GB2048254A

GB2048254A - 19,20-didehydro, 19-hydroxy and 19-oxo-prostaglandin derivatives

Info

Publication number: GB2048254A
Application number: GB8010083A
Authority: GB
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1979-04-02
Filing date: 1980-03-26
Publication date: 1980-12-10
Also published as: IT8021050A0; DE3012249A1; IT1141908B; FR2453152A1; GB2048254B; FR2453152B1

Abstract

Prostaglandins of formula <IMAGE> wherein R32 is -CH=CH2, -C.Me(OH)-CH3, -CH(OH)-CH3 or -CO-CH3..

Description

SPECIFICATION Prostaglandin derivatives This invention relates to prostaglandin derivatives and to processes for preparing them.

For background on prostaglandins, see for example Bergstrom et al., Pharmacol. Rev. 20, 1 (1968). For nomenclature of the prostaglandins, see N. A. Nelson, J. Medic. Chem. 17, (1974).

With respect to the stereochemistry of substituent groups at C-1 5 herein, see R. S. Cahn, J. Chem. Ed.

41,116(1964).

As drawn herein the formulas represent a particular optically active isomer having the same absolute configuration as PGE, 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 substituents in beta configuration, i.e. above the piane.

Included in the background of chemical literature and patents are the following: K. Green et al., J.

Lipid Res. 5, 11-7(1-969), PGE3 and PGF3cr, methyl esters; 8. Samuelsson, U.S. Patent No. 3,857,318, 19-hydroxy-PGE; P. L Taylor et al., Nature-250, (1974) and FEBS Letters 57,22(1975), 19-hydroxy PGE's and -PGF's; W. Marscheck et al., U.S. Patent No. 3,878,046, 11 -deoxy-1 9-hydroxy-PGE,; C. J. Sih et al., J. Am. Chem. Soc. 91,3685 (1969), 1 9-oxo-PGE2 arid -13,14-dihydro-PGE,: J. C, Sih, Prostaglandins 13,831 (1977), (19R)-19-hydroxy-PGE1, -PGE2, -PGF,af, and -PGF2c; Brit. Patent Spec.

No, 1,388,443, Derwent Farmdoc Abstract No. 00520U, reduction of 9,1 9-diketoprostanoic acids; A. F.

Marx et al., tJ.S. Patent No. 4,054,595, 18- and 1 9-hydroxy-prostaglandins; J. E. Pike, U.S. Patent No.

3,922,297, 19-methyl-prostaglandins : R. K. Beerthuis et al., Rec. Trav. Chim. Pays. Bas 90, 943 (1971), cis-A 18-PGE1; K. G. Untch et al., J. Am. Chem. Soc. 100, 6211(1978), dl-19-hydroxy-PGE, and dl-l 3- cis-l 5-epi-l 9-hydroxy-PGE,; German Offenleg. 2,505,519 (Derwent Farmdoc Abstract No. 56027W) or Chem. Abs. 84,43441w, w,20-hydroxy-PGE2 or-PGF2a.

Subsequent to this invention there appeared U.S. Patent No. 4. 127, 812 to H. C. Kluender et al. for 2-decarlooxy-2-hydroxymethyl-19-hydroxy-PGE1 and 19-hydroxy PGE, carbinol analogues.

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. More specifically, there are provided certain.prostaglandin derivatives having a 1 9,20-didehydro, a 19hydroxy, or a 1 9-keto feature.

Accordingly there are provided compounds of formula Ill, wherein the terms D, Q, R, and the like are defined in the TABLE OF DEFINITION OF TERMS FOR FORMULAS herein, together with other terms used hereinafter.

The products of this invention within the scope of formula III are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. A few of those biological responses are: inhibition of blood platelet aggregation, inhibition of gastric secretion and reduction of undesirable gastrointestinal effects from systemic administration of prostaglandin synthetase inhibitors, controlling spasm and facilitating breathing in asthmatic conditions, and decongesting nasal passages.

Because of these biological responses, these novel compounds-are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits and monkeys.

These compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative surgery, and to treat conditions such as arthrosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and long term prophylaxis following myocardial infarcts and strokes.For these purposes, these compounds are sdministered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range of about 0.01 to about 10 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The addition of these compounds to whole blood provides in vitro applications such as storage of whole blood to be used in heart-lung machines. Additonally whole blood containing these compounds can be circulated through limbs and organs, e.g. heart and kidneys, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body.

Blocking of aggregated platelets is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor person or animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 - 1.0 yg./ml. of whole blood. These compounds are also useful in preparing platelet-rich concentrates from blood for use in treating thrombocytopenia or in chemotherapy.

These compounds are also useful in mammals, including man and certain useful animals, e.g. dogs and pigs, to reduce and control excessive gastric secretion, thereby to reduce or avoid gastrointestinal ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract.

For this purpose, these compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range of about 0.01 to about 10 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

These compounds are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the formula Ill-VI compound and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge et al., U.S. Pat. No. 3,781.429, for a disclosure as to the administration of certain prostaglandins of the E and A series. The anti-inflammatory synthetase inhibitor, for example indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration.The formula lil compound is administered along with the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route. The dosage regimen for the formula ill compound in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, and the sensitivity of the particular formula lil compound to be administered. For example, not every human in need of an anti-inflammatory substance experiences the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree.But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of the formula III compound to reduce and then substantially to eliminate those undesirable effects.

These compounds are also useful in the treatment of asthma. For example they are useful as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitates breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder.Doses in the range of about 0.01 to 5 mg. per kg. of body weight are used 1 to to 4 times a day, the exact dose depending on the age, weight and condition of the patient and on the frequency and route of administration. For the above use the compound can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.3, xanthine derivatives (theophylline and aminophylline). and corticosteroids (ACTH and prednisolone).

These compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalation. For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the formula Ill ingredient in dilute solution, preferably at concentrations of about 1 part of medicament to from about 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid, and the like can be employed.

For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can also be used a dispensing agent such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technique are described fully in U.S. 2,868,691 for example.

These compounds are useful in mammals, including man, as nasal decongestants and are used for this purpose in a dose range of about 10 ,us to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for typical application.

These compounds are also useful in treating peripheral vascular disease in humans.

The term peripheral vascular disease as used herein means disease of any of the blood vessels outside of the heart and to disease of the lymph vessels, for example, frostbite, ischemic cerebrovascular disease, arteriovenous, fistula, ischemic leg ulcers, phlebitis, venous insufficiency, gangrene, hepatorenal syndrome, ductus arteriosus, non-obstructive mesenteric ischemia. arteritis lymphangitis and the like. The examples are included to be illustrated and should not be construed as limiting the term peripheral vascular disease. For these conditions the compounds are administered orally or parenterally via injection or infusion directly into a vein or artery.The dosages of such compounds are in the range of 0.01--1.0 j'g. administered by infusions at an hourly rate or by injection on a daily basis, i.e. 1 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. Treatment is continued for one to five days, although three days is ordinarily sufficient to assure long-lasting therapeutic action. In the event that systemit or side effects are observed the dosage is lowered below the threshold at which such systemic or side effects are observed. These compounds are accordingly useful for treating peripheral vascular diseases in the extremities of humans who have circulatory insufficiencies in said extremities, such treatment affording relief of rest pain and induction of heating of ulcers.For a complete discussion of the nature of and clinical manifestations of human peripheral vascular disease and the method previously known of its treatment with prostaglandins see South African Patent No.

74/0149 referenced as Derwent Farmdoc No. 58400V. See Elliot et al., Lancet, January 18, 1975, pp.140--142.

Surprisingly, the formula IV compounds have little or no efect on stimulation of smooth muscle.

The formula-lll 1 9,20-didehydro compounds, however, are extremely potent in causing stimulation of smooth muscle.

The formula-lll 1 9.20-didehydro compounds are not only active in causing stimulation of smooth muscle, but are also hig.hly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof.

Therefore, they are useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 Mg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous.

subcutaneous, or intramuscular injection or infusion during puerperium in the range of 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The formula-lll 1 9,20-didehydro compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50y per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.

The formula-lll 1 9,20-didehydro compounds are further useful for controlling the reproductive cycle in menstruating female mammals, including humans. By the term menstruating female mammals is meant animals which are mature enough to menstruate, but not so old that regular menstruation has ceased. For that purpose the compound is administered systematically at a dose level in the range of 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of mensus or just prior to mensus. Intravaginal and intrauterine routes are alternate methods of administration.

Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first or second trimester of the normai mammalian gestation period.

The formula-lll 1 9,20-didehydro compounds are further useful in causing cervical dilation in pregnant and non-pregnant female mammals for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases of infertility, cervial dilation produced by these compounds is useful in assisting sperm movement to the uterus. Cervical dilation by these compounds is also useful in operative gynecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause perforation 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 compound is administered locally or systemically.The compound, for example, is administered 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.

There are further provided the various processes for preparing the compounds of formula Ill. Thus, for the 1 9,20-didehydro compounds of formula Ill, a process illustrated by Chart I comprises the steps of starting with a lactone of formula VIII and (a) transforming that starting compound to a compound of formula IX, (b) optionally oxidizing the product of step (a) to form a compound of formula Xl and (c) transforming the compound IX or compound Xl to a compound of formula Ill.

For PGF-type formula-lll compounds wherein W is

and R1 is -COOR6, also represented by formula X in Chart 1, the blocking groups of IX are simply removed by hydrolysis and the carboxyl group is optionally esterified. For PGE-type formula-lll compounds wherein W is

and R, is -COOR6, represented by formula Xll in Chart 1, the same procedures are applied to Xi. For PGFss-type compounds wherein W is

and Ri is -COOR the formula-XI compounds are reduced to a mixture of PGFa and PGFB compounds, whereupon the PGF-type compounds are separated, hydrolyzed to remove blocking groups, and optionally esterified.For 9-deoxo-9-methylene-PGE compounds of formula Ill wherein W is

also represented by formula XIV in Chart 1, the 9-oxo group of formula-Xis transformed to a 9methylene moiety applying the sulfoximine procedure of C. A. Johnson et al., J. Am. Chem. Soc. 95, 6462 (1973), to yield XIII and XIV.

Transformation at C-1 and C-2 to alcohol, amine, amide, or tetrazolyl groups within the scope of R1 are made by methods known in the art or disclosed herein. Likewise, transformations at D, Q and X are made by methods known in the art or disclosed herein.

For the 1 9-hydroxy compounds of formula Ill, several processes are available. One process comprises the steps of starting with a lactone of formula XV and (a) transforming that starting material to a compound of formula XVI, (b) optionally oxidizing the product of step (a) to form a compound of formula XVII and (c) transforming compounds XVI or XVII to a compound of formula IV. When the lactone starting materials of formula XV are replaced with mixed C-19(R,S) epimers of formula XVa the corresponding mixed C-i 9 epimeric products of formula IVa are obtained.

Another process for the mixed C-19 epimeric products of formula IVa comprises the steps of starting with a 1 9,20-didehydro compound of formula XVIII (a) hydroxylating it to form a compound of formula a compound of formula XIX and (b) transforming the product of step (a) to a compound of formula XX.

For the 1 9-keto compounds of formula 1H, a process comprises the steps of starting with a 19hydroxy compound of formula XXI or a mixed C-i 9 epimeric hydroxy compound of formula XIX and (a) oxidizing either compound XXI or XIX to form a 1 9-keto compound of formula XXII and (b) transforming the product of step (a) to a compound of formula V.

For. the 1 9-hydroxy-1 9-methyl compounds of formula Ill, one process comprises the steps of starting with a lactone of formula XV or of formula XVa and (a) transforming that lactone to a compound of formula XXI II, (b) transforming the product of step (a) to a compound of formula XXIV and (c) transforming the product of step (b) to a 1 9-hydroxy-1 9-methyl compound of formula lil.

Still another process for the 1 9-hydroxy-1 9-methyl compounds comprises the steps of starting with a 19-keto compound of formula XXII and (a) transforming it to a compound of formula XXV and (b) transforming the product of step (a) to a 19-hydroxy-19-methyl compound of formula lil.

As with the formula-Ill 1 9-hydroxy-1 9-methyl compounds, the transformations of one compound to another with variations of D, Q, W, X, and, at C-l, of R1 or R19, are made for the formula-lV, -V, or -Vl compounds by methods known in the art or disclosed herein, using appropriate blocking grouos.

Charts 1-49, herein, illustrate the above processes and transformations. Those processes not illustrated are based on chemical procedures generally known to those skilled in the art. The steps of the charts will be discussed in detail below and further illustrated in the Examples.

To obtain the optimum combination of biological response specificity, potency, and duration of activity, certain compounds within the scope of formula Ill are preferred. For example it is preferred that Q be

wherein it is especially preferred that R5 be hydrogen or methyl. When C is

it is preferred that R5 be methyl.

Another preference for the compounds of formula lli, as to R1, is that R6 in -COOR6 be either hydrogen or alkyl of one to 12 carbon atoms, inclusive, or a salt of a pharmacologically acceptable cation. Further, when R6 is alkyl, it is more preferred that it be alkyl of one to 4 carbon atoms, and especially methyl or ethyl.

Still another preference for the 1 9-hydroxy and 1 9-hydrnxy-1 9-methyl compounds of formula III is that the 1 9-hydroxy configuration be "R".

19,20-Didehydro Prostaglandin Compounds This section will take up theprocedures for preparing the formula-lll 19,20 didehydro ("b 19") prostaglandin compounds and intermediates illustrated by charts 1-21.

Referring to Chart 1, starting materials of formula VIII are lactones readily prepared from known materials by processes shown in Charts 2-5, and these processes will be discussed at this point. In Chart 2 the formula-XXVI aldehyde is reacted with a Grignard reagent of the formula CH2=CH-(CH2)3- Mg-Hal and the resulting compound XXVII is blocked to form XXVIII. The starting aldehyde XXVI is known in the art (for example see Derwent Farmdoc Abstract No, 28225W, Japanese Patent No. 50-1 8460) or is available by the process in Chart 6, herein, and Preparation 1 (see also Derwent Farmdoc Abstract No. 56066Y, German Patent No. 2703471).

In Chart 6, tricyclic lactone aldehyde XXIX is available from U.S. Patent No. 3,816,462; either the exo or endo form will yield the formula-XXX1I compound. In step (a) compound XXX is formed by the Wittig reaction with the ylid derived from methyltriphenylphosphonium bromide. In step (b) compound XXXI is obtained by hydroxylation. The formula-XXXil diester is then made by stepwise reaction, first using an ortho ester to form a cyclic ortho ester which is then reacted with an hydros formic acid.

Compound XXXIII is obtained in step (d) by solvolysis to remove formyl groups and, for XXXIV, free hydroxyl gorups are blocked in step (e). Acyl groups of XXXIV are removed by basic solvolysis in step (f) and, finally the terminal hydroxyl groups of XXXV are oxidized to form XXXVI in step (g).

In Chart 2, and hereafter, blocking group R15, is as defined in the Table, but preferably is tetrahydropyranyl (THP). Formula-XXVI compounds wherein R1s is not THP are readily obtained from XXXVI of Chart 6 by replacing THP with hydrogen by mild acid hydrolysis and thereafter blocking with an appropriate form of R15 as follows.

When the blocking group R15 is tetrahydropyranyl (THP) or tetrahydrofuranyl, the appropriate reagent, e.g. 2,3-dihydropyran or 2,3-dihydrofuran, is used in an inert solvent such as dichloromethane in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride.

The reagent is used in slight excess, preferably 1.0 to 1.2 times theory, and the reaction is carried out at about 20--500C.

When R,6 is of the formula

as defined herein, including 1 -ethoxyethyl, the appropriate reagent is a vinyl ether, e.g. ethyl vinyí ëther isopropenyl methyl ether, isobutyl vinyl ether, or any vinyl ether of the formula R21-0-C(R22)=CR23R24 wherein R21, R22, R23, and R24 are as defined herein; or an unsaturated cyclic or heterocyclic compound, e.g., 1 -cyclohex-1 -yl methyl ether or 5,6-dihydro-4-methoxy-2H-pyran. See C. B. Reese et al., J.Am. Chem. Soc. 89,3366 (1967). The reaction conditions for such vinyl ethers and unsaturates are similar to those for dihydropyran above.

Again referring to Chart 2, if R5 in Q, is alkyl, e.g. methyl, compound XXVII is oxidized with Jones reagent to form the 3'-oxo compound which is then reacted with a Grignard reagent or other appropriate organometallic reagent to introduce the alkyl group. See for example U.S. Patent No.

3,728,382. The 3'R and 3'S isomers are separated, for example by silica gel chromatography.

Compound XXVIII is then obtained by blocking.

In Chart 3 an aldehyde of formula XXXVII is used. It is available, for example when R14 is acetyloxy, from E. J. Corey et al., J. Am. Chem. Soc. 91, 5675 (1969); when R14 is benzoyloxy, from U.S. Patent 3,778,450; when R14 is hydrogen, see E. J. Corey et al., Tetrahedron Lett. No. 49, 4753 (1971); when R14 is -CH20R18, i.e. blocked hydroxymethyl, by blocking the hydroxymethyl-substituted lactone, for which see Derwent Farmdoc Abstract No. 1 2714W. In step (a), aldehyde XXXVI I is reacted with a Witting reagent derived from a phosphonate of formula CLX

to form compound XXXVI II. For further details of the Wittig reaction see, for example, A.William Johnson, "Ylid Chemistry", Academic Press, N.Y., 1 966.

For intermediates of formula XXXIX in which Q is

the 3'-oxo group of XXXVIII is reduced in step b, for example with zinc borohydride and the isomers are separated, for example by silica gel chromatography. The 3,a isomers are generally preferred. For intermediates in which Q is

the compound XXXVIII is reacted with a Grignard reagent CH3MgHal or with trimethylaluminum and the isomers are separated by silica gel chromatography.

In step (c) the carboxyacyl blocking groups are removed by hydrolysis and hydroxyls are blocked with R15 blocking groups such as tetrahydropyranyl to form XL.

Compounds of formula XL are within the scope of formula'Vill of Chart 1 and are accordingly useful as starting material therein. The remaining steps of Chart 3 produce compounds XLIV which correspond to formula VIII wherein X is -CH2CH2-.

In step (d) intermediate XLI is formed by hydroboration, for example with 9 borabicyclo[3.3.1 nonane ("9-BBN"), for which see Fieser et al., "Reagents for Organic Synthesis", Vol.

2, p.31, 1969, Wiley and Sons, N.Y.

In step (e) compound XLI is reduced catalytically for example with hydrogen at atmospheric pressure over palladium on charcoal to yield XLII.

In step (f) the terminal hydroxy is mesylated or tosylated, for example, using methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a tertiary base such as triethylamine or pyridine to yield XLIII, and finally in step (g) the olefin is restored by methods known in the art. For example, the sulfonate is reacted with the sodium derivative of phenyl selenide and the resulting phenyl selenide is oxidized with excess hydrogen peroxide. See Fieser et al., ibid, Vol. 5, p. 273, 1975. Compounds XLIV are thus obtained. In Chart 4, the lactone XLV is obtained by photoisomerization whereby the latent C13-C14 double bond is isomerized from trans to cis. See for example U.S.Patent No. 4,026,909.Compound XXXVIII is irradiated, preferably of wave length about 3500 Angstroms, until an equilibrium mixture of cis and trans isomers is obtained. The progress is conveniently monitored by thin layer chromatography. The mixture is then separated by conventional methods, for example silica gel chromatography. Thereafter the 3'-oxo groups are replaced by Q in the manner described above, and the acyl groups of R4 are replaced, first with hydrogen, and then with blocking groups R15 to form the compounds of formula XLVI.

In Chart 5 the process is directed to lactones of formula LII wherein there is triple bond at latent C1-C14. The general procedure follows that of U.S. Patent No. 4,029,681. The formula-XL1X monohalo compound is obtained by halogenation of XXXVIII to yield XLVII followed by dehydrohalogenation and dehalogenation. The halogenation is conveniently done with a reagent such as N-bromosuccinimide or alternatively, a solution of bromine in carbon tetrachloride. Dedhydrohalogenation proceeds by addition of a base such as pyridine or methanolic sodium acetate. Dehalogenation is achieved with the usual reagents, for example zinc-acetic acid.

Optionally the formula-XLIX mono-halo - compound is prepared using lactone XXXVll of Chart 3 and a Witting reagent derived from a 1 -halophosphonate. Whereas bromo is shown in Chart 5, chloro derivatives are useful for this procedure.

The formula-L compounds are obtained by replacing the 3'-oxo group with Q, replacing acyl groups at R14 with hydrogen, and then blocking hydroxyl groups with Ruts. Thereafter formula-LI compounds are obtained by dehydrogenation, for example with a strong base such as potassium t-butoxide or sodium methoxide in dimethylsulfoxide or similar aprotic solvent. The formula-LI I lactone resuits from LI on standing with a trace of acid present.

Referring now again to Chart 1, for those compounds in which D is

the transformation of VIII to IX and X is shown specifically in Chart 7 in the sequence VIII - LIII - LIV - LV. In Chart 7 step (a) the formula-Vlli lactone is reduced to lactol Llil and thereafter that lactol is alkylated by the Wittig reaction using an ylid prepared from a phosphonium bromide of the formula

in step (b) of Chart 7 to yield LIV. Thereafter in step (c) the PGF2a-type products of formula LV are obtained by replacing blocking groups R15 at R13 and Q1 with hydrogen and optionally esterifying the acid.When R1 < , and R,1 are fluoro, for example, the products are 2,2-difluoro-1 9,20-didehydro-PGF2o'- type compounds.

In Chart 1, the PGF2a-type products with blocking groups represented by formula IX are optionally transformed to PGE2-type compounds XI using oxidizing agents and conditions which selectively oxidize secondary hydroxy groups to carbonyl groups in the presence of carbon-carbon double bonds. Oxidation reagents known in the art for this purpose include the Jones reagent, i.e. chromic acid, for which see J.

Chem. Soc. 39 (1946). Thereafter the formula-Xll 1 9,20-didehydro-PGE2-type compounds are obtained by deblocking the formula-Xl compounds.

The formula-XIl 1 9,20-didehydro-PGE2-type compounds are also useful for preparing PGF2ss-type compounds within the scope of formula Ill by the general method of carbonyl reduction as is known in the art. See for example U.S. Patent No. 3,796,743 or Bergstrom et al., Acta Chem. Scand. 16, 969 (1962). Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are lithium (tri-tert-butoxy) aluminum hydride, the metal borohydrides, e.g., sodium, potassium and zinc borohydrides and metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride.The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analogous pairs of known isomeric prostanoic acid derivatives. See for example, Bergstrin et al., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965), and Green et al., J. Lipid Research 5, 117 (1964). Especially preferred as separation methods are column or partition chromatography procedures, both normal and reversed phase, preparative thin layer chromatography and countercurrent distribution procedures.

Again following Chart 1, 9-deoxy-9-methylene-1 9,-20-didehydro-PGE2 compounds of formula XIV are obtained from the formula-Xl compounds using procedures known in the art. See for example U.S. Patent No. 3,950,363, applying the procedure of C. A. Johnson et al., J. Am. Chem. Soc. 95, 6462 (1973). Here the carbanion of a sulfoximine of the formula

generated, for example, with an alkyllithium or an alkylmagnesium halide, is reacted with the formula-Xl compound to form a sulfonimidoyl adduct of formula LVI.

Thereafter reductive elimination with, for example aluminum amalgam in the presence of acids such as acetic acid or hydrochloric acid yields the formula-XIV products, generally free of the blocking groups. If formula-Xlil compounds are present they are readily hydrolyzed in the known way to remove blocking groups R,5.

Other formula-lll 1 9,20-didehydro compounds within the scope of D are prepared by the processes of charts 8-1 5. When D is cis-CH2-CH=H7CH2-CH2-. reference is made to chart 8. See also U.S. Patent No. 3,933,889. Lactol Llil is transformed to enol ether LVII, for example by reaction with hydrocarbyloxymethylenetriphenylphosphorane of the formula (C6H5)3P=CH-0R17, although R,7 is preferably alkyl of one to 4 carbon atoms, inclusive. See, for example, S. G. Levine, J.

Am. Chem. Soc. 80, 6150 (1958). The reagent is conveniently prepared from a corresponding quaternary phosphonium halide and a base, e.g. butyllithium or phenyllithium at a low temperature, such as below -1 00C. Methoxymethylene-triphenylphosphonium chloride is particularly useful.

Various other hydrocarbyloxymethylenetriphenylphosphoranes are useful for preparing the formula-LVII intermediates, wherein R,7 is hydrocarbyl, including alkoxy (of 1 to 4 carbon atoms)-, aralkoxy-, cycloalkoxy-, and aryloxymethylenetriphenylphosphoranes. Examples of these hydrocarbyloxymethylenetriphenylphosphoranes are 2-methylbutoxy-, isopentyloxy-, heptyloxy-, octyloxy-, nonyloxy-, tridecyloxy-, octadecyloxy-, benzyloxy-, phenethyloxy-, p-methylphenethyloxy-, 1 -methyl-3-phenylpropoxy-, cyclohexyloxy-, phenoxy-, and p-methylphenoxymethylenetriphenylphosphorane. See for example Organic Reactions Vol. 14, pages 346-348, John Wiley and Sons, Inc., N.Y. (1965).

Consider next step (b) of Chart 8 wherein the formula-LVli enol ether intermediates are hydrolyzed to the formula-LVIII lactols. This hydrolysis is done under acidic conditions for example with perchloric acid or acetic acid in tetrahydrofuran. Reaction temperatures of 1 OOC. to 1 000C. may be employed.

Finally in step (c) of Chart 8, the formula-LIX compounds are obtained by the Wittig reaction using

in step (b) of Chart 7 to yield LIV. Thereafter in step (c) the PGF,ctitype products of formula LV are obtained by replacing blocking groups R15 at R,3 and Q1 with hydrogen and optionally esterifying the acid. When R10 and R11 are fluoro, for example, the products are 2,2-difluoro-1 9,2Odidehydrn-PGF2a'- type compounds.

In Chart 1, the PGF2a-type products with blocking groups represented by formula IX are optionally transformed to PGE2-type compounds Xl using oxidizing agents and conditions which selectively oxidize secondary hydroxy groups to carbonyl groups in the presence of carbon-carbon double bonds. Oxidation reagents known in the art for this purpose include the Jones reagent, i.e. chromic acid, for which see J.

Chem. Soc. 39 (1946). Thereafter the formula-XIl 1 9,20-didehydro-PGE2-type compounds are obtained by deblocking the formula-Xl compounds.

The formula-XI119,20-didehydro-PGE2-type compounds are also useful for preparing PGF2ss-type compounds within the scope of formula Ill by the general method of carbonyl reduction as is known in the art. See for example U.S. Patent No. 3,796,743 or Bergstrom et al., Acta Chem. Scand. 16, 969 (1962). Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are lithium (tri-tert-butoxy) aluminum hydride, the metal borohydrides, e.g., sodium, potassium and zinc borohydrides and metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride.The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analogous pairs of known isomeric prostanoic acid derivatives. See for example, Bergstrin et al., cited above, Granstrom et al., J. Biol. Chem. 240,457 (1965), and Green et al., J. Lipid Research 5, 117 (1964). Especially preferred as separation methods are column or partition chromatography procedures, both normal and reversed phase, preparative thin layer chromatography and countercurrent distribution procedures.

Again following Chart 1, 9-deoxy-9-methylene-1 9,-20-didehydro-PGE2 compounds of formula XIV are obtained from the formula-Xl compounds using procedures known in the art. See for example U.S. Patent No. 3,950,363, applying the procedure of C. A. Johnson et al., J. Am. Chem. Soc. 95, 6462 (1 973). Here the carbanion of a sulfoximine of the formula

Thereafter reductive elimination with, for example aluminum amalgam in the presence of acids such as acetic acid or hydrochloric acid yields the formuia-XIV products, generally free of the blocking groups. If formula-Xlll compounds are present they are readily hydrolyzed in the known way to remove blocking groups R1s Other formula-lll 1 9,20-didehydro compounds within the scope of D are prepared by the processes of charts 8-1 5. When D is cis-CH2-CH=CH-CH2-CH2-, reference is made to chart 8. See also U.S. Patent No. 3,933,889.Lactol dl is transformed to enol ether LVII, for example by reaction with hydrocarbyloxymethylenetriphenylphosphorane of the formula (C,H,),P=CH--OR,,, although R17 is preferably alkyl of one to 4 carbon atoms, inclusive. See, for example, S. G. Levine, J.

Am. Chem. Soc. 80, 6150 (1958). The reagent is conveniently prepared from a corresponding quaternary phosphonium halide and a base, e.g. butyllithium or phenyllithium at a low temperature, such as below O0C. Methoxymethylene-triphenylphosphonium chloride is particularly useful.

Various other hydrocarbyloxymethylenetriphenylphosphoranes are useful for preparing the formula-LVII intermediates, wherein R17 is hydrocarbyl, including alkoxy (of 1 to 4 carbon atoms)-, aralkoxy-, cycloalkoxy-, and aryloxymethylenetriphenylphosphoranes. Examples of these hydrocarbyloxymethylenetriphenylphosphoranes are 2-methylbutoxy-, isopentyloxy-, heptyloxy-, octyloxy-, nonyloxy-, tridecyloxy-, octadecyloxy-, benzyloxy-, phenethyloxy-, p-methylphenethyloxy-, 1 -methyl-3-phenylpropoxy-, cyclohexyloxy-, phenoxy-, and p-methylphenoxymethylenetriphenylphosphorane. See for example Organic Reactions Vol. 14, pages 346-348, John Wiley and Sons, Inc,, N.Y. (1965).

Consider next step (b) of Chart 8 wherein the formula-LVII enol ether intermediates are hydrolyzed to the formula-LVlil lactols. This hydrolysis is done under acidic conditions for example with perchloric acid or acetic acid in tetrahydrofuran. Reaction temperatures of 100C. to 1 O00C. may be employed.

Finally in step (c) of Chart 8, the formula-LIX compounds are obtained by the Wittig reaction using Chem. Soc. 39 (1946). Acetone is a suitable diluent for this purpose, and a slight excess beyond the amount necessary to oxidize the hydroxy groups of the reactant is used.

Referring again to Chart 9, step (a), compound LXI is obtained by conjugative addition with a lithium diaryl cuprate reactant prepared from

wherein Si(A)3 is as defined above. For the synthesis of a cuprate reagent see, for example, Posner, Org.

React. (1972) and Normant, Synthesis 63(1972). See also Posner for typical conditions for addition to an enone.

It is conveniently done in a solvent such as diethyl ether or tetrahydrofuran at about -780C. to OOC. A related addition has been reported by Stork et al., J. Am. Chern. Soc. 97, 4745 (1975).

In step (b) compound LXII is obtained by reduction of the ketone, using methods known in the art, for example with sodium borohydride at about 00 C. or lithium tri(sec-butyl)borohydride. The reduction yields both 90, and 9P hydroxy epimers which are separated, for example by silica gel chromatography.

In step (c) the formula-LX111 compounds are obtained from the formula-LXII compounds above by blocking free hydroxyls with Ris carboxyacyl groups. For example, R18 may represent an aromatic group such as benzoyl, substituted benzoyl, mono-esterified phthaloyl, naphthoyl and substituted naphthoyl, or an aliphatic group such as acetyl or pivaloyl. For introducing those blocking groups, methods known in the art are used.

Thus, an aromatic acid of the formula R,8OH, wherein 18 is an aromatic group within the scope of R18 as defined above, for example benzoic acid, is reacted with the formula-LXll compound in the presence of a dehydration agent, e.g. sulfuric acid, zinc chloride, or phosphoryl chloride; or an anhydride of the aromatic acid of the formula (R18)2O, for example benzoic anhydride, is used.

Preferably, however, an aromatic acyl halide, for example benzoyl chloride, is reacted with the formula-LXll compound in the presence of a tertiary amine such as pyridine, triethylamine, and the like.

The reaction is carried out under a variety of conditions using procedures generally known in the art.

Generally, mild conditions are employed, e.g. 20600 C., contacting the reactants in a liquid medium, e.g. excess pyridine or an inert solvent such as benzene, toluene or chloroform. The acylating agent is used either in stoichiometric amount or in excess. There may be employed, therefore, benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride, and the like, i.e. R18CI compounds corresponding to the above R18 groups. If the acyl chloride is not available, it is made from the corresponding acid and phosphorus pentachioride as is known in the art.

Aliphatic carboxyacylating agents useful for this transformation are known in the art or readily obtainable by methods known in the art, and include carboxyacyl halides, preferably chlorides, bromides or fluorides, and carboxyacid anhydrides. The preferred reagent is an acid anhydride. Examples of acid anhydrides useful for this purpose are acetic anhydride, propionic anhydride, butyric anhydride, pentanoic anhydride, nonanoic anhydride, tridecanoic anhydride, stearic anhydride, (mono, di, or tri)chloroacetic an hydride, 3-chlorovaleric anhydride, 3-(2-bromoethyl)-4,8-dimethylnonanoic an hydride, cyclopropaneacetic anhydride, 3-cycloheptanepropionic anhydride, 1 3-cyclopentanetridecanoic anhydride, phenylacetic anhydride, (2 or 3)-phenylpropionic anhydride, 1 3-phenyltridecanoic anhydride, and phenoxyacetic anhydride.

In step (d) the formula-LXIII compounds are deblocked at C-1 to yield the formula-LX1V alcohols, by selective hydrolysis without removing blocking groups R15 and R,8. For example, if -Si(A)3 is tertbutyldimethylsilyl, tetra-n-butylammonium floride is employed.

In step (e) the formula-LXV compounds are obtained by oxidizing the terminal C-i hydroxyl groups of LXIV to carboxyl groups using methods described herein or known in the art.

In step (f) the formula-LXVl compounds are obtained by selective hydrolysis of the blocking groups, using base hydrolysis to replace acyl blocking groups R13, For example aqueous potassium hydroxide is useful at about 25-1 000C.

Finally in step (g) the formula-LXVll PFG1-type products are obtained by removing the R15 blocking groups by mild acid hydrolysis.

The formula-LXVl compounds are useful for preparing PGE1-type type product followlng Chart 1.

19.20-didehydro compounds of formula 111 whereln D is trans-(CH203-CH=CH-are prepared by the process of Chart II. The starting materials of formula LXXlli are available, for example by esterifying the formula-LXVI compounds of Chart 9 and silylating at C-9. For background in preparing br prostaglandin analogs, see for example U.S. Patent No. 4,024,1 74.

In step (a), selenylation is achieved by first forming 2-lithium derivatives of the formula- LXXIII compounds for example by reaction with a lithium amide formed from a secondary amine such as Nisopropylcyclohexylamine. Thereafter the formula-LXXIV compounds are obtained by reaction with diphenyldiselenide or benzeneselenyl bromide using about 3 equivalents for each molecular equivalent of the C-2 lithium derivative at about -780C.

In step (b) the formula-LXXV A2 compounds are formed by oxidative elimination, for example with hydrogen peroxide or sodium periodate.

In steps (c) and (d) the blocking groups are removed stepwise. Intermediate LXXVI is useful for preparing A2-PGE, compounds.

Compounds of formula III wherein D l5-(CH2)1-O-(CH2)9-Includlng-(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-, and-CH2-O-(CH2)3- are prepared by the process of Chart 12. The starting materials of formula LX are available from the steps of Chart 10, above. In step (a) compound i XXVIII is is obtained by conjugative addition with a lithium diaryl cuprate reactant prepared from Br-(CH2)1-O-(CH2)o-CH2-O-Sl(A)3 following the general procedure for Chart 9 above. Likewise steps (b) through (g) follow the procedures for Chart 9 described above, but proceeding here through intermediates LXXIX, LXXX, LXXXI, LXXXII, and LXXXIII to 3-, 4-, or 5-oxa-PGFla: products represented by formula LXXXIV.

The 5-oxo-PGF1cr products are alternativeiy prepared by the steps of Chart 13 which yield LXXXVI I. Starting materials are lactols LII I, for which see Chart 7 above. Step (a) yields alcohol LXXXV on reduction with aqueous methanolic or ethanolic sodium borohydride. Alternatively the predecessor lactone VIII of Chart 7 is reduced in one step to LXXXV for example with lithium aluminum hydride or diisobutylaluminum hydride at 0-35 C In step (b) the Williamson synthesis yields the formula-LXXXVI intermediates by reaction with a halobutyrate of the formula Hal-(CH2)3-COOR5 or an orthoester of the formula Br-(CH2)3-C(OR9)3.

For background see U.S. Patent No. 3,931,279, column 35. Finally in step (c) product LXXXVII is obtained by removing blocking groups R15 by acid hydrolysis in the usual manner.

Inter-phenylene 1 9,20-didehydro compounds of formula Ill wherein D is

are prepared by the process of Chart 14. The starting materials of formula LX are available from the steps pf Chart 10, above. In step (a) compound LXXXVIII is obtained by conjugative addition with a lithium diaryl cup rate reactant prepared from a compound of the formula

following the general procedure for Chart 9 above. Thereafter steps (b) through (g) follow the procedures for Chart 9, described above, but proceeding through intermediates LXXXIX, XC, XCI, XCII, and XCIII to the inter-phenylene end products XC IV.

The formula-XCllI compounds are useful for preparing PGE1-type products following Chart 1.

Oxa-phenylene 1 9,20-didehydro compounds of formula Ill wherein D is

are prepared by the process of Chart 1 5. Here again the formula-LX starting materials are available from the steps of Chart 10 above. In step (a) compound XCV is obtained by conjugative addition with a lithium diaryl cuprate reactant prepared from a compound of the formula

following the general procedure for Chart 9 above. Steps (b), (c), and (d) follow the procedures for similar steps (b), (c), and (d) in Chart 9 described above, but proceeding through intermediates XCVI, XCVII, and XCVIII. In step (e) the Williamson synthesis yields the formula-XCIX intermediate by reaction with a haloacetate of the formula HaI-CH2-COOR9 or an orthoester of the formula Br-CH2-C(OR)3.

In step (f) compound C is obtained by selective. hydrolysis of the acyl blocking groups, using base hydrolysis and in step (g) the R15 blocking groups are removed by mild acid hydrolysis to yield CI.

The formula-C compounds are useful for preparing PGE,-type products following Chart 1.

Referring to formula Ill for the 19,20-didehydro compounds disclosed herein, the preparation of compounds within the scope of D, Q, R2, R3, R4, W, and X as defined herein has been discussed above and illustrated by Charts 1-15. Still other transformations may be accomplished by chemical processes which are known to those skilled in the art.

Charts 1-15 are generally shown to yield the acid form of the products. If a PGE-type product is obtained as an ester, the acid form is prepared by enzymatic hydrolysis using an esterase enzyme composition obtained from Plexaura homomalla (Esper) 1792, for which see U.S. Patent No.

3,840,434, October 8,1 974. If, as in Chart 11, a lower alkyl ester of a PGF,-type intermediate or product is obtained, that ester is readily converted to the acid form by saponification. The acid is then used to prepare various esters of formula Ill within the scope of R6 by methods known in the art. For example, the alkyl, cycloalkyl, and aralkyl esters are prepared by interaction of said acids with the appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane, 1 -diazo-2-ethylhexane, diazocyclohexane, and phenyldiazomethane, for example gives the ethyl, butyl, 2-ethylhexyl, cyclohexyl, and benzyl esters, respectively. Of these esters, the methyl or ethyl are 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, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art See, for example Organic Reactions, John Wiley 8 Sons, Inc., New York, N.Y. Vol. 8, pp.

389-394 (1954).

An alternative method for esterification of the carboxyl moiety of the acid compounds of formula III comprises transformations of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl iodide.

The phenyl and substituted phenyl esters of the formula Ill compounds are prepared by silylating the acid to protect the hydroxy groups, for example, replacing 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 COOS(CH?)3 back to -COOH. Procedures for this silylation are known in the art and are available. 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) are changed back to -OH by treatment with dilute acetic acid. Procedures for these transformations are known in the art.

A preferred method for substituted phenyl esters is that disclosed in U.S. Patent No. 3,890,372 in which a mixed anhydride is reacted with an appropriate phenol or naphthol. The anhydride is formed from the acid with isobutylchloroformate in the presence of a tertiary amine.

Phenacyl-type esters are prepared from the acid using a phenacyl bromide, for example pphenylphenacyl bromide, in the presence of a tertiary amine. See for example U.S. Patent No.

3,984,454, German Offenlag. 2,535,693, and Derwent Farmdoc No. 1 6828X.

Charts 1 6-20 relate to transformations at C-1 for these 19,20-didehydro compounds.

When a 2-decarboxy-2-hydroxymethyl product is desired, i.e., when R, is -CH2OH, the acid or lower alkyl ester form of Ill is reduced (see Chart 16 CII to CIII) using reagents known to reduce carboxylic acids to corresponding primary alcohols. See for example U.S. Patent No, 4,028,419, as to lithium aluminum hydride or diisobutylaluminum hydride. Useful solvents include diethyl ether, tetrahydrofuran or dimethoxyethane The reaction may be run at -780C to 100 C, although preferably at about 0 C . to 500C.Other carbonyl groups in the mclecule will also be reduced unless suitably protected as oximes, ketals, or similar carbonyl derivatives which are readily restored to carbonyls after the reduction has been accomplished.

A 2-decarboxy-2-hydroxymethyl-PGE type compound may also be prepared by blocking the C-1 alcohol groups as shown in Chart 1 6, formula CV. Thereafter the C-9 hydroxy is oxidized to form CVI and finally the -Si(A)3 blocking group is removed by hydrolysis. It is preferred that -Si(A)3 be tert butyl-dimethylsilyl.

Compounds in which R1 is

are conveniently prepared from the formula-lll products which are acids, i.e. R, is --COOH. For background see U.S. Patent No. 4,085,139. Pug type compounds or 9-methylene compounds are simply converted to a mixed anhydride using an alkyl, aralkyl, phenyl, or substituted phenyl chloroformate in the presence of a tertiary amine. A preferred reagent is isobutylchloroformate.The anhydride is then reacted with ammonia or the appropriate amine (R,) (R8)NH to form the amide wherein R, is

The 2-decarboxy-2-aminomethyl compound is prepared from the amide by carbonyl reduction using methods known in the art, for example lithium aluminum hydride reduction.PGE-type compounds are obtained by oxidation of the PGF-type compounds preferably when the terminal amine group is in the form of an amine salt.

In Chart 17 is shown an alternate procedure for the amine-terminated PGE-type compounds. The starting material of formula CVIII is obtained from a formula-Ill 1 9,20-didehydro PGE-type compound by ketalization with ethylene glycol.-For background see, for example, M. J. Cho et al., J. Medicinal Chem. 20, 1525 (1977). Anhydride CIX is formed in step (a), amide CX in step (b) and amine CXI in step (c). Finally in step (d) the ketal is hydrolyzed to the PGE-type product CXII by methods known in the art. See also U.S. Patent No.3,915,994.

Compounds in which R, is

i.e. the N-sulfonylamides, are prepared from the formula-lll compounds in their acid form. In Chart 1 8 are shown the steps by which those compounds, represented by formula CXIII, are transformed to the sulfonylamides of formula CXV. In step (a) the acid is converted to a mixed anhydride, here shown as CXIV, by reaction with isobutylchloroformate in the presence of a tertiary amine such as triethylamine.

Other mixed anhydrides are also useful. In step (b) the an hydride is then reacted with the sodium derivative of a sulfonylamide of the formula Na-NH-SO2R2 obtained for example by reaction of methanolic sodium methoxide with an equimolar amount of the sulfonylamide. The reaction of step (b) is promoted by the addition of a small amount of hexamethylphosphoramide to insure homogenity.

Compounds in which R1 is

are obtained by either the process of Chart 19 or Chart 20. In Chart 19 the starting lactone LIII is available above, for example see Chart 7. Applying the Wittig reaction and using the ylid prepared from a phosphonium compound of the formula

the formula-CXVI compound is obtained. See U.S. Patent No. 3,928,391. Replacement of blocking groups R15 then yields the products of formula CXVII. Optionally the CXVI compounds are transformed by methods disclosed herein or known in the art to other tetrazolyl compounds, e.g. PGE-type compounds, within the scope of formula III.

In Chart 20 the process goes stepwise from an amide to a nitrile to a tetrazolyl compound. The starting materials CXVIII are available herein, for example from an acid blocked preferentially with R15 at C-i 1 and C-iS 5 and converted to an amide by way of a mixed anhydride, then blocked with silyl groups at C-9.

In step (a) the formula-CXIX nitrile is prepared by dehydration of amide CXVIII with a carbodiirnide See C. Ressler et al., J.Org. Chem. 26, 3354 11961). For example, N.N'-dicyclohexylcarbodiimide (DCC) is useful in pyridine at about room temperature.

In step (b) the tetrazolyl group in CXX is formed from the above nitrile by reaction with sodium azide and ammonium chloride in a medium such as dimethylformamide. See "Heterocyclic Compounds", R. C. Elderfield, ed., John Wiley and Sons, Inc., N.Y., Vol. 8, pages 11-12.

In steps (c) and (d) the blocking groups -Si(A)3 and R15 are replaced by desilylation and mild acid hydrolysis in the usual manner to yield CXXI and then CXXII. Compound CXXI is useful as an intermediate for preparing other tetrazolyl compounds including PGE-type products within the scope of formula Ill.

In Chart 21 is shown a preferred route to the 1 5-alkyl compounds of formula LV. In step (a) intermediate CXXIV is formed by the Grignard reaction on CXXIII using R3MgHal or trialkylaluminum (see E. W. Yankee at al., J. Am. Chem. Soc. 96, 5865 (1974) and references cited therein). Starting material CXXIII is readily available, for example from XXXVI II of Chart 3 by steps disclosed herein or known in the art. Steps (b), (c), and (d) correspond to Chart 7, steps (a), (b), and (c) except that there need not be a blocking group at the 3' position. Products LV, mixed C-i 5 apimers, are separated into the 15S and 15R forms, for example by silica gel chromatography, preferably in the form of their methyl esters.The free acids are readily obtained by saponification of the methyl ester with mild alkaline conditions.

Included in the 19,20-didehydro compounds of formula Ill are the pharmacologically acceptable salts when R6 is a cation. Such pharmacologically acceptable salts useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, e.g. lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines.

Salts containing pharmacologically acceptable cations are prepared from the final formula-lll compounds in free acid form, i.e. wherein R1 is -COOH, by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salts to be prepared.In the case of the inorganic salts, it is usually suitable to dissolve the formula-lll acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired. Amine and quaternary ammonium salts are prepared by similar methods using appropriate solvents.

1 9-Hydroxy Prostaglandin Compounds This second section will disclose the procedures for preparing the formula-Ill 1 9-hydroxy prostaglandin compounds and intermediates illustrated by Charts 22-28.

Referring to Chart 22, there is shown a simple method of forming (19R, S)-1 9-hydroxy-PGF's, i.e., mixed 1 9R and 1 9S isomers. The 19,20-didehydro-PGF compounds of formula CXXVII are available by the methods described in the section above. The olefin is hydrated by oxymercuration-demercuration using mercuric acetate and sodium borohydride for which see Fieser et al., Reagents for Organic Syntheses, Vol. 11, 1969, p. 265. The oxymercuration is done conveniently at about 25 C., after which the mercury is removed by reduction with sodium borohydride, preferably at below 1 OOC. to minimize side reactions.

In Chart 23, (1 9R,S)-1 9-hydroxy prostaglandin compounds are also made by the processes disclosed, but here the approach is through a (1 9R,S)-1 9-hydroxy lactone of formula CXXIX. The formula-VIll 1 9,20-didehydro starting lactones are available by the methods described in the section above. Oxymercuration-demercuration in step (a) followed by blocking with Ris in step (b) then yields CXXIX, which is converted to CXXX and CXXXI by methods known in the art or described herein. The PGE-type compounds of formula-CXXXlll are obtained by oxidizing the formula-CXXX compounds at C-9 to form CXXXII, thereafter removing blocking groups.

Chart 24 illustrates the preparation of other (1 9R,S)-1 9-hydroxy compounds, including 2decarboxy-2-hydroxymethyl compounds of formulas CXLII, CXLIV, and CXLV. Chart 24 llustrates the reduction of carboxylic esters to the hydroxymethyl function and also the reduction of ethylenic unsaturation at C-S and C-1 3. The formula-CXXXIV 1 9,20-didehydro starting materials are available from methods described in the section above. See for example the corresponding acids LIV of Chart 7 which are readily esterified to these lower alkyl esters.

In step (a) the silylated compound CXXXV is formed by the usual silylation reactions, for which see the description for Chart 9 above. Of the various silyl groups, dimethyl-t-butylsilyl is preferred. In step (b) the terminal olefinic groups is hydrated by oxymercuration-demercuration to yield the mixed (1 9R)- and (1 9S)-1 9-hydroxy isomers. In step (c) catalytic hydrogenation over palladium yields a mixture of the PGF1 < x and 13,1 4-dihydro-PGF1a compounds, indicated in formula CXXXVII by a solid and a broken iine at C13-C14. In step (d), 1 9-hydroxyls are blocked, for example with THP. In step (e) the ester is reduced to carbinol CXXXIX using for example, lithium aluminum hydride. In step (f) the newly-formed hydroxyls are blocked, for example with THP.In step (g) the CXL compounds are desilylated to the CXLI compounds, f6r example with a tetra-n-alkylammonium fluoride as described above for Chart 9. In step (h) deblocking, as in dilute acid, yields the PGF-type compounds of formula CXLII which are separated by silica gel chromatography. In step (i) the blocked PGF-type compounds CXLI are oxidized by the usual methods to the CXLIII PGE-type compounds which are deblocked and separated in step (j) to yield CXLIV and CXLV.

If only the PGF-type compounds of formula CXLII are desired, the process is simplified according to Chart 25. In step (a) the 1 9,20-didehydro starting material CXLVI is hydrated by oxymercurationdemercuration to yield CXLVI I. Catalytic hydrogenation then yields CXLVIII, together with the 13,14dihydro compound. CXLVI II is separated and reduced to CXLIX with lithium aluminum hydride and finally in step (d) the blocking groups are replaced with hydrogen using mild acid hydrolysis.

1 9-Hydroxy compounds having specific configuration at C-i 9 are obtained in several ways. Chart 26, herein, illustrates the use of a Grignard reagent prepared from one of the isomers of CLI. For details on the resolution of the (+)-1 -penten-4-ol as its phthalate ester via the brucine salt see J. C. Sih, Prostaglandins, Vol.13, No. 5, pp.831-835 (1977). The starting material XXVI is available, for which see the discussion above for Chart 2. In step (a) the formula-CLII lactone is readily obtained using the Grignard reagent identified above.Other formula-CLIII lactones having the various forms of Q, are prepared by methods known in the art including blocking, or, when Q1 includes 3'-alkyl substitution, forming the 3'-oxo compound by oxidation thereafter applying the Grignard reaction as for Chart 2 above.

Chart 27 shows the steps for forming other lactones, which together with the formula-CLIII lactones of Chart 26 above are useful for preparing 1 9-hydroxy prostaglandins by the processes of Chart 28.

In Chart 27, the formula-XXXVII starting aldehydes are available, as shown above for Chart 3. In step (a) the Wittig reaction is employed using the ylid derived from a phosphonate of formula CLXI. In preparing 1 9-hydroxy end products having specific configuration at C-i 9 the appropriate optically active isomer of CLXI is used. Preferably that isomer is used which yields an end product having highest pharmacological activity as determined by standard biological tests.

Various methods are available for obtaining optically active isomers of CLXI. Preferably the phosphonate is prepared from dimethyl methylphosphonate and an optically active methyl ester of a corresponding 5-hydroxy-hexanoic acid, suitably blocked with R15. Such hexanoic acids are available in resolved state by application of the phthalate ester-brucine salt procedure of Sih cited above. Thus, for example the methyl ester of 5-hydroxy-hexanoic acid is esterified with phthalic acid and the half-ester thus formed is resolved via its brucine salt by fractional crystallization. Thereafter the acid is recovered and converted to the methyl ester and thence to the phosphonate. Other 2-substituted-5-hydroxyhexanoic acids are known or available to those skilled in the art. For example when R3 and R4 are methyl, the methyl ester of 2,2-dimethyl-5-oxo-hexanoic acid is reduced.When R3 and R4 are fluoro, the methyl ester of 5-hydroxy-2-oxo-hexanoic acid is fluorinated, for example with molybdenurn hexafluorideboron trifluoride. See U.S. Pat. No. 3,962,293. These acids are resolved in the same manner as described above and thereafter converted to phosphonates.

Still another method of obtaining the optically active 5-hydroxy-hexanoic acids is by starting with an optically-active co-halopentan-2-ol, for example Br-(CH2)-CH(OHl-CH3, blocking the hydroxyl for example with THP, then forming a Grignard reagent and reacting it with carbon dioxide following Organic Synthesis, Coll. Vol. 1,2nd end.. 1948. H. Gi!man. editor, John Wiley, N.Y.

Continuing with Chart 27, in steps (b). (c), and (d), the 3'-oxo group of CLIV is reduced, the R14 carboxyacyl blocking groups are replaced first with hydrogen and then with R15 blocking groups, and all other free hydroxyl groups such as at Q are also blocked to yield the formula-CLVI intermediate.

Conversion of the trans-CHCH- olefinic group to cis-CH=CH-, to acetylenic -CC-, or to ethylenic -CH2CH2- is accomplished by adaptation of the procedures discussed above for Charts 3, 4, and 5.

In Chart 28 the steps leading to products CLXIV. CLXVI, and CLXVIII are shown. The starting materials CLXII include CLII I of Chart 26 and CLVI, CLVII, CLVIII, and CLIX of Chart 27, and the general procedures described above for Chart 1 are used.

19-Keto Prostaglandin Compounds This third section will disclose the procedures for preparing the formula lit 1 9-keto prostaglandin compounds illustrated by Charts 29-33.

Referring to Chart 29, the formula-CXXXVI 1 9-hydroxy compounds of Chart 24 are oxidized to 19keto compounds. Suitable blocking at C-9, C-1 1, and C-1 5 hydroxyls protects those hydroxyls from oxidation when preparing 1 9-keto-PGF-type compounds of formula CLXX. In preparing 1 9-keto PGE-type compounds of formula CLXXIII, both C-9 and C-1 9 hydroxy groups are preferably oxidized in one step, using for example the Jones Reagent at about -350C.

Chart 30 shows a series of similar reactions for preparing the more general compounds of formula CLXXVII and CLXXX. The starting materials of formula IX are available from Chart 1 above. The formula CLXXV mixed (1 9R,S) or (+) 1 9-hydroxy compounds may be replaced with either the (1 9R) or (19S) compounds available, for example, from Chart 28 above.

Chart 31 shows a sequence of steps for preparing 2-.decarboxy-2-hydroxymethyl-1 9-keto-PGE1 compounds. The formula-CXLIX starting compounds are available from Chart 25 above. In step (a) the C-i hydroxy groups are preferentially blocked by silyl. In step (b) the C-9 and C-1 9 hydroxyls are oxidized, for example with Collins reagent. In step (c) the blocking groups are replaced with hydrogen in the usual way, and the resulting product CLXXXIII and hemiacetal CLXXXIV separated by silica gel chromatography for example. The hemiacetal is converted to the 1 9-keto compound by mild acid, as in acetic acid-water-tetrahydrofuran.

Chart 32 illustrates a process for broadly-defined 2-decarboxy-2-hydroxymethyl-l 9-keto-PGE compounds of formula CXCI. The starting materials CLXXXV are readily available, for example by esterification and silylation of CLXXV of Chart 30 above. Procedures for each step have already been described. Thus, for step (a) the reduction of the ester to carbinol CLXXXVI follows that for step (e) of Chart 24. Intermediate CLXXXVIII is also a convenient source of 1 9-hydroxy products CLXXXIX.

Chart 33 shows steps leading to 2-decarboxy-2-hydroxymethyl-1 9-keto-PGF compounds of formula CXCVI utilizing previously discussed procedures for each transformation. The starting materials CXC II are readily available, for example by esterification and blocking of IX of Chart 1.

1 9-Hydroxy- 9methyl Prostaglandin Compounds This fourth section will disclose the procedures for preparing formula-lll 1 9-hydroxy-1 9-methyl prostaglandin compounds illustrated by Charts 34-49.

Referring to Chart 34, there are shown the process steps from lactone CXXIX to end products CCI and CCIII.

Starting materials of formula CXXIX are available from Chart 23 above. In step (a) the hydroxyls are oxidized to keto groups, for example with Jones reagent. In step (b) the tertiary carbinol is formed, either with methylmagnesium halide or trimethylaluminum. Step (c) is the transformation to a lactol and step (d) is Wittig all < ylation using an ylid as described above for Charts 1 and 7. Removal of blocking groups yields PGF compounds CCI; oxidation of hydroxyls of CC at C-9 leads to PGE-type compounds CCII and CCIII.

Chart 35 illustrates the transformation of 1 9-keto compounds in general, suitably blocked, to 19hydroxy-1 9-methyl compounds. For the acids, trimethylaiuminum in benzene is the preferred reagent in step (a); for esters, the Grignard reagent is useful. The formula-CCV and -CCVII intermediates are useful for making the formula-CCVI, -CCVIII, and -CCX products, applying the general procedures discussed above for Chart 1.

Referring to generic formula III for the 1 9-hydroxy-1 9-methyl compounds, other compounds within the scope of D are available not only by the processes of Chart 35 but by the processes of Chart 36-45.

Chart 36 shows the reduction of the olefinic group in the "upper" (carboxy-terminated) side chain.

For this purpose hydrogenation in the presence of palladium catalyst is useful. Thereafter products CCXIII and CCXV are obtained.

When D is cis-CH2-CH=CH-CH2-CH2-, the steps of Chart 37 are useful. Lactol CXCIX is available from Chart 34 above. Thereafter steps (a), (b), and (c), following the procedures described above for Chart 8, yield product CCXVI II.

Compounds of formula VI (2 compounds) wherein D is trans-(CH2)3-CH=CH- are prepared by the process of Chart 38. Starting materials CCXIX are available from a formula-CClV compound (Chart 35) wherein D is trimethylene by reduction of the carboxyl group to hydroxymethyl, for example with lithium aluminum hydride. Aldehyde compound CCXX is obtained by oxidation of the -CH2OH of CCXIX to -CHO, using for example Collins reagent (pyridine --CrO,) at about 0-1 00C. In step (b) the Wittig reaction is used, with an ylid obtained from (CH3O)2P(O)CH2COOH.

See for example Derwent Farmdoc Abstract No. 5071 5v. Blocking groups,are removed in step (c) in the conventional way to form CCXXI I.

Chart 39 representsEan alternate process to 82 compounds, via selenylation-deselenylation, applying the procedures described for Chart 11 above. Starting material CCXXIII is available herein, for example from CCXll of Chart 36. It is immaterial whether C-i 9 hydroxyls are blocked or not. Blocking at C-9 may be either with Ra5 or silyl. Accordingly steps (a), (b), and (c) yield products CCXXVI.

The 3- and 4-oxa compounds are obtained by the processes of Charts 40 and 41. Those general procedures are known in the art, see for example U.S. Patent No. 3,944,593. Compounds CCXXXI and CCXXXVI II are formed thereby.

The 5-oxa compounds of formula CCXLI are prepared by the steps of Chart 42. The procedures have been described above for Chart 13.

Inter-phenylene compounds of formula CCL are obtained by the procedures of Chart 43 starting with the intermediates of formula CCXLIII. Those intermediates are shown as the products of Chart 44 starting with lactone CXCVIII of Chart 34 and applying the general procedures of Chart 10 above.

Oxa-phenylene analogs of formula CCLXV are produced by the steps of Chart 45, starting with intermediates CCXLI II and following the general procedures of Chart 1 5 above.

-Where the above processes yield an acid, the esters are prepared by any of the methods described for the 1 9,20-didehydro compounds above. Likewise esters are transformed to acids by processes known or described herein.

Charts 46 49 relate to transformations at C-i for these 1 9-hydroxy-1 9-methyi compounds.

Formula-CCLXXI 2-decarboxy-2-hydroxymethyl compounds of Chart 46 are obtained by the general procedures described for Chart 1 6 above.

Amides of formula CCLXXIV and 2-decarboxy-2-amino methyl compounds of formula CCLXXV in Chart 47 are prepared following the general procedures of Chart 17 above. N-Sulfonylamides in which R, is

are prepared as described for the 19,20-didehydro compounds above.

Tetrazolyl-terminated compounds of formula CCLXXVIII and CCLXXXII are obtained according to Charts 48 and 49 applying the procedures of Charts 19 and 20 above.

Compounds of formulas IV-Vl which are not specifically illustrated or exemplified herein are obtained by transformations using chemical processes disclosed herein or known to those skilled in the art.

For example the transformation of R5 in Q from hydrogen to methyl at C-i 5 requires the intermediate 1 5-oxo compound prepared by oxidation, followed by alkylation with Grignard RsMgHal or trimethylaluminum, and subsequent separation of the 1 15a and 1 5P products, for example by chromatography, preferably of the methyl esters. Preparation of esters and salts and various modifications at C-i, e.g., amides and sulfonamides follow the general procedures discussed for the formula-Ill 1 9,20-didehydro compounds.

It should be understood that many of the intermediates disclosed herein are useful not only for the purposes shown but also for many of the above transformations as known in the art.

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

that compounds are claimed not only in their purified form but also in mixtures, for example the formula IV 19-hydroxy compounds in their mixed (R,S) form.

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 when specified otherwise, undiluted (neat) samples are used.

The NMR spectra are recorded on a Varian Am60. A-60D, T-60 or XL-1 00 spectrophotometer in deuterochloroform solution with tetramethylsilane as an internal standard.

Mass spectra are recorded on a Varian Model MAT CH7 Mass Spectrometer, a CEC Modei 11 OB Double Focusing High Resolution Mass Spectrometer, or a LKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ev.) and samples are usually run as TMS (trimethylsilyl) derivatives.

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

"Celite" is a calcium aluminosilicate, useful as a filter aid.

"Collins reagent is chromium trioxide in pyridine. See Tetrahedron Lett. p.3363 (1968).

"DIBAL", herein, refers to diisobutylaluminum hydride.

"Florosil", herein, is a chromatographic magnesium si!icate produced by the Floridin Co. See Fieser et ai., "Reagents for Organic Synthesis" p. 393 John Wiley and Sons, Inc., New York, N.Y.

(1967).

"HPLC", herein, refers to high pressure liquid chromatography.

"Jones reagent" is chromic acid, see J Chem. Soc. p. 39 (1946).

"Rf" herein, refers to the measurement, in thin layer chromatography, of the movement of the sample spot relative to that of the solvent front, on silica gel plates unless specified, and in a solvent system that is identified.

"Skellysolve B", herein, refers to mixed isomeric hexanes.

"THP", herein, refers to tetrahydropyran-2-yl.

"TLC", herein, refers to thin layer chromatography.

"Concentrating", as used herein, refers to concentration under reduced pressure, preferably at less than 50 mm.and at temperatures below 350C.

"Drying", as used herein, refers to contacting a compound, in solution, with an anhydrous agent such as sodium sulfate or magnesium sulfate to remove water and filtering to remove solids.

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

The A-lX solvent system used in thin layer chromatography is made up from ethyl acetate-acetic acid-2,2,4-trimethylpentane-water (90:20:50:100) according to M. Hamberg and B. Samuelsson, J.

Biol. Chem. 241,247(1966).

Preparation I 5α-Hydroxy-3α-tetrahydropyran-2-yloxy-2ss-(trans-2-formylethenyl)- tr- cyclopentaneacetic Acid, y-Lactone (Formuia XXXVI) Refer to Chart 6. The title compound is obtained in seven steps starting with the formula-XXIX tricyclic lactone aldehyde, for which see U.S. Patent No.3,81 6,462.

a. Exo-3-hydroxy-endo-6-vinyl-blcyclo]3.1.0]-hexan-exo-2-aoetlo acid, y-lactone (Formula XXX).

A solution of the formula-XXIX tricyclic lactone aldehyde (20 g.) in 1 50 ml. of benzene is treated at 5-1 00C. with a solution of the ylid prepared from methyltriphenylphosphonium bromide (54 g.) and 95 ml. of 1.6 M butyllithiurn in one liter of benzene (previously heated at reflux for one hr. and cooled).

The addition is completed within 1-1.5 hr., and, after an additional 0.5 hr. stirring, the mixture is filtered and concentrated. The residue is taken up in 100-200 ml. of ethyl acetate-Skellysolve B (40:60) and left standing to crystallize out the by-product triphenyiphosphone oxide. After filtration, the filtrate is subjected to silica gel chromatography, eluting with ethyl acetate-Skellysolve B (40:60). There is obtalned the formul-XXX compound, 16,2 g., an oil, having NMR peaks at 1.3-3.0, 4.6-4.9, and 5.0-5.4 S; and Rf 0.74 (in ethyl acetate-Skellysolve B (50-50)).

b. Endo-6-(1,2-dihydroxyethyl)-exo-3-hydroxy-bi-cyclo[3.1.0]-hexen-exo-2-acetlo acid, 3-lactone (Formula XXXI). A solution of the formula-XXX alkene (step a, 8.0 g.) in 80 ml. of acetone is treated with a solution of N-methylmorpholine oxide dihydrate (9.0 g.) in 12 ml. of water, followed by a solution of osmium tetroxide (130 mg.) in 6.5 ml. of t-butanol. When the reaction is completed, the acetone is removed under reduced pressure. The residue is diluted with 100 ml. of water, saturated with ammonium sulfate, and extracted with tetrahydrofuran. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to yield 12 g. of crude oily product.The oil is subjected to silica gel chromatography to yield the formula-XXXI compound, 8.5 g., an oil, having NMR peaks at 0.7-1,2 1.3-1.9,2.4-3,4 3,4-3,7, 3,7-4,2, and 4,7-5,0 # : R, 0.68 (in methanol dichloromethane (1 5:85)).

c. 3α-Formylkoxy-5α-hydroxy-2ss-(3-proplonyloxys-trans-1-propenyl)-1α-cyclopentanescetio acld, y-lactone (Formula XXXI I). A solution of the formula-XXXl glycol (step b, 7.2 g.) and triethyl orthopropionate (1 5 g.) in 30 ml. of tetrahydrofuran is treated with 3 Ml of trifluoroacetic acid. After one hr. the solvent is removed under reduced pressure and the residue treated with 100 ml. of anhydrous formic acid with stirring. After 15 min. there is added 100 ml. of 1 N. sodium hydroxide and 100 ml. of crushed ice. The mixture is extracted with dichloromethane and the organic phase is washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated.The oil (9.6 g.) thus obtained is subjected to silica gel chromatography, eluting with ethyl acetate-cyclohexane (1:1), to yield the formula-XXXlI compound, 4.1 g., having NMR peaks at 1,1, 1,9-3,0, 4,4-4,6 4,8-5,2, 5.6-5.8, and 8.0 and RfO.49 (in ethyl acetate-cyclohexane (1:1)).

d, 3α, 5α-Dlhydroxy-2ss-(3-proplonyloxy-trans-1-propenyl)-1 o'-cyclopentaneacetic acid, y-lactone (Formula XXXIII). A solution of the formula-XXXII formate (step c, 4.1 g.) in 35 ml. of dry methanol is treated with sodium bicarbonate (0.5 g.). When the reaction is finished in about 2-3 hr., the solvent is removed under reduced pressure. The residue is partitioned between water and dichloromethane, and the organic phase is dried over magnesium sulfate and concentrated. The oily residue is subjected to silica gel chromatography, eluting with ethyl acetate to yield the formula-XXXIII compound,2.8 g., having NMR peaks at 1,13, 3,7-4.3, 4.3-4,7, 4.7-6.2, and 5.5-5.8 d; and Rf 0.65 (in ethyl acetate).

e. 3 α-Tetrahydropyran-2-yloxy-5α-hydroxy-2ss-(3-proplonyloxy-trans- 1 -propenyl)- 10,- cyclopentaneacetic acid, y-lactone (Formula-XXXIV). A solution of the formula-XXXI11 5-hydroxy lactone (step d, 2.8 g.) in 10 ml. of dichloromethane is treated with 5 ml. of dihydropyran and 5 mg. of ptoluenesulfonic acid dissolved in 1 ml. of tetrahydrofuran. After the reaction is finished, in about 0.5 hr., the mixture is washed with 5% aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography, eiuting with ethyl acetate-Skellysolve B (60:40) to yield the formula-XXXIV compound.

f. 3o'-Tetrahydrnpyran-2-yIoxy-5o'-hydrnxy-2-(3-hydrnxy-trans- 1 -propenyl)- 1 acyclopentaneacetic acid, y-lactone (Formula-XXXV). The formula-XXXIV propionate, (step e, 3.0 g.) in 10 ml. of methanol is added to a solution of sodium methoxide (freshly prepared from 20 mg. of sodium in 40 ml. of anhydrous methanol). After the reaction is complete, in about 20 min., the methanol is removed under reduced pressure. The residue is partitioned between dichloromethane and 0.4 M phosphate buffer of pH 4.5. The organic phase is dried over sodium sulfate and concentrated to yield the formula-XXXV compound.

g. 3α-Tetrahydropyran-2-yloxy-5α-hydroxy-2ss-(trans-2-formylethenyl)- 1 a-cyclopentaneacetic acid, y-lactone (Formula XXXVi).-An oxidizing reagent is prepared from chromium trioxide (5.4 g.) and 3,5-dimethylpyrazole (5.2 g.) in 1 50 ml. of dichloromethane, stirred for 15 min. To the solution is then added the formula-XXXV 3-hydroxy compound (step f, 1.8 g.) dissolved in 20 ml. of dichloromethane.

After the reaction is finished, in about 5 min., the mixture is washed with 5% aqueous bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography, eluting with acetone-dichloromethane (1:9) to yield the formula-XXXVl compound.

EXAMPLE 1 3 5 α-Dihdroxy-2ss-[(3R,S)-3-hydroxy-trans-1,7-octadlenyl]-1 a-cyclopentane-acetic Acid y-Lactone,3-tetrahydropyran-2-yl ether and also 3,3'-bis-(tetrahydropyran-2-yl ether) (Formula XXVIII) I. Via Lactone XXVI. Refer to Chart 2.

A. A solution of lactone XXXVI, i.e.5Q-hydroxy-3a-tetrahydropyran-2-yloxy-2ss-(trans-2- formylethenyl)-1 a-cyclopentaneacetic acid, y-lactone (2.775 g., Preparation 1) in 40 ml. of diethyl ether and 10 ml. of tetrahydrofuran is treated at 70C C. with 1 -pentenylmagnesium bromide (prepared from 5-bromo-1-pentene (4.11 5 g.) and magnesium (0.667 g.) in 40 ml. of diethyl ether) added dropwise over 17 min. The mixture is then stirred at about-60 C, for 22 min. and quenched with saturated aqueous ammonium chloride. Sodium sulfate powder is added for coagulation and the solids filtered off. The filtrate, together with ether washings, is dried and concentrated to an oil, 3.109 g.The product is chromatographed, eluting with methylene chloride-acetone (6:1) to obtain the mono-THP ether, mixed C-iS 5 epimers, 2.427 g., having Rf 0.34 and 0.29 (in methylene chloride-acetone (4:1)), NMR peaks at 6.20-5.4, 5.2.78, 4.68, 4.3-3.2, 3.02-2.4, 2.35-1.85, and 1.8-1.2 5, infrared absorption at 3450, 2995, 1775, 1200, 1180, 1120, 1075, 1030, 1020, 975, 920, 870, and 816 cm-1, and mass spectral lines at 422.2446,407,353,337,321,320,269,251, and 85.

b. The above mono-THP ether is treated in methylene chloride solution with excess dihydropyran in the presence of pyridine hydrochloride at about 250C. for 16 hr. The mixture is diluted with about 300 ml. of methylene chloride and washed with 5% aqueous sodium bicarboante, water, and brine, and dried. Concentration yields the formula-XXXVIII bis-THP ether title compound, vlz. 3α,5α-dihydrox6- 2-[(3R,Sl-3-hydrnxy- trans-i ,7-octadienyl]-1 a-cyclopentaneacetic acid y-lactone, 3,3'- bis(tetrahydropyran-2-yl ether).

II. Via Lactone XXXVII. Refer to Chart 3. A phosphonate reagent is first prepared. Methyl 5 hexanoate is prepared from 5-hexenoic acid by reaction with methanol and concentrated sulfuric acid in refluxing ethylene dichloride, thereafter washing and distilling the product. The anion of dimethyl methylphosphonate, prepared from dimethyl methylphosphonate (82 g.) and 400 ml. of 1.6 M butyllithium in 800 ml. of tetrahydrofuran at -55 to 600 C. is treated with methyl 5-hexenoate (41 g.) added in 65 ml. of tetrahydrofuran over about 10 min. The mixture is stirred at -750C. for 2 hr. and then at about 250C. for 18 hr. Acetic acid (26 ml.) is added and the solvent removed under reduced pressure. The residue is taken up in water and ether-methylene chloride (3:1).The organic phase, combined with extractions of the aqueous phase, is washed with cold aqueous sodium bicarbonate and brine, dried, and concentrated. There is obtained on distillation, dimethyl 2-oxo-heptenylphosphonate.

a. The formula-XXXVI bicylic aldehyde wherein R is benzoyl, i.e. 2-hydroxy-4-benzoxy-5carboxaldehyde-cyclopentanyl acetic acid y-lactone (U.S. Patent 3,778,450, 14.5 g.) is added in methylene chloride solution (100 ml.) to the ylid prepared from 25.5 g. of the above phosphonate and 4.2 g. of sodium hydride (57 /0 dispersion) in tetrahydrofuran (500 ml.) first at 0 and then at 200 C. The reaction mixture is warmed from 0 to about 250C. for one hr., then acidified with 10 ml. of acetic acid and concentrated. The residue is diluted with water and extracted with ether-methylene chloride (3:1).

The extracts are washed with cold dilute hydrochloric acid, water, cold aqueous sodium bicarbonate and brine, dried, and concentrated. The residue is chromatographed to yield the formula-XXXVlll 3-oxo trans-i ,7-octadienyl lactone with benzoate blocking group.

b. The formula-XXX1X 3-hydroxy compound, i.e. 5-hydroxy-3-benzoxy-2P-[(3R,S)-3-hydroxy trans-1,7-octadienyl)-1 α-cyclopentaneacetlc acid y-lactone is obtained on reduction with zinc borohydride. Forthis purpose sodium borohydride (3.78 9.) and anhydrous zinc chloride (13.7 g.) are reacted in 1 ,2-dimethoxyethane at 0-25 C. The solution of the reagent is cooled to-20 C. and treated dropwise under nitrogen with a solution of the above 3-oxo compound (10.0 g.) in 75 ml. of dimethoxyethane. When the reaction is completed as shown by TLC, excess borohydride is destroyed by careful addition of water and stirring. The mixture is filtered and the filtrate washed with water and brine, dried, and concentrated. The residue is chromatographed.

c. The benzoate group is removed by treatment of the above product of step b (3.55 g.) with potassium carbonate (1.23 g.) in methanol at about 250C. for 1.25 hr. The solvent is removed under reduced pressure and the residue is acidified with cold aqueous potassium hydrogen sulfate and extracted with ethyl acetate. The organic phase is washed with water and brine, dried, and concentrated. The residue is lactonized in refluxing benzene for 1 8 hr. and is thereafter chromatographed to yield the unblocked alkadienyl lactone, i.e. 3α,5α-dihdyroxy-2ss-[(3R,S)-3-hydroxy- trans ,7-octadienylj-1 -cyclopentaneacetic acid y-lactone.

The above unblocked lactone is treated with excess dihydropyran in the presence of pyridine hydrochloride and worked up as in I-b above to obtain the formula-XXVIII bis-THP ether title compound.

EXAMPLE 2 3α,5α-Dlhydroxy-2ss-[(35)-3hydroxy-trans-1,7-octadlentyl]-1α-cyclopentaneacetic Acid y-Lactol, 3,3'-bis-(tetrahydropyran-2-yl Ether) (Formula Llil) I. Refer to Chart 7. There is first.prepared the (3S)-mono-THP 1 7-octadienyl lactone following the procedures of Chart 2 and Example 1-I. A Grignard reagent is prepared in 170 ml. of ether from magnesium (3.14 g.) and 5-bromo-1-pentene (20.80 g.) added dropwise.The reaction mixture is refluxed for one hr., then cooled and added to a solution of the formula-XXVI aldehyde, i.e. So-hydroxy- 3α-tetrahydropyran-2-yloxy-2ss-(trans-2-formylethenyl)-1α-cyclopentaneacetlc acld, #-lactone (24,43 g., Preparation 1) in 260 ml. of diethyl ether at - 70 C. over a perlod of 22 min. The mlxture is stirred for an additional 45 min. at --700, then poured into a mixture of saturated ammonium chloride solution (900 ml.)-ice-ether (300 ml.). The organic phase is separated, combined with extracts of the aqueous layer, dried, and concentrated. The residue is chromatographed, eluting with acetone-methylene chloride (1:8) to (1:6) to yield the mixed 3(S) and 3(R) mono-THP lactones.They are separated by high pressure liquid chromatography on a series of Merck "B" prepacked columns, eluting with acetonemethylene chloride (1:10), to yield the mono-THP 3(S) isomer, 7.92 g. having R, 0.34 (in acetonemethylene chloride (1:4)), and the same spectral properties reported in Example 1-I-a. There is also obtained the mono-THP 3(R) isomer, 8.83 g., having Rf 0.29 and substantially the same spectral properties.

Continulng with the abovs 3(S) compound, namely 3α,5α-dihydroxy-2ss-[(3S)-3-hydroxy-trans- 1 ,7-octadienyll-1 o-cyclopentaneacetic acid y-lactone, 3-(tetrahydropyran-2-yl ether), there is next prepared the formula-Vill bis(THP ether) intermediate. The above 3(5) compound (7.92 g.) is treated in 55 ml. of methylene chlorlde with pyridine hydrochloride 9about 0.7 g.) and dlhydropyran (3,42 g.) at about 25 C. After 2 hr. the mlxture is warmed and stlrred at 32-35 C. for 4 hr. The mixture is cooled in en lce bath, diluted with 100 ml. of methylene chlorlde, washed with cold 50% sodlum blcarbonate and brine, dried, and concentrated to the bis(THP ether) intermediate, 9.88 g. having R, 0.70 (in acetone-methylene chloride (1:6)).

Ii. The lactone of part 1(9.82 g.) is treated in 100 ml. oftoluene at -680C. with diisobutylaluminum hydride (22.65 ml. of 1.5 M. toluene solution) added dropwise over 8 min. The mlxture is stirred at - 75 for one hr. and then 10 ml. of saturated aqueous sodlum sulfate added, The mixture is warmed to room temperature, dlluted wlth 700 ml. of dlethyl ether, and trasted wlth powdered sodium sulfate. The solids are removed on a Celite filter. The filtrate is dried and concentrated to yield the formula-LIII lactol title compound, having Rf 0.35 (in acetone-methylene chloride (1:6)).

EXAMPLE 3 18,20-Didchydro-PGF2α, 11,1 5-bis-(tetrahydropyran-2-yl Ether) (Formula LiV) and Methyl Ester Refer to Chart 7. The lactol of Example 2 (9.87 g.) is alkylated by the Wittig reaction. The Wittig reagent is first prepared from 4-carboxybutyl triphenylphosphonium bromide (35.1 g.) added to the reaction product of sodium hydride (7.6 g.) and 180 ml. of dimethyl sulfoxide previously warmed to 70-750C. for 1.5 hr. and then cooled to about 250C. for 25 min. then treated with the formula-LI II (3S) lactol in 65 ml. of dimethylsulfoxide added dropwise over 25 min. and stirred additional 30 min.

The mixture is acidified in ice water with 2 N potassium hydrogen sulfate and then extracted with ether.

The organic phase is washed with brine, dried, and concentrated to yield the formula-LIV bis-THP free acid.

The acid is then esterified with ethereal diazomethane and the resulting methyl ester is chromatographed to yield the title methyl ester 9.37 g., having Rf 0.62 (in acetone-methylene chloride (1 :6)), and NMR peaks at 6.18-4.56,4.37-3.29, 3.65, and 2.78-1.11 5.

EXAMPLE 4 1 9,20-D1dehydro-PGF2o' and 19,20-Didehydro-PGF2a, Methyl Ester (Formula LV).

Refer to Chart 7.

The bis-THP ether of the tltie aold (Example 3) la hydrolyzed to acetlo acld : water : tetrehydrofuran (20:10:3) at 40 C. for 3 hr. The solvents are removed under reduced pressure and the residue is chromatographed on silica gel, eluting with ethyl acetate-hexane (1:1) to yield the title acid.

The bis-THP ether of the title methyl ester (Example 3) is likewise hydrolyzed in acetic acid:water:tetrahydrofuran(20:10:3) following the same procedure to yield the title compound having Rf 0.48 (in ethyl acetate-methanol (10:1)), and mass spectral lines at 582.3570, 567, 551, 541, 513, 492,423,402, and 217.

EXAMPLE 5 1 9,20-Didehydro-(1 5R)-PGF2o, Methyl Ester (Formula LV).

Refer to Chart 7. Following the procedures of Examples 2-4, but utilizing the (3R) isomer of Example 2-I, namely 3α,5α-dlhydroxy-2ss-[(3R)-3-hydroxy-trans-1,7-octadienyl)-1α cyclopentaneacetic acid y-lactone, 3(tetrahydropyran-2-yl ether) there is prepared the corresponding formula-VIII (3R) bis(THP ether) intermediate and the formule-Llll lactol, then by Wittig alkylation the formula-LIV 19.20-didehydro-(15R)-PGF2α, 11,15-bis-(tetrahydropyran-2-yl ether). Finally, after esterification and hydrolysis of the blocking groups, the title compound is obtained, having Rf 0.66 (TLC on silica gel in ethyl acetate-methflnol (10:1)).

EXAMPLE 6 19,20-Dldehydro-PGF2α, Methyl Ester (Formula LV) and 1 9,20-Didehydro-1 SR-PGF2or, Methyl Ester (Formula LV).

Following the procedure of Example 2-Il, the (3R,S) mono-THP lactone of Example 2-1(1.720 g.) is reduced to the corresponding lactol, using 26.3 ml. of 0.56 M diisobutylaluminum hydride at about --750C. There is obtained 1.660 g. of lactol, having Rf 0.17 (in methylene chloride-acetone (4:1)), and infrared absorption at 3450, 2995, 1130, 1200, 1070, 1020, 975, 915, 870, and 815 cm-'.

Following the procedure of Exarnple 3; the above lactol (1.620 g.) is alkylated by the Wittig reaction using the ylid prepared from 4-carboxybutyl triphenylphosphonium bromide (9.105 g.) to yield the corresponding acid. The acid is esterified in methanol-ether with ethereal diazomethane to yield 3.497 g. The ester is chromatographed, eluting with ethyl acetate-Skellysolve B (1:1), to yield the mono-THP mixed C-1 S epimers, 1.536 g., having Rf 0.47 and 0.38 (in ethyl acetate-Skellysolve B (1:1)) and infrared absorption at 3450,2990, 1740,1430,1200,1020, 975,910,870 and 815 cm-1, The above mono-THP product is hydrolyzed in acetic acid-water-tetrahydrofuran (20:10:3) at 400 C. for 3 hr., thereafter concentrating.The resulting oil is chromatographed, eluting with ethyl acetate-Skellysolve B (160%) to yield first the (15R) title compound, 0.070 g., then a mixture, and finally the (15S) title compound, 0.083 g. The (15R) compound has Rf 0.66, the (15S) has Rf 0.48 (in ethyl acetate-methanol (10:1)), and both have mass spectral peaks at 582.3570,567,551,541, 513, 492,423,402, and 217.

EXAMPLE 7 1 9,20-Didehydro-PGE2, Methyl Ester (Formula Ill).

Refer to Chart 1. The formula-lX 1 1,1 5-bis(tetrahydropyran-2-yl ether), available from Example 3, is oxidized by the Jones reagent. Thereafter the THP blocking groups are replaced by hydrogen to yield the title compound.

EXAMPLE 8 1 9,20-Didehydro-PGF2o', p-Acetylphenyl Ester The mixed anhydride is first prepared. A solution of 1 9,20-didehydro-PGF2o' (Example 4) in methylene chloride is treated with triethylamine (2 equiv.) and isobutyichloroformate (1.01 equiv.) at about 25 C. for 0.5 hr. Solid p-hydroxyacetophenone (1.01 equiv.) is added and stirring continued for 4 hr. The mixture is diluted with methylene chloride, washed with water, 0.1 N sodium hydroxide, water, and brine, dried, and concentrated. The product is chromatographed on silica gel eluting with acetonehexane to yield the title compound.

EXAMPLE 9 19,20-Didehydro-PGF2α, Sodium Salt A solution of 1 9,20-didehydro-PGF2o', (Example 3) in methanol is neutralized with a solution of sodium carbonate in water. The mixture is concentrated to a small volume, diluted with acetonitrile and concentrated to a residue of the title compound.

EXAMPLE 10 1 9,20-Didehydro-PGF2o', Amide Refer to Chart 1 7. The formula-CIX mixed anhydride is prepared following the procedure of Example 8. There ls then added at about -5 C, asaturated solution of ammonla in acetonltrlle and the mlxture stlrred at -5 C. for 10 mln. The resotion mlxture la dlluted with brlne and water (6:1) and extracted with ether. The organic phase is washed with brine and 2 N hydrochloric acid, then with brine and 5% sodium bicarbonate, finally with brine, dried and concentrated. The residue is chromatographed on a HPLC silica gel column, eluting with acetone to yield the title compound.

EXAMPLE 11 1 9,20-Didehydro-PGF2o', Methanesulfonamide (Formula CXV) Refer to Chart 18. A solution of mixed an hydride in dimethylformamide (prepared from 1 9,20didehydro-PGF2 of Example 4 by reaction with isobutylchloroformate in the presence of triethylamine as in Example 8) is treated, with stirring, at OOC. with about 4 equivalents of methanesulfonamide sodium salt (prepared from methanesutfonamide and methanolic sodium methoxide in methanol, concentrating and azeotroping with benzene), thereafter adding sufficient hexamethylphosphoramide to insure a homogenous mixture. The mixture is stirred at about 250C. for 16 hr., then acidified with cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried, and concentrated. The residue is chromatographed on silica gel, eluting with methanol-methylene chloride, to yield the title compound.

EXAMPLE 12 3α,5α-Dihydroxy-2ss-(3-oxo-trans-1,7-cotadienyl)-1α-cyclopentaneacetio Acid) Lactone, 3-tetrahydropyran-2-yl Ether (Formula CXXIII) Refer to Chart 21.The formula-XXXVIII 3-oxo intermediate of Example 1-Il-a is deblocked by treatment with potassium carbonate in methanol at about 250C. for 1.25 hr., following the procedure of Example 1-Il-c. Thereafter, the THP ether is formed with excess dihydropyran in the presence of pyridine hydrochloride to yield the title compound.

Alternatively, the 3-hydroxy mono-THP lactones of Example 2 are oxidized by Jones reagent. Thus, the mono-THP 1 ,7-octadienyl lactone (8.83 g.) is treated in acetone at -350C with Jones Reagent (17 ml. of 2.67 M) added dropwise. Then stirring is continued for 35 min. and finally isopropanol (6.0 ml.) added with additional stirring. The mixture is added to a mixture of 5% sodium bicarbonate and icewater and extracted with ether. The organic phase is washed with brine, dried, and concentrated to yield the title compound, 7.63 g., having Rf 0.52 (in ethyl acetate-Skellysolve B (2:1)).

EXAMPLE 13 3cE,5ch-Dihydroxy-2jB-[(3R,S)-3-hydroxy-3-methyl-trans- 1 ,7-octadientyi]- 1- cyclopentaneacetic Acid y-Lactone, 3-tetrahydropyran-2-yl ether (Formula CXXIV).

Refer to Chart 21. The formula-CXXIII 3-oxo lactone (Example 12, 7.63 g.) in 500 ml. of tetrahydrofuran is treated at -780C. with methylmagnesium bromide (35.4 ml. of 3.1 M) added dropwise over 20 min. Stirring is continued for 2.5 hr. at about -600C. and then the reaction is quenched with 400 ml. of saturated aqueous ammonium chloride and 300 ml. of ice water and ether is added. The organic phase is separated, combined with organic extracts of the aqueous phase, dried, and concentrated.The residue is chromatographed, eluting with ethyl acetate-Skellysolve B (2:1) to yield the mono (THP ether) of the title compound having R, 0.27 (in ethyl acetate-Skellysolve B (2:1)), NMR peaks at 6.20-5.40, 5.40-4.52, 4.30-3,18. 3.07-1.35, and 1.23 S; and infrared absorption at 3400, 2850, 1740, 1620, 1420, 1330, 1150, 1110, 1060, 1020, 965, 900, 960, and 805 cm~l.

EXAMPLE 14 3α,5α-Dihydroxy-2ss-[(3R,S)-3-hydroxy-3-methyl-trans-1,7-cotadlenyl]-1α- cyclopentaneacetic Acid y-Lactol, 3-tetrahyd ropyran-2-yl Ether (Formula CXXV) Refer to Chart 21. The formula-CXXIV lactone, (Example 13, 5.20 g.) in 100 ml. of toluene at --680C. is treated with diisobutylaluminum hydride (23.8 ml. of 1.5 M. toluene solution) added dropwise over 8 min.Thereafter following the procedure of Example 2-Il, there is obtained the formula-CXXV lactol title compound, 3.79 g., having Rf 0.31 (in acetone-methylene chloride (1:3)), NMR peaks at 6.18-5.37, 5.33-4.29, 4.25-3.21, 3.05-1.34, and 1.26 5, and IR absorption at 3350, 2900, 1640, 1440, 1340, 1260, 1200, 1120, 1060, 970, 910, 865, and 810 cm-1 EXAMPLE 15 (16R.S)-15-Methyl-19,20-didehydro-PGF2α, 1 1 -tetrahydropyran-2-yl Ether, Methyl ester (Formula CXXVI).

Refer to Chart 21. The formula-CXXV lactol (Example 14, 3.79 g.) is subjected to the Wittig reaction following the prooedure of example 3, nd thereafter esterlfled to yleld the formula-CXXVI title compound, having, R, 0,34 (in acetone-methylene chlorlde (1:6)), NMR paaks at 6.18-5.20, 5.20-4.55, 4.27-3.17, 3.65, 2.67-1.34, and 1.27 5, and infrared absorption at 3400, 2900, 1720, 1630, 1430, 1340, 119Q1120,,1065, 1010, 985, 900, 860, and 805 cm-1 EXAMPLE 16 1 5-Methyl-1 9.20-dldehydro-PGF2α, Methyl Ester (Formula LV) and (15R)-15-Methyl- 1 9,20-didehydro-PGF2cs, Methyl Ester (Formula LV).

Refer to Chart 21. The product of Example 1 5 is hydrolyzed to replace tetrahydropyranyl groups in the usual way, for which see Example 4. The 1 5-epimers are separated by silica gel chromatography to yield the title compounds.

EXAMPLE 17 3α,5α-Dthydroxy-2ss-[(3R,S) (7R,S)-3,7-dlhydroxy-trans-1-cotenyl]-1α- cyclopentaneacetic Acid y-Lactone, 3,3'-bis(Tetrahydropyran-2-yl Ether) (Formula CXXIX) Refer to Chart 23. The title compound is obtained by oxymercuration-demurcuration, The formula Vlll alkadlenyl lactone, 1. e. 3α,5α-dihdyroxy-2ss-[(3R,S)-3hydroxy-trans-1,7-octadianyl]-1α- cyclopentaneacetio acld p-lactons, 3,3'-blsitetrahydropyran-2-yl ether) (Example 1, 14,54 g.) is added dropwlas to a stlrred suspenslon of merourio aostate (14.948 g.) in 120 ml. of water and 120 ml. of tetrahydrofuran and the mixture is stlrred at about 25 C. for 22 hr. The mlxture is cooisd in an lce bath and trested wlth sodium borohydrlde (3.752 g.) added in portlone over 8-8 mln.The temparature is raisled to about 25 C. and stlrring contineud for 3 min. The mixture la dlluted with ether (300 ml.) decanted from mercury, separated, and the organic phase combined with ether extracts of the aqueous phase. The organic phase is washed with brine, dried, and concentrated to an oil,15.88 g.The oil is chromatographed on silica gel, eluting with acetone-methylene chloride (1 :4to 2:4) to obtain the formula CXXIX 7-hydroxy title compound, 11.566 g., having Rf 0.38 (TLC on silica gel in acetone methylene chloride (1 :3)), NMR peaks at 5.50, 5.00,4.63,4.20-3.10, 3.00-1.20, and 1.15 5, and infrared absorption at 3500, 2990, 1775, 1120, 1020, 970, 910, 865, 810, and 730 cm-1 EXAMPLE 18 2-Decarboxy-2-hydroxymethyl-(1 9R,S)-1 9-hydroxy-PG E1 (Formula CXLIV) and 2-Decarboxy-2-hydroxymethyl- 13,1 4-dihydro-( 1 9R,S)-1 9-hydroxy-PGEr (Formula CXLV).

Refer to Chart 24. The formula-CXXXV compound is first prepared. The formula-CXXXIV compound, namely 1 9,20-didehydro-PGF2a, 11 , 1 S-bis(tetrahydropyran-2-yI ether), methyl ester (Example 3, 2.60 g.) is silylated with dimethyl-t-butyl-chlorosilane (1.465 g.) in 10 ml. of dimethylformamide and 1.325 g. of imidazole for 16 hr. at about 250C. The mixture is diluted with icewater and extracted with diethyl ether. The extracts are washed, dried, concentrated, and chromatographed to yield the formula-CXXXV 1 9,20-didehydro-9(dimethyl-t-butylsilyl)-PGF2cE, 1,1 5- bis(tetrahydropyran-2-yl ether), methyl ester having Rf 0.69 (in ethyl acetate-Skellysolve B (1:4)).

II. The formula-CXXXVl compound is prepared by oxymercuration-demercuration. The formula CXXXVI compound (1 1.30 g.) in 100 ml. of tetrahydrofuran is added dropwise over a 15 minute period to a stirred suspension of mercuric acetate (7.76 g.) in 1 00 ml. of water and 100 mi. of tetrahydrofuran at about 250C. After 3.75 hr. the mixture is cooled to 50C. and treated with sodium borohydride (1.46 g.). The mixture is stirred an additional 5 min. without cooling, then diluted with ether and filtered. The organic phase, together with ether-extracts of the aqueous phase, is dried and concentrated.The residue is chromatographed, eluting with ethyl acetate-Skellysolve B (1:2 to 1:1) to yield the formula CXXXVI compound, 9-(dimethyl-t-butylsilyl)-(1 9R,S)-1 9-hydroxy-PGF2a, 11,1 5-bis(tetrahydropyran-2yl ether), methyl ester, 8.86 g., having Rf 0.23 (TLC on silica gel in ethyl acetate-Skellysolve B (1:2)), and NMR peaks at 5.72-5.1 5, 4.76-4.46, 4.28-3.09, 3.58, 2.74-1.22, 1.08, and 0.87 5.

III. The above material is reduced with hydrogen over palladium (5%)-on-carbon catalyst (0.250 9.) in 75 ml. of ethyl acetate containing about 0.3 ml. of acetic acid. Additional catalyst and acetic acid are added as necessary to obtain 106 ml. uptake of hydrogen. The product (CXXXVII) is a mixture of the PGE1 and 13,1 4-dihydro compounds in a ratio of about 0.4/0.6.

IV. The above formula-CXXXVIl compounds (about 2.55 g.) are treated with dihydropyran (1.50 mT.) and pyridine hydrochloride (0.120 g.) in 40 ml. of methylene chloride for 15 hr. at about 250C. The mixture is diluted with 1 75 ml. of methylene chloride, washed with 5% aqueous sodium bicarbonate, water, and brine, dried and concentrated to the formula-CXXXVIII compounds, 2.765 g.

V. The above methyl esters are reduced with lithium aluminum hydride (0.278 g.) in 10 ml. of diethyl ether with stirring for 1.5 hr. at about 250C. The mixture is chilled and quenched with saturated aqueous sodium sulfate, diluted with ether, and treated with powdered sodium sulfate. The mixture is filtered, washed with ether, concentrated and dried to an oil, 2.542 g. represented by formula CXXXIX.

VI.Theformula-CXXXIX C-1 alcohols are blocked by treating with dihydropyran (1.40 ml.) and pyridine hydrochloride (0.120 g.) in 40 ml. of methylene dichloride for about 17 hr. at about 250C. After the usual work-up there is obtained 2.829 g. of an oil represented by formula-CXL.

VII. The above product is desilylated in preparation for oxidation at C-9. The product of VI is treated with n-tetrabutylammonium fluoride (12 ml. of 0.75 M in tetrahydrofuran with 15 ml. of tetrahydrofuran) for about 6.5 hr. at 250C. and one hr. at 400C. There is added an additional 3 ml. of reagent and the reaction continued at 400 C. for one hr. The mixture is diluted with 250 ml. of ether, washed with brine, water, and brine, dried and concentrated. The mixture is chromatographed to yield an oil, 1.970 g., represented by formula CXLI.

VIII. The formula-CXLI product of VII above is oxidized with Jones reagent, using 1.85 ml. (2.67 M) in 65 ml. of acetone, quenching with 3 ml. of isopropanol, to yield 1.910 g. of the mixed formula CXLIII compounds.

IX. The product of VIII is hydrolyzed to remove blocking groups, using 80 ml. of acetic acid-watertetrahydrofuran (20:10:3) for 4 hr. at about 45"C. The solvents are removed azeotropically with benzene to give an oil, 1.680 g. The residue is chromatographed by HPLC, eluting with acetonemethylene chloride (2:1), to yield (after some mechanical losses) the PGE1-type title compound (0.114 g.) and the less polar 13,14-dihydro-PGE1-type title compound (0.230 g.), CXLIV and CXLV respectively.

EXAMPLE 1 9 2-Decarboxy-2-hydroxymethyl-( 1 9R,S)-1 9-hydroxy-PGF1or and 2-Decarboxy-2-hydroxymethyl-1 3,1 4-dihydro-( 1 9R,S)-1 9-hydroxy-PGF1cr Refer to Chart 24. The formula-CXLI compounds are deblocked in dilute acid to yield CXLII, the mixed title compounds, which are separated by silica gel chromatography.

EXAMPLE 20 2-Decarboxy-2-hydroxymethyl-( 1 9R,S)- 1 9-hydroxy-PG F1 (Formula CL) I. Refer to Chart 25. The formula-CXLVI starting material, namely 1 9,20-didehydro-PGF2a, 11,15bis-(tetra-hydropyran-2-yl ether), methyl ester (Example 3), is first oxymercurated. A stirred suspension of mercuric acetate (7.76 g.) in 100 ml. of water and 100 ml. of tetrahydrofuran is treated with 19,20 didehydro-PGF2ce, methyl ester (9.25 g.) in 100 ml. of tetrahydrofuran added dropwise at 250C. in about 15 min. The mixture is stirred at about 250 C. for 3.75 hr., cooled to 50C. and treated with portions of sodium borohydride (1.46 g.) demercurate. Stirring is continued for 5 min. while warming to about 25 C.The mixture is diluted with ether (about one 1.) and filtered through Celite. The organic phase is dried and concentrated to crude CXLVI I. The residue is chromatographed, eluting with ethyl acetate, to yield CXLVII, namely (1 9R,S)-1 9-hydroxy-PGF2cr, 11,1 5-bis(tetrahydropyran-2-yl ether), methyl ester, having Rf 0.38 (in ethyl acetate-Skellysolve B (4:1)), and NMR peaks at 5.89-5.03, 4.83-4.52, 4.28-3.17, 3.65, 2.78-1.28, and 1.18 5.

Il. Next la prepared the formuls-CXLVIII corresponding PGF,α compound, Compound CXLVII above (1.270 g.) In 40 ml. of ethyl acetate together with 0.130 g. of 5 percent palladlum-on-carbon catalyst is reduced with hydrogen at one atmosphera at about 25 C. The catalyst ls flltersd of and the flltrate la concentrated to yield the formula-CXLVIII compound, namely (1 9R,S)-1 9-hydroxy-PGF1o', 11,1 5- bls(tetrahydropyran-2-yl ether0, methyl ester, 1.230 g., havlng NMR peaks at 5.50, 4.70, 4.30-3.20, 3.67, 2.50, 2.70-1.20, and 1,15 #, nd infrared absorptlon at 3500, 2995, 1730, 1430, 1200, 1020, 970, 865, and 805 cm~'.

III. The corresponding C-1 alcohol is obtained by reduction. A solution of compound CXLVIII above (1.230 g.) in 15 ml. of ether is added to an ice-cold suspension of lithium aluminum hydride (0.337 g.) in 10 ml. of ether. An additional 20 ml. of ether is added and the mixture is stirred at about 250C. for one hr. Thereafter about 7 ml. of saturated aqueous sodium sulfate is added dropwise, and solid sodium sulfate to coagulate aluminum salts, and the mixture is filtered. The filtrate is concentrated to an oil, 1.150 g. The procedure of reduction is repeated if necessary to convert unreacted formula-CXLVIII material.The resulting oil is chromatographed by HPLC on a Merck "B" column, eluting with ethyl acetate-Skellysolve B (9:1)), to yield the formula-CXLIX compound, namely 2-decarboxy-2 hydroxymethyl-(1 9R,S)- 1 9-hydroxy-PGF1or, 11,1 5-bis(tetrahydropyran-2-yl ether), 0.985 g., having NMR peaks at 5.50, 4.70, 4.25-3.20, 2.80, 2.60-1.20, and 1.15 us, and infrared absorption at 3400, 2990, 1430, 1120,1020, 970, 900, 860, and 805 cm-1.

IV. The formula-CL title compound ls obtalned on deblocklng the formula-CXLIX compound above in acstlc acld-water-tetrahydrofuran (20:10:3) at about 40-45 C for 45 mln., concentrationg, nd chromatographing.

EXAMPLE 21 8-(Dlmethyl-t-butylsllyl)-1 9-keto-PGF2a, bis(Tetrahydropyranyl Ether) (Formula CLXIX) and 1 9-Keto-PGF2or, Methyl Ester (Formula CLXX) Refer to Chart 29. The formula-CXXXVI product of Example 18 (0.500 g.) in 8 ml. of methylene chloride is added to Collins reagent (prepared from chromic anhydride (0.526 g.) in pyridine (0.831 g.)) nd methylens ohloride at 0 C. The mixture la stirred at about 25 C. for 1.2 hr., then dllutsd wlth 200 ml. of sther, filtered, and concentrated. The resldue (0.502 g.) conslats of the formuls-CLXIX 9-silyl11,1 S-bis(THP ether)-1 9-keto compound.

lI. The product of lis hydrolyzed in tetrahydrofuran-acstlc acld-water (3:20:10) at 47-50 C. for 4 hr. The mixture is concentrated and then obromatographed aluting with acetone-methylene chlorlde (1:1). There is obtained the title compound, 0.126 g., having Rf 0.33 (TLC on silica gel in acetonemethylene chloride (1:1)), NMR peaks at 5,87-5.06, 4.80-3.12. 3,86, 2,68-0.84 and 2.13 5; infrared absorption at 3350, 2900, 1730, 1430, 1350,1220,11 160, and 965 cm-1, and mass spectral lines at 693,3545, 583, 513, 508, 493, 423, 418, 217, and 187, EXAMPLE 22 (1 5R)-1 9-Keto-PGF2a (Formula CLXX) Refer to Charts 24 and 29.Following the procedures of Examples 3, 18, and 21 but replacing the (3S) lactone isomer of Example 3 with the corresponding (3R) isomer obtained in Example 2, there is obtained the title compound, having Rf 0.27 (TLC on silica gel in methylene chloride-acetone (1:1)), NMR peaks at 5.70-5.15 4.10, 3.67, 3.20, 2.17, and 2.70-1.20 5; infrared absorption at 3300, 2990, 1710, 1420, 1350, and 965 cm~1; and high resolution mass spectral line at 598.3516.

EXAMPLE 23 19-Kato-13,14-dihydro-PGF, α, Methyl Ester (Formula 111) 1. The formula-CXXXVi product fo Example 18-11,1s. 9-dimethyl-t-butylsilyl-(19R,S)-19-hydroxy PGF2a, 11 , 1 11,1 5-bis(tetrahydropyran-2-yl ether), methyl ester (2.0 g.) is reduced at C5-C6 and C13C4 by catalytic hydrogenation in 75 ml. of ethyl acetate using 200 mg. of 5% palladium-on-carbon catalyst to a mixture of the corresponding PGF1cg and 13,14-dlhydro-PGF,α products which is further hydrogenated to the 13,1 4-dihydro compound.

II. Following the oxidation procedures of Example 21, the corresponding 9-silyl-1 1-1 5-bis(THP ether 3,1 4-dihydro-1 19-kato-PGF1α, methyl ester is obtained.

Thereafter, by hydrolysis in tetrahydrofuran-acetic acid-water, the title compound is obtained. The TLC and NMR data show the presence of a less polar acetal form as well as the 1 9-keto form. Rf 0.26, 0.54, and 0.67 (TLC on silica gel in A-lX solvent); NMR peaks at 4.52--3.30, 3.62, 3.38, 3.00--0.87, 2.08, and 1.185; and mass spectral lines at 512.3336, 528, 517, 497, 427, 422, 412, 369, and 217.

EXAMPLE 24 2-Decarboxy-2-hydroxymethyl-l 9-keto-PGE, (Formula CLXXXIII).

I. Refer to Chart 31. The formula-CXLIX compound, namely 2-decarboxy-2-hydroxymethyl-(1 9R,S)-1 9- hydroxy-PGF1α, 11,16-bls(tetrahydropyranyl ether) (Example 20--111, 0.985 g.) is blocked at C-1 with silyl by treating in 6 ml. of ice-cold dimethylformamide with 0.135 g. of dimethyl-t-butylsilyl chloride and 0.122 g. of imidazole. The mixture is stored atO-S0C.,for2 hr.,then treated with additional 0.135 g. of dimethyl-t-butylsilyl chloride and 0.122 g. of imidazole. Finally, after 18 hr. at O-50C., the mixture is again treated with 0.085 g. of silyl reagent and stored at 0--50C. for 3 hr.The mixture is quenched with crushed ice (about 10 g.), stirred, diluted with water, and extracted with ether. The organic phase is washed with water, and brine, dried, and concentrated to an oil, 1.125 g. The oil is chromatographed by HPLC, eluting with ethyl acetate-Skellysolve B (1:1), to yield the formula-CLXXXl compound, 0.475 g.

having NMR peaks at 5.50, 4.70, 4.30-3.30, 2.70-1.25,1.15,0.90, and 0.03 5, and infrared absorption at 3500,2995,1460,1226,1100,1020,835, and 770 cm1.

II. The C-9 and C-i 9 hydroxy groups of the formula-CLXXXI compound of I are oxidized, using Collins reagent following the procedure of Example 21 but using 1.036 g. of chromic anhydride and 1.66 ml. of pyridine in 54 ml. of methylene chloride with 0.475 g. of CLXXXI above. There is obtained the formula-CLXXXII compound, namely 2-decarboxy-2-hydroxymethyl-1 9-keto-PGE1, 1-dim ethyl-t- butylsilyl ether, 11,1 5-bis(tetrahydropyran-2-yl ether), 0.428 g., having NMR peaks at 5.60, 4.70, 4.30--3.10, 2.10, 2.85--1.10, 0.90 and 0.05 5, and infrared absorption at 2990, 1730, 1710, 1460, 1340,1200,1100,970,830, and 770 cm~1.

Ill. The product of il above is deblocked in 15 ml. of acetic acid-water-tetrahydrofuran (20:10:3) at 40-46 C. for 3 hr. The solvents are removed azeotropically with chloroform under reduced pressure.

The residue is chromatographed, eluting with acetone-methylene chloride (1:1) to yield the formula CLXXXIII title compound, 0.042 g., and its formula-CLXXXIV hemiacetal, 0.052 g. The hemi-acetal is converted to the 1 9-keto form in acetic acid-water-tetrahydrofuran. The 1 9-keto compound has NMR peaks at 5.65 4.15,3.60,3.00,2.13, and 2.65-1.205, infrared absorption at 3400,2990, 1715, 1350, 1220, 1070, and 965 cm~1, and high resolution mass spectral peak at 570.3626.

EXAMPLE 25 (1 9R,S)-1 9-Hydroxy-PGF2or, Methyl Ester, 9,19-bls(dimethyl-t-butylsilyl ester), 11,15- bis(tetrahydropyran-2-yl ether) (Formula CLXXXV) Refer to Chart 32. Following the procedure of Example 18-I the formula CXXXVI 1 9-hydroxy compound of Example 18-11(4.34 g.) is silylated to yield the title compound, 4.84 g.

EXAMPLES 2-Decarboxy-2-hydroxymethyl-(19R,S)-19-hydroxy-PGF2α,9,19-bls(dimethyl-t-butyl silyl ether), 11,1 5-bis(tetrahydropyran-2-yl ether) (Formula CLXXXVI) Refer to Chart 32. The formula-CLXXXV product of Example 25 (4.84 g.) in 35 ml. of ether is added dropwise to a suspension of lithium aluminum hydride (0.943 g.) in 125 ml. of ether at about 250C. After 4.5 hr. an additional 0.472 g. of lithium aluminum hydride is added and again after another hour. The mixture is heated at reflux for 30 min., then cooled in an ice bath and quenched with gradual addition of 55 ml. of saturated aqueous sodium sulfate. Anhydrous powdered sodium sulfate is added and the mixture filtered.The filtrate is concentrated to yield the title compound, having Rf 0.58 (TLC on silica gel in ethyl acetate-Skellysolve B (1:2)) and NMR peaks at 6.73-5.00. 4.76-4.43,4.32-3,12, 2.75-1.19, 1.08,0.87, and 0.84 #.

EXAMPLE 27 2-Decarboxy-2-hydroxymethyl-(19R,S)-19-hydroxy-PGF2α, 9,19-bis(dlmethyl-t-butyl- silyl ether), 1,11,15-tris(tetrahydropyran-2-yl ether) (Formula CLXXXVII).

Refer to Chart 32. The formula-CLXXXVI product of Example 26 (4.67 g.) in 25 ml. of methylene chloride is treated with dihydropyran (0.941 g.) in the presence of a catalytic amount of pyridine hydrochloride at about 250C. After 5 hr. additional dihydropyran (0.52 g.) is added. Finally the mixture is diluted with 150 ml. of methylene chloride, washed with 5% aqueous sodium bicarbonate and brine, dried, and concentrated to yield the title compound, 5.25 g., having Rf 0.71 (in ethyl acetate-Skellysolve B(1:2)).

EXAMPLE 28 2-dscarboxy-2-hydroxymethyl-(19R,S)-18-hydroxy-PGF,α,1,11,15- tris(tetra hydropyran-2-yl ether) (Formula CLXXXVIII) Refer to Chart 32. The formula-CLXXXVII compound of Example 27 (5.19 g.) is desilylated by treatment in tetrahydrofuran with 8 equivalents of tetra(n-butyl)ammonium fluoride at 400C. The reaction mixture is diluted with 150 ml. of ethyl acetate, washed with brine and water and brine again, dried, and concentrated.The residue is chromatographed, eluting with ethyl acetate-Skellysolve B (2:1) to yield the title compound, 3.10 g., having Rf 0.35 (in ethyl acetate-Skellysolve B (2:1)) and NMR peaks at 5.75-5.12 4.84-4.50.4.350-3.15 2.73-1.05, and 1.16#, EXAMPEL 29 2-Decarboxy-2-hydroxymethyl-(19R,S)-19-hydroxy-PGF,α,1,11,15- tris(tetrahydropyran-2-yl.ether)(Formula CLXXXVIII) Following the procedure of Example 23 the formula-CLXXXVIII product of Example 28 is catalytically hydrogenated to the PGF1a title compound, having Rf 0.32 (in ethyl acetate-Skellysolve B (2:1)) and NMR peaks at 5.73-5.27, 4.89-4.45, 4.33-3.15,2.83-1.00. and 1.188.

EXAMPLE 30 2-Decarboxy-2-hydroxymethyl-1 9-keto-PG E, (Formula CXCI) Refer to Chart 32. Following the procedure of Example 21 the formula-CLXXXVIII product of Example 29 (1.90 g.) is oxidized and then hydrolyzed to the title compound, 0.360 g. The product is contaminated with a small amount of the corresponding cis-A5-13,14-dihydro compound. Data for the product are ; R1 0.24 (in acetone-msthylane chlorlde (1:1)), NMR peaks at 5.80-5.55, 5.55-5.28 (lmpurity), 4.60-3.22, 3.63, 2.82-0.95, and 2.08 3, nd infrared absorptlon at 3300, 2850, 2800, 1700, 1420, 1390, 1340, 1300, 1230, 1150, 1065, 1000, 960, and 720 cm-1.

EXAMPLE 31 2-Decarboxy-2-hydroxymethyl-(1 9R,S)-1 9-hydroxy-PGF2a (Formula CLXXXIX) Refer to Chart 32. Following the procedure of Example 21, the formula-CLXXXVlII compound of Example 28 is deblocked by acid hydrolysis in tetrahydrofuran-acetic acid-water (3:20:10) at about 40-450C. to yield the title compound.

EXAMPLE 32 2-Decarboxy-2-hydroxymethyl- 1 9-keto-PG E2 (Formula CXCI) Refer to Chart 32. The formula-CLXXXVIII compound of Example 28 (1.2 g.) is oxidized with Jones reagent (3.6 ml. of 2.67 M) added dropwise to the acetone solution at -350C., thereafter stirring at about-20 C. for 35 min. The reaction is quenched wlth isopropanol (6.0 ml.) and stlrring contlnued for 5 min. The mixture is poured into 250 ml. of 5% squeous sodium bicarbonate and 150 ml. of les water and extracted with ether. The organic phase is washed with brine, dried, and concentrated. The residue is hydrolyzed to remove blocking groups in tetrahydrofuran-acetic acid-water (3:20:10) at 300 C. for 16 hr. and the solution is concentrated.The residue is chromatographed on a high pressure Merck "B" column eluting with acetone-methylene chloride( 1 :1 ) containing 1% acetic acid, to yield the title compound, 0.310 g., having Rf 0.30 (in acetone-methylene chloride (1:1)) and NMR peaks at 5.84-5.52, 5.52-5.00, 4.58.3.78, 3.78-3.16, 2.98-0.90, and 2.07 5.

EXAMPLE 33 3α,5α-Dlhydroxy-2ss[(3RS]-3-hydroxy-7-oxo-trans- 1 -octenyl)- 1 a-cyclopentaneacetic Acid lactone, 3,3'-bis(Tetrahydropyran-2-yl Ether) (Formula CXCVI I).

Refer to Chart 34. The formula-CXXIX 7-hydroxy lactone (Example 17, 10,02 g.) in 300 ml. of acetone is treated at -300C. with Jones reagent (14.95 ml. of 2.67 M) added dropwise within 10 min.

The mixture is stirred at -25 to -200C. for additional 18 min., then quenched with 20 ml. of isopropanol and stirred 5 min. more. The mixture is added to 500 ml. of cold 5% sodium bicarbonate and 800 ml. of ethyl acetate, separated, and the organic phase is combined with ether extracts of the aqueous phase. The organic phase is washed with 5% sodium bicarbonate, ice water, and brine, dried and concentrated to yield the title compound, 9.93 g., having Rf 0.64 (TLC on silica gel in acetone methylene chloride (1 :3), and NMR peaks at 5.50, 5.00, 4.63, 4.25-3.0), 2.13, and 3.00-1.20 5.

EXAMPLE 34 3α,5α-Dihydroxy-2ss[(3R,S)-3,7-dlhydroxy-7-methyl-trans- 1 -octenyll- 1 cr- cyclopentane-acetic Acid y-Lactone, 3,3'-bis(Tetrahydropyran-2-yl Ether) (Formula CXCVIII) Refer to Chart 34. The Formula-CXCVII 7-oxo lactone (Example 33, 0.500 g.) in 33 ml. of diethyl ether is treated at-780C. with 2 equivalents of methylmagnesium bromide (0.766 ml. of 2.9 M) added dropwise over one min. The mixture is stirred at --780 for 30 min. more, then treated with an additional 2 equivalents of methylmagnesium bromide at --780 for 2 hr. The mixture is added to 40 ml. of saturated aqueous ammonium chloride and extracted with ether. The organic phase is washed with brine, dried, and concentrated.The concentrate is chromatographed on a HPLC column, eluting with acetonemethylene chloride (1:5) to yield the title compound, 0.391 9., having Rf 0.39 (TLC on silica gel In acetonsmethylene chloride (1:3)), NMR peaks at 6.66-5.33, 5,184,81, 4,81-4,47, 4,29-3,18, 2,87-1,28, and 1,16 #, lnfrared absorption at 3650, 3000, 1770, 1480, 1440, 1430, 1350, 910, 865, 840, 810, 765, and 735 cm~1, and mass spectral lines at 523.3118, 439, 437, 436, 421, 395, 131,and 85.

EXAMPLE 35 3α,5α-Dlhydroxy-2ss-[(3R,S)-3,7-dlhydroxy-7-methyl-trans-1 -octenyl)- 1 cr- cyclopentane acetaldehyde y-Lactol, 3,3'-bis(Tetrahydropyran-2-yl Ether) (Formula CXC IX).

Refer to Chart 34. The formula-CXCVIII 7-hydroxy-7-methyl lactone (Example 34, 6.98 g.) in 100 ml. of toluene is reduced at -78"C. with diisobutyl aluminum hydride (DIBAL) (25 ml. of 1.5 M in toluene) added dropwise over 13 min. The mixture is stirred at --780 for one hr., treated with additional DIBAL (5 ml.), stirred for 2.25 hr. and again treated with DIBAL (5 ml.). After 0.75 hr. more stirring, the mixture is warmed to -400 over 30 min., then cooled to 780 and carefully quenched with saturated aqueous sodium sulfate. The mixture is diluted with 850 ml. of diethyl ether, stirred with powdered sodium sulfate (20 g.) until the aluminum salts coagulate, then filtered. The filtrate is concentrated and then chromatographed on silica gel eluting with acetone-methylene chloride (1:2 to 1:1) to yield the title lactol compound, 4.89 g. The product has Rf 0.24 (TLC on silica gel in acetone-methylene chloride (1:2)), NMR peaks at 5,77-5.0, 4.88-4.33, 4.33-3.18, and 1.15 5, infrared absorption at 3500, 3000, 1750, 1730, 1470, 1450, 1440, 1370, 1340, 1200, 1120, 910, 866, and 810 cm-1, and mass spectral lines at 527.3201, 426, 336, 247, 246, 131, and 85.

EXAMPLE 36 19-Hydroxy-19-methyl-PGF2cz, Methyl Ester, 11,1 5-bis(Tetrahydropyran-2-yl Ether), Mixed C-1 5 Epimers (Formula CC).

Refer to Chart 34. The Wittig reagent is first prepared from 4-carboxybutyl triphenylphosphonium bromide (16.19 g.) added to the reaction product of sodlum hydride (3.51 g.) and 85 ml. of dlmethylsulfoxide prevlously warmed to 70-76 C. for 1.5 hr. and then cooled to bout 25 C. The mixture is stirred at about 250C. for 25 min., then treated with the formula-CXCIX lactol (Example 35, 4.89 g.) in 35 ml. of dimethylsulfoxide added dropwise over 1 5 min. and stirred additional 30 min. The mixture is added to one liter of ice-water containing 250 ml. of 2N potassium hydrogen sulfate and then extracted with ether. The organic phase is washed with brine, dried, and concentrated. The product, in 100 ml. of ether and 5 ml. of methanol. is esterified with diazomethane.The solution is concentrated and then chromatographed on a HPLC column eluting with ethyl acetate-Skellysolve B (1:1) to yield the title compounds, 4.08 g. having Rf 0.20 (TLC on silica gel in ethyl acetate-Skellysolve B (2:1)) and 0.60 (TLC on silica gel in acetone-methylene chloride (1:2)), NMR peaks at 5.77-5.29, 4.89-4.60, 4.34-3.16,3.67, 2.82-1.33, and 1.205, and infrared absorption at 3550. 3000, 1740, 1430, 1350, 1200, 1130, 1070, 1020, 970, 900,865, and 810 cm~'.

EXAMPLE 37 19-Hydroxy-19-methyl-PGF2a, Methyl Ester and its (15R) Epimer (Formula CCI).

Refer to Chart 34. The mixed formula-CC bis(THP ether) compounds (Example 36, 0.590 g.) are hydrolyzed in 33 ml. of acetic acid-water-tetrahydrofuran (20:10:3) at about 250C. overnight. The mixture is concentrated from toluene and then ethyl acetate. The residue is chromatographed on a HPLC column eluting with acetone-methylene chloride (3:2) to obtain, first, the (15R) title compound, 0.129 g. The (15R) compound hs R, 0.38 and the (15S) compound has R, 0.27 (TLC on sillca gel in acetone-methylene chloride (3:1)). The 15S compound has NMR peaks at 5.75-5.04, 4.32-3.03.

3.65,2,66-1.31. and 1.17 #, infrared absorption at 3450, 3000, 1740, 1430, 1360, 1200, 1150, 965, 920, and 900 cm-1, and mese spectral lines at 671,4000, 686, 596, 581, 513.

506, 491,423, 397, 333, 307, 243, and 217. The (15R) compound has very nearly the same spectral properties.

EXAMPLE 38 1 9-Hydroxy-1 9-methyl-PGE2, Methyl Ester, and its (15R) Epimer (Formula CCIII) Refer to Chart 34. The mixed formula-CC bis(THP ether) PGF2sr compounds (Example 36, 0.602 g.) are oxidized with Jones reagent following the procedure of Example 12, and then are hydrolyzed to replace THP blocking groups following the procedure of Example 37. The mixed C-1 5 epimers are separated by chromatography on a HPLC column, eluting with acetone-methylene chloride (1:1) to obtain, first, the 15R title compound, 0.119 g. and then the 15S title compound, 0.138 g. The 15R compound hs R, 0.48 and the 16S compound has R, 0.36 (TLC on sllica gel ln acetone-methylene chlorlde (3:1)).The 15S compound has NMR eaks at 5.83-5.02. 4.66-3.33, 3.68, 3.04-1.34, and 1.20 #, infrared absortlon at 3450, 3000, 1740, 1430, 1360, 1300, 1230, 1150, 1070. 1000, 965, 900, and 760 cmi', and mass spectral lines at 597.3441. 581. 522, 507. 439, 349. 295. and 131. The 15R compound has very nearly the same spectral properties.

EXAMPLE 39 19-Hydroxy-19-methyl-PGF2cr, Methyl Ester (Formula CCVI) Refer to Chart 35. The formula-CLXXVI 9-sllyl-11.15-bis (THP sther)-19-keto compound (Example 21, 0.500 g.) in 50 ml. of benzane is treated at about 25 C. with 2,3 equivalents of trimethylaluminum added dropwise over one min. The mixture is stlrred for 30 mln. and then added to 50 ml. of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated. The residue is chromatographed to yield the corresponding 19-hydroxy-19- methyl compound which is then deblocked in tetrahydrofuran-acetic acid-water (3:20:10) to yield the title compound, having the same properties as the product of Example 37.

EXAMPLE 40 15,19-Dlmethyl-19-hydroxy-PGF2α, Methyl Ester and ite (15R) Eplmer (Formule CCVI) Refar to Charts 30 and 35. As starting materlal there is used the formula-CXXVI productof Example 15, namely (15R,S)-15-methyl-19,20-dldehydro-PGf2α, 11-tetrahydropyranyl sther, methyl ester (Example 15). After saponlfication and recovery as the fres acid, the compound ls treated first with the silylating agent, and then with dihydropyran in the presence of pyridine hydrochloride to form a formula-CLXXIV compound of Chart 30. Thereafter the 15methyl 1 9-keto compound of formula CLXXVI is prepared using procedures described herein.

Finally, following the steps of Chart 35, the title compounds are obtained and separated by silica gel chromatography using procedures described herein or known in the art.

EXAMPLE 41 1 9-Hydroxy-1 9-methyl-PGF1{e, Methyl Ester, and its (1 5R) Epimer. (Formula CCXIII).

I. Refer to Chart 36. The mixed formula-CC bis (THP ether) of the PGF2cr compounds (Example 36, 1.5 g.) in 60 ml. of ethyl acetate are reduced at C5-C6 by hydrogenation at about 250C. in the presence of 200 mg. of 5% palladium-on-carbon with slighly over the theory for one equivalent of hydrogen. The solids are filtered off and the filtrate concentrated to yield the corresponding formula-CCXII bis(THP ether) of the PGF1or compounds having Rf 0.28 (TLC on silica gel in acetone-Skellysolve B (1:2)).

II. The above compounds are hydrolyzed to the title compounds following the procedure of Example 37, thereafter separating them by HPLC eluting with acetone-methylene chloride (1:1). The (15SA) tltle compound has R, 0.23 (TLC on slllcs gel in acetone-Skellysolve B (3:1)), NMR peaks at 5.85-5.05, 4.52-3.23,3,67,2,68-1.27, and 1.19 #, infrared absorption at 3450, 3000, 1740, 1440, 1360, 970, and 900 cm~1, and high resolution mass spectral line at 688.4380.The ( 1 5R) title compound has R, 0.29 (TLC on silica gel in acetone-Skellysolve B (3:1)), NMR peaks at 5.85-5.09, 4.33-3.0, 3.65, 2.68-1.28, and 1.20 5, infrared absorption at 3450, 2950, 1740, 1440, 1360, 970, 905, 825, and 765 cm-1, and high resolution mass spectral line at 688.4394.

EXAMPLE 42 19-Hydroxy-19-methyl-PGE1, Methyl Ester and its (15R) Epimer. (Formula CCXV).

Refer to Chart 36. The formula-CCXII bis(THP ether) of the PGF,sg compounds (Example 41, 0.900 g.) are oxidized with Jones reagent following the procedure of Example 33 and then are hydrolyzed to replace THP blocking groups following the procedure of Example 37. The mixed C-1 S epimers are separated by chromatography on a HPLC column, eluting with acetone-methylene chloride (1:1). The (15S) compound has Rf 0.33 (TLC on silica gel in acetone-methylene chloride (2:1)), NMR peaks at 5.80-5.40, 4,55-3,33, 3,65 3,00-0.80 and 1.20 #, infrared absorption at 3450, 2950, 1740, 1430, 1360, 1240, 1 150, 1070, 1040, 1000, 965, 910, and 730 cm-1, and high resolution mass spectral line at 599.3590.The (15R) compound has Rf 0.39 (TLC on silica gel in acetone-methylene chloride (2:1)), NMR peaks at 5.85-5.52, 4.38-3.58, 3.67, 3,58-2,81, 2.81-1.03, and 1.205, infrared absorption at 3450, 2950, 1740, 1430, 1260, 1150, 1070, and 965 cm-', and high resolution mass spectral line at 628.3900.

EXAMPLE 43 1 9-hydroxy-1 9-methyl-i 3,1 4-dihydro-( 1 5R)-PGE1, Methyl Ester.

The formula-CCXV 18-hydroxy-1 9-methyl-( 1 SR)-PGE1, methyl ester (Example 42, 0.148 g.) is hydrogenated again over 5% palladium-on-carbon, following the procedure of Example 41. The product is chromatographed by HPLC, eluting with acetone-methylene chloride (1:2) to yield the title compound, 0.031 g. having R, 0.35 (TLC on silica gel in acetone-methylene chloride (2:1)), NMR peaks at 4.44-3.60, 3.66, 3.46--3.08, 2.96--1.08, and and 1.21 5, infrared absorption at 3500, 3000, 1740, 1430, 1270, and 1 150, and high resolution mass spectral peak at 601.3797.

EXAMPLE 44 1 9-Hydroxy-1 9-methyl-i 3,1 4-dihydro-( 1 5S)-PGE1, Methyl Ester The formula-CCXIII 1 9-hydroxy-1 9-methyl-PGE,, methyl ester (Example 42, 0.179 g.) is converted to its bis(THP ether) and hydrogenated again following the procedure of Example 41.

Thereafter the THP groups are replaced by hydrolysis and the product chromatographed by HPLC eluting with acetone-methylene chloride (2:3) to yield the title compound, 0.031 g. The compound has Rf 0.41 (TLC on silica gel in acetone-methylene chloride (2:1)), and spectral data similar to that for the 1 5R epimer (Example 43).

EXAMPLE 45 2-Decarboxy-2-hydroxymethyl-1 9-hydroxy-1 9-methyl-PGF2or, 11,15 bis(tetrahydropyran-2-yl ether), Mixed C-i S Epimers. (Formula CCLXVII).

Refer to Chart 46. The formula-CCLXVI 19-hydroxy-1 9-methyl-PGF2cr, methyl ester, 1 5bis(tetrahydropyran-2-yl ether) (Example 36, 1.98 g.) in 65 ml. of ether is added dropwise in 20 min. to a stirred suspension of lithium aluminum hydride (0.530 g.) in 130 ml. of ether at about 250C. The mixture is stirred for 2.5 hr. and then quenched by careful addition of saturated sodium sulfate solution. There is then added 400 ml. of ether and 10-12 g. of powdered anhydrous sodium sulfate and, after about 30 min. stirring, the solids are filtered off and the filtrate is concentrated to yield the title compounds. They have Rf 0.30 (TLC on silica gel in ethyl acetate) and NMR peaks at 5.82-5.00, 4.86-4.57, 4.36-3.17, 2.88-1.31, and 1.19 6.

EXAMPLE 46 2-Decarboxy-2-hydroxymethyl-l 9-hydroxy-1 9-methyl-PGF2a and its (15R) Epimer.

(Formula CCLXVIII).

Refer to Chart 46. Following the procedures of Example 37 the bis(THP ether) compounds of Example 45 are hydrolyzed and chromatographed to yield the title compounds.

EXAMPLE 47 2-Decarboxy-2-hydroxymethyl-1 9-hydroxy-1 9-methyl-PGE2 and its (15R) Epimer.

(Formula CCLXXI).

I. Refer to Chart 46. There are first prepared the formula-CCLXlX monosilyl compounds. The formula-CCLXVII bis(THP ether) compounds (Example 45, 1.88 g.) in 18 ml. of dimethylformamide are treated at OOC. with imidazole (0.332 g.) and t-butyldimethylsilyl chloride (0.529 g.) After 40 min. there is added ice-water (200 ml.) and ether (200 ml.) and the layers are separated. The organic phase is washed with water, dried, and concentrated. The residue is chromatographed on a HPLC column, eluting with ethyl acetate-Skellysolve B (2:3) to yield the mixed formula-CCLXIX monosilyl compounds, 1.8 g., having Rf 0.27 (TLC on silica gel in acetone-methylene chloride (1:6)).

II. The above compounds are oxidized with Collins reagent prepared from pyridine (3.05 9.) in 65 ml. of methylene chloride and chromic anhydride (1.93 g.).The above compounds (1.8 g.) in 40 ml. of methylene chloride are added dropwise over 8 min. to the reagent at OOC. Thereafter the mixture is stirred at about 2S0C. for one hr., diluted with ether and filtered. The filtrate is concentrated to yield the title compounds as their 1 -silyl, 11,1 S-bis(THP ether) derivatives of formula CCLXX. The blocking groups are replaced by hydrolysis in 66 ml. of acetic acid-water-tetrahydrofuran (20:10:3) at about 25 C. for 16 hr. and finally at about 400C. for 4 hr.The products are separated by HPLC chromatography, eluting with acetone-methylene chloride (1 :1) to yield the (15R) compound, 0.332 9., having Rf 0.20 (in acetone-methylene chloride (2:1)) NMR peaks at 6.88-5.08, 4.483,36, 3.20-2.84.

2.78-1.35, and 1.20 #, infrared absorption at 3450, 2950, 1730, 1360, 1230, 1150, 1060, 1040, 965,920, 840, 820, and 760 cm~l, and mass spectral lines at 641.566, 551,483, 476, 393, 339, and 131, The (15S) compound, 0.417 9., has R1 0.13, NMR peaks at 5.98-5.03, 4.66-3.21, 3.04-1.33 and 1.20 5, and infrared and mass spectral properties similar to those of the (15R) compound.

EXAMPLE 48 2-Decarboxy-2-hydroxymethyl- 19-hydroxy-1 9-methyl-PGE, and its (15R) Epimers.

Following the procedures of Examples 45 and 47, the mixed 15-apimers of 19-hydroxy-1 9 methyl-PGF1cr, methyl ester, as their 11,1 S-bis(THP ethers) (Example 41-1, 0.726 9.) are reduced first to their 2-decarboxy-2-hydroxymethyl counterparts. There are next prepared the corresponding monosilyl bis(THP ether) compounds, which are oxidized with Collins reagent to form the PGE compounds.

Finally, the blocking groups are replaced by hydrolysis to yield the title compounds. The (15R) compound, 0.130 9., has Rf 0.35 (TLC on silica gel in acetone-methylene chloride (1:1)), NMR peaks at 5.84-5.29, 4.83-3.05, 2.95-1.96, and 1.17 9, infrared absorption at 3400, 2950, 1740, 1460, 1370, 1230, 1150, 1070, 970. 900. and 765 cm-', and high resolution mass spectral peak at 643.4037. The (15S) compound, 0.115 g., has Rf 0.26, NMR peaks at 5,82-5.26, 4.92-3.03.

2.93-1.25, and 1.155, and infrared absorption similar to the 15(R) compound.

FORMULAS

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CHART 49

TABLE DEFINITION OF TERMS FOR FORMULAS As alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one to 2 fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive, the A groups being the same or different.

D is (1) cis-CH=CH-CH2-(CH2)@-CH2- (2) cis-CH=CH-CH2-(CH2)g-CF2- (3) cis-CH2-CH=CH-CH2-CH2- (4) trans-(CH2)3-CH=CH- (S) -(CH2)3-(CH2)5-CH2- (6)-(CH2)3-CH2-CF2 (7) -(CH2)3-O-CH2- (8)-(CH2)2-O-(CH2)2 (9) CH2-0-(CH2)3-

wherein g is zero, one, two, or three.

Hal is chloro, bromo, or iodo.

Cis

wherein R5 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.

Q1 is

wherein R5 is hydrogen or alkyl of one to 4 carbon atoms, inclusive and Rt5 is a blocking group as defined below.

C2 is

wherein R9 is alkyl of one to 4 carbon atoms, inclusive.

R1 is (1) -COOR6 (2) -CH2OH (3) -CH2N(R7) (R8)

wherein R5 is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive;

wherein R25 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or (o) a pharmacologically acceptable cation; wherein R, and R8 are hydrogen, alkyl of one to 1 2 carbon atoms, inclusive, benzyl, or phenyl, being the same or different, and wherein R29 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive, R2is hydrogen, hydroxy, or hydroxymethyl.

R3 and R4 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen orfluoro.

R5is hydrogen or alkyl of one to 4 carbon atoms, inclusive.

R6is (a) hydrogen, (b) alkyl of one to 1 2 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive;

wherein R28 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2 naphthyl, or (o) a pharmacologically acceptable cation.

R7 and R8 are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different.

R9 is alkyl of one to 4 carbon atoms, inclusive.

R10 and R11 are hydrogen or fluoro.

R12is alkyl of one to 12 carbon aotms, inclusive.

R1 is hydrogen, -OR15, or QH2OR15, wherein R15 is a blocking group defined below.

R14is hydrogen, -OR18, or QH2OR18, wherein R18 is a carboxyacyl blocking group defined below.

R15is a blocking group including tetrahydropyranyl, tetrahydrofuranyl, or a group of the formula

wherein R21 is alkyl of one to 1 8 carbon atoms. inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R22 and R23 are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, inclusive, or when R22 and R23 are taken together, -(CH2)5- or -(CH2)b-O-(CH2)c-wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R24 is hydrogen or phenyl.

Rl6 is hydrogen or methyl.

R17is hydrocarbyl of one to 18 carbon atoms, inclusive.

R.8 is carboxyacyl including

wherein "T" is alkyl of one to 4 carbon atoms, inclusive, bromo, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, and "e" is zero to 5, inclusive, provided that not more than two T's are other than alkyl, and that the total number of carbon atoms in the T's does not exceed 10 carbon atoms.

wherein R2, is alkyl of one to 4 carbon atoms, inclusive,

wherein "T" and "e" are as defined above, or

wherein R25 is hydrogen, alkyl of pne to 19 carbon atoms, inclusive, or alkyl of 7 to 12 carbon atoms, inclusive, wherein alkyl or aralkyl are substituted with zero to 3 halo atoms.

R19is the same as R1 but with the proviso that R19 is not -COOH or - COOR12 wherein R,2 is alkyl of one to 12 carbon atoms, inclusive, when (A) R2 is hydroxy, R3 and R4 are hydrogen, Q is

and either (1) D is -cis-CH=CH-CH2-(CH2)g-CH2 and X is trans-CH=CH-, or (2) D is -(9H2)3-(CH2)9-CH2- and X is trans-CH=CH- or -CH2CH2-, (B) R2, R3, and R4 are hydrogen, W is

D is-(CH2)3-(CH2)g-CH2-, and X is trans-CH=CH-, or (C) R2, R3, and R4are hydrogen, Q is

D is cis-CH=CH-CH2-(CH2)g-CH2-and X is trans-CH=CH-.

R20 is the same as R1 but with the proviso that R20 is not -COOH or-COOR12 wherein R,2 is alkyl of one to 12 carbon atoms, inclusive, when Q is

R2 is hydroxy, R3 and R4 are hydrogen, W is

and either (1) D is cis-CH=CH-CH2-(CH2)g-CH2-and) X is trans-CH=CH-, or (2) D is -(CH2)3-(CH2)g-CH2-and X is-CH2CH2 R21 is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive.

R22 and R23 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, being the same or different, or, when R22 and R23 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 cisone, 2, or 3 with the proviso that b plus cis 2,3, or 4.

R24 is hydrogen or phenyl.

R25 is hydrogen, alkyl of one to 19 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.

wherein alkyl or aralkyl are substituted with zero to 3 halo atoms.

R26 is alkyl of one to 3 carbon atoms, inclusive.

R27 is alkyl of one to 4 carbon atoms, inclusive.

R28is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl.

R29is hydrogen, alkyl of one to 12 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl in which the alkoxy group consists of one to 4 carbon atoms, inclusive.

R30is alkyl of one to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one or 2 chloro or alkyl groups of one to 3 carbon atoms, inclusive.

R31 is R1,R19, or R20.

R32 is -CH=CH2 or -C(CH3) (OH)-CH3 when R3, is R1, -CH(OH)-CH3 when R3, is R,9, or -CO-CH3 when R31 is -R20.

(T)5 is alkyl of one to 4 carbon atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, and e is zero to 5, inclusive, provided that not more than two T's are other than alkyl, and that the total number of carbon atoms in the T's does not exceed 10 carbon atoms.

THP is tetrahydropyran-2-yl.

wherein A is as defined above.

W"' is

Xis cis-or trans-CH=CH-, -C=C-, or-CH2CH2-.

a is 3, 4, or 5.

b is one, 2, or 3.

c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4.

e is zero, one, 2, 3, 4, or 5.

g is zero, one, 2, or 3.

jis one, 2, or 3.

p is one, 2, or 3 with the proviso that j plus p is 4.

Claims

1. A compound of the formula

wherein D is (1) cis-CH=CH-CH2-(CH2)g-CH2-, (2) cis-CH=CH-CH2-(CH2)9-CF2-, (3) cis-CH2-CH=CH-CH2-CH2-, (4) r'ans-(CH2)3-CH=CH-, (5)-(CH2)3-(CH2)g-CH2 (6) -(CH2)3-CH2-CF2-, (7) -(CH2)3-O-CH2-, (8) -(CH2)2-O-(CH2)2-, (9) -CH2-O-(CH2)3-, (10)-W3-(CH2)2-or (11)-W3-O-CH2 in which W3 is 1 ,3-phenylene and g is one, 2 or 3:Q is α-OH:ss-H, α-OH : ss-CH3, α-H : ss-OH or cr- CH3:pOH; R2 is hydrogen, hydroxyl or hydroxymethyl; R3 and R4 are independentiy selected from hydrogen, C1-4 alkyl and fluorine, provided that -CR3R4- is not-CFAlkyl- ; W is oxo, methylene, α-OH : ss-H or α-H : ss-OH ; R3, is (1)-COOR6 (2) -CH2OH (3) -CH2-NR7R8 (4) -CO-NR7R8 (S) -CO-NH-COO-R29 or (6) 5-tetrazolyl in which R6 is hydrogen, C1-12 alkyl, C3-10 cycloalkyl, C7-12 aralkyl, phenyl, phenyl substituted one to 3 times by chlorine atoms or C1-3 alkyl radicals, -W4-CO-CH3, -W4-NH-CO-W4-NH-CO-CH3,-W4-NH-CO-Ph,-W4-NH-COCH3, -W4-NH-CO-NH2,-W4-CH=N-NH-CO-NH2, 2-naphthyl, -CH2-CO-Ph, -CH2-CO-W4-Br,-CH2-CO-W4-Ph,-CH2-CO-W4-NO2, -CH2-CO-W4-NH-CO-P h, (2-naphthyl)carbonylmethyl or a pharmacologically acceptable cation, W4 being 1 ,4-phenylene and Ph being phenyl;R7 and R8 are independently selected from hydrogen, C1-12 alkyl, benzyl and phenyl; and R29 is hydrogen, C1-12 alkyl, phenyl, phenyl substituted one to 3 times by chlorine atoms or C1-3 alkyl radicals, hydroxycarbonylphenyl or (C1-4 alkoxylcarbonylphenyl : X is cis-CH-CH-, trans-CH=CH, -C=C-or-CH2CH2- ; and R32 is-CH=CH2, -C(CH3)2(OH),-CH(OH)-CH3 or -CO-CH3, with the provisos that R32 is only -CH(OH)-CH3 when R31 is R19 as defined herein and that R32 is only -CO-CH3 when R31 is R20 as defined herein.

2. A compound according to claim 1, selected from the group consisting of: 1 9,20-Didehydro-PGF2α, methyl ester, 1 5(R)-1 9,20-Didehydro-PGF2α, methyl ether, 2-Decarboxy-2-hydroxymethyl-19,20-didehydro-PGF2α, 2-Decarboxy-2-hydroxymethyl- 11 -deoxy- 1 9,20-didehydro-PGF2cr, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19,20-didehydro-PGF2α, 2-Decarboxy-2-hydroxymethyl-19,20-didehydro-PGF2ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19,20-didehydro-PGF2ss.

2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19,20-didehydro-PGF2ss, 2-Decarboxy-2-hydroxymethyl-1 9,20-didehydro-PGE2, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19,20-didehydro-PGF2, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19,20-didehydro-PGE2, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-19,20-didehydro-PGE2, 2-Deca rboxy-2-hydroxymethyl-9 -d eoxo 9-methyl ene- 1 -deoxy-1 9 ,20-didehydro-PG E2, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-11α-hydroxymethyl-19,20- didehydro-PGE2, 2-Decarboxy-2-hydroxymethyl-4,5, 19.20-tetradehydro-PGF,α;, 2-Decarboxy-2-hydroxymethyl-4,5, 19,20-tetradehydro- 15(S)-1 5-methyl-PGF,rY, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydero-16,16-difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-PGFO1α, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-15(S)-15-methyl-PGF1α.

2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-11-deioxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-11-deoxy-16,16-difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-15(S)-15methyl-PGF1α.

2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-11-deoxy-11α-hydroxymethyl16,1 6-difluoro-PGF1or, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-PGF1α, 2-DecarSoxy-2-hydroxymethyl-4,5, 1 9,20-tetradehydro-l 5(S)-1 5-methyl-PGF,P, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexcadehydor-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5, 13,14,1 9,20-hexadehydro-l 6,1 6-difluoro-PGF,P, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-15(S)-15-methyl-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5, 13,14,1 9,20-hexadehydro-ll -deoxy-PGF"B, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-11-deoxy-16,18-difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-11α;-hydroxymethyl-PGF1,ss, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-15(S)-15- methyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-1-deoxy-11α-hydroxymethyl- PGF1ss.

2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-11-deoxy-11α-hydroxymethyl- 16.16-difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5, 1 9,20-tetradehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-15(S)-15-methyl-PGE, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,S,i 3,14,1 9,20-hexadehydro-i 1 -deoxy-1 6,1 6-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-11α;-hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-15(S)-15methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-11-deoxy-11α-hydroxymethyl- PGE1, 2-Decarboxy-2-hydroxymethyl-4,S, 1 3,14,1 9,20-hexadehydro- 11 -deoxy- 11 chydroxymethyl- 16,1 6-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-9-deoxo-9-methylene-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-9-deoxo-9-methylene-15(S)-15-methyl PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-9-deoxo-9-methylene-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14,19,20-hexadehydro-9-deoxo-9-methylene-16,16difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydor-9-deoxo-9-methylene-15(S)-15-methyl PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,1 3,14,1 9,20-hexadehydro-9-deoxo-9-methylene-l -deoxy PGE1, 2-Decarboxy-2-hydroxymeth6l-4,5,13,14,19,20-hexadehydro-9-deoxo-9-methylene-11-deoxy 16,1 6-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-11α- hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-11α hydroxymethyi-l 5(S)-1 5-methyl-PGE,, 2-Decarboxy-2-hydroxymethyl-4,5, 13,14,1 9,20-hexadehydro-9-deoxo-9-methylene-l l-deoxy- 11α;-hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5, 13,14,1 9,20-hexadehydro-9-deoxo-9-methylene-l -deoxy 11 or-hydroxymethyl-1 6,1 6-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-16,16-difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3,1 9,20-tetradehydro-l 5(S)-1 5-methyl-PGF,cw, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-PGF1α.

2-Decarboxy-2-hydroxymethyI-2,3,1 9,20-tetradehydro-1 1 -deoxy-1 6,1 6-difluoro-PGF1or, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-15(S)-15-methyl-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehdyro-11-deoxy-11α-hydroxymethyl-16,16 diffuoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-15(S)-15 methyl-PGF1or, 2-Deca rboxy-2-hydroxymethy1-2,3, 1 9,20-tetradehydro-PGF,P, 2-Decarboxy-2-hydroxymethyl-2.3,1 9,20-tetradehydro-l 6,1 6-difluoro-PGF,P, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-15(s)-methyl-PGF1ss.

2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehdyro-11-deoxy-PGf1ss, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehdyro-11-deoxy-16,16-difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-15(S)-15-methyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehdyro- 11 -deoxy- 11 a-hydroxymethyl-PG F1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehdyro-11-deoxy-11α;-hydroxymethyl-16,16- difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11 -deoxy-11 a-hydroxymethyl-15(S)-15- methyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-11α;-hydroxymethyl-16,16- difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-11-deoxy-11α-hydroxymethyl-15(S)-15methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-9-deoxo-9-methylene-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-9-deoxo-9-methylene-16,16-difluoro PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro- 9-deoxo-9-methylene-15(S)-15-methyl PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-16,16 difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-15(S) 1 5-methyl-PGEt, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-11α;- hydroxymethyl-PGe1, 2-Decarboxy-2-hydroxymethyl-2,3,19,20-tetradehydro-9-deoxo-9-methylene-11-deoxy-11α- hydroxymethyl-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3,1 9,20-tetradehydro-9-deoxo-9-methylene-1 1 -deoxy- 110,- hydroxymethyl-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-19,20-didehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl-16,16-dimethyl-19,20-didehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl-16,16-difluoro-19,20-didehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl-13,14-dihydro-19,20-didehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19,20-didehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl- 1-deoxy-1 6,1 6-dimethyl-1 9,20-didehdyro-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-difluoro-19,20-didehydro-PGF1α;, 2-Decarboxy-2-hydroxymethyl- 11 -deoxy- 13,1 4-dihydro-1 9,20-didehydro-PGF1or, 2-Decarboxy-2-hydroxymethyl- 1 1 -deoxy- 1 1 a-hydroxymethyl- 1 9,20-didehydro-PG For 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-dimethyl-19,20-didehydro PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-difluoro-19,20-didehdyro PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-13,14-dihydro-19,20 didehydro-PGF1α;, 2-Decarboxy-2-hydroxymethyl-19,20-didehydro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-16,16-dimethyl-19,20-didehydro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-16,16-difluoro-19,20-didehydro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-13,14-dihydro-19,20-didehydro-PGF2ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19,20-dldehydro-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-dimethyl-19,20-didehydro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-16,16-difluoro-19,20-didehydro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-13,14-dihdyro-19,20-=didehydro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19,20-dimethyl-19,20-didehydro 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyls-16,16-dimethyl-19,20-didehydro 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α;-hydroxymethyl-16,16-dimethyl-19,20-didehydro- PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-difluoro-19,20-didehydro- PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-13,14-dihdyro-19,20-didehydro- PGF1ss, 2-Decarboxy-2-hydroxymethyl-19,20-didehydro-PGE3, 2-Decarboxy-2-hydroxymethyl-16,16-dimethyl-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-16,16-difluoro-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-13,14-dihydro-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-dimethyl-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-difluoro-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-13,14-dihydro-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-11α-hydroxymethyl-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-11α-hydroxymethyl-16,16-dimethyl-19,20-dldehydro- PGe1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-difluoro-19,20-didehydro- PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α;-hydroxymethyl-13,14-dihdyro-19,20-didehydro- PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-16,16-dimethyl-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-16,16-difluoro-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-13,14-dihydro-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-11-deoxy-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-11-deoxy-16,16-dimethyl-19,20didehdyro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-11-deoxy-16,16-difluoro-19,20-didehydro PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-11-deoxy-13,14-dihdyro-19,20-didehydro PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-11-deoxy-11α;-hydroxymethyl-19,20- didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-11-deoxy-11α-hydroxymethyl-16,16- dimethyl-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxy-9-methylene-11-deoxy-11α-hydroxymethyl-1,314- dihydro-19,20-didehydro-PGE1, 2-Decarboxy-2-hydroxymethyl-19(R)-19-hdyroxy-PGF2α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19(R)-19-hydroxy-PGF2α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-19(R)-19-hydroxy-PGF2ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19(R)-19-hydroxy-PGF2ss.

2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19(R)-19-hydroxy-PGF2ss, 2-Decarboxy-2-hydroxymethyl-19(R)-19-hydroxy-PGE2, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19(R)-19-hydroxy-PGE2, 2-Decarboxy-2-hydroxymethyl-11α-hydroxymethyl-19(R)-19-hydroxy-PGE2, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-19(R)-19-hydroxy-PGE2, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-19(R)-19-hydroxy-PGE2, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-11α-hydroxymethyl-19(R)-19- hydroxy-PGE2, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-15(S)-15-methylo-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehdyro-19(R)-19-hydroxy-PGF1α;, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-16,16-difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-15(S)-15-methyl PGE1α, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-PGF1,α, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-16,16 difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5-dideoxy-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5-dideoxy-19(R)-19-hdyroxy-11-deoxy-11α-hydroxymethyl15(S)-15-methyl-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5-dideoxy-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl15(S)-15-methyl-PGE1α;, 2-Decarboxy-2-hydroxymethyl-4,5,13,14j-tetradehydro-19(R)-19-hydroxy-11-deoxy-11αhydroxymethyl-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-11αhydroxymethyl-16,16-difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-15(S)-15-methyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehdyro-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehdyro-19(R)-19-hydroxy-16,6-dilfuoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-15(S)-15-methyl PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-16,16difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl- PGF1ss.

2-Decarboxy-2-hydroxymethyl-4,5-didehdro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl- 15(S)-15-methyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-11α- hydroxymethyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-11α;- hydroxymethyl-16,16-difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-16,16-difloro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-15(S)-15-methyl PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydrop-19(R)-19-hydroxy-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehdyro-19(R)-19-hydroxy-11-deoxy-16,16difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-11α;-hydroxymethyl- PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl- 15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-11α- hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-11-deoxy-11α;- hydroxymethyl-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hdyroxy-9-deoxo-9-methylene-15(S)15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-9-deoxo-9-methylene PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-9-deoxo-9-methylene16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-15(S)15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-9-deoxo-9-methylene11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-9-deoxo-9-methylene11-deoxy-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11 deoxy-11α-hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11 deoxy-11α-hydroxymethyl-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-9-deoxo-9-methylene 11-deoxy-11α-hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-4,5,13,14-tetradehydro-19(R)-19-hydroxy-9-deoxo-9-methylene 11-deoxy-11α-hydroxymethyl-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-1i(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-16,16-difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3-didehydeo-19(R)-19-hydroxy-15(S)-15-methyl-PGF1α;, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-16,16-difluoro PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-15(S)-15-methyl PGF1,α 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl16,16-difluoro-PGF1α, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl15(S)-15-methyl-PGF1α;, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-16,16-difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-15(S)-methyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-16,16-difluoro-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-15(S)-15-methyl PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl- PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl- 16,16-dimethyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α;-hydroxymethyl- 15(S)-15-methyl-PGF1ss, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-16,16-difluro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-15(S)-15-methyl PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxymethyl- PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α-hydroxyemthyl- 16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-11-deoxy-11α ;-hydroxymethyl- 15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-16,16difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-15(S)-15methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11deoxy-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11deoxy-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11deoxy-15(S)-15-methyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11 deoxy-11α;-hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11 deoxy-11α-hydroxymethyl-PGE1, 2-Decarboxy-2-hydroxymethyl-2,3-didehydro-19(R)-19-hydroxy-9-deoxo-9-methylene-11 deoxy-11α-hydroxymethyl-16,16-difluoro-PGE1, 2-Decarboxy-2-hydroxymethyl-19(R)-19-hydroxy-PGE1α, 2-Decarboxy-2-hydroxymethyl-16,16-dimethyl-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-16,16-difluoro-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-13,14-dihydro-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-dimethyl-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-difluoro-19(R)-19-hydroxy-PGF1α;, 2-Decarboxy-2-hydroxymethyl-11-deoxy-13,14-dihydro-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19(R)-19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-dimethyl-19(R)19-hydroxy-PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-difluoro-19(R)-19-hydroxy PGF1α, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-13,14-dihydro-19(R)-19-hydroxy PGF1α, 2-Decarboxy-2-hydroxymethyl-19(R)-19-hydroxy-PGF1ss.

2-Decarboxy-2-hydroxymethyl-16,16-dimethyl-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-16,16-difluoro-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-13,14-dihydro-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-dimethyl-19(R)-19-hydroxy-PGF1ss.

2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-difluoro-19(R)-19-hydroxy-PGF1ss.

2-Decarboxy-2-hydroxymethyl-11-deoxy-13,14-dihydro-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19(R)-19-hydroxy-PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-dimethyl-19(R)-hydroxy- PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxyh-11α-hydroxymethyl-16,16-difluoro-19(R)-19-hydroxy- PGF1ss, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α;-hydroxymethyl-13,14-dihdyro-19(R)-19-hydroxy- PGF1ss, 2-Decarboxy-2-hydroxymethyl-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-16,16-dimethyl-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-16,16-difluoro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-13,14-dihdyro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-dimethyl-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-16,16-difluoro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-13,14-dihydro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-19(R)-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-16,16-dimethyl-19(R)-19-hydroxy- PGE1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α;-hydroxymethyl-16,16-difluoro-19(R)-19-hydroxy- PGe1, 2-Decarboxy-2-hydroxymethyl-11-deoxy-11α-hydroxymethyl-13,14-dihdyro-19(R)-19-hydroxy- PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-16,16-dimethyl-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-16,16-difluoro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-13,14-dihydro-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-19(R)-19-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-16,16-dimethyl-19(R)-19hdyroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-16,16-difluoro-19(R)-19hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-13,14-dihdyro-19(R)-19hydroxy-PGE1, 2 -Decarboxy-2-hydroxymethyl-9-deoxo-9-methyiene-1 1 -deoxy- 1 or-hydroxymethyl- 19(R)-1 9hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-11α-hydroxymethyl-16,16- dimethyl 9(R)-1 9-hydroxy-PGE1, 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-11α-hydroxymethyl-16,16- fluoro-1 9(R)-1 9-hydroxy-PGE1, and 2-Decarboxy-2-hydroxymethyl-9-deoxo-9-methylene-11-deoxy-11α-hydroxymethyl-13,14- dihydro-1 9(R)-1 9-hydroxy-PGE1.

3. A compound as claimed in claim g substantially as herein described.

4. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.