NO147836B - NEW 16-ARYLOXY SUBSTITUTED OMEGA TETRANOR PROSTAGAGININES FOR USE AS FERTILITY CONTROLLING AGENT, ANTI-PREGNANCY OR BRUNCH CYCLE SYRCHANGE AGENT - Google Patents

Description

The present invention relates to certain new analogues of

naturally occurring prostaglandins for use as a fertility regulating agent, pregnancy termination agent or agent for synchronizing the estrus cycle in domestic animals.

Prostaglandins are C-20 unsaturated fatty acids that have various physiological effects. Prostaglandins of the E and A series are 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. one.; 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 effect of PGE^ and PGE2 is as a bronchodilator (Cuthbert,

Brit. With. J. 4:723-726, 1969).

Yet another important physiological effect of the natural prostaglandins is in connection with the reproductive cycle.

PGE2 is known to have the ability 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 is useful for regulating fertility (Karim, Contraception,

3^, 173 (1971) ) . Patents have been obtained for a number of prosta-

glandins 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 and F^ for regulation of the reproductive cycle (southern

African patent 69/6089).

Additional known physiological effects for PGE^ are

for the inhibition of gastric acid secretion (Shaw and Ramwell, in:

Worcester Symp. on Prostaglandins, New York, Wiley, 1968,

pp. 55-64) and also for the platelet agglomeration (Emmons et al.,

Brit. With. J. 2:468-472, 1967).

It is known that such physiological effects can only

is produced in vivo for short periods of time after the administration of a prostaglandin. A large body of material indicates that the reason for this rapid cessation of action is that the natural prosta-

glandins are rapidly and efficiently deactivated metabolically by S-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 therein).

It is of course desirable to provide analogues

of prostaglandins that have physiological effects that correspond 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 followed by systemic administration of natural prostaglandins (see Lancet, 536, 1971).

According to the invention, a new 16-aryloxy-substituted-w-tetranorprostaglandin is provided for use as a contraceptive, with the formula

and C^-epimers thereof; wherein Ar is phenyl or monosubstituted phenyl, wherein the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy; W is a single bond or cis-double bond; Z is a single bond or trans double bond; M is oxo, or X is tetrazolyl; a group of the formula -COOR<1>, where R' is hydrogen or p-biphenyl, with the proviso that R<1> is not hydrogen when W is a cis-double bond, or X is a group of the formula

where R" is acetyl, benzoyl, alkyl-

sulfonyl with from 1 to 3 carbon atoms or phenylsulfonyl.

The new compounds of formula I can be prepared by:

(a) reaction of a compound of the formula:

wherein Ar, M, W, X and Z are as defined above, and THP is 2-tetrahydropyranyl, with aqueous acetic acid to form the desired compound of formula I wherein Ar, M, W, X and Z are as defined above; (b) selective hydrogenation with hydrogen in the presence of a palladium-on-charcoal catalyst of a compound of formula I or the trialkylsilyl ester of a compound of formula I wherein X is COOH, Ar, X and M are as defined above, and W and Z are double bonds, to form the desired compound of formula I where Ar, X and M are as indicated above, W is a single bond and Z is a trans double bond; and optionally converting the compounds of formula I where X is COOH into esters thereof by reaction with suitable esterification agents.

Preferred compounds according to the invention are:

(i) PGF compounds of the formula:

and the C-3 epimers thereof, wherein Ar, W, Z and X are as indicated above; and (ii) the PGE compounds of the formula:

and the C 1 -epimers thereof, where Ar, W, Z and X are as indicated above.

The intermediate used in the preparation of the PGF compound of formula IA above is a compound of the formula:

and the C-^i- epimer thereof, and the Cg- and C^^-epimers thereof;

where THP is 2-tetrahydropyranyl, and Ar, W, Z and X are as stated above for formula I. The intermediate of formula IIA can be prepared by a process comprising:

(a) reaction of a compound of the formula:

where Ar, THP and Z are as indicated above, with a ylide of the formula: where X is as indicated above, with the proviso that when X = COOR<1>, the compound of formula VA is first reacted with a ylide of the formula: and optionally the resulting product is esterified to form a compound of formula IIA wherein Ar, X and Z are as indicated above, and W is a cis-double bond, and optionally the compound thus formed is then hydrogenated to give a compound of formula IIA wherein Ar, X and Z are as above, and W is a single bond; (b) hydrogenating a compound of formula IIA above, wherein Ar and X are as defined above, W is a cis double bond and Z is a trans double bond, to form a compound of formula IIA above wherein Ar is as defined above , and W and Z are single bonds; (c) selectively hydrogenating a compound of formula IIA above, wherein Ar and X are as defined above, W is a cis double bond and Z is a trans double bond, to form a compound of formula IIA wherein Ar and X are as indicated above, W is a single bond and Z is a trans double bond.

The intermediate used in the preparation of the PGE compound of formula IB above is a compound of the formula: and the C^^ epimer thereof, where Ar, W, Z, X and THP are as indicated above, and this intermediate of formula IIB can be prepared by reacting a compound with the formula

where Ar, THP, X, W and Z are as above, with chromic acid in aqueous sulfuric acid and acetone.

Further intermediates which can be used in the preparation of the compounds according to the invention are those which have the following formulas III, IV, V and VI.

The intermediate with the formula:

where Ar is phenyl or monosubstituted phenyl where the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy, and Q is p-biphenylcarbonyl, can be prepared by reacting a compound of the formula: where Q is as indicated above; with a compound of the formula:

where Ar is as stated above.

The intermediate of the formula: where Ar is phenyl or monosubstituted phenyl where the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy, and Q<1> is hydrogen or p-biphenylcarbonyl, can be prepared by reduction of a compound of formula III: where Ar and Q is as indicated above, to form a compound of formula IV where Ar and Q are as indicated above, and optionally the 8a and 83 isomers are separated; and optionally reacting a compound of formula IV where Ar is as indicated above and Q is biphenylcarbonyl, with K^ CO^ to form a compound of formula IV where Q is hydrogen; and optionally the 8a and 80 isomers are separated.

The intermediate with the formula:

where Ar is phenyl or monosubstituted phenyl where the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy; THP is 2-tetrahydropyranyl; Z is a single bond or a trans double bond; and Y is 0 or may be prepared by reacting a compound of the formula: where Ar and Z are as defined above, and Y is =0, with 2,3-dihydro-pyran in the presence of an acid catalyst to form a compound of the formula V where Ar and Z are as above, and Y is =0; reacting a compound of formula V wherein Ar and Z are as above and Y is =0 with diisobutyl aluminum hydride to form a compound of formula V wherein Ar and Z are as above and Y is

by catalytic reduction of a for-

bond of formula IV wherein Ar is as defined above, Z is one

■ trans double bond and Y is =0, to form a compound of formula V where Ar is as indicated above, Y is =0 and Z is a single bond.

The intermediate with the formula:

where Ar is phenyl or monosubstituted phenyl where the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy, can be prepared by reacting a lower alkyl ester of the formula: where Ar is as indicated above, with a dialkylmethylphosphonate of the formula:

Preferred compounds are 16-phenoxy-PGE 2 ~ p-biphenyl ester, 16-phenoxy-PGF 2 α ~ p-biphenyl ester and 16-phenoxy-PGF 2 J 3 ~ p-biphenyl ester.

Other preferred prostaglandins are as follows:

A compound of formula I wherein X is -CO-NHR",

R" is acetyl, W is a cis-double bond, and Ar is phenyl.

A compound of formula I wherein X is tetrazolyl, W is a cis double bond, Z is a trans double bond and Ar is phenyl.

A compound of formula I wherein X is -CO-NHR", R" is methylsulfonyl, W is a cis double bond, Z is a trans double bond and Ar is phenyl.

A compound of formula I wherein X is -CO-NHR", R" is methylsulfonyl, W is a cis double bond, Z is a trans double bond, and Ar is m-methoxyphenyl.

A compound of formula I wherein X is -CO-NHR", R" is acetyl, W is a cis double bond, Z is a trans double bond and Ar is m-methoxyphenyl.

New intermediates with the formula below can be produced by the methods described here.

and Cg- and C^,--epimers thereof;

where Ar is phenyl or monosubstituted phenyl where the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy,

THP is 2-tetrahydropyranyl, W is a single bond or a cis double bond, Z is a single bond or trans double bond, and X is

a) p-phenyl-phenoxycarbonyl,

b) tetrazolyl, or

c) a group of the formula -CO-NHR" where R" is acetyl, benzoyl, alkylsulfonyl with 1 to 3 carbon atoms or phenylsulfonyl. The starting material for the new compounds according to the present invention is available commercially and can be produced according to well-known methods in the field. For the production of e.g. Dimethyl-2-oxo-3-phenoxypropylphosphonate, the starting material for the synthesis of 16-phenoxy-prostaglandins, cools a solution of dimethylmethylphosphonate in tetrahydrofuran to -78° in a dry nitrogen atmosphere and then adds dropwise n-butyllithium in hexane. After stirring, methyl-2-phenoxy-acetate is added dropwise. After 3 to 4 hours at -78°, the reaction mixture is warmed to ambient temperature, neutralized with acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in water, the aqueous phase is extracted into chloroform and the combined organic extracts are backwashed, dried and concentrated to give the desired product.

To prepare 16-phenoxy-prostaglandins one needs substituted phenoxy-acetic acids which are prepared by condensation of a suitable phenol with a haloacetic acid or ester in the presence of base as indicated by J. M. Petersen, Acta Chem. Scandinavica, 5_, 519 (1951) or M. Beroza, Agri. Food Chem., A, 49 (1956). The condensation of bromomethyl acetate with sesmol in the presence of sodium methoxide thus gives 3,4-methylenedioxyphenoxy-acetic acid methyl ester. In a similar way, p-chlorophenoxy-acetic acid, 3,4,5-trimethoxyphenoxy-acetic acid and p-phenyl-phenoxy-acetic acid are prepared.

The steps leading to the production of the compounds according to the invention are illustrated in the reaction schemes below.

As shown in Scheme A, the first step in the complete synthesis {1 -> 2) is the condensation of the appropriate ester with a dialkyl methylphosphonate to give ketophosphonate 2. These esters are obtained as previously described.

1 2 —> 3 the ketophosphonate 2_ is reacted with the known

[Corey et al., J. Am. Chem. Soc. , 9J3 , 1491 (1971)] aldehyde H, and one obtains, after chromatography or crystallization, the enone _3.

The enone 3^ can be reduced with zinc borohydride or with trialkyl borohydrides, such as lithium triethylborohydride, to a mixture of alcohols, 4 and 5 which can be separated by column chromatography. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually used as solvents, although it is sometimes preferred to use methanol to ensure specific reduction. Further transformation of A_ is shown in Scheme B: 4^ —> 6 is a base-catalyzed hydrolysis where the p-biphenylcarbonyl protecting group is removed. This is conveniently carried out using potassium carbonate in methanol or methanol-tetrahydrofuran solvent. j5 —> 1_ comprises the protection of the two free hydroxyl groups with an acid-labile protecting group. Any sufficiently acid labile group is satisfactory; the most common is tetrahydropyranyl, which can be introduced into the molecule by treatment with dihydropyran and an acid catalyst in an anhydrous medium. The catalyst is usually p-toluenesulfonic acid. 2 —> _8 is a reduction of the lactone 1_ to the hemiacetal 8^ using diisobutyl aluminum hydride in an inert solvent. It is preferred to use low reaction temperatures and -60 ti]. -70°C is common. However, a higher temperature can be used if over-reduction does not take place. 8 is purified if desired by column chromatography. 8 —>• 9 is a Wittig condensation where hemiacetal 8 is reacted with (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in dimethylsulfoxide, in the presence of sodium methylsulfinyl methide.

9 is cleaned as indicated above.

The transfer _9 —> _12 is an acid hydrolysis of the tetrahydro-pyranyl groups. An acid which does not cause destruction of the molecule during the removal of the protecting group can be used, however this is usually carried out by using 65% aqueous acetic acid. The product is cleaned as indicated above.

9 —> 10 is an oxidation of the secondary alcohol 9 to

to the ketone 10. This can be achieved by using an oxidizing agent that does not attack the double bonds; however, it is usually preferred to use Jones reagent. The product is cleaned as indicated above. 10 —> 11. is carried out in the same way as j) —> 12. The product is cleaned as stated above. As illustrated in form C, _5 can be used instead of 4_ i scheme B, and prostaglandin derivatives 12' and 11' are obtained

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

In 3 —> 1_9 + 19', the enone 3^ is reduced to the tetrahydro compound by using reducing agents which are complex metal hydrides, LiAlH^, NaBH^, KBH^, LiBH^ and Zn(BH4)2. Particularly preferred is NaBH^. The products <_>19 and 19^_ are separated from each other by column chromatography.

Moreover, the compounds 4_ and 5_ in scheme A can be catalytically reduced with hydrogen to _19_ and 19', respectively. The step in which the double bond is reduced is not critical, and the hydrogenation of (> or 1_ in Scheme B can also provide useful intermediates for 13,14-dihydroprostaglandin analogues of the present invention. This reduction can be achieved either with a homogeneous catalyst such as tris( triphenylphosphine)chlororhodium, or with a heterogeneous catalyst such as platinum, palladium or rhodium.

The transfer of 19 and 19' to the respective prostaglandins follows the pathway shown in Scheme B when _4 is replaced by 19 and 19' and. gives the 13,14-dihydro-PGE2, PGA2 and PGF2 series of prostaglandin derivs.

Scheme E illustrates the preparation of the various reduced 15-substituted-oj-pentanorprostaglandin primers: _19 —> 2_2 is carried out as illustrated in Scheme B for 4^ —> j).

22 can be used both as a precursor to a 13,14-dihydro-15-substituted-aj-pentanorprostaglandin of the "2-series" or as an intermediate to 2_3, a precursor to a 13,14-dihydro-15-

substituted-w-pentanorprostaglandin of the "1 series".

22 —> 2_3 is carried out by catalytic hydrogenation using the catalyst described for the reduction of 4_ —> _19 in scheme D. The intermediates of type 2JL are prepared by selective hydrogenation of the 5,6-cis double bond at low temperature using catalysts such as those described for 4 -> 19 and _17 -> 23. Particularly preferred in this reduction is the use of palladium on carbon as a catalyst and a reaction temperature of -20°. The intermediates of type 2J. are not only precursors to 15-substituted-io-pentanorprostaglandins of the "1-series" via the route _9 —> _15 in Scheme B, but also a precursor to the compounds of type 2_3 via the route already discussed for 22 —> 23.

15-substituted-io-pentanorprostaglandins of the and F .^ series can further be obtained directly from the corresponding prostaglandin analog of 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 analog with dimethylisopropyl-chlorosilane and triethylamine, the reduction is achieved as above for 9 —> 2J1 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 finished.

The C^^-epimers of 2^1, 22 and 23 can be used as precursors

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

In the preceding methods where purification by means of chromatography is desired, preferred chromatographic supports are neutral A^O^°9 silica gel and 60-200 mesh silica gel. Chromatography is conveniently performed in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane as further illustrated in the examples.

It will be seen that the preceding formulas indicate optically active compounds. However, it will be clear that the corresponding racemates will have valuable biological activity due to their content of the above-mentioned biologically active optical isomer,

and such racemates are also covered by the preceding formulas and by the claims. The racemic mixtures are easily prepared by the same methods used to synthesize the optically active compounds, by simply using the corresponding racemic precursors instead of the optically active starting materials.

In numerous in vivo and in vitro tests we have demonstrated

that the new prostaglandin analogues have physiological effects that are comparable to the effects of the natural prostaglandins. These tests include, among other things, a test of the effect on isolated

smooth muscle from guinea pig uterus, guinea pig ileum and rat uterus, the inhibition of histamine-induced bronchospasm in guinea pigs and the effect of blood pressure in dogs, the inhibition of stress-induced ulceration in rats, the inhibition of gastric acid and pepsin secretion in rats and

dog, the inhibition of collagen- or ADP-induced platelet agglomeration and aborticidal action in rats and guinea pigs by luteolytic and non-luteolytic mechanisms.

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, antithrombogenic action, antiulcer action, smooth muscle action [useful as a fertility regulator and pregnancy termination agent],

and fertility-regulating effect via a mechanism that does not affect the smooth muscle, e.g. luteolytic mechanisms, and the synchronization of the estrous cycle in livestock.

The new compounds according to the present invention have

more selective action profiles than the corresponding naturally occurring prostaglandins, and in many cases have a longer duration of action. 16-f-enoxy-ui-tetranor-prostaglandin-E2, which has a smooth muscle-stimulating effect comparable to PGE2, is ineffective in the inhibition of histamine-induced bronchospasm

in guinea pigs. Moreover, although the threshold dose for the hypotensive response of 16-f enoxy-w-tetranor-PGE,, in dogs is higher than for PGE2, the duration of action is markedly prolonged compared to PGE2. 15-substituted-w-pentanor prostaglandins of PGEQ, <F>0/3' F13'<F>2j3 °^ 13,14-dihydro-PGF2^ have a similar stimulating effect on smooth muscle.

Particularly useful for fertility regulation and termination of pregnancy are 16-phenoxy-w-tetranorprostaglandins of the E2, F_ and F~ series based on special excellent stimulating

2a ^ 20 r sr

effect of smooth muscle, and at the same time reduced blood pressure effects. Similarly, substituted w-pentanor prostaglandins of the PGE^ PGFQa, PGF1q, and 13,14-dihydro-PGF^ series are useful for fertility regulation and termination of pregnancy on the basis of their stimulating effects on

smooth muscle.

The new prostaglandins with an 0-OH in the 15-position are

generally less powerful, although they are often more selective than the corresponding α-hydroxyl pimers. Furthermore, prostaglandins having a 3-hydroxyl at C-15 are valuable intermediates to prostaglandins having an α-hydroxyl at C-15 via

a recycling process comprising an oxidation and reduction in C-15.

The new compounds according to the present invention can be used in a variety of pharmaceutical formulations containing the compound, and they can be administered in the same way as natural prostaglandins in a variety of routes, such as intravenous, oral, intravaginal, intra- and extra-amniotic.

For the induction of abortion, tablets or an aqueous suspension or alcoholic solution of 16-phenoxy-w-tetranor-prostaglandin can be suitably administered in oral doses of approx. 0.1-20 mg and 1-7 doses per day. For intravaginal administration, a suitable formulation is lactose tablets or an impregnated tampon of the same agent. For such treatments, suitable doses are approx.

0.1-20 mg/dose and 1-7 doses are used. For intra-amniotic administration, a suitable formulation is an aqueous solution containing 0.05-10 mg/dose and 1-7 doses are used. For extra-amniotic administration, a suitable formulation is an aqueous solution containing 0.005-1 mg/dose and 1-5 doses are used. Alternatively, the 16-phenoxy-co-tetranor-prostaglandins according to the present invention can be introduced intravenously to induce abortion in doses of 0.05-50 ug/minute during 1-24 hours.

For synchronization of the estrous cycle in pigs, sheep, cows or horses, a solution or suspension containing 0.03-30 mg/day of 16-phenoxy-io-tetranor-prostaglandin is administered subcutaneously from 1-4 days.

For the production of the above-mentioned dosage forms or

the numerous other possible forms use various reaction-initiated diluents, excipients or carriers. • 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, stabilizers or other therapeutic agents such as antibiotics.

It is possible to carry out various modifications in the top side chain of the prostaglandins according to the present invention; such modifications do not, as a rule, change the basic biological effect of the prostaglandins, although they may further increase the selectivity and duration of the effect and reduce the toxicity. E.g. can introduce a tetrazolyl group in the C 1 position as described in US patent application 177,102 and in the examples. E.g. 16-phenoxy-PGE2-tetrazolyl has the same application as 16-phenoxy-PGE^-esters; namely induction of labor or abortion.

Another modification in the upper side chain can be carried out in the prostaglandins according to the present invention by replacing the carboxyl group in the C 1 position with a carboxamide group. Alternatively, the new compounds according to the present invention of formula I (where X is CO-NHR" and where R" is as indicated above), can be prepared from compounds 9 and 10 in scheme B (or the corresponding 15-epimers or 15-lower alkyl -derivatives of _9 and 10) by reacting the appropriate isocyanates, followed by hydrolysis with dilute acid. The use of N-methylsulfonyl-16-phenoxy-PGE2-carboxamide is e.g. the same as for 16-phenoxy-PGE2~esters.

A particularly useful ester is the p~"bipheny ester. Such esters are prepared in the examples by simply adding p-phenylphenol to the prostaglandin in methylene chloride in the presence of a dehydrating agent, e.g., dicyclohexylcarbodiimide, and stirring overnight. Although they are not more potent in in vitro experiments on smooth muscle, aborticidal evaluation of 16-phenoxy-a)-tetranor-PGE2 and PGF2c(-p-biphenyl esters shows that these p-biphenyl esters have physiological effects that are markedly greater than the free acids.

The following preparations illustrate the preparation of starting materials and intermediate products used in the preparation of the compounds according to the invention, and the examples illustrate the preparation of the compounds according to the invention. In these preparations and examples, all temperatures are given in °C and all melting and boiling points are uncorrected.

Preparation A

Pyrnetyl-2-oxo-3-phenoxypropylphosphonate

A solution of 33.2 g (268 mmol) of dimethyl methylphosphonate (Aldrich) in 360 ml of dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution, 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) was added dropwise over 18 minutes and at such a rate that the reaction temperature did not rise above -65°. After a further 5 minutes of stirring at -78°, 22.2 g (134 mmol) of methyl-2-phenoxyacetate were added 4 times at a rate such that the reaction temperature was lower than -70° (20 minutes). After 3.5 hours at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 mL water, the aqueous phase extracted with 100 mL portions of chloroform (3x), the combined organic extracts were backwashed (50 mL H 2 O), dried (MgSO 4 >), concentrated (water aspirator) to a crude residue and distilled, b.p. 172-175° (0.5 mm) and 24.6 g of dimethyl-2-oxo-3-phenoxypropylphosphonate are obtained.

Nuclear magnetic resonance spectrum (CDCl^) showed a

doublet centered at 3.75 6 (J = 11.5 eps, 6H) for

0

(CH30)-P-), a singlet at 4.7 6 (2H for CgB^O-CH^-CO- , a doublet centered at 3.24 6 (J = 23 eps, 2H)«

0

II

-C-CH2~P- and a multiplet at 6.8-7.5 6 (5H) for aromatic protons.

Production B

2-[ 3g- p- phenylbenzoyloxy- 5a- hydroxy- 2S-( 3- oxo- 4- phenoxy- trans-1- buten- l- yl) cyclopent- la- yl] acetic acid, y~ lactone

Dimethyl 2-oxo-3-phenoxypropylphosphonate (5.4 g) (21 mmol)

in 200 ml of anhydrous ether was treated with 7.9 ml (19 mmol)

2.5M n-butyllithium in n-hexane (Alfa Inorganics, Inc.) in a dry nitrogen atmosphere at room temperature. After stirring for 5 minutes, a further 400 ml of anhydrous ether was added, followed by 6.0 g (17 mmol) of 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-26-

formylcyclopentan-la-yl]acetic acid, γ-lactone in one portion and 50 ml of anhydrous ether. After 35 minutes, the reaction was quenched with 5 ml of glacial acetic acid and washed with 100 ml of saturated sodium bicarbonate solution (4x), 100 ml of water (2x), 100 ml of saturated saline solution (1x), dried (MgSO 4 ) and evaporated, and gives 5.2 g of 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-20-(3-oxo-4-phenoxy-trans-l-buten-l-yl)-cyclopent-la-yl]acetic acid, y- lactone as a solid after column chromatography (silica gel, Baker, 60-200 mesh); sm.p. 112-114° after crystallization from methylene chloride-hexane.

The infrared spectrum (KBr) of the product showed absorption bands at 1775 cm <-1> (strong), 1715 cm <1> (strong), 1675 cm <1 > (moderate) and 1630 cm ^ (moderate) due to carbonyl groups and at 970 cm^ for the trans double bond.

Manufacturing C

2-[3a-p-phenylbenzoyloxy-5a-hydroxy-20-(3a-hydroxy-4-phenoxy-trans-l-buten-l-yl)cyclopent-la-yl]acetic acid, y-lactone

To a solution of 5.1 g (10.5 mmol) of 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-20-(3-oxo-4-phenoxy-trans-l-buten-l-yl)-cyclopent -la-yl]acetic acid, γ-lactone in 30 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise to 11 ml (5.5 mmol) of a 0.5 M zinc borohydride solution. After stirring at room temperature for 2 hours, a saturated sodium bitartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes and then 250 ml of dry methylene chloride was added. After drying (MgSO 4 ) and concentration (water aspirator), the resulting semi-solid material was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ether as eluent. After elution of less polar impurities, a fraction containing 896 mg of 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-2ø-(3a-hydroxy-4-phenoxy-trans-l-buten-l-yl)cyclopent- la-yl] acetic acid, γ-lactone, a 600 mg fraction of mixed 4 and 5 and finally a fraction

(1.5 g) of 2-[3α-p-phenylbenzoyloxy-5α-hydroxy-20-(30-hydroxy-4-phenoxy-trans-l-buten-yl)cyclopent-la-yl]acetic acid, γ-lactone .

Infrared spectrum (CHC1-.) of 4_ had strong carbonyl absorptions at 1770 and 1715 cm -1 and an absorption at 970 cm<-1 >for the trans double bond.

in

Manufacturing D

2-[3a,5a-dihydroxy-20-(3a-hydroxy-4-phenoxy-trans-l-buten-l-yl)-cyclopent-la-yl]acetic acid, γ-lactone

A heterogeneous mixture of 846 mg (1.7 mmol) of 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-20-(3a-hydroxy-4-phenoxy-trans-l-buten-l-yl) cyclopent-la -yl]acetic acid, γ-lactone, 10 ml of absolute methanol and 120 mg of finely powdered anhydrous potassium carbonate were stirred at room temperature for 20 hours, and then cooled to 0°. To the cooled solution was added 1.75 ml of a 1.0N aqueous hydrochloric acid. After stirring at 0° for a further 10 minutes, 10 ml of water were added with the simultaneous formation of methyl-p-phenyl-benzoate which was collected by filtration.

The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (4 x 10 ml), the combined organic extracts were washed with saturated sodium bicarbonate (10 ml), dried (MgSO 4 > and concentrated to give 445 mg of viscous, oily 2-[ 3α-5α-dihydroxy-20-(3α-hydroxy-4-phenoxy-trans-1-buten-1-yl)-cyclopent-la-yl]acetic acid, γ-lactone.

Infrared spectrum (CHC1_.) showed a strong absorption at

-1 -1 1772 cm for lactone carbonyl and medium absorption at 965 cm for trans double bond. Preparation E 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy-20-(3a-tetrahydropyran-2-yloxy-4-phenoxy-trans-l-buten-l-yl)cyclopentla-yl]- acetic acid, γ-lactone To a solution of 445 mg (1.46 mmol) 2-[3α,5α-dihydroxy-20-(3α-hydroxy-4-phenoxy-trans-1-buten-yl)cyclopent-la-yl ]-acetic acid, γ-lactone in 5 ml of anhydrous methylene chloride and 0.4 ml of 2,3-dihydro-pyran at 0° in a dry nitrogen atmosphere was added 5 mg of p-toluenesulfonic acid, monohydrate. After stirring for 15 minutes, the reaction mixture was mixed with 100 ml of ether, the ether solution was washed with saturated sodium bicarbonate (1 x 15 ml), then saturated brine (1 x 15 ml), dried (MgSO 4 ) and concentrated to give 752 mg (>100%) of impure 2-[5a -tetrahydropyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl)-cyclopent-la-yl]-acetic acid, γ-lactone. Infrared (CHC1,) spectrum had a medium absorption at -1 -1970 cm for trans double bond and at 1770 cm for lactone carbonyl. Preparation F 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-23-(3α-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl)cyclopent-la-yl] -acetaldehyde, γ- hemiacetal A solution of 690 mg (1.46 mmol) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3a-tetrahydropyran-2-yloxy-4-phenoxy-trans -1-buten-1-yl)cyclopent-la-yl]acetic acid, γ-lactone in 8 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere. To the cooled solution was added dropwise 2.0 ml of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) at such a rate that the internal temperature did not rise above -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 100 ml of ether, washed with 50% sodium potassium tartrate solution (4 x 20 ml), dried (Na2SO4) and concentrated, and 613 mg of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)- 23-(3α-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl)cyclopent-1-yl]acetaldehyde, γ-hemiacetal.

Production G

9a- hydroxy- lla, 15a- bis-( tetrahydropyran-2- yloxy)- 16- phenoxy- cis- 5- trans- 13- co- tetranor- prostadiic acid

To a solution of 1.6 g (3.6 mmol) of (4-carboxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 ml of dry dimethyl sulfoxide was added 3.24 ml (6.5 mmol) of a 2, ON SOLUTION OF SODIUM METHYL SULFINYL METHIDE IN DIMETHYL SULFOXIDE. To this red ylide solution was added dropwise, a solution of 613 mg (1.29 mmol) of 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3a-tetrahydropyran-2-yloxy-4-phenoxy -trans-l-buten-l-yl) cyclopent-la-yl] acetaldehyde, γ-hemiacetal in 5.0 ml of dry dimethylsulfoxide over 20 minutes. After further stirring for 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 once with water (10 mL), dried (MgSO 4 ) and evaporated to a solid residue. There the solid residue was triturated with ethyl acetate and the filtrate was concentrated, and 754 mg of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-u)- tetranorprostadic acid.

Infrared spectrum (CHC1_) showed a strong band at

-1

1720 cm for the carboxyl group.

Production H

9- oxol-lla, 15a- bis- ( tetrahydropyran-2- yloxy)- 16- phenoxy- cis- 5- trans- 13- u)- tetranor- prostadic acid

To a solution, cooled to -10° under nitrogen, of 754 mg (1.3 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13 -w-tetranor-prostadic acid in 13 ml of analytical grade acetone was added dropwise to 0.56 ml

(1.41 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 then 75 ml of ethyl acetate was added, washed with water (3 x 10 ml), dried (MgSO 4 > and concentrated,

and 752 mg of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-a3-tetranor-prostadioic acid is obtained which was chromatographed on silica gel using ethyl acetate as eluent, and 505 mg of the pure product is obtained.

Production I

2- [ 3a- p- phenylbenzoyloxy- 5a- hydroxy- 20-( 3- hydroxy- 3- methyl- 4-phenoxy- trans- l- buten-l- yl) cyclopent- la- yl] acetic acid, y- lactone

To a solution of 2-[3α-p-phenylbenzoyloxy-5α-hydroxy-20-(3-oxo-4-phenoxy-trans-l-buten-l-yl)cyclopent-la-yl]acetic acid, γ-lactone cooled to -78° in ether-THF, an equivalent of a 2N solution of methyllithium in ether is added dropwise. After stirring at -78° for 15 minutes, the reaction was stopped by the addition of glacial acetic acid, which was sufficient to bring the pH

up to 7. The mixture was diluted with methylene chloride, washed

with water, saturated brine, dried (NaSO^) and concentrated to give the oily epimeric alcohols. The crude product is purified by column chromatography on silica gel, and the desired 2-[3a-p-phenylbenzyloxy-5a-hydroxy-23-(3-hydroxy-3-methyl-4-phenoxy-trans-l-buten-l-yl) is obtained -cyclopent-la-yl]acetic acid, γ-lactone.

Production J

2-[ 3a- p- phenylbenzyloxy- 5a- hydroxy- 23-( 3a- hydroxy- 4- phenoxy-but- l- yl)- cyclopent- la- yl] acetic acid, y- lactone

A heterogeneous solution of 2.5 g of 2-[3a-p-phenyl-benzoyloxy-5a-hydroxy-23~(3a-hydroxy-4-phenoxy-trans-l-buten-l-yl)-cyclopent-la-yl ]acetic acid, γ-lactone and 0.25 g of 5% palladium on charcoal in 30 ml of absolute methanol are stirred at 1 atmosphere of hydrogen for 4 hours. The mixture is then filtered and concentrated to give 2-[3α-p-phenylbenzoyloxy-5α-hydroxy-23-(3-oxo-4-phenoxy-but-1-yl)cyclopent-la-yl]acetic acid, γ-lactone .

An excess of sodium borohydride is added to a solution of 1.9 g of the impure hydrogenation product above in 20 ml of absolute methanol and the solution is stirred at room temperature under nitrogen for 2 hours and then concentrated. The residue is diluted with 0.1N hydrochloric acid and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with saturated saline, dried (Na 2 SO 4 ) and concentrated. The purification of the crude residue by means of silica gel chromatography gives 2-[3a-p-phenylbenzyloxy-5a-hydroxy-23-(3a-hydroxy-4-phenoxy-but-1-yl)cyclopent-la-yl]-acetic acid, y -lactone and 33-hydroxy-epimer.

Production K

9a- hydroxy- lla, 15a- bis-( tetrahydropyran-2- yloxy)- 16- phenoxy-13- trans- iota- tetranorprostenic acid

A heterogeneous mixture of 800 mg of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-w-tetranor-prostadioic acid and 80 mg of 5% palladium on charcoal in 10 ml of absolute methanol is stirred at 1 atmosphere of hydrogen at -22° for 5 hours. The mixture is then filtered and the filtrate is concentrated, and 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-13-trans-α)-tetranorprostenic acid is obtained.

Hydrolysis with acetic acid and water in the usual way gives

16-fencksy-PGF^ .

Production L

4-(tetrazol-5-yl)butyltriphenylphosphonium bromide

A mixture of 5-bromovaleronitrile (16.2 g, 0.10 mol),

triphenylphosphine (26.2 g, 0.10 mol) and toluene (100 ml) were

acted under reflux with stirring under nitrogen for 16 h. The resulting thick white suspension was de-

cooled to room temperature and filtered. The residue was washed with benzene and air-dried to give 33.0 g of a white, crystalline solid, m.p. 230-232°, which was 4-cyanobutyltriphenyl-phosphonium bromide.

Analysis: Calculated for C23H23<B>rNP: C 65.10, H 5.47, N 3.30

Found: C 65.01, H 5.40, N 3.19.

A mixture of the above phosphonium salt (10.0 g, 23.5 mmol), ammonium chloride (1.60 g, 30.0 mmol), lithium chloride (0.032 g,

0.76 mmol), sodium azide (1.91 g, 29.3 mmol) and dimethylformamide (50 mL) were heated to 127° (oil bath) under nitrogen with stirring for 18 h. The resulting suspension was cooled and filtered. The residue was washed with dimethylformamide and the combined filtrate and washing solutions were concentrated (aspirator-

pressure, approx. 45°). The oily residue was crystallized from water at 0° and air dried to give a white crystalline solid (8.11 g), m.p. 100-102°. The product was recrystallized from methanol-ether to give white prisms (7.18 g), m.p. 197-

206°. An analytical sample was prepared by recrystallization from 2-propanol, and a white, crystalline powder is obtained,

sm.p. 212-213°, which was 4-(tetrazol-5-yl)butyltriphenylphosphonium-

bromide.

Analysis:

Calculated for <C>2?H24H4PBr: C 59.10, H 5.17, N 11.99, P 6.63, Br 17.09 Found: C 59.35, H 5.28, N 12.31, P 6.78, Br 17.26.

Production M

1-(tetrazol-5-yl)-9a-hydroxy-lla, 15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-gj-tetranor-prostadien

To a solution of 4-(tetrazol-5-yl)butyltriphenylphosphonium-

bromide (1.49 g) under a dry nitrogen atmosphere in 6.0 mL of dry DMSO was added to 3.24 mL of a 2.0 M solution of sodium methyl sulfinyl methide in DMSO. To this solution was added dropwise a solution of 615 mg of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-23-(Sa-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-butene- 1-yl)-cyclopent-la-yl] acetaldehyde, γ-hemiacetal in 5.0 mL dry DMSO 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 acidified with 0.1N HCl and extracted with ethyl acetate. The obtained residue was chromatographed after evaporation of the solvent, and pure 1-(tetrazol-5-yl)-9a-hydroxy-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5 is obtained -tr ans-13-oj-tetranor-prostadien.

Production N

[ 4-( methanesulfonylaminocarbonyl) butyl]- triphenylphosphonium bromide

A mixture of 0.950 g (0.01 mol) methanesulfonamide and

1.80 g (0.01 mol) of 5-bromovaleric acid chloride was heated on a steam bath until gas evolution ceased (about 5 minutes). The brown reaction mixture was allowed to cool and was dissolved in methylene chloride. The methylene chloride solution was treated with Darco, filtered and diluted with hexane under cooling to give white crystalline N-methanesulfonyl-5-bromovaleramide, weight 2.22 g (86.0% yield) melting at 88-89°.

Nuclear magnetic resonance spectrum (CDCl^) showed a broad singlet at 4.26-3.95 6 for N-H, a multiplet at 3.66-3.23 6 for -CH^Br, a singlet at 3.31 6 for SO2-CH3 , a multiplet at 2.63-2.20 6 for -CH 2 CO and a multiplet at 2.12-1.52 6 for CH 2 -CH 2 . Infrared spectrum (CHCl^) showed a strong absorption at 1720 cm 1 due to the carbonyl group.

A solution of 2.20 g (8.57 mmol) of N-methanesulfonyl-5-bromovaleramide, prepared as above, 2.24 g (8.57 mmol) of triphenylphosphine and 20 ml of acetonitrile was heated under reflux under nitrogen overnight above. The solution was then concentrated by rotary evaporation and the resulting solid was triturated with hot benzene (4x). The triturated solid was recrystallized from absolute ethanol:ether to give white crystalline [4-(methanesulfonylaminocarbonyl)butyl]triphenylphosphonium bromide, weight 2.80 g (63.7% yield) melting at 190-191<C >C.

Infrared spectrum (KBr) of the product showed a strong absorption at 5.85 µl due to the carbonyl group. Nuclear magnetic resonance spectrum (CDCl^) showed a complex multiplet at 8.14-7.27 6 for aromatic protons, a multiplet at 4.00-3.30 6 for -CH^P. a singlet at 3.12 6 for -SO 2 CH 3 , a multiplet at 3.00-2.38 6 for CH 2 CO and a multiplet at 2.23-1.38 6 for CH 2 CH 2 . Titration of the solid product indicated that the pK a1/2 was 5.25.

Production 0

1-(tetrazol-5-yl)-9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-phenoxy-cis-5-trans-13-oj-tetranorprostadien

To a solution of 4-(tetrazol-5-yl)butyltriphenylphosphonium bromide (1.49 g) in a dry nitrogen atmosphere in 6.0 ml of dry DMSO was added 3.24 ml of a 2.0M solution of sodium methylsulfinyl methide in DMSO. To this solution was added dropwise a solution of 615 mg of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2-0-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-trans-1 -buten-1-yl)-cyclopent-la-yl] acetaldehyde , γ-hemiacetal in 5.0 ml of dry DMSO 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 acidified with 0.1N HCl and extracted with ethyl acetate. The obtained residue was chromatographed after evaporation of the solvent, and 680 mg of pure, colorless, oily 1-(tetrazol-5-yl)-9a-hydroxy-11a,15a-bis-(tetrahydropyran-2-yloxy)-16- f enoxy-cis-5-trans-13-to-tetranorprostadien.

Production P

1-( tetrazol-5- yl*- 9- oxo- lla, 15a- bis-( tetrahy dropyran- 2- yloxy)-16- f enoxy- cis- 5- trans- 13- a>- tetranor- prostadiene

To a solution, cooled to -15° under nitrogen, of 600 mg of 1-(tetrazol-5-yl)-9a-hydroxy-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5 -trans-13-oj-tetranor-prostadien in 12 ml of analytical grade acetone was added dropwise to 0.6 ml of Jones reagent. After 30 minutes at -10°, 0.6 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and was combined with 75 ml of ethyl acetate, washed with water (3 x 10 ml), dried (Na 2 SO 4 ) and concentrated, and 510 mg of colorless, oily 1-(tetrazol-5-yl)-9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-io are obtained -tetranorprostadien.

Manufacturing Q

N- methanesulfonyl- 9a-hydroxyl- lla, 15a- bis-(tetrahydropyran-2- yl-oxy)- 16- phenoxy- cis- 5- trans- 13- a)- tetranor- prostadienamide

To a solution of 1.7 g of [4-methanesulfonylaminocarbonyl)-butyl]-triphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 ml of dry DMSO was added 3.2 ml (6.5 mmol) of a 2.OM solution of sodium methylsulfinyl methide in DMSO . To this red ylide solution was added dropwise a solution of 610 mg (1.29 mmol) of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-23-(3α-(tetrahydropyran-2-yloxy)-4- phenoxy-trans-l-buten-l-yl)cyclopent-la-yl]acetaldehyde, γ-hemiacetal in 5 ml of dry DMSO 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 (3 x 20 mL) and the combined organic extracts were washed once with water (10 mL), dried (Na 2 SO 4 ) and evaporated to an oil. Chromatography on silica gel gives 684 mg of pure, oily N-methanesulfonyl-9a-hydroxy-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-u>-tetranorprostadienamide.

Production R

N-methanesulfonyl-9-oxolla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-a)-tetranor- prostadienamide

To a solution, cooled to -10° under nitrogen of 400 mg

0.4 ml Jones reagent was added dropwise to 8 ml acetone of analytical quality. After 30 minutes at -10°, 0.4 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and then combined with 60 ml of ethyl acetate, washed with water (3 x 10 ml), dried (Na 2 SO 4 > and concentrated, and 380 mg of colorless, oily N-methanesulfonyl-9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-o)-tetranor-prostadienamide are obtained.

Production S

N- acetyl- 9a- hydroxy- lla, 15g- bis-( tetrahydropyran-2- yloxy)- 16-phenoxy- cis- 5- trans- 13- cate- tranor- prostadienamide

To a solution of 5.32 g of [4-(acetamido-carbonyl)butyl]-triphenylphosphonium bromide in a dry nitrogen atmosphere in 10 ml of dry DMSO was added 17.7 ml of a 2.0M solution of sodium methyl sulfinyl methide in DMSO. To this red ylide solution was added dropwise a solution of 0.524 g (1.1 mmol) of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-20-(3α-(tetrahydropyran-2-yloxy)-4- phenoxy-trans-l-buten-l-yl)cyclopent-la-yl]acetaldehyde, γ-hemiacetal in 10 ml of dry DMSO 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 (3 x 25 mL) and the combined organic extracts were washed once with water

(10 ml), dried (Na 2 SO 4 ) and evaporated to an oil. Chromatography on silica gel gives 0.66 g of pure, oily N-acetyl-9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-oj-te tr anor -prostadienamide.

Production T

N- acetyl- 9- ox- olla, 15a- bis-(tetrahydropyran- 2- yloxy)- 16- phenoxy-cis- 5- trans- 13- a>- te tr anor- prostadienamide

To a solution, cooled to -10° under nitrogen, of 394 mg of N-acetyl-9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-io -tetranor-prostadienamide in 10 ml acetone of analytical quality was added dropwise to 0.27 ml Jones reagent. After 30 minutes at -10°, 0.4 ml of 2-propanol was added, and the reaction mixture was stirred for a further 5 minutes, and then combined with 60 ml of ethyl acetate, washed with water

(3 x 10 mL), dried (Na 2 SO 4 ) and concentrated, to give 390 mg of colorless oily N-acetyl-9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis- 5-trans-13-w-tetranor-prostadienamide.

Example I

p- biphenyl- 9- oxola, 15a- dihydroxy- 16- phenoxy- cis-5- trans-13- a)- tetranor- prostadienoate

To a solution of 50 mg (0.13 mmol) 9-oxo-lla,15a-dihydroxy-16-phenoxy-cis-5-trans-13-co-tetranor-prostadic acid and 63 mg (0.4 mmol) p -phenylphenol in 10 ml of dry methylene chloride was added to 825 mg (0.4 mmol) of dicyclohexylcarbodiimide and the solution was stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography, and the desired p-biphenyl ester is obtained, m.p. 100-102°.

Analysis: Calculated for C^H^Og: C 75.53, H 6.71

Found: C 75.65, H 6.83.

Example II

p- biphenyl- 9a, lia, 15a- trihydroxy- 16- f enoxy- cis- 5- trans- 13- ai-tetranor- prostadienoate

To a solution of 106 mg of 9a,11a,15a-trihydroxy-16-phenoxy-cis-5-trans-13-a)-tetranor-prostadic acid and 189 mg of p-phenylphenol in 30 ml of dry methylene chloride was added 600 mg of dicyclohexylcarbodiimide and the solution was stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography, and 80 mg of pure p-biphenyl ester is obtained,

sm.p. 101-103°.

Analysis: Calculated for C^H^Og: C 75.25, H 7.06

Found: C 75.38, H 7.30.

Additional data for this compound is given in the table below.

Example III

1-(tetrazol-5- yl)- 9a, lia, 15a- trihydroxy- 16- phenoxy- cis- 5-trans-13- ai- tetranor- prostadiene

A solution of 300 mg of 1-(tetrazol-5-yl)-9a-hydroxy-lla,15a-bis(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-a)-tetranorprostadien in 6 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-7, 100-200 mesh) using mixtures of chloroform: ethyl acetate as eluent. After elution of less polar impurities, colorless, oily 1-(tetrazol-5-yl)-9a,11a,15a-trihydroxy-16-phenoxy-cis-5-trans-13-oi-tetranorprostadiene was obtained, weight 220 mg (80 % dividend). Biological data are provided below (Compound 6).

Example IV

N- methanesulfonyl- 9a, lia, 15a- trihydroxy- 16- phenoxy- cis- 5- trans-13- co- tetra anor- prostadienamide

A solution of 250 mg of the intermediate prepared in Preparation Q in 5 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 h and then concentrated to a crude oil, which was purified by column chromatograph on silica gel (Mallinckrodt CC-7, 100-200 mesh)

by using mixtures of chloroform:ethyl acetate as eluents. After elution of less polar impurities, colorless, oily N-methanesulfonyl-9a,11a,15a-trihydroxy-16-phenoxy-cis-5-trans-13-oj-tetranor-prostadienamide was obtained, weight 180 mg. The product was found to be homogeneous by liquid-liquid chromatography. Biological data for this compound are given below (Compound 4).

Example V

N- methanesulfonyl- 9- oxola, 15a- bis- dihydroxy- 16- phenoxy- cis- 5-trans- 13- a)- te tranor- prostadienamide

A solution of 260 mg of the intermediate prepared in Preparation R in 6 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 20 hours and then concentrated to a crude oil which was purified by column chromatography on silica gel (Mallinckrodt CC-7, 100-200 mesh) by using mixtures of chloroform: ethyl acetate as eluents. After elution of less polar impurities, colorless N-methanesulfonyl-9-oxo-lla,15a-bis-dihydroxy-16-phenoxy-cis-5-trans-13-o)-tetranor-prostadienamide was obtained, weight 130 mg. The product crystallized from ether as colorless crystals, m.p. 76°. Biological data for the compound are provided below.

Example VI

N- methanesulfonyl- 9- oxola, 15a- dihydroxy- 5- cis- 13- trans- 16- f enoxy- gj- tetranorprostadienamide

To 1.0 mmol of 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-w-tetranorprostadic acid (Preparation H) in 40 ml of THF is added 2 ml of triethylamine . After stirring for 15 minutes at room temperature, 10.0 ml of 0.1 mol methanesulfonyl isocyanate in THF was added. After a further 1 hour of stirring, the reaction mixture was neutralized with acetic acid, and the solvent was removed by evaporation (in vacuo). The resulting residue was taken up in methylene chloride and washed successively with water and sodium bicarbonate to give,

after drying and evaporation of solvent, N-methanesulfonyl-9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-co-tetranorprostadienamide. This intermediate is then hydrolyzed overnight with acetic acid-water, and purified by column chromatography, and the desired N-methanesulfonyl-9-oxo-lla, 15a-dihydroxy-5-cis-13-trans-16-phenoxy-oj-tetranor is obtained -prostadienamide. Spectral data for the compound are given below.

Example VII

N- acetyl- 9a , lia , 15a- trihydroxy- 16- phenoxy- cis- 5- trans- 13-a)-tetrano r- prostadienamide

A solution of 0.39 g of N-acetyl-9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-w-tetranor-prostadienamide in 5 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 hours and then concentrated to a crude oil, which was purified by column chromatography on silica gel (CC-7) using mixtures of chloroform :ethyl acetate as eluent. After elution of less polar impurities, a colorless oil was obtained, N-acetyl-9a, lia, 15a-trihydroxy-16-phenoxy-cis-5-tr ans-13-to-te tr anor-prostadienamide, weight 95 mg. Spectral data for the compound are given in the table below.

Example VIII

N- acetyl- 9- ox- olla,15a-bis- dihydroxy- 16- phenoxy- cis- 5- tra ns-13 - lu - te tr anor- prostadienamide

A solution of 390 mg of N-acetyl-9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-oi-tetranor-prostadienamide in 8 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 20 hours and was then concentrated to a crude oil which was purified by column chromatography on silica gel using chloroform-ethyl acetate mixtures as eluents. After elution of less polar impurities, colorless, oily N-acetyl-9-oxo-lla, 15a-bis-dihydroxy-16-phenoxy-cis-5-trans-13-co-tetraIIOr-prostadienamide was obtained, weight 7 6 mg . Spectral data for the compound are given in the table below.

The following table sets out spectral data for a number of compounds according to the invention including the products from Examples VI, VII and VIII.

The table is followed by biological data illustrating the stronger and more selective antifertility effect of the compounds according to the invention with less side effects than previously known compounds.

Antifertility effect of the new compounds of formula I

I. Applied biological experimental methods.

A. In vitro spasmogenic effect on guinea pig uterus -

a test for impeding fertilization/abortion-inducing effect.

B. Determination of the effect on blood pressure in an anesthetized dog - a test of an unusual side effect observed with prostaglandins.

C. Determination of in vivo diarrhea-inducing activity in mice - a test of a common side effect observed with prostaglandins. D. Determination of in vivo abortifacient activity in rats - a test of antifertilization/abortifacient activity by a non-smooth muscle mechanism (ie, luteolytic activity). II. Advantages compared to previously known compounds.

The abortifacient effect in rats, where PGF2a is more active than PGE2, works by a luteolytic mechanism. The compounds are thus active anti-fertilization/abortion-inducing agents by this mechanism, as well as agents for synchronizing the estrous cycle in domestic animals so

such as horses and cattle.

The following data show that the compounds of formula I are 3 to 1000 times more active than PGF2q (compound 1)

in this type of investigation. Moreover, compound no. 5 exhibits a significantly lower (10x) blood pressure effect than PGF2 and one would thus expect it to have less of this side effect. Furthermore, compounds 2 and 3 show a much more favorable therapeutic index with respect to the commonly observed side effect of diarrhea, compared to

PGF„.

2a

Antifertility effect of additional compounds of formula I

I. Applied biological experimental methods.

A. In vitro spasmogenic effect on guinea pig uterus -

a test for impeding fertilization/abortion-inducing effect.

B. Determination of the effect on blood pressure in an anesthetized dog - a test of an unusual side effect observed with prostaglandins. C. Determination of in vivo diarrhea-inducing activity in mice - a test of a common side effect observed with prostaglandins. D. Determination of in vivo abortifacient activity in guinea pigs - an antifertilization/abortifacient test by a smooth muscle mechanism (ie, uterine stimulation).

II. Advantages compared to known compounds.

The following data clearly show that the new compounds (compounds 8-27) are more active and selective than both the PGE 2 (compound 7) and the ICI compounds (compound 28). The new compounds according to the invention are thus better contraceptives and abortifacients than the known compounds.

Specifically, changes in blood pressure are a side effect that is sometimes observed when PGE^ is administered to humans. Since the new analogues show 40-7200 times lower blood pressure effect than PGE2 (4-720 times lower than the ICI compound), the analogues according to the invention have much less of this side effect.

Diarrhea is possibly the most common side effect observed when prostaglandins are administered to humans. Although the compounds according to the invention exhibit similar diarrheal activity as the previously known analogues, the new compounds according to the invention have a several times better abortion-inducing effect than PGE2 (10-300 times) or the ICI analogues (3-100 times). The therapeutic index for the compounds according to the invention is thus 20-1875 times higher than for PGE2 and 10-937 times higher than for the ICI compounds.

Claims (1)

New 16-aryloxy-substituted two-tetranorprostaglandins for use as a fertility control agent, pregnancy termination agent or agent for synchronizing the estrus cycle in domestic animals, characterized in that they have the formula: where Ar is phenyl or monosubstituted phenyl, where the substituent is halogen, trifluoromethyl, lower alkyl or lower alkoxy, W is a single bond or a cis double bond, Z is a single bond or a trans double bond, M is oxo, or , X is tetrazolyl, a group of the formula -COOR<1>, where R' is hydrogen or p-biphenyl, with the proviso that R' is not hydrogen when W is a cis-double bond, or X is a group with the formula , where R" is acetyl, benzoyl, alkylsulfonyl having 1-3 carbon atoms or phenylsulfonyl, and their C 1 -epimers.