NO143741B - ANALOGY PROCEDURE FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE PROSTAGLAND CONNECTIONS OF THE E AND F SERIES - Google Patents

Description

The present invention relates to the production of certain

new analogs of naturally occurring prostaglandins. It particularly concerns the preparation of new 15-substituted io-pentanorprostaglandins using new intermediates.

The prostaglandins are C-20 unsaturated fatty acids that have different physical effects. Prostaglandins of the E and A series are e.g. powerful vasodilators (Bergstrom et al,

Acta Physiol. Scand. 64:332-33 1965 and Bergstrom et al, Life Sci. 6:449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration (Weeks and King, Federation Proe. 23:327, 1964, Bergstrom et al., 1965, op. eit, Carlson et al., Acta Med. Scand. 183:423-430, 1968, and Carlson

et al., Acta Physiol. Scand. 75:161-169, 1969). Another well known

physiological action for PGE 2 and PGE 2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).

Yet another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. ^ GE2

is known to induce labor (Karim, et al., J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman, et al., Contraception, 4, 293 ( 1971) and be

■useful for the regulation of fertility (Karim, Contraception, 3^

173 (1971)). Patents have been obtained for a number of prostaglandins of the E and F series for inducing labor in mammals (Belgian patent 754,158 and West German patent 2,034,641) and for PGF^, F2 °9 F^ for regulation of the reproductive cycle (South African patent 69 /6089). It has been shown that luteolysis can occur as a result of the administration of <p>GF2a [Labhsetwar, Nature 230, 528

(1971)] and prostaglandins Can thus be used for regulation of

the fertility of a procedure where stimulation of the smooth muscles is not necessary.

Other known physiological effects of PGE^ are in the inhibition of gastric acid secretion (Shaw and Ramwell, In: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, pp. 55-64) and also

of the platelet agglomeration. (Emmons, et al., Brit. Med. J. 2:468-472, 1967).

It is well known that such physiological effects can be induced in vivo for only a short time after the administration of a prostaglandin. Literature indicates that the reason for this rapid cessation of action is that the natural prostaglandins are quickly and efficiently deactivated metabolically by /3-oxidation of the carboxylic acid side chain and by oxidation of the 15a-hydroxyl group (Anggard, et al., Acta. Physiol.. Scand. , 81^ 396 (1971) and references cited herein).

It has been shown that the placement of a 15-alkyl group in the prostaglandins increases the duration of action probably by preventing the oxidation of the Cl5 hydroxyl group [Yankee and Bundy, JACS 94,

3651 (1972)], Kirton and Forbes, Prostaglandins, 1, 319 (1972).

It has of course been considered desirable to produce analogues of prostaglandins which have physiological effects which are similar to the natural compounds, but where the selectivity of action and the duration of action have been increased. Increased selectivity of action will be expected to reduce the serious side effects, especially stomach and intestinal side effects, which are often observed after systemic administration of natural prostaglandins (Lancet, 536, 1971).

According to the present invention, a method is provided for the production of physiologically active prostaglandin compounds of the E or F series with the formula:

where

Ar is α- or (3-furyl, α- or (3-thienyl, α- or 3-naphthyl, phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or monosubstituted phenyl wherein the substituent is halogen, trifluoromethyl, phenyl, lower alkyl or lower alkoxy, W is a single bond or a cis-double bond;

Z is a single bond or trans double bond;

n is an integer from 0 to 5,

with the proviso that when Ar is phenyl, substituted phenyl or naphthyl, n is 0 or 1 and Z is a single bond;

the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups in C8-, C^- and C^t-positions and pharmaceutically acceptable salts thereof. The procedure is characterized by

(a) a compound of the formula:

where Ar, n, M, W and Z are as indicated above, and THP is 2-tetrahydropyranyl, is reacted with a suitable acid; (b) a compound of formula I above wherein M is oxo is reacted with a suitable reducing agent to form a compound of formula I wherein M is and Ar, n, W and Z are as indicated above, optionally separating 9a- and 93 the -isomers; (c) a compound of formula I above wherein Ar, R, n and M are as defined above, W is a single bond or a cis double bond when Z is a trans double bond, and W is a cis double bond when Z is a single bond, is catalytically hydrogenated to form a compound of formula I above wherein Ar, n and M are as defined above, and W and Z are single bonds; (d) a compound of formula I above wherein Ar, n and M are as above and W and Z are double bonds is selectively hydrogenated to form a compound of formula I wherein Ar, n and M are as above, W is a single bond and Z is a trans double bond; and optionally the 9a-, 11a- and 15a-lower alkanoyl-, -formyl- or -benzoyl esters of any free hydroxyl groups are prepared by reacting the compound of formula I with a suitable acylating agent,

and optionally a pharmaceutically acceptable salt of a compound of formula I is prepared.

New compounds produced by the method according to the invention include the following: 13,14-dihydro-15-phenyl-iu-pentanor-PGE2, 13,14-dihydro-16-phenyl-0)-tetranor-PGE2,

16-phenyl-II>-tetranor-13,14-dihydro-PGE.^,

16α-thienyl-α>-tetranor-PGE2,

163-thienyl-α-tetranor-PGE2

17α-thienyl-co-tris-nor-PGE2;

17α-furyl-io-tris-nor-PGE2

17a-furyl-u)-tris-nor-PGF2a and

17α-thienyl-co-tris-nor-PGE2,

17ÉJ-furyl-u)-trisnor-PGE2

170-furyl-a)-trisnor-PGF2a,

173-thienyl-u)-trisnor-PGF2a,

170-thienyl-u-trisnor-PGE2

and the C15-epimers of these compounds, such as 15-epi-16-phenyl-13,14-dihydro-u-tetranor-PGE2.

It should be understood that the term "prostaglandin of the "zero" series, e.g. pGEQ, denotes prostaglandins in which the 5-6 and 13-14 double bonds are saturated, i.e. PGEQ is 5-6, 13-14, tetrahydro--PGE2 .

Also, the terms "zero-series"^ "one-series" or "two-series" here mean the degree of unsaturation in the side chains, e.g. is

PGE2 and PGF2q prostaglandins of the "two series", while PGE^ and

- PGFla is prostag^an_di;ne.r;;-avj."enrisjelr-ieh". ^-The designation "- iåyere' -L"''<*1>'~ alkyl group" here is understood to include alkyl groups containing from 1 to 4 carbon atoms. i

Preparation of the starting materials used in the process according to the invention, and the actual process for the preparation of the new prostaglandin analogues of formula I are illustrated in the following reaction schemes. '

As shown in Scheme A, the first step is the condensation of the appropriate ester with a dialkyl methyl phosphorate to give oxofqsphonate 2. \the desired methyl Sst is with dimethyl methylphosphonate. '■. / '• ""'//

In 2_ —>_3 oxophosphonate 2. is reacted with the known [Corey et al., J. Org. Chem. , 37., 3043 (1972)] aldehyde H and gives, after chromatography or crystallization, the enone s3..

The enone 3. can be transferred to,,a mixture of tertiary alcohols

13 and 14 by reaction with the appropriate lithium alkyl or Grignard

. reagent and the isomers 13. and 14 can be separated^ by column or high-pressure liquid chromatography. The enone 3. can be reduced with zinc borohydride to a mixture of alcohols, 4 and 5 can be 'separated as indicated above. Lithium triethylborohydride is particularly preferred when it is preferably with 1-2 reduction. In this reaction ethers such as tetrahydrofuran or 1,2-dimethoxyethane are used as solvents, although methanol is sometimes preferred to ensure a specific reduction. Further transfers of 4 is shown in Scheme B. 4 — > 6 is a base-catalyzed transesterification in which the p-biphenyl-carbonyl protecting group is removed. This is conveniently carried out with potassium carbonate in methanol or methanol-tetrahydrofuran4 solvent 6_ — > 1_ involves the protection of the two free hydroxyl groups with an acid-labile protecting group. Any sufficiently acid-labile group is satisfactory, however the most common is a tetrahydropyranyl, which can be incorporated into the molecule by treatment with dihydropyran and an acid catalyst in an alcohol-free medium. The catalyst is usually p-toluenesulfonic acid. \ 7 ,.. __■

1_ —> 8 is a reduction of the lactone 7_ to the hemiacetal £3

by using diisobutylaluminum hydride in an inert solvent. Low reaction temperatures are preferred and -60 to -70°C is common. However, a higher temperature can be used if no over-reduction takes place. 8^ is purified if desired by means of column chromatography. 8 9^ is a Wittig condensation where the hemiacetal 8_ is reacted with (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in dimethylsulfoxide in the presence of sodium methylsulfinyl methide. 9_ cleaned as mentioned above.

The transfer 9_ —? 12. is an acid hydrolysis of the tetrahydro-pyranyl groups. Any acid can be used which does not cause destruction of the molecule when the protecting group is to be removed; this is usually carried out by using 65% aqueous acetic acid. The product is cleaned as mentioned above.

9_ —> 10 is an oxidation of the secondary alcohol 9_ to the ketone 10. This can be carried out by using any oxidizing agent which does not attack the double bonds; however, Jones reagent is usually preferred. The product is cleaned as indicated above.

10 —> 11 is performed in the same way as ,9 —* 12_. The product is cleaned as indicated above.

As indicated in Scheme C, ~5_- can be substituted

instead of 4 in scheme B, and gives the prostaglandin derivatives 12_' and 11' .

Scheme D illustrates the synthesis of the precursors of 13,14-dihydro-15-substituted-w-pentanorprostaglandins.

In .3 - > 19_-» 19_', the enone .3 is reduced to the tetrahydro compound by using any complex metal hydride reducing agent, LiAlH^, NaBH^T KBH^, LiBH^ and Zn (BH4) 2.'<; > NaBH4 is particularly preferred. The products, 19_ and 19.', are separated from each other by column or high-pressure liquid chromatography.\

Moreover, the .kan.-compounds 4 and 5_ are catalytically reduced with hydrogen to 19. and 19'. Which step as the double bond

is reduced by is not critical; and hydrogenation at 6^ or -7_ in scheme B will also provide useful intermediates for 13,14-dihydro-prostaglandin analogs of the present invention. This reduction can be achieved either with a homogeneous catalyst such as tristriphenylphosphine rhodium chloride or with a heterogeneous catalyst such as platinum, palladium or rhodium.

The conversion of JL9_ and 19 1 to the respective prostaglandins follows the pathway shown in Scheme B when 4 is replaced by .19 or 19' and gives the 13,14-dihydro-PGE,, - and PGF^ series of prostaglandin derivatives.

Scheme E illustrates the preparation of the various reduced 15-substituted-oj-pentanorprostaglandin precursors: 19 22. is carried out as indicated in Scheme B for 4 — f 9_. 22_ can be used both as a precursor to a 13,14-dihydro-15-substituted-<<j-pentanorprostaglandin of the "2-series" or as an intermediate to 23., a precursor to a 13,14-dihydro-15- substituted-Cv>-pentanor-prostaglandin of the "1 series". 22. —> 23. is carried out by catalytic hydrogenation using the catalyst described for the reduction of 4 — in .19 in scheme D. Intermediates of the type 21 are prepared by selective reduction of the 5-6 cis double bond at low temperature by use catalysts such as those described for 4 —> 19. and 17. —> 23.. Particularly preferred for this reduction is the use of palladium on carbon as a catalyst and a reaction temperature of -20°. Intermediates of the type 2_1 are not only precursors to 15-substituted- -pentanorprostaglandins of the "1-series" following the path 9_ —> 15. in Scheme B, but also a precursor to the compounds of the type 2_3 via the path already discussed for 2_2_ —> 23.. 15-substituted-w-pentanorprostaglandins of the E^ and F .^ series can be obtained directly from the corresponding prostaglandin analog in the "2 series" by first protecting the hydroxyl group by introducing dimethylisopropylsilyl groups, selectively reducing the cis double bond, and removing the protecting group. The introduction of the protecting group is usually achieved by treating the prostaglandin analogue with dimethyl-isopropyl-chlorosilane and triethylamine, the reduction is achieved as indicated above for 9. —* 21. and the removal of the protecting group is achieved by contacting the reduced protected compound with 3:1 acetic acid: water for 10 minutes and until the reaction is essentially complete.

The C^,--epimers of 21^, 22_ and 23. can be used as precursors

to the 15-epi series of prostaglandin derivatives described above.

In the preceding methods, where purification by chromatography is desired, suitable chromatographic supports are included

neutral alumina and silica gel and 60-200 mesh silica gel are usually preferred. Chromatography is suitably carried out in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane which will be further illustrated in the following examples.

In numerous in vivo and in vitro samples we have shown. that the new prostaglandin analogues have physiological effects that are comparable to the natural prostaglandins (see above). These tests include, among other things, a test on the effect on isolated smooth muscle from guinea pig uterus, guinea pig ileum and rat uterus, the inhibition of norepinephrine-induced lipolysis in isolated rat fat cells, the inhibition of histamine-induced bronchospasm in the guinea pig effect, on dog blood pressure, the inhibition of stress-induced ulceration in the rat, inhibition of pentagastrin-induced hydrochloric acid secretion in the rat and dog and the inhibition of ADP- and collagen-induced platelet agglomeration....

The physiological responses observed in these tests are useful in determining the applicability of the test substance for the treatment of various natural and pathological conditions. Such specific uses include: antihypertensive action, bronchodilator action, vasodilator action, antithrombogenic action, antiarrhythmic action, cardiac stimulant action, antiulcer action, smooth muscle activity [useful as an antifertility agent, for inducing labor and as an abortifacient], and antifertility action through a mechanism that does not affect smooth muscle, e.g. luteolytic mechanisms.

The new compounds of formula I are

possessing high selective action profiles compared to the corresponding naturally occurring prostaglandins and, in many cases, having a longer duration of action. A good example of the therapeutic importance of these prostaglandin analogues is the action of 13,14-dihydro-16-phenyl-o-tetranorprostaglandin-E2

which has a hypotensive effect of much improved strength and duration compared to PGE2 itself. At the same time, the smooth muscle stimulating effect is markedly reduced in comparison with PGE2-

Similarly, the other 13,14-dihydro^L6-Ar-substituted PGE2 analogs, the novel 16-Ar-substituted PGEQ (tetra-hydro-PGE2) and 16-Ar-substituted-PGE2 prostaglandins of the present invention and especially 16-α-thienyl-α>-tetranor-PGE2

and 16-0-naphthyl-G>-tetranor-PGE2 the desired hypotensive effect.

In addition, 16-Ar-substituted prostaglandins are of the E series

particularly powerful when it comes to the inhibition of gastric acid secretion.

By oral administration, and are consequently useful for the treatment of peptic ulcer and hyperactivity in the stomach. It should be noted that the 15-substituted-13,14-dihydro-<*)-pentanorprostaglandins of the present invention are particularly useful because of their increased selectivity. 16-Ar-substituted-<»>-tetranor-13,14-dihydro-PGE2 has e.g. highly selective hypotensive action while 17-Ar-substituted-&>-tris-nor-13,14-dihydro has a highly selective smooth muscle action. Moreover, the 15-Ar-substituted-6>-pentanor-13,14-dihydro-E2-prostaglandins produced according to the invention have a high selective bronchodilator effect.

Similarly, 17-furyl-to-trisnorprostaglandin-F2a and

E2 excellent smooth muscle stimulatory action useful for fertility regulation, abortion and labor induction, while at the same time having blood pressure lowering effects. Moreover, the other new 17-substituted-α>-trisnorprostaglandins of the E and F series prepared according to the present invention, i.e. 17,18,19 and 20-Ar-substituted

prostaglandins of the E and F series

desired smooth muscle stimulating effect. The new 15-Ar-substituted u-pentanorprostaglandins of the F series can also be used for inducing labor and abortion, and for regulation of fertility, while 16-Ar-substituted-oj-tetranorprostaglandins of the F series are useful for fertility regulation via mechanisms which does not affect smooth muscle.

Moreover, 16-thienyl-w-tetranorprostaglandin-E2 and 16-p-biphenyl-a)-tetranorprostaglandin-E2 show high bronchodilator activity with reduced non-vascular smooth muscle activity. In a similar way, the other 16-Ar-substituted-u-tetranorprostaglandin-E₂ and E₂ analogues produced according to the present invention show the desired bronchodilator effect.

All the prostaglandins prepared according to the invention are also useful in the form of their salts with pharmaceutically acceptable cations. Esters of Cg, and C^, where the acyl group is lower alkanoyl, formyl or benzoyl, also have the same applicability as for the prostaglandins from which they are derived. In some cases, a lower frequency of unwanted side effects is obtained when certain esters are used compared to the corresponding non-esterified prostaglandins. These compounds include diesters in the case of prostaglandins of the E series and triesters in the case of the F series. Such esters can be easily prepared using standard methods known in the art.

Prostaglandin analogues that have a beta-hydroxyl group

at C15 have an effect equivalent to their epimers. In some cases, the selectivity of these compounds is greater than that of the epimeric compounds.

The new compounds produced according to the invention can be used in a number of different pharmaceutical preparations containing the compound or a pharmaceutically acceptable salt thereof, and they can be administered in the same way as natural prostaglandins in a number of ways such as intravenously, extra- and intra-amniotically, oral and topical, and includes, among other things, aerosol, intravaginal and intranasal.

For induction of abortion it may be suitably administered

an aqueous suspension of 17-substituted-co-trisnorprostaglandin of the E and F series or tablets in oral doses of approx. 1-20 mg, and 1-7 doses are used per day. For intravaginal administration, a suitable formulation is lactose tablets or an impregnated tampon of the same agent. For such treatments, suitable doses will be from approx. 1-20 mg/dose for the 17-α-furyl-PGF2 derivative or from approx. 10-200 mg/dose for the 17-a-furyl-PGE2 derivative, and 1-7 doses are used.

Alternatively, for abortion, intra-amniotic 17-substituted-co-trisnorprostaglandins can be administered in doses of 5-40 mg,

1-5 times per day, or intravenous administration in doses of 5-500 µg/min. in a period of approx. 1-24 hours.

Alternatively, for abortion, 17-substituted-o>-trisnorprostaglandins can be administered by extra-amniotic administration in doses of 0.5-50 µg/minute for a period of 1-24 hours.

Another suitable use for the 17,18,19 and 20-Ar-substituted-prostaglandin analogs of the present invention is for the induction of labor. For this purpose, an ethanol/saline solution of a 17-substituted-α>-trisnor-PGF2Q can be used! or PGE2~derivative as an intravenous addition in an amount of approx. 0.05-50 µg/minute for approx. 1-10 hours or orally in the form of capsules, tablets,

solutions or suspensions in doses of 0.005-5 mg, using 1-7 doses.

For the induction of bronchodilation, a suitable dosage form will

be an aqueous ethanolic solution of 16-Ar-substituted-tetranor-PGE^ or PGE2 used as an aerosol by using fluorinated hydrocarbons as propellant in an amount of approx. 3-500 µg/dose with up to 16 doses per day. To increase the nasal power, a suitable dosage form would be an aqueous solution of 16-Ar-substituted-tetranor-PGE-^ or PGE 2 used in the form of nasal drops in an amount of 1-100 µg/dose as needed.

16-Ar-substituted-w-tetranorprostaglandins of the and 13,14-dihydro-E2 series are useful antiulcer agents. For the treatment of peptic ulcer, these doses are administered orally in the form of aqueous suspensions, solutions or preferably in the form of capsules or tablets in doses of 0.001 to 0.10 mg/kg per dose,

up to 12 doses per day.

The above-mentioned 15-substituted-<t>-pentanorprostaglandins of the "en" series can be prepared synthetically as outlined in scheme F. In the first step, the hemiacetal U is reacted with 4-carbo-hydroxy-n-butyl-triphenylphosphonium bromide, and gives the intermediate W.

W —> X includes the treatment with diazomethane; followed by acetic anhydride and pyridine; followed by reduction with palladium on carbon in ethanol:acetic acid; followed by oxidation with dimethylsulfoxide, dicyclohexylcarbodiimide and pyridinium trifluoroacetate.

X —> Y includes treatment with sodium or lithium salt

of the suitable phosphonate (2) and purification by column chromatography.

Y —^ Z. includes reduction with zinc borohydride or lithium triethylborohydride, hydrolysis and separation of Cl5 epimers by column chromatography.

Z_ —* ZJL involves treatment of dihydropyran with an acid catalyst followed by mild aqueous base hydrolysis.

Zl —) PGFiQ and PGE^j^-15-substituted w-pentanor prostaglandins follow the same method as indicated for PGI^q, and PGE2

the series above.

Each of the new compounds prepared according to the present invention is also useful in the form of their C 1 -esters. Examples of preferred esters are those where the esterifying group is alkyl with from 1-12 carbon atoms; cycloalkyl from 3 to 8 carbon atoms; aralkyl from 7 to 9 carbon atoms; phenyl or ?-naphthyl or monosubstituted phenyl or ?-naphthyl where the substituent is: halogen, lower alkyl, lower alkoxy or phenyl. Particularly preferred are p-biphenyl esters. These specific esters are valuable because they are easily crystallizable, and that they can thereby be recovered in very pure form and in excellent yield, whereas prostaglandins usually give serious crystallization problems. The new para-biphenyl esters have the effects of the corresponding new mother compounds and in addition they have the advantage that they have a flattening activity against the time curve which is often advantageous. They also have reduced effects on smooth muscle in the stomach and intestines, which results in a reduction in side effects such as diarrhoea. The new compounds in the form of para-phenylphenol esters are prepared by methods that have already been described by suitable substitution of the corresponding intermediates used in the preceding reaction schemes. The compounds 9 and 10 can thus e.g. is esterified with para-phenylphenol in the presence of dicyclohexylcarbodiimide and gives para-phenylphenol esters of precursors to 15-omega-pentanor-prostaglandin para-phenylphenol esters. These can, via steps 9-12, 10-11 and 11-12, be transferred to the new para-phenylphenol esters mentioned above. Compounds 11 and 12 can also be esterified in the same way with para-phenylphenol and dicyclohexylcarbodiimide and give the desired esters. In addition, the para-biphenyl ester group can be introduced in an earlier step by using in steps 8-9 a tri-para-phenylphenol-ortho-ester-phosphonium bromide of the structure [(C6H5)3POCH2CH2CH2CH2C(OR)3]Br<®>, where R is similar to para-phenylphenol, and gives the corresponding orthoester of 9 which can be carried through steps 9-15, and gives the desired para-phenylphenol esters.

16-Ar-substituted-u)-tetranorprostaglandins of the Ej , E^ , EQ and 13,14-dehydro-E2 series are useful hypotensive agents

(these are also 15-Ar-substituted-Cc>-pentanorprostaglandins of the E series). For the treatment of hypertension, these drugs can conveniently be administered as an intravenous infusion in doses of

about. 0.5-10 µg/kg or preferably in the form of capsules or

tablets in doses of 0.005 to 0.5 mgAg/day.

Various reaction-initiated diluents, excipients or carriers can be used for the production of any of the above-mentioned dosage forms or any of the numerous other possible forms. Such substances include e.g. water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for drugs. If desired, these pharmaceutical preparations can contain additional substances such as preservatives, wetting agents, stabilizing agents or other therapeutic agents such as antibiotics.

The following examples are given to illustrate the invention.

In these examples, all temperatures are given in °C, all melting

and boiling points are uncorrected and all biological test data are expressed as % effect of PGE2 or administered at the same level

(ie, PGE2 = 100) unless otherwise stated.

Blood pressure of dog.

Mixed-breed dogs were anesthetized with sodium pentobarbitol, 30 mg/kg/i.v. Femoral arterial blood pressure was measured with a mercury manometer and recorded on a soot-blackened paper and heart rate

heat was determined from electrocardiograms recorded from subcutaneous electrodes. The drugs were given through a cannula into a femoral vein.

Isolated gastrointestinal and reproductive tissue

All measurements were performed in a 2 ml tissue bath using a "Phipps-Bird Linear Motion Transducer model ST-2". The tissues were allowed to respond to a stable maximum, at which point they were washed and returned to baseline conditions. All - determinations are performed as an average of at least three individual tissues at each indicated dose. Data for the analogues were compared with the dose response obtained for a neutral PG in a given tissue. For potency comparisons, a standard dose of natural PG was chosen; and all reactions were calculated in % of the reaction to this. Additional data were recorded as minimum effective dose (MED) and equivalent effective dose (CED) to establish detection levels of the compound for each tissue. A standard equivalent dose (SED) was determined. This value is defined as the amount of the compound (ng/ml)

which produces a reaction equivalent to the tissue's reaction to a given dose of standard PG.

The biological data given below were obtained by

to apply the following test methods:

Histamine-induced bronchoconstriction - guinea pig

Bronchodilator effects were investigated in Reed-Willet

unanesthetized female guinea pigs (200 to 250 g) that had fasted overnight according to the method of Van Arman, Miller and O'Malley (1). At pre-challenge intervals following the oral or aerosol administration of water or the test substance in water, each animal was treated with histamine aerosol as follows: a 0.4% aqueous solution of histamine was placed in a "Vaponephrine Standard Nebulizer" (Vaponephrine Company, Edison, New Jersey) and injected into a closed 2.0 x 2.0 x 30.4 cm clear plastic container for 1 minute under an air pressure of

0.42 kg/cm 2. Immediately thereafter, the guinea pigs were placed in the container. The respiratory state (an expression of bronchoconstriction) of the guinea pig after 1 minute in the container was indicated as follows: 0. normal respiration; 1, somewhat deep breathing; 2, heavy breathing;

3, very heavy breathing and ataxia; 4, unconsciousness. The scores for a control group and an experimental group (8 animals/group) were added together and compared and the difference expressed as % protection (1)

Marvinileum:

Ileum was dissected from 200-300 g male guinea pigs killed by cervical dislocation. The tissue was suspended in 2 ml of Tyrode's solution (2) at 37°C. PGE2 (30 ng/ml and/or PGF2a

(30 ng/ml) was used to determine tissue effect.

Marsvinuterus ( 3):

Females that had not previously given birth (300-400 g) and were not in heat were killed by cervical dislocation. The dissected uteri were incubated in 2 ml of a modified Krebs solution (12) at 37°C. Uterine interaction was determined using PGE2

(1.0 ng/ml) and-or PGF2q! (10 ng/ml).

1. VAN ARMAN, C.G., Miller, L.M. and 0'Malley, M.P.: SC-10.049:

a catacholamine bronchodilator and hyperglycemic agent.

J. Pharmacol. Exp. Ther. 133 90-97, 1961.

2. Hale, L.J. oath. Biol. Lab Data. p. 92, 1958.

3. Clegg, P.C., P. Hopkinson and V.R. Pickles. J. Physiol. 167:1, 1963. 4. W.S. Umbreit, R.H. Burris and J.F. Stauffer. Monometric Techniques 148, 1957. Example 1 (starting material) 2-[5g-hydroxy-3a-(tetrahydropyran-2-yloxy)-2P-(3a-{tetrahydropyran-2-yloxy)-4-phenylbut-1-yl)cyclopentyl- 1g-yl]acetaldehyde, β-hemiacetal ( 25a) ; A solution of 1457 mg (3.2 mmol) of 2-[5o;-hydroxy-3α!-(tetrahydropyran-2-yloxy)-2/3-(3α-{tetrahydropyran-2-yloxy}-4-phenylbut- 1-yl) cycl opent-la-yl ] acetic acid, ^-lactone (24a) in 15 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added dropwise 5.0 ml of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) at such a rate that the internal temperature did not exceed approx. -65° (3 minutes). After further stirring for 30 minutes at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was added with 150 mL of ether, washed with 50% sodium potassium tartrate solution (1 x 50 mL), dried (Na 2 SO 4 ), concentrated and chromatographed, yielding 1200 mg (81.5%) of 2-[5α-hydroxy-3α-(tetrahydropyran-2 -yloxy)-2Æ-(3α-(tetrahydropyran-2-yloxy}-4-phenylbut-1-yl)cyclopent-1-yl]acetaldehyde, γ-hemiacetal (25a). Example 2 9a-hydroxy-IIQ;, 15a-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-CJ-tetranorprostenic acid (22a): 10.8 ml (21.1 mmol) of a 1 .96M solution of sodium methylsufinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1200 mg (2.6 mmol) 2-[ 5a-hydroxy-3a-(tet rahydropyran-2-yloxy)-2/3-(Sa-ft et rahydropyran-2-yloxy }-4-phenyl-but-1-yl)cyclopent-la-yl]-acetaldehyde, ^-hemiacetal (25a) in 7.0 ml of dry dimethylsulfoxide over 20 minutes. After a further 2 hours of stirring at room temperature, the reaction mixture was poured onto ice water.

The basic aqueous solution was acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate

(3 x 100 ml) and the combined organic extracts were washed a

times with water (50 ml), dried (MgSO 4 ) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered.

The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ethyl acetate as eluent. After the removal of high R^ impurities, 880 mg of 9α-hydroxy-lla!, 15α-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-u>-tetranor-prostene (22a) acid was obtained.

Infrared spectrum (CHC1.) of 22a showed a carbonyl-

-1 J

adsorption at 1715 cm

The product obtained (22a) can be converted to 16-phenyl-co-tetranor-13,14-dihydro-PGF2a by hydrolysis with a 65:35 mixture of acetic acid and water and purification by column chromatography on Mallinckrodt CC-4 silica gel using ethyl acetate as eluent.

Example 3 9-oxo-lla, 15af-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-CD-tetranorprostenic acid (26a):

To a solution, cooled to -10° under nitrogen, of 880 mg

(1.68 mmol) of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-w-tetranorprostenic acid (22a) in 15 ml of analytical grade acetone was added dropwise 0 .75 ml (2 mmol) of Jones reagent.

After 20 minutes at -10°, 0.75 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and was then mixed with 100 ml of ethyl acetate, washed with water (3 x 25 ml), dried (MgSO 4 ) and concentrated , and gives 775 mg of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-««*-tetranor-prostenic acid (26a). Infrared spectrum (CHCl^) showed carbonyl adsorptions at

1710 and 1735 cm"<1>.

Example 4

9- oxo-lla, 15a- dihydroxy- 16- phenyl- cis- 5-w- tetranorprostenic acid (27a): A solution of 772 mg of 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)- 16-phenyl-cis-5-ur-tetranorprostenic acid (26a) in 7.0 mL of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 20 h and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography

on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate as eluent. After elution of less polar impurities, the oily 9-oxo-lla,15a-dihydroxy-16-phenyl-cis-5-N-tetranorprostenic acid (27a) weight 361 mg was obtained.

Infrared spectrum (CHCl3) showed carbonyl bands at 1710 and 1735 cm<-1>. Biological effect: marsvinuterus 1; guinea pig histamine aerosol test 0; blood pressure, dogs 400 (long duration effect).

Example 5

9-oxol- lla, 15a- dihydroxy- 16- phenyl-*~ >- tetranor- prostanic acid ( 28a) :

A heterogeneous solution of 34 mg (0.089 mmol) of 9-oxo-lla,15a-dihydroxy-16-phenyl-cis-5-trans-13-cO-tetranor-prostadic acid (lia)

and 13 mg of 5% palladium on carbon in 3 ml of absolute methanol was

hydrated (1 atm) at 0° for 2 hours. The reaction mixture was filtered and evaporated, yielding 30 mg of 9-oxo-11,15o!-dihydroxy-16-phenyl-tα-tetranorprostanic acid (28a). Infrared spectrum (CHCl.,) of 28a

-1 -1

showed carbonyl absorptions at 1715 cm and 1735 cm , a broad 0H region and no trans double bond adsorption.

Additional compounds of formula (a)

Example 6

9- oxola?, 15a- dihydroxy- 16- p- biphenyl- w- tetranorprostanic acid

A heterogeneous solution of 9-oxo-lla,15a-dihydroxy-16-p-biphenyl-cis-5-trans-13-co-tetranorprostadic acid and 5% palladium on carbon in absolute methanol was hydrated (1 atm) at 25° in 2 hours. The reaction mixture was filtered and evaporated to give 9-oxo-lla, 15a-dihydroxy-16-p-biphenyl-^tetranorprostanic acid, m.p. 120-123°. Infrared spectrum (KBr,) showed carbonyl absorptions at 1715 cm <1>

and 1735 cm -1 , a broad OH region and no absorption for the trans double bond.

Example 7

2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2/3- (3a-It rahydropyran-2-yloxy^-4-(2-thienyl)-trans-1-buten-l - y1) cyclopent-la-yl] acetaldehyde, y- hemiacetal ( 8d) ;

A solution of 1.2 g (2.5 mmol) of 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2/3-(3a-^tetrahydropyran-2-yloxy-4-(2- thienyl)-trans-l-buten-l-yl)cyclopent-la-yl]acetic acid, /-lactone (7d) in 25 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution, 3.4 ml of 0.8 M diisobutylaluminum hydride in n-hexane (Alfa Inorganics) was added dropwise at such a rate that the internal temperature did not exceed approx. -65°

(15 minutes). After a further 45 minutes of stirring at -78°

anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 150 mL of ether, washed with 50% sodium potassium tartrate solution (4 x 20 mL), dried (Na 2 SO 4 ) and concentrated to give a quantitative yield of oily 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)- 2/3-(3 a-£t et rahydropyran-2-yloxy}-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1-yl]acetaldehyde,

✓-hemiacetal (8d). Infrared spectrum showed a broad absorption at 3400 cm -1 for the hydroxyl group. In the same way, the corresponding /3-thienyl compounds were prepared.

15a-0THP IR: 970 cm"<1>

15/3-OTHP IR: 970 cm"<1>.

Example 8

9a-Hydroxy-lla, 15a-bis(tetrahydropvran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-oj-tetranor- prostadienoic acid (9d) : To a solution of 2.6 g (6 mmol) of (4-carbohydroxy-n-butyl)-triphenylphosphonium bromide under a dry nitrogen atmosphere in 5.0 mL of dry dimethyl sulfoxide was added to 5.7 mL (11.4 mmol) of a 2.2 M solution

of sodium methylsufinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1.03 g (2.2 mmol) of 2-[5a-hydroxy-3o!-(tetrahydropyran-2-yloxy)-2/3- (Sa-^tetrahydropyran-2 -yloxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-la-yl]-acetaldehyde, ^-hemiacetal (8d) in 5.0 mL of dry dimethylsulfoxide over 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured onto ice water.

The basic aqueous solution was washed twice with ethyl acetate (20 mL) and acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were washed 1 time with water (10 mL), dried (MgSO 4 ) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and the filtrate concentrated, giving 1.02 g of 9α-hydroxy-11G!, 15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans -13-"J-tetranor-prostadienic acid 9d. Infrared spectrum shows a strong band at 1700 cm 1 together with absorptions between 2800 to 2600 cm for the carboxyl group.

The product in this example (9d) can be transferred to 16-(2-thienyl)-«^-tetranorprostaglandins of the F series ( F2a' Fla' F0a^

via the procedure in example 11. In the same way, '

the corresponding /3-thienyl compounds are prepared.

15a<-0THP IR:1710, 970 cm"<1>

15/3-OTHP IR:1710, 970 cm"<1>.

Example 9

9- oxo-lla!, 15o;- bis-( tetrahydropyran-2- yloxy)- 16-( 2- thienyl)- cis- 5-trans- 13- M>- tetranor- prostadionic acid ( lOd) : To a solution cooled to -10° under nitrogen of 1.02 g (1.86 mmol) of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans- 13-uA-tetranor-prostadioic acid (9d) in 18 mL of analytical grade acetone was added dropwise to 0.82 mL (2.04 mmol) of Jones reagent. After 20 minutes at -10°, 0.2 60 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and was then combined with 75 ml of ethyl acetate, washed with water

(3 x 10 mL), dried (MgSO 4 ) and concentrated to give 952 mg of 9-oxo-lla;, 15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans -13--o-tetranor-prostadic acid (10d) which was chromatographed on silica gel using ethyl acetate as eluent and gives 760 mg of pure 10d. In the same way, the corresponding /3-thienyl compounds which are epimeric at .

Example 10 9-oxo-lia, 15a'-dihydroxy-16-(2-thienyl)-cis-5-trans-13- <«j-tetranor-prostadienic acid (lid): A solution of 760 mg (1.39 mmol ) 9,oxo-11a,15a-bis-tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-u>-tetranor-prostadioic acid (10d) in" 3.0 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 hours and then concentrated by rotary evaporation.The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate After elution of less polar impurities, semi-solid 9-oxo-lla, 15 a-dihydroxy-16-phenyl-cis-5-trans-13--o-t ranor-prostadienic acid (lid) was obtained, weight 369 mg . ^

"Infrared spectrum shows carbonyl absorptions at 1730 and 1705 cm dg a weak band at 972 cm'<1> for the 13,14-trans, double bond. - ..... _

The product according to this example (lid) can be transferred to 16-(2-thienyl)-u>-tetranorprostaglandin where E-, and En via the methods in examples 17 and 16. In the same way, the corresponding /J-thienyl compounds can be prepared.

15a-0H IR: 1715, 1740, 970 cm 15/3-OH IR: 1715', 1740,' 9-70 cm"<1>

Example H - y - i . OL' I «.SI 9a, lia, 15a- trihydroxy- 16-( 2- thienyl) - cis- 5- trans- 13- ~ >- tetranor-prostadienic acid ( 12d) : ' A mixture of 0.76 g of 9a- hydroxy-11a,"15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5'-trihs-13-n^-tetraniprostadienic acid (9d) in 5 ml of a 65:35 mixture of acetic acid:water is stirred under nitrogen at room temperature overnight and then concentrated under reduced pressure to a viscous oil. The crude product is purified by column chromatography on Mallinckrodt CC-4 silica gel using ethyl acetate as eluent. After elution of less polar impurities, the desired 9a,11a,15a-trihydroxy-16-(2-thienyl)-cis-5-trans-13-cO-tetranorprostadic acid (12d) was obtained as a viscous, colorless oil, weight 51 mg.

The obtained product (12d) can be transferred to 16-(2-thienyl)-w-tetranorprostaglandin via the method in example 96. 12d can also be transferred to 16-(2-thienyl)-^-tetranorprostaglandin-F0^, via the method in example 16.. ^ .....

Example 12 (starting material)

2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2/3-(3o;-tetrahydropyran-2-yloxy-4-2(thienyl)but-1-yl)cyclopent-lg-yl]acetaldehyde , /- hemiacetal ( 25d ): A solution of 1600 mg (3.2 mmol) of 2-[ 5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2/3-(3a- tetrahydropyran-2-yloxy-4 -2 (thienyl)-but-1-yl)cyclopent-la-yl]acetic acid, /-lactone (24d) in 15 ml of dry toluene is cooled to -78° in a dry nitrogen atmosphere. 5.0 ml of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) is added dropwise to the cooled solution at such a rate that the internal temperature does not exceed approx. -65° (3 minutes).

After a further 30 minutes of stirring at -78°, anhydrous methanol is added until gas evolution ceases and the reaction mixture is allowed to warm to room temperature. The reaction mixture is combined with 150 ml of ether, washed with 50% sodium potassium tartrate solution (1 x 50 ml), dried (Na 2 SO 4 ), concentrated and chromatographed to give 2-[5a-hydroxy-3a-(tetrahydropyran-2- yloxy)-2/3-( 3α-[tetrahydropyran-2-yloxyJ-4-2(thienyl)but-1-yl)cyclopent-1-yl1-acetaldehyde, ^-hemiacetal (25d).

Example 13 9a-hydroxyl-lla, 15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-iA>-tetranorprostenic acid (22d): To a solution of 5150 mg (11.6 mmol) (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 10.1 ml of dry dimethylsulfoxide is added to 10.8 ml (21.1 mmol) of a 1.96M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution is added dropwise a solution of 1300 mg (2.6 mmol) 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2/3-(Sa-tt etrahydropyran-2-yloxyj-4- (2-t i enyl)but-l-yl)cyclopent-1 α-y1]-acetaldehyde, ^-hemiacetal (25d) in 7.0 ml of dry dimethylsulfoxide in the course of 20 minutes. After stirring for a further 2 hours at room temperature, pour the reaction mixture into ice water. The basic, aqueous solution is acidified to pH^ with 10% aqueous hydrochloric acid. The acidic solution is extracted with ethyl acetate (3 x 100 ml)

and the combined organic extracts are washed once with water

(50 ml), dried (MgSO 4 ) and evaporated to a solid residue. This solid residue is triturated with ethyl acetate and filtered. The filtrate is purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ethyl acetate as eluent. After the removal of. high R^-f impurities are obtained 9α-hydroxy-lla,15α-bis-(tetirahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-w-tetranor-prostene (22d) acid.

The product obtained above (22d) can be transferred to 16-(2-thienyl)-u)-tetranor-13,14-dihydro-PGF2Q! via the procedure in example 11.

Example 14

9-oxol-lla, 15a-bis-(tetrahydropyran-2-yloxv)-16-(2-thienyl)-cis-5---^-tetranorprostenic acid ( 2 6d) :

To a solution cooled to -10° under nitrogen of 950 mg (1.68 mmol) of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-* *>-tetranorprostenic acid (22d) in 15 ml in acetone of analytical quality is added dropwise to 0.75 ml (2 mmol) of Jones reagent. After 20 minutes at -10°, 0.75 ml of 2-propanol is added and the reaction mixture is stirred for a further 5 minutes and then combined with 100 ml of ethyl acetate, washed with water (3 x 25 ml), dried (MgSO 4 ) and concentrated, giving 9 -oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-u>-tetranorprostenic acid (26d) „ Example 15 9-oxo-lla,15a- dihydroxy- 16 -(2-thienyl)-cis-5-w-tetranorprostenic acid (27d) : A solution of 800 mg of 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis -5-w-tetranorprostenic acid (26d) in 7.0 ml of a 65:35 mixture of glacial acetic acid:water is stirred under nitrogen at 25° for 20 hours bg then concentrated by rotary evaporation. The resulting crude oil is purified by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate as eluent. After elution of less polar impurities, oily 9-oxo-lla, 15a-dihydroxy-16-(2-thienyl)-cis-5-a>-tetranorprostenic acid (27d) is obtained.

Example 16 9-oxo-lla,15a-dihydroxy-16-(2-thienyl)-u;-tetranorprostanic acid (28d): A heterogeneous solution of 37 mg (0.089 mmol) of 9-oxo-lla,15a-dihydroxy-16- (2-thien<y>l)-cis-5-trans-13-^tetranorprostadic acid (lid) and 13 mg of 5% palladium on carbon in 3 ml of absolute methanol are hydrated (1 atm.) at 0° for 2 hours. The reaction mixture is filtered and evaporated to give 9-oxo-lla, 15α-dihydroxy-16-(2-thienyl)-t>O-tetranorprostanic acid (28d). Example 17 9-oxolla. 15a-dihydroxy-16-(2-thienyl)-trans-13-uj-tetranorprosten-svre (29d): A solution of 50 mg of 9-oxo-lla,15a-dihydroxy-16-(2-thienyl)-cis- 5-trans-13-u>-tetranorprostadic acid (lid) in 5 ml of dry ether was treated with 448 mg (3.6 mmol) of dimethylisopropylchlorosilane and 360 mg (3.6 mmol) of triethylamine at 25° for 48 hours. The reaction mixture is cooled to 0°, methanol is added and the resulting solution is washed with water (3 x 2 ml), dried (MgSO 4 ) and evaporated to a residue. The crude residue is then taken up in 6 ml of methanol and 30 mg of 50% Pd/C and the resulting suspension is hydrated for 4 hours at -22° (CCl 4 /dry ice). After filtration through a super cell and evaporation, the hydrated product is hydrolysed in 2 ml of acetic acid-water (3:1) for 10 minutes, diluted with water (20 ml) and extracted with ethyl acetate (4 x 15 ml). The combined organic extracts are washed with water (2 x 10 mL), dried (MgSO 4 ) and evaporated to give 9-oxo-11a,15o!-dihydroxy-16-(2-thienyl)-trans-13-u^-tetranor -prostenic acid (29d).

Example 18

Methyl- 9Q?- acetoxy- llQ'- ( tetrahydropyran-2- yloxy) - 15- ox o- trans- 13-16- ( 3- thienyl) - u/- tetranorprostenoate

To a suspension of 110 mg (2.61 mmol) of a 57.0% dispersion of sodium hydride in mineral oil in 20 ml of dimethoxyethane was added 646 mg (2.61 mmol) of dimethyl-2-oxo-3-(3-thienyl) propyl phosphonate. The mixture is stirred at room temperature for 1 hour under nitrogen. To this suspension is added a solution of 0.947 g (2.37 mmol) of impure methyl 7-[29-formyl-3a-(tetrahydropyran-2-yloxy)-5a-acetoxycyclopent-la-yl]heptanoate in 4 ml of dimethoxyethane. The resulting somewhat cloudy brown solution is stirred at room temperature for 2 hours under nitrogen. The reaction is then stopped by addition of glacial acetic acid to pH~7 and concentrated by rotary evaporation. The crude product is purified by column chromatography on silica gel and gives the desired methyl 9a-acetoxy-11-(tetrahydropyran-2-yloxy)-15-oxo-trans-13-16-(3-thienyl)-uj-tetranorprostenoate.

Example 19

Methyl-9o!-acetoxyl- (tetrahydropyran-2-yloxy)-15-hydroxy-trans-13-16-(3-thienyl)-m-tetranorprostenoate.

To a solution of 1.60 g (2.17 mmol) of the enone prepared in Example 39 in 6.5 ml of dimethoxyethane was added dropwise 2.17 ml (1.08 mmol) of a 0.5 M Zn(BH4)^- solution in dimethoxyethane. After stirring at room temperature under nitrogen for 3 hours, the reaction was stopped by the dropwise addition of a saturated aqueous solution of sodium bitartrate until gas evolution ceased. The heterogeneous solution is stirred at room temperature for 5 minutes, diluted with methylene chloride, dried (anhydrous magnesium sulfate) and

is concentrated, giving methyl-9a-acetoxy-lla-(tetrahydropyran-2-

y 1 oxy)-15-hydroxy-t rans.-13-i 6-(3 -1 ienyl) 1 et ranorpros t erioate.

Example 20 Methyl-9a-acetoxy-llcv,15/3-dihydroxy-trans-13-16-(3-thienyl)-o>-tetranorprostenbate and metvl-9a-acetoxy-llQ',15a-dihydroxy-trans-13- 16- ( 3- thienyl) - c»>- tetrahorprostenoate

A solution of 1.60 g (2.16 mmol) of impure THP ether prepared

in example, 98 ml of a 65:35 mixture of acetic acid:water is stirred at 40-2° under nitrogen for 2.5 hours. The reaction mixture is then concentrated and gives an impure epimeric diol mixture.

.. •;...<. ■ . '; ;•. ■•;>-.•• - -, .. T v.' ■. :i-0': .. 0 - •• .• Jo-.':•:.<; : The crude product is purified by column chromatography on silica gel, and gives the desired "methyl-9a-acetoxy-lla, 15^-"dihydroxy-trans-13-16-(3-thienyl)-w-tetranorprobstenoate and the epimeric methyl-9a- acetbksy-11a,15a-dihydroxy-trans-13-16-(3-thienyl)-urtetranorprostenoate.

Example 21 "~'~~~.~' t^~ Methyl- 9a- acetoksv-lla, 15a- bis- ( tet f ahvdro' pyråh- 2- yloxy)~ trans- " ' . 13- 16-( 3- thienyl) - herbal tranorprostenoate ""

A mixture of 0.223 g (0.510 mmol) was chromatographed

diol in example 99, 0.14 ml (1.53 mmol) dihydropyran, 4.2 ml _,.. methylene chloride bg 1 crystal of p-toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for 20 minutes. The reaction mixture is then diluted with ether, washed with saturated aqueous sodium bicarbonate, dried (anhydrous magnesium sulfate) and concentrated. . •- - .'■ -:-; v.. ' .''— •. ■:?<■- :■

and gives the desired methyl-9α-acetoxy-lla, 15α-bis-(tetrahydropyran-2.-..,..,......,( . yloxy)-trans'-13-16- (3-thienyl ) -u*-t et ranorpr os t enoat. ^ ....... ^ .• w,

Example- 2 2 ■ -; - .. ' •■" v rf ».•>.-•. i'.': f->3'-' ~" t> •..» . "

1 Env mixture of 65 mg (0.15 mmol) of the chromatographed diol prepared in Example 99, 0.45 ml (0.45 mmol); 1?", O-N: aqueous sodium hydroxide, 0.45 ml tetrahydrofuran and 0.45 ml absolute methanol r .... stirred under nitrogen at room temperature for 1.5^ hours _ _.. The solution-Vurgj^Sr es " then by adding ay, 0.45 ml 1, ON aqueous hydrochloric acid (pH of acidified solution was approx. 5).. The acidified solution is extracted with ethyl acetate (4 x 2 ml). The combined extracts... are dried (anhydrous magnesium sulfate) and concentrated to give the desired 9α,11α,15α-trihydroxy-trans-13-16-(3-thienyl)-cortetranorprostenic acid.

Example 23

9a- Hydroxyl, 15a-bis-(tetrahydropyran-2-yloxy)- trans- 13- 16-(3- thienyl) - tetranorprostenic acid

A homogeneous solution of 0.263 g (0.436 mmol) of the crude bis-THP ester prepared in Example 100, 1.3 mL (1.30 mmol)

1.ON aqueous sodium hydroxide solution, 1.3 ml of methanol and 1.3 ml of tetrahydrofuran are stirred under nitrogen overnight. The reaction is then stopped by the addition of 1.30 ml (1.30 mmol). of a 1.0N aqueous hydrochloric acid solution. The solution is diluted with ethyl acetate. The organic layer is dried (anhydrous magnesium sulfate) and concentrated,

and gives the crude product. The crude product is purified by column chromatography on Baker "Analyzed" silica gel (60-200 mesh), and gives 9a-h<y>drox<y>-lla, 15a-bis-(tetrahydropyran-2-yloxy)-trans-13-16- (3-thienyl)-w-tetranorprostenic acid.

Example 24

9-oxol-lla, 15a-bis-(tetrahydropyran-2-yloxy)-13-trans-16-(3-thienyl)-co-tetranorprostenic acid

To a solution, cool under nitrogen to -15 to -20°

of 0.201 g (0.371 mmol) of chromatographed acid prepared in example 103 in 4.0 ml of acetone is added dropwise 0.163 ml (0.408 mmol) of Jones reagent. The reaction is stirred cold for 15 minutes and then stopped by the addition of 0.194 ml. isopropanol. The reaction is stirred cold for 5 minutes and then diluted with ethyl acetate.

The organic solution is washed with water (2x) and saturated brine (1x), dried (anhydrous magnesium sulfate) and concentrated to give the desired 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-13-trans -16-(3-thienyl)-w-tetranorprostenic acid.

Example 25

9- oxola, 15a- dihydroxyv- 13- trans- 16-( 3- thienyl) - iQ- tetranorprostenic acid

A homogeneous solution of 0.179 g (0.328 mmol) of crude THP ether from Example 103 in 2 ml of a 65:35 mixture of acetic acid: water is stirred under nitrogen at 40 ± 2° for 5 hours. The reaction is concentrated by rotary evaporation followed by oil pumping. The crude product is purified by column chromatography on silica gel (Mallinckrodt CC-7), and gives the desired 9-oxo-11a,15a-dihydroxy-13-trans-16-(3-thienyl)-c,-tetranorprostenic acid.

Example 26 (Starting material)

2-[5Q?-hydroxy-3Q?-(tetrahydropyran-2-yloxy)-2/3-(3a-tetrahydropyran-2-yloxyJ-5-(2-furyl)-trans-l-penten-l-yl) cyclopent- lg-yl]-acetaldehyde, /- hemiacetal ( 8j): A solution of 1.6 g (3.4 mmol) 2- 15a-hydroxy-3Q?-(tetrahydropyran-2-yloxy)-2/3- (3α-tetrahydropyran-2-yloxy-5-(2-furyl)-trans-l-penten-l-yl)cyclopent-la-yl]acetic acid, ^-lactone (7j) in 16 ml of dry toluene was cooled to - 78° in a dry nitrogen atmosphere.

To the cooled solution, 4.68 ml of 0.8 M diisobutylaluminum hydride in n-hexane (Alfa Inorganics) was added dropwise at such a rate that the internal temperature did not exceed approx. -65°

(15 minutes). After a further 45 minutes of stirring at -78°

anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 150 mL of ether, washed with 50% sodium potassium tartrate solution (4 x 20 mL), dried (Na 2 SO 4 ) and concentrated to give a quantitative yield of oily 2-[5α-hydroxy-3α-(tetrahydropyran-2-yl oxy) -2/3-(3 a-^.t a rahydropyran-2 - yloxy}-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1-yl]acetaldehyde, ^- -hemiacetal (8j).

Example 27

9a-hydroxy-lla, 15o;-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-^-trisnorprostadic acid (9j);

7.0 ml (14.0 mmol) of a 2 ,OM solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1.3 g (2.81 mmol) of 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2/3- (3«-{tetrahydropyran-2- yloxy}-5-(2-furyl)-trans-l-penten-l-yl)cyclopent-la-yl]-acetaldehyde, ^-hemiacetal (8j) in 5.0 ml of dry dimethylsulfoxide over 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured onto ice water.

The basic aqueous solution was washed twice with ethyl acetate

(20 ml) and acidified to pH~3 with 10% aqueous hydrochloric acid. The sour-

The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were washed once with water (10 mL), dried (MgSO 4 ) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent

60-200 mesh) by using ethyl acetate as eluent.

After removal of high R f impurities, 1.53 g of 9a-hydroxy-11a,15a-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-wj-trisnor were obtained -prostadic acid (9j) .

Example 28

9-oxol-lla, 15a-bis-(tetrahydropyran-2-yloxy)-17-(2- furyl)-cis-5- trans- 13-v>- trisnorprostadic acid (lOi):

To a solution cooled to -10° under nitrogen of 1.1 g

(2.01 mmol) 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)~cis-5-trans-13-i*>-trisnor-prostadic acid (9j) in 20 ml

analytical grade acetone was added dropwise to 0.88 mL (2.2 mmol)

of Jones' reagent. After 20 minutes at -10°, 0.260 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and 75 ml of ethyl acetate was added, washed with water (3 x 10 ml), dried (MgSO 4 ) and concentrated, and yields 425 mg of 9-oxo-lla, 15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-u)-trisnor-prostadic acid (10j).

Example 29

9- oxo-lla, 15a- dihydroxy- 17-( 2- furyl)- cis- 5- trans- 13- uJ- trisnor-prostadic acid ( lii): A solution of 425 mg (0.782 mmol) of 9-oxo-lla, 15a-bis-t rahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-i*>-trisnor-prostadic acid (10j) in 3.0 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 h and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate as eluent.

After elution of less polar impurities, crystalline 9-oxo-11a, 15a-dihydroxy-17-(2-furyl)-cis-5-trans-13-i>-trisnor-prostadienic acid (llj) m.p. 98-99°, weight 204 mg.

The product according to this example (llj) can be transferred to 17-(2-furyl)-<^-trisnorprostaglandins-Ej and Eq via

the procedures in Examples 17 and 16.

Example 30

9a , lia , 15a?- trihvhydroxy- 17-( 2- furyl) - cis- 5- trans- 13- cv>- trisnor-prostadienic acid ( 12j): A solution of 700 mg (0.334 mmol) 9a;-hydroxy-lla ;, 15α-bis-tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-L^-trisnorprostadic acid (9j) in 5 ml of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at 25° for 20 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate as eluent. After elution of less polar impurities, oily 9a, 11a, 15o!-trihydroxy-17-(2-furyl)-cis-5-trans-13-LO-trisnor-prostadienic acid (12j) was obtained, weight 10.8 mg.

Infrared spectrum (CHC1-.) showed a carbonyl absorption at

-1 -1

1710 cm and an absorption at 965 cm for a trans double bond.

The product according to this example (12j) can be transferred to 17-(2-furyl)-uJ-trisnorprostaglandins-F^ and F0a via the methods in examples 17 and 16.

Claims (1)

Analogous process for the preparation of physiologically active prostaglandin compounds of the E or F series with the formula: where Ar is α- or β-furyl, α- or β-thienyl, α- or β-naphthyl, phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or monosubstituted phenyl wherein the substituent is halogen, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; W is a single bond or a cis-double bond; Z is a single bond or trans double bond; n is an integer from 0 to 5, with the proviso that when Ar is phenyl, substituted phenyl or naphthyl, n is 0 or 1 and Z is a single bond; the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups in the Cg, C^ and C^ positions, and pharmaceutically acceptable salts thereof, characterized in that (a) a compound of the formula: where Ar, n, M, W and Z are as indicated above, and THP is 2-tetrahydropyranyl, is reacted with a suitable acid; (b) a compound of formula I above wherein M is oxo is reacted with a suitable reducing agent to form a compound of formula I wherein M is and Ar, n, W and Z are as indicated above,' and optionally the 9a and 9f isomers are separated; (c) a compound of formula I above wherein Ar, R, n and M are as defined above, W is a single bond or a cis double bond when Z is a trans double bond, and W is a cis double bond when Z is a single bond, is catalytically hydrogenated to form a compound of formula I above wherein Ar, n and M are as defined above, and W and Z are single bonds; (d) a compound of formula I above wherein Ar, n and M are as above and W and Z are double bonds is selectively hydrogenated to form a compound of formula I wherein Ar, n and M are as above, W is a single bond and Z is a trans double bond; and optionally the 9a-, 11a-, 15a-lower alkanoyl, -formyl- or -benzoyl esters of any free hydroxyl groups are prepared by reacting the compound of formula I with a suitable acylating agent, and optionally a pharmaceutically acceptable salt of a compound of formula I is prepared.