as compositions including a suitable pharmaceutlcal carrier, for example as an ointment, lotion, paste, jelly, spray1 ~r aerosol, using topical bases such as petrolatum, lanolin, poly-ethylene glycols, and alcohols. These compounds, as the active ingredients; constitute from about 0.1~ to about 15% by weight of the composition, preferably from about 0.5% to about 2%.
In addition to topical administration, injection may be employed, as intradermally, intra or peri-lesionally, or subcutaneously, using appropriate sterile saline compositions.
These compounds are useful as antiflammatory agents for inhibiting chronic inflammation in mammals including the swelling and other unpleasant effects thereof using methods of treatment and dosages generally in accord with U.S. Patent 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 e~ample, they are surprisingly more specific with regard to potency and have a substantially longer duration of biological activity. They have the further advantage that they may be administered effectively orally, sublingually, intravaginally, ~1/ d,r!~ -2 2 -~ 2871A

buccally, or rec~ally as well as by the usual methods.
Each of these novel analogs is therefore useful in p!ace of the known prostaglandin F a -~type compounds for at least o~e of the pharmacological purposes known for them, and is surprisingly and unexpectedly more useful for that purpose because it has a different and narruwer spectrum of ~iolog-ica~ activity than the known prostag1andin, and therefore ;s more specific in its activity and causes smaller and ~ewer undesired side effects than the known prostaglandin~
Moreover, because of its pro~on~ed activity, fewer and smaller doses of these novel compounds can frequently be used to attain the desired result.
There are further provided the various processes for preparing the 5-iodo compounds of formula 1, the enol ethers of formula ll, the hemi-ketals of formula lll, and the 6-keto compounds of formula IV.
Thus, for the formula-l, -Ill, and -IV compounds, the : process comprises the steps of startin~ with a compound of the formula OH

W-CH=CH-L-Rt Q

wherein L, Q, Rl, R4, and X are as ~ fined above, includ-ing -COOH for R " and wherein ~ is ~ ~ 2871 ORl3 OR~3 CH2 ~'' ~',or <~
CHzOR 13 ' 10 wherein R~3 is hydrogen, tetrahydropyranyl, tetra-hydrofuranyl, 1-ethoxyethyl, or a group of the formula I H
R 14 -O -C C, -R 17 Rl5 R1ff wherein Rl4 is alkyl of one to 18 carbon atoms, in-clusive, cycloalkyl of 3 to 10 carbon atoms, inclu-sive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein Rl5 and and R1~ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, in~lusive, or, when R 15 and Rl~ are taken together, -(CH2)a- or -(CH2)b-O-(CH2)c- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b p1us c is 2, 3J or 4, and wherein R17 is hydrogen or phenyl; and (a) iodinatir,g and cyclizing to form a compound of the formula .. _. .. ..

.~6~ 2871A

:. i ~ V-O -CH-CH~L R~

I ~~W X

~ X-C-R~
Q
wherein ~ , Ll, ~, Rl, R4, Y, W, and X are as defined above, (b) subj ecting the product of step "a" to dehalogen-ation and hydrolyS;5 to form a keto compound of the formula OH
V~ O

) `'Xll . ~ X-C-R4 Q

and a hemi-ketal compound of the formula OH

20 . ~ ~V-O;C-CH~ -L -Rt J-w X, _~f~x-C-R4 . ~ Q
wherein J~ L, Q, R1, R4, V, W, X, and __ are as defined above, and (c) separating the products.
In this disclosure of the process~for the formula-l, -III, and -IV compounds, the symbol ~ includes all of the ring systems of the symbol ~ defined above,together wIth those in which there i5 a blocking group within the ~ .

?871A

scope of ~13 at C-ll. The compounds produced, as repre-sented by formulas X, Xl, and Xll, are inclusive of the formula~ Ill, and -IV compounds together wieh those in which there is ~he blocking group from the formula IX
starting material. The compounds with blocking groups are useful as intermediates in further transformations of the formula-X, -Xl, and -Xll products.
For the formula-ll enol ethers, the process employs dehydroiodination of formula-l iodo compounds. Accordingly, the process comprises the steps of starting with a compound of the formula H0 W-CH=CH-L-Rl ~ Xlll ~

Q

wherein ~ , L, Q, R1, R~, V, W, and X are as defined above, including -COOH for Rl, and (a) iodinating and cyclizing to form an iodo compound of the formula y-0-CH-~H-L-R~
, ~ I
~ ,~,W

~/C -R 4 o wherein ~,L, Q, Rl, R~, V, W, and X are as deflned above;
(b) subjecting the product of step "a" to dehydro-..

287 lA
~ ~n~

iodination with a tertiary amine or a reagent selected from the group consisting of sodium or potassium superoxide, sodi-um or potass;um carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium ace~ate, sodlum or potassium trifluoroacetate, sodium or potassium bicarbonate, silver acetate, and a tetraalkylammonium super-oxide of the formula (R12)4N02 wherein R-~2 is alkyl of one to 4 carbon atoms, inclusive to form the enol ethers; and (c) separating the products.
Reference to Chart A~ herein, will make clear the steps for preparing the formula-I, -III, and -IV products of this invention.
In Chart A, the terms are defined as follows:
~ .
~ J ~s oh OH O CH2 , , ~ , or ~ H20H
For those instances in which the formula-X, -XI, and -XII
compounds are desired, corresponding to the formula-I, III, and IV products, the C-ll hydroxyls o~ Xlll are suitably protected with blocking groups within t ~e scope of Rl3 as defined above and D then becomes ? as defined above, L is (1) -(CH2~d-C(Rz)2-^" ' ~L~16~36~ 2871A

CHART A
H

~,W -CH=CH-L -R
~ Xlll y-~ CH-~H-L-R~

ll l ( b\

OH o ~ ,W -C -CHz L -R 1 ( d ) ~ X -1i -R 4 Q ~,l`(c) $H 1 .
~V-O-C -CHz -L -R

: 30 Q

-2a-` ~ 6~ . 287iA

(2) -CH2-O-CH2-Y- or (3) -CH2CH=CH-wherein d is zero to 5; R2 is hydrogen~ methy), or fluoro~ being the same or different with ~he proviso that one R2 is not methyl when the other is fluoro;
and Y is a valence bond or -(CH2)k-wherein k ls one or 2;
a iS

O, H H , R8 OH, or R8 OH

wherein R8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive;
Rl is (1) -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 ~ to 10 carbon atoms, inclusive, (c) ara1kyl 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
(b) ~ -NH-C ~ NH l-CH3, -. .

~ 6 ~ ~ 2871A

`

{--3 (h) ~ NH-C-CH3, O

(;) ~ N~-c-NH2 ~ ~ CH=N-NH-C-NH2, or (k) (l) -CH-C-RIo R

wherein Rlo is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl;

wherein R1, is hydrogen or benzoyl;

. . .
(m) hydrogen; or (n) a pharmacologically acceptable cation; and wherein Rg is hydrogen or alky! of one to 4 carbon atoms, inclusiveJ being the same or different;
wherein R4 is (1) ~~~CyH2g-CH~.
3 R~

:

. ~30 ~ 287lA
Rs (2) -C-Z ~ (T)s or R~

(3) -CH2 ,,CH2CH3 H , C=C ~H

wherein CgH29 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 Rs and R~
` is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R5 nor R6 is fluoro whe-n Z is oxa (-0-); wherein Z represents an oxa atom (-o-) or CjH2j wherein CJH2j is.. .
a va1ence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR5R6- and the phenyt ring;
wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or -OR7- wherein R7 is hydrogen or alkyl 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-ferenti wherein V is a valence bond or -CH2-; wherein W is -(CH2)h-wherein h is one or 2; and wherein X is .

.

" ~16~628 . 2871A

.
(1) trans-CH=CH-(2) cis-CH=CH-(3) -C-C- or (4) -CH2CH2-.
Examples of alkyl of one to 12 carbon atoms~ inclusive, are methyl, ethyl/ propyl, butyl, pentyl, hexyl, hepty1, octyl, nonylJ decyl, undecyl, dodecyl~ and isomeric forms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms, : inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2J3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, Z-methylcyclobutyl, 3-propylcyclobuty1, 2,3J4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl J
3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-buty1cyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, 3 and cyclodecyl .

-Examples of ar~lkyl of 7 to 12 carbon atoms, lnclusive, are benzyl 9 phenethyl, l-phenyle~hyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and l-(2-naphthylmethyl).
Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl 9 m-tolyl, o-tolyl 9 p-ethylphenyl, p-tert-butylphenyl, 2,5-dlmethylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.
Referring to Chart A the starting materials of formula XIII
are known in the art or are readily available by processes known in the art. For example, as to PGF2a see U.S; Pat. No.
3~706,789 (SO Bergstrom et al, December 19, 1972); as to 15-methyl- and 15-ethyl-PGFz~, see U.S. Patent No. 3,728,382 .~he Upjohn Company`, April 17, 1973); as to 16,16-dimethyl~
PGF2a, see U.SO Patent No. 3r903,131 (The Up~ohn Company, September 2, 1975); as to 16,16-~ -33-.
' ~ ! ' $
.
difluoro-PGF~a co~n~oundg, 8ee The Upjohn Company's U.S. Patent Nos. 3,962,293 (June 8 9 1976) and 3,969,380 (July 13, 1976);
as to 16-phenoxy-17,18919,20-tetranor-PGF2a, see Netherlands Patent 7306462 (November 13, 1973, The Upjohn Company); as to 17-phenyl-18,19,20-trinor-PGF2a, see U.S. Patent No. 3,987,087 (October 19, 1976, The Upjohn Company); as to ll-deoxy-PGF2a9 see Netherlands Patent 7309856 (January 28, 1974, The Up~ohn Company); as to PGD29 see U.S. Patent No. 3,767,813 (October 239 1973, B. Samuelsson); as to 2a,2b-dihomo-PGF2a, see Derwent Farmdoc No. 61412S and U.S. Patent No. 3,852,316 (December 3, 1974, The Upjohn Company) and 3,974,195 (~ugust 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-PGF2a, see U.S. Patent No. 3,931,289 (January 6, 1976, The Upjohn Company); as to substituted phenacyl esters, 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-decar~oxy-2-hydroxymethyl compounds, see U.S. Patent No. 3,636,120 (January 18, 1972, The Upjohn Company); as to C-2 tetrazolyl derivatives, see Pfizer9 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 Offen. 2,460,285 (July 3, 1975, Ono Pharmaceutical Co.); as to 2,2-dimethyl-PGF2a analogs, see Belgian Patent 779898 (August 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 ll~-PGF~a compounds, see U.S. Patent No. 3,890,371 (June 17, 1975, The Up~ohn Company)9 as to ll-deoxy-PGFza, see Derwent Farmdoc No.
10795V; as to ll-deoxy~ hydroxy-methyl-PGF2a, see U.S. Patent No. 3,931,282 (January 69 1976, Syntex (U.S.A.) Inc.) and the ~ -34-

5~ 6~2~
aforementloned U.S. Patent No. 3,950,363; 8S to 16-methylene-PG~a, see Derwent Farmdoc No. 19594W and Ger. Offen. 2,440,919 (March 13, 19759 Ono Pharmaceutical Co.); as to 17,18-didehydro-PGF2~ compounds9 see U.S. Patent No. 3,9209726 ~November 18, 19759 The Upjohn Company3; as to 3-(or 4-) oxa-17,18-didehydro-PGF2~ compounds, see U.S. Patent 3,920,723 (November 18, 19759 The Upjohn Company); as to 15-oxo-PGF~a, see U.S. Patent NoO
3,728,382 (April 17, 1973, The Upjohn Company); as to 15-deoxy-PGF2a, see Canadian Patent 9619489 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, 1973); as to ~-homo-PGF2a 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, 1976 to The Upjohn Company.
As to 2-decarboxy-2-amino-PGF2a compounds, see U.S. Patent No. 4,085,1399 issued April 18, 1978 to the Upjohn Company.
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 alkali carbonate or bicarbonate, or an organic solvent system such as dichloro-methane containing iodine in the presence of an alkali metal carbonate. The reaction is carried out at temperatures below 25~C9 preferably about 0-5~C for 10-20 hr. Thereafter the - reaction is quenched with sodium sulfite and sodium carbonate and the formula-l compound separated from the reaction mixture.
In step "b" of Chart A the iodo compound 1 is converted to the 6-keto compound by contact~ng with silver carbonate and perchloric acid. The reaction is done in an inert or~anic medium such as tetrahydrofuran and iR followed with TLC to -determine completlon, normally ln-1S-24 hr. at about 25C.
The reaction is preferably done in absence of light.
In step "c" of Chart A the 6-keto compound IV ~ 3 equilibrated in solution to a mixture of the formula-lll and formula-lV compounds. This is accomplished merely by preparing a solution of the formula-lV compound in an : 30 j ..
~ 35a-. .
. ' .

.

2~

organic solvent, e.g. acetone or dichloromethane, and let-ting it stand for several days. The resulting mixture is concentrated and separated, for example by silica gel chromatography, to yield the formula-III hemi-ketal.
Step "d" of Chart A provides an alternate route to the formula-III hemi-ketal. The formula-I iodo compound is treated in alcoholic solution, e.g. methanol, with aqueous alkali metal hydroxide, e.g. potassium hydroxide, at a temperature in the range of 0 to 30 C. for several hours. After acidification there is obtained a mixture of the acid form of the formula-I compound and the formula-III
hemi-ketal together with some of the formula-IV compound, which are separated, for example, by silica gel chroma-tography or by fractional crystallizationO
The novel compounds of formulas I, III, and IV
wherein Rl is other than -COOH, e.g., the esters wherein R3 of -COOR3 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 sub-stituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are prepared from the corresponding acids of formulas I, III, and IV, i.e., wherein R1 is -COOH, by methods known in the art. For example, the alkyl, ; cycloalkyl, and aralkyl esters are prepared by interaction of sald acids with the appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane~
l-diazo-2-ethylhexane, diazocyclohexane, and phenyldiazo-methane, for example~ giyes the ethyl~ butyl, 2-ethylhexyl, cyclohexyl, and benzyl esters, respectively. Of these esters, the methyl or ether are mab/l~

~i . 287 lA

.. .. .
preferred~
Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. after the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferablv about one to about ten minutës, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example Organic Reactions, John Wiley & Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).
An alternative method for esterification of the car-boxyl moiety Or the novel compounds of formulas I, ilI, and IV comprises Lrans~ormations of the ~ree acid to the cor-responding silver sal,t, followed by interaction of that saltwith an alkyl iodide. Examples of suitable iodides are methyl9 iodide, ethyl iodide~ butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide~ benzy~
iodide, phenethyl iodide, and the like. The silver salts are prepared by conventional methods, for example, by dis-solving the acid in cold di!ute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding Lhe stoichiometric amount of silver nitrate.
The phenyl and substituted phenyl esters of the 3 Sormula I, III, and IV compounds are prepared by silylating ~62~ 2871A

the acid to protect the hydroxy groups, for example, re~
placing each -OH with -O-Si-(CH3)3. Doing that may also change -COOH to -COO-Si-(CH3)3. A brief treatment of the silylated compound with water will change -COO-Si-(CH3)3 back to -COOH. Procedures for th;s silylation are known in the art and are discussed hereinafter. Then, treatment of the silylated compound with oxalyl chloride gives the acid chloride which is reacted with phenol or the appropriate substituted phenol to give a silylated phenyl or substituted phenyl ester. Then the silyl groups, e.g., -O-Si-(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 preparing the formula-ll products of this in-vention.
In Chart B the terms D~ 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 starting materials XIII are subjected to iodination and cyclization to yie1d the formula-l iodo compounds.
In step "b" of Chart B the iodo compound I is con-verted to the formula-lI enol ether compound by contacting it with a dehydroiodination reagent. For such reagents see, for example, Fieser and Fieser, "Reagents for Organic Synthesis" p. 1308, John Wiley and Sons, Inc.~New York, N.Y. (1967). Preferred for the reaction of step "b" are tertiary amines and reagents selected from the group con-sisting of sodium or potassium superoxide, sodium or potas-3 sium carbonate, sodium or potassium hydroxide, sodium or potas-Cha rt B
~OH
~ ~ W-C~CH-L-R

5 . _~) -C-R7 Xl l l Q

. (a) ., V-O-ICH-CH-L-R
W

~) ~ .
- X - lC - R.. , I

Q
(b ) "' V- O- C= CH- L-R

X~ R.g, I I

; Q

-39 ~

sium benzoate, sodium or potassium acetate, sodium or potassium trifluoroacetate, sodium or potassium bicarbonate, silver acetate, and a tetraalkylammonium superoxide of the formula (R12~NOz wherein Rl2 is alkyl of one to 4 carbon atoms,inclusivel Of the tertiary amines, preferred amines are 1,5-diazabicyclo[4.~.0]nonene-5 ("DBN"), 1,4-diazabicyclo[2.2.2]octane ("DABCO"), and 1,5-diazabicyclo[5.4.0lundecene-5 ("DBU").
Other preferred reagents are sodium or potassium superoxide and tetramethylammonium superoxide. For Further informa-tion on the superoxides see Johnson and Nidy, J. Org. Chem.
40, 1680 (1975). For larger scale preparation the electro-chemical generation of superoxide is recommended. See Dietz et al., J. Chem. Soc. (B), 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 maintain basic conditions, e.g. with triethylamine, to avoid acidic decomposition or structural changes of the product. Purification is achieved by crystallization and consequent separation from impurities or starting mater-ial left in the mother liquor, or by column chromatography.
For chromatographic separation a column of magnesium sili-cate ("Florisil~") is preferred over silica gel. Decompos-, 30 ition of the product is avoided by pretreating the column with triethylamineO
Ester groups such as the p-phenylphenacyl group on the C-1 carboxyl or 4-bromobenzoate on C-ll and C-15 hydroxyls are unchanged by the transfor~ations of Chart B, and, if present on the formula-Xlll stcrting material, are also present on the formula-ll productO For the final products of formula 11 which are esters the preferred method of preparation is from formula-l iodo compounds which are corresponding esters.
Especially useful for administration because of their form as free-flowing powders and their ease of dissolving are sodium salts. They are obtained from the formula-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 H
. OH, for example 9-deoxy-6,9-epoxy-5-iodo-PGFla 1,15-lactone and 9-deoxy-6, 9-epoxy- ~ -PGFlc~, 1, 15-lactone .
For their preparation, analogous methods are used to those disclosed in U.S. Patent No. 4,067,991 issued January 10, 1978, , .2~ -to The Upjohn Company.
It should be understood that although the Charts hav~
formulas drown with a specific configuration for the reactants and products, the procedural steps are intended to apply not only to the other optically active isomers and cis/trans geometric isomers, but also to mixtures, including racemic mixtures or mixtures of enantiomeric forms.
If optically active products are desired, optically active starting materials or intermediates are employed or, if racemic starting materials or intermediates are used, the products are resolved by methods known in the art for prostaglandins.
The products formed from each step of the reaction are often mixtures and, as known to one skilled in the art, may be used as such for a succeeding step or, optionally, separated by conventional methods of fractionation, column chromatography, liquid-liquid extraction, and the like, before proceeding.
To obtain the optimum combination of biological response specificity, potency, and duration of activity, certain compounds within the scope of formulas l-lV are preferred. For example it is preferred that R be wherein it is especially preferred that R8 be hydrogen or methyl.
Another preference, for the compounds of formulas 1, 111, and lV as to Rl, ls that R3 in -COOR3 be either hydro ~ 42 ~

6 ~ ~ 2871~

gen or alkyl of one to 12 carbon atoms, inclusive~ It is further preferred that R3 be alkyl of one to 4 carbon atoms3 inclusive, especially methyl or ethyl, for optimum absorption on administration. For the compounds of formula-ll, it is preferred that R3 not be hydrogen but rather an alkyl ester or a salt of a pharmacologically acceptable cation.
For purposes of stability on long storage, it is also preferred that R3 be amido-substituted phenyl or subs~ituted phenacyl, as illustrated herein.
As to variations in D it is preferred that D be ~ ~ ' or ~
oh o As to variaeions in R4, it is preferred that Rg be n-pentyl 1,1-dimethylpentyl 1,1-difluoropentyl -CH2-O- ~ or -C2H4 ~

As to variations in L, it is preferred that L be -(CH2)3-, -(CH2)g~, or -(CH2)s~, especially -(CH233-.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is further illustrated by, but not limited to, the following examples.
All temperatures are in degrees centigrade.
Infrared absorption spectra are recorded on a Perkin-Elmer*model 421 infrared spectrophotometer. Except whe~
specified otherwise, undiluted (neat) samples are used.
The NMR spectra are recorded on a Varian*A~60, A-60D~
or T-~O spectrophotometer in deuterochloroform solutions with tetramethylsilane as an internal standar~
Mass spectra are recorded on a Varian*Model MAT CH7 Mass Spectrometer, a CEC Model 110B Double Focusing High Resolution 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.
"Skellysolve*B", herein, refers to mixed isomeric hexanes.
"DBN", herein, refers to 1,5-diazabicyclo[4.~.0~nonene-"DABCO", herein, refers to 11~4-diazabicyco~2.2.2]octane.
- "D~U", herein, refers to 1,5-diazabicyclo[5.4.0~un-decene-5.
"DIBALi', herein, refers to diisobutylaluminum hydride.
"~lorisi)*", herein, is a chromatograpllic magnesium silicate produced by the Floridin Co. See Fieser et al.
"Reagents for Organic Synthesis" p. 393 John Wiley and Sons, Inc., New York~ N'Y. (1967).
"TLC"~ herein, refers to thin layer chromatography.
Silica gel chromatography, as used herein, is under-stood 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.
"Concentrating", as used herein, refers to concentration * - Trademarks .~ . 2871A
, 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-OPOX
5 10,11-didehydro-PGF2~ and its 9~-epimer~
A mixture of PGA2~ methyl ester (1.74 9.) and 12 ml.
of tetrahydrofuran is treated at -78 C. with 24 ml. of 10~ DIBAL in to1uene. After one hour's stirring at -78 C, the mixture is quenched with 100 ml. of tetrahydrofuran-~; 10 saturated aqueous ammonium chloride (1:1) and warmed to about 25 C. The mixture is acidified with sodium bi-sulfate and extracted with ethyl acetate. The organic phase is washed with sodium bisulfate, sodium carbonate, and brine, dried over sodium sulfate, and concentrated to yield 1.8 9.
The crude product is subjected to column chromatography to separate the title compounds, in the order: -11-deoxy-10,11-didehydro-PGF2a, methyl ester~
: 11-deoxy-10,11-didehydro-9~-PGF2~, methyl ester, 11-deoxy-10,11-didehydro-PGF2a, and 11-deoxy-10,11-didehydro-9~-PGF2a.
Example 1 9-Deoxy-6,9-epoxy-5-iodo-PGF1a, Methyl Ester (Formula I: L is -(CH2)3-, R1 is -COOCH3, R4 is n-pentyl, V is a valence bond, W is -CH2-, X is trans-CH=CH-, ~ is ~"
-~
. ~H

2~

and Q is ~ ).
OH

Refer to Chart A, step "a". A suspension of the formula-Xlil PGF2~, methyl ester as its 11,15-bis(~etrahydropyranyl) ether (2.0 9.) in 23 ml. of water is treated with sodium bi-carbonate (0.7 9.) and cooled in 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 g.) and sodium carbonate (0.76 g.) in 10 ml. o~ water is added.
After a few minutes the mixture is extracted with chloroform.
The organic phase is washed with brine~ dried over sodium sulfate, and concentrated to yield mainly the bis(tetra-hydropyranyl) ether of the title compound; 2.2 9.J 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 (TL~ on silica gel in acetone-dichloromethane (30:70)). 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 forrnula-Xlll compounds or their C-ll ethers, there are obtained the corresponding formula-l iodo compounds:
15-Methyl-pGF2a 15-Ethyl-PGF2a 16,l6-Dlmethyl-pGF2a 16,l6-Difluoro-pGF2a 16-Phenoxy-17,18J19,20-tetranor-PGF2a .

; ' ' .

~ 6~

17-Phenyl-18,19,20^trinor-PGF2a 11-Deoxy-PGF2a 2a,2b-Dihomo-PGF
3-oxa-PGF2~
; 5 3-Oxa-17-phenyl 18,19,20-trinor-PGF2a.

, Example 2 6-Keto-PGF1a, Methyl Ester (Figure IV:
~ , L, Q, R1, R4, V, W, and X as de-fined in Example 1).
Refer to Chart AJ step "b". A solution of the formula-I iodo compound, methyl ester (Example 1, 0.45 9.) in 20 ml. of tetrahydrofuran is treated with silver carbonate (0.250 9.) and perchloric acid (90~, 0.10 ml.), and stirred at about 25 C. for 24 hr. The mixture is diluted with 25 ml.
f ethyl acetate and the organic phase~is washed with saturated sodium carbonate solution and brine, dried, and concentrated to an oil, 0.41 9. Separation by silica gel chromatography eluting with ethyl acetate-Skellysolve B
(3:1) yields the formula-IV title compound as a more polar material than the formula- I starting material. The pro-duct is an oil, 0.32 9.~ having R~ o.38 (TLC on silica gel in acetone-dichloromethane (1:1)); infrared spectral peak at 1740 cm 1 for carbonyl; NMR peaks at 5.5, 3~2-4.8J 3.7, 2.1-2.7 ~
xample 3 9-Deoxy-6,9-epoxy-6-hydroxy-PGFla, Methyl Ester (Formula III: ~ , L, Q, R1, R4, V, W, and X as defined in Example 1, and ~ indicates attachment in alpha or beta configuration).
Refer to Chart A, step "c". A so1ution of the formula-6~ 287l~

IV 6-keto compound (Example 2, 0.2 9.) in io ml. of ac~tbne is left standing at abou~ 25~ C. for 2 days. It is then concentrated and subjected to silica gel chromatography to yield the formuia-llltitle compound having Rf 0.50 (TLC on silica gel in acetone-dichloromethane (~
Examele 4 9-Deoxy-6,9-epoxy-5-iodo-PGFla (Formula 13 and 9-Deoxy-6,9-epoxy-6-hydroxy-PGFla (Formula lll): ~ , L, 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 (Exampl~ 1, 1.0 9.) in 30 ml. of methanol is treated with 20 ml. of 3N aqueouS potassium hydroxide at about 0 C. for about 5 min., then at about 25 C. for 2 hr. The mixture is acidified with 45 ml. of 2N potassium acid sulfate and 50 ml. of water to pH 1.0, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sul-fate and concentrated to an oil, 1.3 9. The oil i5 subjected to silica gel chromatography, eluting with acetone-dichloro-methane (30:70 to 50:50) to yield,first the formula l compound and later, the formula:lllcompound as a more polar fraction.
The formula- l cor;?ound is an oil, 0.33 g., having Rf 0.33 (TLC on silica gel in acetone-dichloromethane tl 1) plus 2~ acetic acid); infra red spectral peaks at 3360, 2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050, 1015, 970, and 730 ~m~l; and mass spectral peaks (JMS derivative) at 681, 625, 606, 569, 535, 479, and 173.
The formula-lllcompound is a solid 0.113 9., melting 3 93-98 C., recrystallized from acetone-Skellysolve 8 and ~ z ~ 2871A
' meltiny at 95-105.2 C~; containing no iodine; having R~
0.1~ (TLC on silica gel in acetone-dichloromethane ( 1~1 ) plus 2~ acetic acid) and having mass s~ectral peaks (TMS
derivative) at 587J 568~ 55~J 497, 435, 478, 407, 395, 388, and 17~.
The formula1llcompound, above, is methylated with - diazomethane to form the methyl estPr, having idential properties with the product of Example 3 herein.
Following the procedures of Examples 2 and 4, but replacing the formula- I iodo compound therein with those formula-l iodo compounds described subsequent to Example 1, there are obtained the corresponding formula-lV and -lii compounds. Further following the procedures of Example 3 but utilizlng ~he thus-obtained formula-lV compou nds there are also obtained the corresponding formula~llcompounds by that method.
Exam?!e 5 9-Deoxy-6~9-epoxy-~5-pGF~ Methyl Ester rFor~ula ll: L is -(CH2)3-, Q is ~"
H OH

R1 is -COOCH3, R4 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 g.) 0.25 ml. of 1,5-diazabicyclo-[4.3.0)nonene-5 (DBN), and 15 ml. of benzene is left standing at about 25 C. for 72 hr. and then warmed to 45 C. for 4 hr. The resulting mixture is then cooled, mixed with ice water and a small amount of diethyl ether, ~6~ 6 ~ ~
, and the layers separated. The organic phase is dried over magnesium sulfate and concentrated to the title compound~
an Oj1J 0.20 9. The product is crystallized from cold (-10 C.) hexane to yield 0.14 g., softening at about 25 C., having Rf 0.51 (TLC on silica gel in ethyl acetate);
NMR peaks at 5.5, 4.57, 3.8-4.3, 3.62, 3.53, and 0.9 ~;
infrared absorption at 1755 and 1720 cm ~; and mass spectral peaks (TMS derivative) at 495, 479, 4~9, 423.2724, 349, 199, and 173.
Following the procedure of the above Example but re-placing DBN with DBU, using 0.75 ml. DBU with 0.5 9. iodo compound, there is obtained 0.44 9. product.
Example 6 9-Deoxy-6,9-epoxy-~5-PGFla, Methyl Ester (FormlJla ll: L is -(CH2)3-, Q is ~ "
H OH, Rl is -COOCH3~ R4 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 is added and the heating continued for 6 h,. more. The mixture is left stirring at about 25 C.
for 60 hr., then heated again for 8 hr. at 40-50 C. The reaction mixture is cooled, washed with ice water mixed with a few drops of triethylamine, and dried over magnesium sul-fate, to yield the title compound, an oil, 0.9 9. The product is dissolved in 8 ml. of diethyl ether and crysta1-lized from cold (-10 C.) hexane containing a trace of tri--50~

;~1 6~ ~ 2 8 2871A

ethylamine~to yield crystals o~46 g,, mushy at 25 C. Addi-tional fractions of crystals, Q.33 g., are combined and sub-jected to chromatographic puri~ication on a Florisil column pretreated with triethylamine, using hexane-ethyl acetate-triethylamine (75:25:0.5), eluting with ethyl acetate (50-75~)-hexane containing 0.25% triethylamine to yield 0.21 g~ of the title compound which crystallizes on chilling.
Example 7 9-Deoxy-6~9-epoxy-~5-pGFla~ Methyl Ester (Formula ll).
Refer to Chart B. A mixture of the formula-l 9-deoxy-6,9-epoxy-5-iodo-P~Fla, methyl ester (Example 1, 0.213 9.) in 3 ml. of dimethylformamide is treated with a fresh solution of potassium superoxide (0.45 9.) in 10 ml. of dimethylformamide containing dicyclohexyl-18-crown-`~
6 (0.75 g.) in an ice bath. A-fter about 30 min. the ~ .._. ... _ reaction mixture is quenched in ice water, thereafter extracted with diethyl ether. The organic phase is dried over magnesium sulfate and concentrated to yield the title compound~ having the same Rf by TLC as the product of Example 5.
The above product is subjected to column chromatography on Florisil~ pretreated with triethylamine (5%)-dichloro-methane. The product is eluted with ethyl acetate-hexane-triethylamine (50:50:0.1) to give the title compound, o.o76 9., having Rf 0.45 (TLC on silica gel in acetate-dichlorornethane (3:7) 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 compound is likewise obtained:

~ 6 ~ 8 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 and silver acetate.
Example 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 mi,Yture of the formula-l iodo acid compound (Example 4, Formula 1, 0.20 9.) , p-phenylphenacyl bromide (0.50 g.)g 0.4 ml. of diisopropylethylamine, and 10 ml.
of acetonitrile is stirred at about 25 C. for 40 min. It is mixed with dilute aqueous citric acid and brine and extracted with ethyl acetate. The organic phase is dried and concentrated. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (25-100~-Skellysolve B to yield the title 5-iodo compound as a 3o colorless oil, 0.20 g.

.

B. The product of Part A above (0.20 9. ) is treated wl th 0. 4 ml O of DBN i n 15 ml of benzene at 42 C. for 22 hr.
The reaction mixture is cooled, washed with ice-water con-taining sodium chloride, dried over magnesium sulfate and 5 concentrated to the second title compound, an oil, 0.12 9.
The oil is crystallized From benzene-hexane. All fractions are combi n~ti and subjected to chromatographic separation on a Florisi l column pretreated wi th hexane-ethyl acetate-triethylamine (80:20:0.5), eluting with ethyl acetate to 10 yield the forrnula-l I compound, an oil. Crystallization from ether-hexane yields crystals, 0.016 9., m. 71-2 C.
(si nteri ng at 65-7 C.).
Examp ~e ~ 9 - Deox ,v -6, 9 -epoxy -5 - i odo - PGF la~ Methy l Es ter 11,15 -bi s ( 4-Bromobenzoate ) and 9-Deoxy-6,9-epoxy-~S-PGFla, Methyl Ester, 11, 15 -bi s ( 4-Bromobenzoate ) .
A A mi xture of the f ormu l a - I i odo compound ( Examp l e 1, 0.494 9. ) in 5 ml . pyridi ne cooled in an ice bath, is treated with 0.657 9. of 4-bromobenzoyl chloride 20 with stirring. The mixture is left stirring 16 hr., then poured into cold 10% sulfuric acid and extracted with ethyl acetate . The organi c phase i s washed wi th sodi um bi carbonate solution and brine, driecl, and concentrated. The residue is subjected to si lica gel chromatography to yield the5-iodo ti tle compoundJ 0.70 9., a colorless oi l, havi ng NMR peaks at 7.3-8.0, 5.65, 3.8-5.5, 3.65, and 0.9 ~.
B The product of Part A above (0 20 g.) is treated wi th 0. 4 ml . of DBN i n 15 ml . of benzene at 42 C. for 22 hr . The react i on mixture i s cooled, washed wi th i ce 30 water, dried, and conc~intrated to the second ti tle compound, 6 ~ 8 an oil, 0.18 9 The preparation is repeated with 0.50 9. of the iods compound, 1 ml. of DBN and 25 ml. of benzene.
The combined products are subjected to chromatographic 5 separation on a Florisi ~column pretreated with hexane-ethyl acetate-triethylamine (gO:lo:l), eluting with hexane-ethyl acetate triethylamine (90: 10 :0.25) to yield the second title compound, 0.37 g., a colorless oil, having NMR peaks at 7.2-7.8, 5.6, 4.9-5~4, 4.6, 4.0, 3.6, and 0.9 ~.
Example 10 9-Deoxy-6,9-epoxy-~5-PGFla~ Sodium Salt.
A mixture of 9-deoxy -6,9 -epoxy-~5 - PGFIa~ methyl ester (Example 5, 0.030 g. ) i n 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 ml. of water, frozen at about -75 C. and lyophilized overnight. The title compound is obtained as a white free-flowing powder.
The procedure above is repeated using larger quantities.
From 0.150 g. of the enol ether methyl ester there is ob-tained 0.155 g. of the title compound as a white free-flow-ing powder. A sample of the material dissolved in methanol-water shows practically no mobility by TLC on silica gel plates in acetone-dichloromethane (3:7), compared with the starting material which has Rf 0.45 (TLC on silica gel in acetone-dichloromethane (3:7) using plates pretreated i n triethylamine-(5%)-dichloromethane).
Following the procedures of Examples 1, 2, 3, 5, and 7, but employin~ corresponding starting materials as described above, there are prepared the formula ~ Ill, and -IV compounds, namely 3 9-deoxy-6,9-epoxy-5-iodo-PGFla-, -5l~-287lA -1-F
.6~6~ ~

9-deoxy-6,~9-epoxy-~5-PGFla-~
9-deoxy-6,9-epoxy-6-hydroxy-PGF~-, and 9-deoxy-6,9~epoxy-6-keto-PGFI type compounds, in methyl ester form wherein R~ is -COOCH3, having the following structural features:
16-Methyl-;
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-trinor-;
17_(p-fluorophenyl)-18J19,20-trinor-;
16-Methyl-17-phenyl-18,19,20-trinor-, 16,16-Dimethyl-17-phenyl-18J19J20-trinor-;
16-Fluoro-17-phenyl-18,19J20-trinor-;
16,16-Difluoro-17-phenyl 18,19,20-trinor-;
16-phenoxy-l7Jl8ilgJ2o-tetranor-;
16-(m-trifluoromethylphenoxy)-17J18J19J20-tetranor-;
16-(m-chlorophenoxy)-17J18J19,20-tetranor-;
16-(p-fluorophenoxy)-17J18J19,20-tetranor-;
16-Phenoxy-18,19J20-trinor-;
16-Methyl-16-phenoxy-l8JlgJ2o-trinor-;
13,14~Didehydro- 16-~r-t-hy~ 4-~idehydr 16~l6-Dimethyl-l3J 14-didehydro-;
16-Fluor,o-l~i,14-didehydro-16J16-Difluoro-13,14-didehydro-; -17-Phenyl-18,19,20-trinor-13,14-didehydro-;
17-(m-trifluoromethyiphenyl)-18,19,20~trinor-13,1~~
dldehydro-;

2871A~

17-(m-chlorophenyl)-18,19,20~trinor-13,14~di~ehydro~;
17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;
16-Methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16,16-Dimethyl-17 phenyl-18,19,20-trinor-13,1~-dide-hydro-;
16-Fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16,16-Oifluoro-17-phenyl-18,19,20-trinor-13~14-didehy-dro ;
16-Phenoxy-17J18,19,20-tetranor-13,14-didehydro-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-didehydro-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-1~,14-dide-hydro-;
16-Phenoxy-18,19J20-trinor-13,14-didehydro-;
16-Methyl-16-phenoxy-18,19,20-trinor-13,14-d;dehydro-;
13,14-Dihydro-; .
16-Methyl-13,14-dihydro-;
16,16-Dimethyl-13,14-dihydro-;
16-Fluoro-13,14-dihydro-;
16,16-Difluoro-13,14-dihydro-;
17-Phenyl-18,19,20-trinor-13,14-dihydro-;
17- (m~tr i ~luorcrnethyl phenyl )-18,19,20-trinor-13,14 dihydro-;
17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;
17 (p-fluorophenyl)-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-~luoro-17-phenyl-18,19J20-trinor-13,14-dihydro-;
16,16-Difluoro-17-phenyl-18,19J20-trinor-1~,14 ~ 2871A-1-t dlhydro-;
16-Phenoxy~17,18,,19J20-tetranor-13,,14-dihydro-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetr~nor~
1~,14-dihydro-; .
16-(m-chlorophenoxy)-17,18,19,20-tetranor-1~,14~
dihydro-;
16-(p-fluorophenoxy)-17,18,19,20-tetranor-1~,14 dihydro-;
16-phenoxy-18,19,20-trinor-1~,14-dihydro-;
16-Methyl-16-phenoxy-18,19,20-trinor-l~J14-dihydro-;
2,2-Difluoro-;
2,2 Difluoro-16-methyl-;
2,2-Difluoro-1~,16-dimethyl-;
2,2-Difluoro-16-fluoro-, 2,2-Difluoro-16,16-difluoro-;
2,2-Difluoro-17-phenyl-18~19,20-trinor-;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trlnor-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-;
2,2-Dirluoro-17-(p fluorophenyl)-18,19,20-trinor-;
2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-;
2,2-Difluoro-16,16-dimethyl-17-phenyl-18~19,20-trinor-;
2,2-Difluoro-16-fluoro-17-phenyl--8,19,20-trinor-;
2,2-Difluoro-16,16-~ifluoro-17-phenyl-18,19,20-trinor-;
2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-;
-2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,1~,20-~etranor-;
2,2-Difluoro 16-(m-chlorophenoxy)-17,18,19,20-.
tetranor~;
2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-.
' , - ` ' l.~L6i~il62:~3 2871A-l-F

tet ranor-;
2,2-Dt fluoro-16-phenoxy-18,19,20-trinor-; ;
2,2-D i f 1 uoro-16-methy 1 -16-phenoxy-18,19J20- tr i nor-;
2,2-D i f luoro-16-methyl -16 phenoxy-18,19,20-trinor-;
2,2-Di fluoro-16-methyl-13,14-didehydro~;
2,2-Difluoro-16,16-dimethyl-13,14-didehydro-;
2,2-Di fluoro-16-f luoro-1~,14-didehydro-;
2,2-Difluoro-16,16-difluoro-13,14-didehydro-;
2,2-Di fluoro-17-phenyl-18,19,20-trinor-13,14-dide-hyd ro-;
2,2-Di f luoro-17- (m-tri fluorornethylphenyl )-18,19,20-tr7nor-13,14-didehydro-;
2,2-Difluoro-17- (m-ch1orophenyl)-18,19,20-trinor-13,14-- didehydro-;
2,2-Di fluoro-17- (p-fluorophenyl )-18,19,20-trinor-13,14-didehydro-;
2,2-Di fluoro-16-methyl-17-phenyl-18,19,20-trinor-1~,14-didehydro-;
2,2-Di fluoro-16,16-dimethyl-17-phenyl -18,19,20-trinos-13,14- d i dehyd ro-;
2,2,16-Trifluoro-17-phenyl -18,19,?0-trinor-13,14-didehydro-;
2,2,16,16-Tetraf luoro-17-phenyl -18,19,20-tri nor-13,14-didehydro-;
- 25 2,2-Difluoro-16-phenr~ y-17,18,19,20-tetranor-1~,14-didehydro-;
2,2-Difluoro-16-(rn-trifluor~nethylphenoxy) 17,18,1~3,20-tet ranor-13,14-d i dehyd ro-;
2,2-D i f luoro-15- (rn-ch lorophenoxy)-17,18J19,20~etra-nor - 13,14- d i deh yd ro-;
-58 ~

, -2871A Yl -F
i2~
.

2~2 -a ifluoro-16-phenoxy-18,19,20-trinor 13,14-did~-hydro-;
2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro~;
2,2-Difluoro-13,14-d;hydro-.;
2,2-Difluoro-16-methyl-13,14-dihydro-;
2,2-Difluoro-16,16-dimethyl-13,14-dihydro-;
2,2,16-Trifluoro-13,14-dihydro-;
2,2,16,16-Tetrafluoro-13~14-dihydro-;
2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18~19,20-trinor-13,14-dihydro-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-1~,14-dihydro-;
2,2-Difluoro-17-(p-fluorophenyl)-18,19~20-trinor-13,14-dihydro-;
2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;
2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trlnor-13,14-dihydro-;
. 2,2,16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;
2,2~16,16-Tetraflu~~o-17-phenyl-18,19,20-trinor-13,14-dihydro-;
2,2-Difluoro-16-phenox.y-17,18,19,20-tetr~nor-13jl4-dihydro-;
2,2-Difluoro-16-~m-trif1uoromethylphenoxyj-17,18,19p20-tetranor-13914-dihydro-;
2~2-~ifluoro-16-(~-chlorophenoxy~-17,18,19920-,;

.

.

2~37 lA -1 - F

.

tetranor-13J14-dihydro-;
2,2-D.ifluoro-16-tp-fluorophenoxy)-17,18,19,20-tetranor~l~J14-dThydro-; -2,2-Dlfluoro-16-phenoxy-18,19,20-trinor-1~,14-dihydro~;
2,2~Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro ;
16-Methyl cis-13; r' 16,16-Dimethyl-cis-13~;
16-Fluoro-cis-13-;
16,16-Difluoro-cis-13-;
17-Phenyl-18,19,20-trinor-cis-13-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-;
: 17-(m-chlorophenyl)-18,19,20-trinor-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-18,19,20-trinor~cis-13-;
16-Fluoro-17-phenyl-18,19,20-trinor-ci$-13-;
16~16-Difluoro-17-phenyl-18,19,20-trinor-cis-13-;
16-Phenoxy-17,18,19,20-tetranor-cis-13-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis.-13-;
16-(m-chlorophenoxy)-17,18J19,20-tetranor-cis-13-;
16-(p-fluorophenoxy~-17,18,19,20-tetranor-cis-13-;
16-Phenoxy-18,19,20-trinor-cis-13-;
16-Methyl-16-phenoxy-18,19,20-trinor-cis-13-.
2,2-Difluoro-cis-13-;
2,2-Dtfluoro-16-methyl-cis-13-;
2,2-Difluoro-~6,16-dimethyl-cis-13-;

2,2-Difluoro-16-fluoro-cis-13-;

. -60-'' . ' .

~ 2871A-1-F

.

. _.. .
2,2-Difluoro-16916-difluoro-cis-13~;
2,2-Difluoro-1.7-phenyl-18,19,20-trinor~cis~1.3-;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-cis-13-;
2j2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-cis 13-;
2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-cis-13-;
10 2,2-Difluoro-16,16-dimethyl-1~-~hc-,y'-18,19,20-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-trlnor-cis-13-;
2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-;
2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-;
2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-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-methyl-16-phenoxy-18,19,20-trinor-cTs-13-;
- 2~2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-c1s-13-;
3-Oxa-;
3-Oxa-16-methyl-;
3 3-Oxa-16,16-dimethyl~;

-6i -6;~ 2871A -l -F

3-Oxa-16-fluoro~
3-Oxa-16,16-dif1uoro-;
~-oxa-l7-phenyl-l8~lg~2o-trlnor-;
3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trino~-;
3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-;
3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor~;
3-Oxa-16-methyl-17-phenyl-18J19,20-trinor-;
3-oxa-l6~l6-di~ethyl-l7-phenyl-l8~l9~2o-trinor-;
3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-;
3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-;
- 3-Oxa-16-phenoxy-17,18,19,20-tetranor-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetra-nor-;
` 3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-te~ranor-;
3-Oxa-16-(p-fluorophenoxy)-17,18,19J20-tetranor-;
3-Oxa-16- phenoxy-18,19,20-trinor~;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-;
~Oxa-13l14-didehydro-;
3-Oxa-16-methyl-1~,14-dtdehydro-;
3-Oxa-16,16-dimethyl-13,14-didehydro-;
3-Oxa-16-fluoro-13,14-didehydro-;
3-Oxa-16~i6-di f1uoro-1~14-didehydro-;
3-oxa-l7-phenyl-l8~l9~2o-trinor-l3~l4-didehydro-;
3-Oxa-17-(m-trifluoromethylphenyl)^18,19,20-trinor-13,14-didehydro-;
3-Oxa-17-(m-chloropheny1)-18,19,20-trinor-13,14-didehydro-;
3-Oxa-17~(p-f1uorophenyl)-18,19,20-trinor-13,14 dldehydro~;
:: 30 ~-Oxa-16-methyl-17^phenyl-18,19,20-trinor-13,14-,' .. .

287 lA -1 -F

dTdehydro~;
3-Oxa-16~16-dimethyl-17-phenyl-18,19,20-trinor~
13,14-d;dehydro~;
3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;
3-Oxa-16,16-difluoro-17 phenyl-18,1g,20-trinor-13,14-didehydro~;
3-Oxa-16-phenoxy-17,18,19,20-tetranor-13~14-didehydro-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tëtranor-13,14-didehydro-;
3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-;
3-oxa-l6-pheno~y-l~3~l9~2o-trinor-l3~l4-didehydro-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;
3-Oxa-13,14-dihydro-;
3-Oxa-16-methyl-13,14-dihydro-;
3-Oxa-16,16-dimethyl-13,14-dihydro-;
} Oxa-16-fluoro-13,14-dihydro-;
~Oxa-16,16-difluoro-13,14-dihydro-;
".' 3-Oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-;
3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;
3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro~
3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-~ dlhydro-;
~-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-dlhydro-;

1'16~62~3 2~71i4-1-F
.

3~0xa-16,16-Dimethyl-17-phenyl-lB~19,23-trinor-13,14-dThydro-;
3-Oxa-16-fluoro-17-phenyl-18,~,2~-~r;nor~ 14-dihydro-;
3-Oxa-16,16-difluoro-17-phe~yl~18,19, ~-trîno~-13,14-dihydro-;
3-Oxa-16-phenoxy-17,18,19,20-te~ranor-1~,14-dThydro-;
3-Oxa-16-(m-trifluoromethyl~h~noxy3-17,18,19920 tetranor-13,14-dihydro-;
3-oxa-l6-(m-chlorophen~xy~ Jlg~2~-tetranor- ~~~~~
13 J 14-dihydro-;
3-Oxa-16-(p-fluorophen~xy)-17,1B,19,20-te~ranor-13,14-dihydro-;
3-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihyd~o-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-tr;nor-13,14-dihydro-;
3-Oxa-cis-13-;
3-Oxa-16-methyl-cis~
3-Oxa-16,16-dimethyl-cis-13-;
3~0xa-16-fluoro-cis-13-; .
3-Oxa-16,16-difluoro-cis-13-;
3-Oxa-17-phenyl-18,19,~0-trinor-cis-13-;
3-Oxa-17-(m-trifluor~methylphenyl)-18,19,20-trinor-: 25 cis-13-;
~-Oxa-17-(m-chlorophenyl)-1~ 0-tr;nor-cis-13-;
3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-cis-13--;
3-Oxa-16-methyl-17-phenyl-~ g,2o-trinor-cis-l3-;
3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-1~-;

I

287 lA -1 -F

. . _ . ..
3-Oxa-16~fluoro-17-ph~nyl-18,19,20-trinor-cis-13-;
3-Oxa-16,16-difluoro-17-phenyl-18,19~20-trinor-cis-1 3~0xa-16-phenoxy-17,18,19,20-tetranor-cis-13-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19320-tetranor~c i s~l~o 9 3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-13-;
3-Oxa-(p-fluorophenoxy)-17,~8,19,20-tetranor~cis-1~ ;
3-Oxa-16-phenoxy-18,19,20-trinor-cis-13-;
3~0xa-16-methyl~16-phenoxy-18,19,20-trinor-cis-13-;
3-oxa-l3sl4-dihydro-trans-l4Jl5-didehydro-;
3~0xa-16-methyl-13,14-dihydro-trans-14,15-didehydro-;
3-Oxa-16,16-dimethyl-13,14-dihydro-trans 14,15 didehydro-;
3-Oxa-16-fluoro-13,14-dihydro-trans-14,15-didehydro-;
3-Oxa-16,16~difluoro-13,14-dihydro-trans-14,15-didehydro~
3-Oxa-I7-phenyl-18,19,20-trinor-13,14-dihydro~trans-14,15-didehydro-;
3-Oxa-17-(m-trifluorumethylphenyl)-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;
3-Oxa-17-(m-chlorophenyl)-18~19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;
3-Oxa-17-(p-fluorop!.enyl)-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;
3 -Oxa-16-methyl -17-phenyl -18,19J20-trinor-1~,14-dihydro-trans-14,15-didehydro-;
:~ 3-Oxa-16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-dlhydro-trans-14,15-didehydro-;
: 30 3-Oxa-16-fluoro-17-phenyl-18,19,29-trinor-13,14-, 287 lA

dihydro-trans-14,15-didehydro-;
, ~-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor~
13,14-dihydro-trans-14,~5-didehydro-;
3-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14 dihydro-trans-14~15-didehydro-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19~20-tetranor-13,14-dihydro-trans-14,15-dihydro-;
3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14 dihydro-trans~14,15-didehydro-;
3-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor~
_ . . . _ _ . . .
13~14-dihydro-trans-14,15-didehydro-;
3-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-~rans-14,15-d~idehydro-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-.
Likewise following the procedures of Examples 1, 2, 3, 5, and 7, but employing correspond;ng starting materials as described above, there are obtained the formula -I/ -II, -III, and -IV compounds, namely 9-deoxy-6,9-epoxy-5-iodo- PG Fl a~
: 9-deoxy-6,9-epoxy- ~5-PGF1a-, 9-deoxy-6,9-epoxy-6-hydroxy-PGF1a-, and 9-deoxy-6,9-epoxy-6-keto-PGFla-type compounds, in methyl ester form wherein R1 is -COOCH3, havin~ the following structural features:
: 2,3-Didehydro-;
2,2-Dimethyl-;
. 2a,2b-Dihomo-;

4-Oxa-4a-homo~;
7a-Homo~;

. 1~6~ 6Z~.~ 2871A-1-F

_ . _ . . ....... . _ . .. _ ... _ ll-Deoxy-10,11-didehydro-;

11-Keto-;
ll-Deoxy-;
ll-Deoxy-ll-methylene-;
11-Deoxy-ll-hydroxymethyl-;
15~-;
15-Keto-;
15-Deoxy-;
15-Methyl-15(S)-;
15-Methyl-15(R)-; and 17,18-Didehydro-. _ .
,-67-A~pendix 1. 2-Decarboxy-2-amino PGF Compounds Chart G, below, shows the steps for preparing start ing materials of formula Xlll for Chart A wherein Rl is -CH2N(R3)2o Accordingly in Chart G, the formula Cl PGF2~-or ll-deoxy PGF2~-type free acid is transformed to the various 2-decarboxy-2-aminomethyl or 2-decarboxy-2-(sub-stituted amino)methyl-PGFa- 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 to a formula 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~

Chart G

HO
, C ~2 - Z ~ Qtl ~ Cl RB Y 1 -11--Il~R7 .. . ~
n o HO
~, ,CH2 -Z 1 -C -0 -C -R I
~ Cll Ml L1 / O
H0~ ll ~"C H2 - Z ~ - C -IYH2 \~ C l l l F~B I I h I M, L
.
., HO ~
. ~ ~,CH2-Zl~CH2NH2 .. . ~ ' CIV
, Y 1 -C--C~R7 R~3 11 ,1 Ml L

\~ H CH2 -Z I -C -N=N=~i ~V

` Y 1 -C--C -R7 R~3 Ml L

.
Cha r t G ( cont i nued HO CH2 - Z ~ -NH -COOR 1 ~ ' CVI' \~ ~ -R7 R,~ Ma Ll .
.' ' ~
HO -- 10 ` CH?-Z~-NH2 . . ..
S l~ .cvll R Y 1 ICl 1l -R7 .. ~
'" .

~ ,CH2-Zl-NHL2 <~ , CVIII
Y ~ -C--C -R7 R8 1 1 ll .
Ll M~

~0 ~C~12 -Z 1 -NL2COOR
<~ CIX ' Y I fi--C -R7 ,, ' 1 ' , HO
, CH2-Zl-NL2L9 ~ CX
~ y~ 7 R~ Ml Ll ~70 -:, --trTethylam7ne) Reaction diluents include water in com^
bination ~ith water miscible organic solvents (e~g., tetra-. .
hydrofuran). This mixed anhydride is then transformed to either the formula Clll PG-type, amide or formula CV PG-type~
azide.
tor prepara~ion of the PGF2a-type, amide ~formula Clll~
the formula Cll mixed acid anhydride is reacted with liquid ammonia or ammonium hydroxide.
Alternatively, the formula Clll compound is prepared from the formula Cl free acid by methods known in the art for tr3nsformation 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 diazo~ethane)~ and a methyl ester thus prepared is transformed to the formula Clll amidé
employing the methods described for the transformation of the formula Cll mixed acld anhydride to the formu1a Clll amTde.
Thereafter the formula C1V 2-decarboxy-2-aminomethyl-PGF2a- or 11-deoxy-PGF2a-type compound is prepared from the formula Clll compound by carbonyl reduction. Methods known in the art art are employed in this transformation For example, lithium aluminum hydride is conveniently employed.
The ~ormula Cll compound is alternatively used to pre-pare the formula CV azide. This reaction is conveniently cat-ried out employing sodium azide by methods known in the art, See for example, Fieser and Fieser, Reagcnts for Organlc Synthesis vol, 1, pgs. 1041-1043, wherein reagents 3~ and reactlon conditlons for the azide ~ormation are dis-.

cussed.
Flnally, the formula CVI urethane is prepared from the formula CV a2ide reaction with an alkanol, aralkanol, pheno1, or substituted phenol. For example, when methanol is em-ployed the formula CVI compound is prepared wherein Rl ismethyl. This formula CVI PG-type product is then employed in the preparation of either the formula CVII or CVIII pro-duct.
In the preparation of the formula CVII primary amine from the formula CVI urethane, methods known in the art are employed. Thus, for example, treatment of the formula CVII urethane with strong base at temperatures above 50~ C.
are employed. For example, sodium potassium or lithium hydroxide is employed.
Alternatively, the formula CVI compound is employed in the preparation of the formula CVIII compound. Thus, when Ll is alkyl the formula CVIII compound is prepared by reduction of the formula CVI urethane wherein R1 is alkyl. For this purpose, lithium aluminum hydride is the conveniently employed reducing agent.
Thereafter, the formula C~lll product is used to prepare the corresponding CIX urethane by reaction of the formula CVIII secondary amine (wherein L2 is alkyl3 with an alkyl chloroformate. The reaction thus proceeds by methods known in the ar!~ for the preparation of carbamates from corresponding secondard amines. Finally, the formula CX
product wherein L2 and L3 are both alkyl is prepared by reduction of the formula CIX carbamide. Accordingly, methods hereinabove descrlbed for the preparation of the formula CYIII compound from the formula CVI compound are 6~
.
used. Thus~ Chart A provides a method whereby each of the various PGF2a- or 11-deoxy-PGF2~-type products vf this invention is prepared. Optional ly, the varlous reaction steps herein may be proceeded by the employment of block-S ing,groups according to R~oJ thus necessitating their sub-sequent hydrolys7s in preparing each of the various products above. Methods described hereinabove for the introducti~n and hydrolysis of blocking groups according to Rlo are em-ployed.
Finally, the processes described above for convertiny the formula Cll compound to the formula CV compound and the various compounds thereafter, result in shortening the 8a-side chain of the formula Cl compound by one carbon atom. Accordingly, the formula Cl starting material should 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,2b-dihomo starting material must be employed.

In Chart G, Yl is trans-CH=CH-j -C-C-, or -CH2CH2-;
wherein Ml is Rs OH
or wherein R5 is hydrogen or methyl;
. wherein L1 is R9 R4, - R9 R4, or a mixture of . R3 R4 and R3 R4~

25 wherein R3 and R4 are hydrogen, methyl, or fluoro, ~eing the same or different, with the proviso that one of R3 and R~ is fluoro only when the other is hydrogen or fluoro;
wherein ll Is (1) cis-CH=CH-CHz-(CH2)9-CH2-.
3 (2) cis-CH=CH-CH2-(CH2)9-CFz-, (3) cis-cH2-cH=cHv(c~2)9-cH2~, (4) -(CH2)3-(CH2)g CH2-, (5) -(CH~ )3- (CHz)9-CF2^, (6) -CH2-O~CH2-(CH2)9 CH2-~
~7) -C-C-CH~(cH2)9-cH2-9 (8) -CH2-C~C-(CH2)g CHz-, ~9) ~ CH2 (CH2) , or (lo) ~ o-(CH2)9-, w~erein g is one, 2, or 3;
where i n R7 i s ~1) -(CH2)m-CH9~

(2) -o ~ ( )5 ~3) -CH2 ~ (T~s ~ - -- _ ?5 ~herein m is one to 5, inclus ive, T is chloro, fluoro, tri fluoromethyl, alkyl of one to 3 carbon atoms, inclu-slve, or a1ko~y of one to 3 carbon atoms, inclusive, and s is zero, one, 29 or 3, the various ~'s betng the same 30 or dl fferentg with the provlso that not more than th~o T's are other than alkyl, with the further proviso that R7 is _~( T ) S

wherein T and s are as defeind above, only when R3 and R~
are hydrogen or methyl, being the same or different; and wherein Xl is -CH2NL2L3, wherein L2 and L3 are hydrogen, alkyl of one to 4 carbon- atoms, inclusive, or -COORl, wherein R
is as defi ned above -3n 6;~:~

Preparation 2: 2-Decarboxy-2-azidomethyl-PGF , or 2-nor-2~
PGF2a, azide (Formula CV: Zl is CH=CH-(CH2)3 or C~=CH-(CH2)2, respectively, 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 R7 is n-butyl)O

A. To a cold solution 10C.) of PGF2a ~7.1 g.), 125 ml. of acetone, 10 ml. of water, and 2.2 g. of triethyl-amine is added with stirring 3.01 g. of isobutylch~o~o~-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 0C. for one hr. at which 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 below 30C., to yield 2-nor-PGF2a, azide.

B. 2-Decarboxy-2-azidomethyl-PGF2a, is prepared by the ~ollowing reaction sequence:

cb/ - 77 -~ 0 6 ~

- (1) A solution of t-butyldimethylsilyl chloride ~10 9.~, imidazole ~9.14 9.), and PGF2a (3 9.) in 12 ml. ~f d;methyI-formamide are ~agnetically stirred under nitrogen atmo5phere for 24 hr~ The resulting ~ixture is then co~led in an ice bath and the reaction quenched by addition of ice water.
The resulting mixture is then diluted with 150 ml. of water and extracted with diethyl ether. The co~bined ethereal extracts are then washed with water, saturated-ammonium chloride, a sodium chloride solution~ and ther~-after dried over sodium sulfa~e. Solvent is removed under vacuum yielding PGF2,s, t-butyldimethylsilyl ester, 9,11,15-tris-(t-butyldimethylsilyl ether). NMR absorptions are observed at0.20, 0.~0, o.8~, o.87, o.8g, 1.07-2.50, 3 10-4.21, and 5.38 ~. Characteristic infrared absorptions are observed at 970, 1000, 1060, 1250, 1355, 1460, 1720, and 2950 cm. 1.
(2) To a magnetically stirred suspension of lithium 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 40 ml.
-of diethyl ether. After stirring at ambient ternper~ture for one hr., the resulting product ;s cooled in an lce water bath and saturated sodium sulfate is added drop~Jise until the appearance of a milky suspension. The resulting pro-duct is coagulated with sodium sulfate, triturated with diethyl ether~ and the solvent is removed by suction fil-tration. Concentration of the diethyl ether under vacuum yfelds 7 014 g. of 2-decarboxy-2-hydroxymethy~-pGF2a~
9,11,15-tris-(t-butyldimethylsilyl ether) N~R absorp-tfons are observed at 0.03, 0.82, o.87, 1.10-2 .60, 3.30^

.

62~3 .
4.30, and 5,37 ~, Characteristic infrared absorptions are observed at 775, B40J 970., 1065, 1250, 1460, 2895, 299~7 and 3350 ~mO 1, (3) p-Toluenesulfonyl chloride [3.514 9.), pyridine ~44 ml.)9 and the reaction product of subpart (2), 7.014 9., are placed in a freezer at -20 C. for 3 days. Thereafter,

7~200 9. of 2-dec~rboxy-2-p-toluenesulfonyloxymethyl-pGF
9,11,15-tris-(t-butyldimethylsilyl ether), is recovered.
NMR absorptions are observed at 0.10, 0.94, 0.97, 1.10, 2.50, 2.50J 4.03, 3.80-4.80, 5.45, 7.35, and 7.80 6. Infra-red absorptions are observed at 775, 970, 1180, 1190, 1250J
1~60~ 1470, 29001 and 299~ cm.~~.
(4) The reac:tion product oF subpart (~) (2.13 g.) is placed in 42 ml. of acetic acid, tetrahydrofuran, and water (3:1:1) containing 0.25 ml. of 10 percent aqueous hy-- drochloric acid. The reac~ion mixture becomes homogeneous after vigorous stlrring for 16 hr at room temperature. The resulting solution is then diluted with 500 ml. of ethyl acetate; washed with saturated sodium chloride and ethyl acetate; dried over sodium sulfate; and evaporated under reduced pressure, yielding 1.301 9. of an oil. Crude pro-duct is chro~atographed on 150 9. of silica gel packed with ethyl acetate. Eluting with ethyl acetate yields 0.953 g, of 2-decarboxy-2-p-toluenesulfonyloxym ethyl-PGF2~.
(5) The reaction product of subpart (4)J ~0.500 9.) ;n 5.0 mlO of dimethylformamide was added to a stirred sus-pension of sodium azide (1.5 9.) in 20 ml. of dimethylfor~
mamide. Stirring is contfnued at ambient temperature for 3 hr. The reaction mixture is then diluted with water ~0 (75 ml.), extracted with dlethyl ether (500 ml.), and the ,' the etheralextracts washedsuccessively w;thwater, sa~u-rated sodiu~,chloride, and dried cversodiu~ sulfate. Re~oval ofthe diethyl etherunder reduced pressure y;elds o.~64 9. of 2-decarboxy-2-azid~nethyl-PGF2Q. A characteristic azido infrared absorption is observed at 2~10 cm.~l.
,. .
` ! . " ~

Preparation 3: 2-Decarboxy-2-aminomethyl-PGF2~ ~Formula CXXV: Zl i5 CiS-C~=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 R7 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 20 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-c-/ - 81 -6~

fate, and evaporated under reduced pressure to yield 0,30~ 9.
of a slightly yellow oil. This oil (100 mg .) is then pur~
ified by preparative thin layer chromato3raphyJ yieldlng 42 9. of title product. NMR absorptions are observed at 0.90, 1.10-2.80, 3.28, ~.65-4.25, and 5.45 ~O Charaeter;s-klc tn~rared absorptions are observed at 970, 1060, 1460, 2995, and ~400 cm.~a, The m3ss spectru~ shows parent peak at 699.4786 and other peaks at 628, 684, 595, 217, and 27~.
i0 ~0 .

z~

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 require formation of the desired lactone. Selective methods for selective deri~atization of all but one hydroxy of a prostaglandin or prostaglandin analog which contains two or more hydroxys are known in the art. Suitable derivatives are the ~ cyclic phenyl- or butyl-boronates of 9a,11a-cb/ ~ 83 -`; ``

or 9~ dihydroxylated prostaglandins and prostaglandin I analogs, acylates such as acetate, silyl ethers such as ¦ trimethylsilyl-, t-butyldimethylsilyl-, and triphenylsilyl and the like. Such functional derivatives are known in the prostaglandin art and are used with stereoselectivity or where stereoselectivity is not achievable, with careful purification of the mixtures produced, -to obtain the desired functionally protected prostaglandins,and prostag-landin analogs as exemplified further in the examples~
Optionally if desired, one or more hydroxy groups are pro-tected by oxidation to a ketone before or after lactoni-zation. After lactonization, the ketone is reduced again to produce a free hydroxy group of the same configuration or of opposite configuration to that originally present.
However, it is not essential in all cases to protect hydroxy groups which may be present but are not desired to participate in the lactone formation. Lactone formation occurs at different relative rates with differ-ent. hydroxy groups depending on the stereochemlstry, steric bulk in the Yicinity of the hydroxy group, and ring size. Moreover it is possible to separate 1,9-, 1~11 , and 1,15-lactones as exemplified below for PGF

1,9-, 1,11-, and 1,15-lactones. Thus 15-methyl=15-hydroxy- and 16,16-dimethyl-15-hydroxy prostaglandin analogs are sterically hindered in the vicinity of C-15 and lactone function at 15 will not compete with lactone function with a 9- or ll-hydroxy group. As a corollary, in order to make a lactone with a hindered hydroxy group such as 15-methyl-15-hydroxy- or 16,16-dimethyl-15-hydroxy-~ it is essential that other hydroxy groups which may be present be protected. It is also necessary ,~ ~

mab/
,.

to extend the duration of the reaction until analysis of the reaction mixture indicates that some desired product is formed.
Prostaglandins known in the art as their lower alkyl (e.g. methyl, ethyl) ester but not as their free acid may be converted to the free acid for use in lactone function by chemical hydrolysis by known methods. If the involved prostaglandin is unstable toward chemical hydrolysis, as with PGE2 methyl ester, PGD2 methyl ester, and the like, it is preferred to obtain the free acid by enzymatic hydrolysis, for example by using the process of U.S. patent No. 3,761,356, issued September 25, 1973 to The Upjohn Company.
With these limitation~, and options for pro-tecting concommitant by present hydroxy groups, select-ively hydrolyzing the functionally protected hydroxy groups without hydrolyzing the desired lactone, separating undesired products from those desired, and modi~ying the lactones by subsequent chemistry obvious to those skilled in the art, such as oxidatlon, reduction, alkylation and the like, it is possible to prepare the l,9-, l,ll-, and 1,15-lactones of prostaglandins and of prostaglandin analogs of biological importance.
The preferred method for lactone function between the carboxyl group and the 9-, 11-, or 15-hydroxyl - group is the method described by Corey et al., J. Am. Chem.
Soc. 96, 5614 (1974), as further-described by Corey et al., J. Am. Chem. Soc. 97~ 653 (1975) and as exemplified further herein. Optionally other methods may be used, if desired, such as those of Masamure et al,~ J. Am. Chem. Soc. 97, 3515 (1975) and Gerloch et al., HelV Chem. Acta 57, ~661(1974).
.

~ - 85 -; mab/~
. . ..

Preparation 4: PGF2~, 1,15-lactone A solution of 5.5 g of PGF2a and 1.7g ~ 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 was removed by distillation at atmospheric pressure. Addi-tional methylene chloride was added to bring the volume ka~X
to the original 150 ml. This cycle-distillation of methylene chloride followed by replacement with fresh methylene chloride-was repeated three times, after which all the solvent was removed in vacuo to produce the 9,11-cyclic boronate of PGF2~ as a residue.

The residue was dissolved in 180 ml of anhydrous, oxygen-free xylene arld treated with 5.128 g of 2,2'-dipyridyl disulfide followed by 6.27 g of triphenylphosphlne. After 18 hours at 25 under a nitrogen atmosphere, thin layer chromatographic analysis of an aliquot ~solvent: lQ 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 atmosphere. After the addition was complete, 100 ml of xylene was distilled off and the cb/ - 86 -~6~6~8 solution was heated at reflux ~or 24 hours. rl~he reaction mixture was then cooled and the xylene was removed in vacuo (35 bath temperature) to give a residue. The residue was taken up in 500 ml oE tetrahydro-furan and treated with 10 ml of 30% hydrogen peroxide and 100 ml of saturated aqueous sodium bicarbonate. The three-phase mixture was stirred vigorously for 30 min. at 25, then concentrated in vacuo to give a residue. The residue was taken up in brine/ethyl acetate and extracted thoroughly with ethyl acetate. The combined organic layer was washed with three portions of lN aqueous potassium bisulfate, and once with water, aqueous sodium bicarbonate and brine. After drying over sodium sulfate, the solvent was removed to afford a viscous yellow oil which was chromatographed on 500 g of Mallinckrodt acid-washed CC-4 silica. The column was packed with 25% et'hyl acetate/hexane and eluted (100 ml fractions) with 50% ethyl acetate~hexane. Fractions 26-40, containing the product and no prostaglandin~related impurities, ,were ccmbined. ~he desired product was crystallized from 40'mI'of 1:1' ether~hexane~ thereby affording pure lactone, M.P. 110-111.
The lactone exhibited infrared absorption at 3500, 3370, 3290, 3000, 1700, 1320, 1310, 1290, 1260, 1105, 1080! 1055, 970, and 730 cm 1 and NMR peaks at 6.00-5.75 (vinyl; multiplet; 2H), 5.75-4.95 (vinyl and C-15H; multiplet; 3H), 4.30-3.85 (C OH; multiplet; 2H) and 2.65 p.p.m. (OH; broad singlet; shifted downfield on cooling; 2H). The mass spectr~m of the bistrimethylsilyl derivative exhibited fragments - at 480 ~M~), 465 (M-CH3)~ 436 (M~CO2), 409 (M-C5Hll), 39Q, 380, 364, 238, 217.

Anal- Calc d- for C20H324 C~ 71-39; H~ g-59-Found: C, 70.73; H, 9.31.
In like manner, but substituting ethyl acetate hexane for ether/hexane for recrystallization, PGF2~ 1,15-lactone was obtained: m.p. 110.0-111.7; [~]EtOH -71 ' mab/; ~

Preparation 5: 17-Phenyl-18,19,20-trinor-P~F2~,1,15-lactone A solution of l~-phenyl-18,19,20-trinor-PGF2a, t776 m~) and 1-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-half of the original volume. After 90 minutes, all of the methylene chloride was removed in vacuo to afford cyclic boronate of the starting ~rostaglandin.
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 25 the reaction mixture was diluted with 500 ml of anhydrous, oxygen-free xylene and was heated at reflux fo~ 18 hr. The ~ylene was removed in vacuo to give a residue. The residue was taken up in 50 ml of tetrahydrofuran containing 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 water. This mi~ture was stirred vigorously for 30 min.
then concentrated under reduced pressure to give a residue.
The residue was taken up in brine/ethyl acetate and extracted , tho~oughl~ with ethyl acetate. The combined extracts were washed with aqueous sodium bisulfate, water, aqueous sodium bicarbonate and brine, then dried over sodium sulfate a~d concentrated to afford a residue of crude 17-phenyl-18,19, 20-trinor PGF2~, 1,15-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 PGF2a, 1,15-lactone. The lactone crystallized upon trituration and after two recrystallizations from ethyl acetate/hexane exhibited m.pO 116-117.
- cl~/ - 8 R

The infrared spectrum exhibited peaks at 3460, 3400 shf 3020, 1705, 1650, 1~05, 1495, 1325, 1300, 1~65, 1150, 110~, 1040, 1020, 1000, 970 and 700 cm 1 and the mass spectrum showed ~ragmen~s at m/e 370 tM-18), 352, 334, 308, 298, 261, 243, 225. ~No M+ peak was apparent.) Anal. Calc'd. for C23H30O4: C, 74.56; H, 8.16.
Found : C, 74.27; H, 7.97 Preparation 6: 17-Phenyl-18,19,20-trinor-PGE2, 1,15-lactone 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 of nitrogen for 2 hr. The mixture was then diluted with 400 ml of anhydrous, oxygen-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-red spectrum exhibited peaks at 3440, 3000, 1725, 1605, 1500, 133~, 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, 296,277, 264, 259, 241 ~no M+ apparent).
Preparation 7: 16-Phenoxy-17,18,19,20-tetranor-PGF2a,1,15-lactone 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.
The crude product was purified by chromatography over neutral silica packed in 50% ethyl acetate/hexane and eluted w th 50% ethyl acetate/hexene followed by 70% ethyl acetat~

cb/ 89 -hexane. Those fractions containing homogeneous product as judged by TLC were combined to afford crystalline 16-pheno~y-17, 18,19,20-tetranor-PGF2a, 1,15-lactone. The lactone thus obtained was recrystallized from ethyl acetate/hexane to afford pure product, m.p. 185-186. The mass spectrum of the trimethylsilyl derivative exhibited a peak at M+ 516.2738 ~theory for C28~44Si2O5 516.2727) and fragments at m/e 501, 426, 423, 409, 400, 333, 307, 217 and 181.
Preparation 8: PGFla, 1,15-lactone and 15-epi-PGFla, 1,15-lactone Following the procedure of Example 1 but substituting PGFla for PGF2a there was obtained a crude product containing PGFl~, 1,15-lactone as a viscous yellow oil.
The crude product was purified by chromatography on 700 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-PGFla, 1,15-lactone ~15R)-PGF2a, 1,15-lactone]. The infrared 20 spectrum exhibited peaks at 3450, 1730, 1585, 1250, 1100, 970 and 735 cm 1 and the NMR spectrum showed peaks (~CMcl3) 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 whe~
sample is cooled; OH; 2H).
The major product, eluted later from the column ~fractions 21-28), were combined to afEord purified PGFla, 1,15-lactone.
The purified PGFla, 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 30 peaks at vmax 3520, 3480, 3380, 1710, 1300, 1290, 1265, 1250, 1235, 1160, 1110, 1075, 1055, 1000 and 965 cm 1 The NMR
spectrum showed peaks (~CMcl3) at 6.0-5.75 (vinyl; multiplet;

cb/ - 90 9.~ ,06~

2H; 5~60-5.00 (C-15H; multiplet; lH), 4.25-3.80 ~CHOH; multiplet;
2H) and 3.0~ ppm ~OH; singlet) Preparation 9: 13,14-Didehydro-8~,9~ ,12a PGF2a 1,15-lactone and 13,14-didehydro PGF2u 1,15-lactone Following the procedure of Example 1 but substituting 13, 14-didehydro-8~, 9~ , 12a PGF2~also known as ent-13-dehydro-15-epi-prostaglandin F2a lcompound 2 of J. Fried and C.
- H.Lin, J. Med. Chem. 16, 429 (1973)~ and 13,14-didehydro PGF2a for PGF2a, there are produced 13,14-didehydro-8~,9~ ,12a-PGF2a 1,15-lactone, and 13,14-didehydro-PGF2a 1,15-lactone, respectively.
Preparation 10: 13,14-didehydro-8~ ,12a-PGE2 1,15-lactone and 13,14-didehydro-PGE2 1,15~1actone Following the procedure of Example 2 but substituting 13,14-didehydro-8~ ,12a-PGE2 [also known as ent-13-dehydro-15 epi-PGE2 ~from 2a of J. Fried and C. H. Lin. J. Med. Chem.
16, 429 tl973)] 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.
- 20 Preparation 11: 13,14-dihydro PGF2a 1,15-lactone Following the procedure of Example 1 but substituting 13,14-dihydro PGF2a for PGF2a, there is produced 13,14-dihydro PGF2a 1,15-lactone Preparation 12: (15S)-15-methyl PGF2a 1,15-lactone Following the procedure of Example 1 but substituting ; ~15S) 15-methyl PGF2a for PGF2a and eY~tending the reaction time in refluxing xylene from 24 hours to 48 hours there i5 produced crude (15S)-15-methyl PGF2a, 1,15-lactone. The crude lactone is purified by repeated chromatography and, further, if desired, by TLC purification to afford in low yield ~lSS)-15-methyl-PGF2a, 1,15-lactone in essentially pure form.
Preparatlon 13 16,16-dimethyl PGF a 1,15-lactone Following the procedure of Example 15 but substituting 16,16-dimethyl PGF2~ for ~15S) 15-methyl PGF2~ there is produced 16,16-dimethyl PGF2a, 1,15-lactone.
Pre~aration 14:
Following the procedure of Example 8 but substituting 16~m-trifluoromethylphenoxy-17,18,19,20-tetranor PGF2, 16-m-chlorophenoxy-17,18,19,20-tetranor PGF2~, and 16-p-fluoro-phenoxy-17,18,19,20-tetranor PGF2a for 16-phenoxy 17,18,19,20 tetranor PGF2~ there are obtained the corresponding 1,15-lactones.
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 (16S) 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 PGE 1,15-lactone Following the procedure of Example 3 but substituting ~5S) 15-methyl PGF2a 1,15-lactone for PGF2~ 1,15-lactone, there is produced ~15S) 15-methyl P OE 2 1,15-lactone.
Preparation 18: ll-deoxy PGE2 1,15-lactone Following the procedure of Example 2 but 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~ 1,15-lactone.
Preparation 19: (15S) ll-deoxy-15-methyl PGE2 1,15-lactone and ll-deoxy-16,16-dimethyl PGE2, 1,15-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 extending the reflux period in xylene from 2 cbf - 92 -~606;2~

hours to 48 hours there are produced the corresponding 1,15-lactones~ The crude lactones are purified by repeated chroma-tography and further, if desired, by TLC purification to afford in low yield (lSS) ll-deoxy-15-methyl PGE2 1,15-lactone and 11-deoxy-16,16-dimethyl PGE2 1,15-lactone, respectivel~, in essentially pure form.
Preparation 20: ll-deoxy PGF ~ 1,15-lactone A solution of ll-deoxy PGE2 1,15-lactone ~0.5 g) in methanol t50 ml) is treated at 0 with sodium borohydride 19 ~500 mg) added in 50 mg portions every Z 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 11-deoxy PGF2~, 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 to the known 11-deoxy PGF2~ are combined to afford ll-deoxy PGF2a 1,15-lactone ; 20 in essentially pure form.
In like manner, substituting ~15S) ll-deoxy-15-methyl - PGF2~ 1,15-lactone, 11-deoxy-16,16-dimethyl PGE2 1,15-lactone PGE2, 1,15-lactone, ~15S) 15-methyl PGF2 1,15-lactone, 16,16-dimethyl PGE2 1,15-lactone and PGEl 1,15-lactone for ll-deo~y 25 PGE2 1,15-lactone there are produced the 1,15-lactones of (15S) ll-deoxy 15-methyl PGF2~, 11-deoxy-16,16-dimethyl PGF2~, PGF2a, ~15S) 15-methyl PGF2~, and PGFl~, respectively.

~b~ ~ ~3 -SUPPLEMENTARY DISCLOSURE
. _ _ When this application was filed, it was not known which isomer, SE form or SZ 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 cons dering Examples 5 to 7 and 10 of the principal disclosure, it should be~noted that the prefix "5Z-" properly belongs before each title heading, for example, Example 5, line 17 on page 49: 5Z-9-Deoxy-6,9-epoxy-~5 -PGFla Methyl Ester.

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 (I) a keto compound of the formula 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;
wherein R3 is alkyl of one to 12 carbon atoms, inclusive, cyclo-alkykl 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;
wherein X is (1) trans-CH=CH-(2) cis-CH=CH- or (3) -CH2CH2-;
and (II) a hemi-ketal of the formula wherein L, Q, R3, R4, and X are as defined above, and wherein ? indicates attachment in alpha or beta configuration;
which comprises the steps of starting with a compound of the formula wherein L, Q, R3, R4, and X are as defined above, and (a) iodinating and cyclizing to form a compound of the formula wherein L1, Q, R3, R4, and X are as defined above, (b) subjecting the product of step "a" to dehalo-genation and hydrolysis to form the keto and hemi-ketal compounds, and (c) separating the products.

2. Keto and hemi-ketal compounds of the formulae and 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 keto and hemi-ketal compounds of the formulae and which comprises the steps of (1) starting with a compound of the formula (2) iodinating and cyclizing to form a compound of the formula and (3) subjecting the product of step 2 to dehalogenation and hydrolysis to form the keto and hemi-ketal compounds, and (4) separating the products.

4, 6-Keto-PGF1.alpha., methyl ester and 9-deoxy-6,9-epoxy-6-hydroxy-PGF1.alpha., methyl ester, whenever prepared or produced by the process defined in claim 3 or by the obvious chemical equivalent.