NO752734L - - Google Patents

Description

Physiologically active prostaglandin derivatives and method for their production.

The present inventions relate to new prostanic acid derivatives, and in particular new 11-epi-prostanic acid derivatives which have a luteolytic effect. The new compounds are therefore advantageous for use as contraceptives or for regulating the estrous cycle in animals. The compounds can also be used to induce labour, or as hypotensives, to alleviate bronchospasm or as inhibitors of gastric secretion or platelet aggregation.

The present invention relates to 11-epiprostanic acid derivative of the formula:

where R<1> is a carboxy or hydroxymethyl radical or an alkoxycarbonyl or alkoxymethyl radical with up to 11 carbon atoms, R 2 is a hydroxy radical or an alkoxy radical with 1-4 carbon atoms, A is an ethylene or vinylene radical, Y is an ethylene or trans -vinylene radical, X is a direct bond, an alkylideneoxy radical with 1-6 carbon atoms where alkylidene-2 3 the group is attached to -CHR - and the oxygen atom is attached to R, or an alkylene radical with 1-6 carbon atoms, and R<3>is a phenyl or naphthyl radical which may be unsubstituted or substituted with one or two substituents selected from halogen atoms, fluoro, hydroxy, phenyl or trifluoromethyl radicals, alkyl, alkenyl or alkoxy radicals each with 1-5 carbon atoms, or dialkylamino radicals where the alkyl group contains 1 -3 4 5

carbon atoms, R is a hydroxy radical and R is a hydrogen atom or R4 and R<5> together form an oxoradical, and, for compounds where R<1> is a carboxy radical, pharmaceutical or veterinary acceptable salts thereof.

A suitable meaning for R1 equal to an alkoxy-

;!carbonyl radical is, for example, a methoxycarbonyl, ethoxy

1 carbonyl, butoxycarbonyl, hexyloxycarbonyl or decyloxycarbonyl radical, in particular such an alkoxycarbonyl radical with up to 6 carbon atoms, and a suitable meaning for R* equal to an alkoxymethyl radical is, for example, a methoxymethyl, ethoxymethyl, hexyloxymethyl or decyloxymethyl radical.

A suitable meaning for R 2 equal to an alkoxy radical is, for example, a methoxy, ethoxy, propoxy or butoxy radical.

A suitable meaning for X equal to an alkylideneoxy radical is, for example, a methyleneoxy-, ethylideneoxy-(-CH(CH.j) .-0- ), isopropylideneoxy (-C(CH3)2.0-), 1-methylpropylideneoxy -

(-C(CH3)(C2H5).0-).0-) or 1-ethylpropylideneoxy (-C(C2H5)2.<0->)<->radical, and a suitable meaning for X equal to an alkylene radical is for for example a methylene-, ethylidene-, isopropylidene-, propylidene-,

1-methylpropylidene, 1-ethylpropylidene, ethylene, 1-methylethylene, 1,1-dimethylethyl, 2-methylethylene or trimethylene radical.

3 A suitable value for a halgen substituent in R "is, for example, a chlorine, bromine or fluorine atom, and a suitable value for an alkyl, alkenyl or alkoxy substituent in R3

is, for example, a methyl, ethyl, propyl, allyl, methoxy, ethoxy or propoxy radical. A fitting meaning for one

3 dialkylamino substituent in R is, for example, a dimethylamino radical.

A suitable pharmaceutical or veterinary acceptable salt is, for example, an ammonium, alkylammonium containing 1-4 alkyl substituents each with 1-6 carbon atoms, alkanolammonium containing 1 to 3 2-hydroxyethyl radicals, or an alkali metal salt, for example a triethylammonium, ethanolammonium, diethanolammonium, sodium or potassium salt.

It will be seen that the compounds of formula I contain five asymmetric carbon atoms, namely carbon atoms 8,9,11,1.2 and 15, the relative configuration of the first four being fixed, so that it is clear that these compounds exist in at least two optically active forms . It will be understood that the useful properties of the racemates (comprising the compound of formula I and its mirror image) may be present to varying extents in optical isomers, and that the invention encompasses the racemic form and an optically active form having the same useful properties, as it is known how the optically active forms can be obtained and the respective biological properties determined. It will also be understood that the present invention relates to both C-15 epimers, that is to say epimers at the -CHR<2-> carbon atom of the lower side chain.

A preferred group of prostane derivatives according to the present invention comprises compounds where R" is a carboxy, hydroxymethyl, methoxycarbonyl, or ethoxycarbonyl radical, R<2> is a hydroxy radical, A is a cis-vinylene radical, Y is a trans-vinylene radical, X is a direct bond or a"2 methyleneoxy radical, where the methylene group is bound to -CHR - and 3 3

the oxygen is bound to R , and R is a chlorophenyl or trifluoromethylphenyl radical.

A preferred meaning for R 3 when X is a methyleneoxy radical is a 3-chlorophenyl or 3-trifluoromethylphenyl radical, and a preferred meaning for R 3 when X is a direct bond is a 4-trifluoromethyl radical.

Particularly preferred 11-epi-prostanic acid derivatives according to the present invention are 16-(3-chlorophenoxy)-9a,113,15a-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienic acid, 16-( 3-chlorophenoxy)-9a,118,15a-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid, methyl-16-(3-chlorophenoxy)^9a,118,-15a- trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadien-oate, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-5-cis7l3-trans-prostadien- i,9a,113#15a-tetraol, 16-(3-chlorophenoxy)-113,15-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid and 9a, 113r15a-trihydroxy-15-(4-trifluoromethylphenyl)-16,17,18,-19,20-pentanor-5-cis,13-trans-prostadioic acid.

The 11-epi-prostanic acid derivative according to the invention can be prepared according to known methods for the preparation of chemically analogous compounds. A further feature of the present invention is thus a method for the preparation of an 11-epi-prostanic acid derivative which is characterized by: (a) for compounds where R1 is a carboxy radical, and

X is not a direct bond, hydrolyzes a compound of the formula:

13 where R , R , A and Y have the meanings given above, R<6> is a tetrahydropyran-2-yloxy or C4_10-alkoxydialkylmethoxy radical, for example a 1-methoxy-1-methylethoxy radical, R7 is an alkoxy radical with 1-4 carbon atoms or a tetrahydropyran-2-yloxy- or C4<_10-alkoxydialkylmethoxy radical, for example a 1-methoxy-8 1-methylethoxy radical, and R has the above 4 meanings for R , or a tetrahydropyran-6 2-yloxy radical } or R is a hydroxy radical or an aroyloxy radical of up to 15 carbon-7 8 atoms, R is a hydroxy radical and R is an aroyloxy radical of up to 15 carbon atoms, and for the preparation of a salt, reacts the product obtained with a base; or (b) for compound where R<1>is a carboxy radical, A is a vinylene radical and X is a direct bond, reacts a lactol of the formula:

2 3 where R and R have the meanings given above, with a (4-carboxybutyl)triphenylphosphonium salt, for example a bromide, in the presence of a strong base, and for the preparation of a salt, react

the obtained product with a base; or

(c) for compound where R* is an alkoxycarbonyl radical, reacts the corresponding compound of formula I, where R<1> is a carboxy radical, with a diazoalkane of 1-10 carbon atoms, or with , a salt thereof, for example a silver or sodium salt, with an alkyl halide, for example an alkyl iodide; or (d) for compound where R 1 is a hydroxymethyl radical, reduces a corresponding compound of formula I, where R 2 is an alkoxycarbonyl radical, for example with a complex metal hydride such as lithium aluminum hydride traps (e) for compound where R 2 is an alkoxy radical, reacts a corresponding compound of formula I, where R 2 is a hydroxy radical, with an alkyl halide of 1-4 carbon atoms, for example an alkyl iodide, in the presence of a strong base, for example sodium hydride; or (f) for compound where A is a trans- vinylene radical,

separates a mixture consisting of the compound where A is a trans-vinylene radical and the corresponding compound where A is a cis-vinylene radical.

The hydrolysis in method (a) can be carried out with an acid, for example aqueous acetic acid or a sulphonic acid, for example toluene-p-sulphonic acid in a C1-4-alkanol when R 6 or R<7> is a tetrahydropyranyloxy radical, or buffered citric acid (for example pH 3) when R<6> or R<1> is an alkoxydialkylmethoxy radical, or it can be carried out with a base, for example an alkali metal carbonate, such as potassium carbonate, when R 6 or R<7> is an aroyloxy radical, and it can be carried out at ambient tempera- trip or at an elevated temperature up to 60°C.

In method (b), when the strong base used is a sodium base, for example methanesulfinylmethyl sodium in dimethylsulfoxide, or potassium t-butoxide, the product I obtained is essentially a product where A is trans-vinylene, while if n- butyllithium in sulfolane is used as the strong base, the product obtained is one that contains a mixture of the bond where A is trans-vinylene and the compound where A is cis-vinylene, and the mixture can be separated into its components according to method (f) above.

In method (f), a suitable method for separating the 5-trans compound from a mixture of the 5-trans and 5-cis compounds is chromatography, for example on silica gel impregnated with silver nitrate, but other common methods for separating cls-trans mixtures can also be used, for example fractional crystallization.

Starting material of the formula III, which is used in the method according to the invention, where R<2> is a hydroxy radical can be obtained by reacting a lactone iEVc5mea an azodicarboxylate ester in the presence of triphenylphosphine and benzoic acid, and one obtains di-benzoate V which is hydrolyzed to the diol VI. The reduction of the lactone with diisobutylaluminum hydride gives the desired starting material III, (R<2>o hydroxy).

Many of the lactones of formula IV are known compounds, and any new compounds can be prepared according to known methods for the preparation of known lactones of formula

Starting material of formula III, where R<2> is an alkoxy radical, can be obtained by reacting a corresponding compound VI, where R 2 is a hydroxy radical, with an alkyl halide, for example an alkyl bromide or iodide, in the presence of one equivalent of a strong base, for example sodium hydride, followed by the reduction of the product with diisobutylaluminum hydride, as indicated above, to give the desired starting material III (R<2>alkoxy).

Starting material of formula II used in the method according to the invention, where A is a vinylene radical,

6 7 8

R and R are both a tetrahydropyran-2-yloxy radical, and R is a hydroxy radical, can be obtained by reacting the corresponding compound VI with dihydropyran, and one obtains a bis-(tetrahydropyran-2-yl ether), which is reduced with diisobutylaluminum hydride, as stated above for compound VI, and the resulting lactol is reacted with a (4-carboxybutyl)triphenylphosphonium salt, as stated above for a lactol III, and a starting material II is obtained, where A is cis-vinylene, if methanesulfinylmethyl sodium is used or potassium t-butoxide as the strong base, or a mixture of the compounds of formula II, where A is trans-vinylene and cis-vinylene, if n-butyl lithium in sulfolane is used as the strong base, from which mixture starting material II, where A is trans-vinylene, can be obtained by chromatography on silica gel impregnated with silver nitrate.

Corresponding starting materials of formula II, where R 6 and R 7 are both an alkoxydialkylmethoxy radical, can be prepared in a similar way by using an alkoxyalkane, for example 2-methoxypropene in the presence of dihydropyran. 6 7 Starting material of formula II, where R and R are both a tetrahydropyran-2-yloxy radical and R<5> and R<8> together form an oxo radical, can be obtained by oxidation of the corresponding compound II, where R 8 is a hydroxy radical , for example with Jones * reagent.

Starting material of formula II used in the method according to the invention, where Y is a trans-vinylene-8 6 7

radical, R is an aroyloxy radical and R and R are both a hydroxy radical, can be obtained by treating the known lactone, 4B-dimethoxymethyl-2,3,3aB,6a8-tetrahydro-5a-hydroxy-2-oxocyclopenteno[b ]furan (VII) with an azodicarboxylic acid ester in the presence

of triphenylphosphine and benzoic acid, and one obtains the benzoate of the C-5 epimer of VII (VIII), which is hydrolyzed and then protected as tetrahydropyranyl ether (IX). The lactone is reduced with diisobutylaluminum hydride to lactol X, and the lactol is reacted with a phosphonium salt of the formula Ph.J(CH~)-.COOH.Br" in the presence of a strong base, and a cyclopentanol derivative XI is obtained, where A is cis-vinylene if methanesulfinylmethyl sodium or potassium t-butoxide is used as the strong base, or a mixture ay cyclopentanol derivatives XI, where A is cis-vinylene and trans-vinylene when n-butyllithium in sulfolane is used as the strong base, from which mixture the cyclopentanol derivative XI ,

Bz benzoyl, THP = tetrahydropyran-2-yl, PB » 4-phenylbenzoyl, where A is trans-vinylene radical, can be separated by chromatography on silica gel Impregnated with silver nitrate. Alternatively, the mixture may be processed via one or more subsequent synthesis steps, and the corresponding trans intermediate may be separated by a suitable subsequent step. A cyclopentanol derivative XI by reaction with de diazomethane to the methyl ester XII. The methyl ester XII is reacted with an acylating agent derived from an aromatic acid, for example 4-phenylbenzoyl chloride, and a 4-phenylbenzoate ester XIII is obtained, which is selectively hydrolyzed in two steps, first to remove the tetra-hydropyranyl protecting group (XIV), and then to hydrolyze the acetal , and the aldehyde (XV) is obtained. The aldehyde XV is treated with a phosphonate (CH30)2PO.CH2CO.XR3 or a phosphorane Ph3P:CH.CO.XR<3> in the presence of a strong base, and one obtains the enone XVI, the reduction of which with aluminum tri-isopropoxide or diisobornyloxy aluminum isopropoxide gives the desired starting material II, where 6 7 A is a vinylene radical, Y is trans-vinylene, R = R hydroxy,

8

and R ■ aroyloxy.

Starting material of formula II used in the method according to the invention, where A is a vinylene radical,

6 8

Y is a trans-vinylene radical, R and R are both an aroyloxy radical and R 7 is a hydroxy radical can be obtained from the methyl ester XII by selective hydrolysis of tetrahydropyranyl radical, for example with toluene-p-sulfonic acid in tetrahydrofuran, to a

diol XVII, which is reacted with an acylating agent derived from an aromatic acid, for example 4-phenylbenzoyl chloride, and one obtains a bis-(phenylbenzoate ester) XVIII, which is selectively hydrolyzed with dilute, aqueous acid to the corresponding aldehyde XIX. The aldehyde XIX is reacted with a phosphonate or phosphorane as indicated

above, and the enone XX is obtained, which is reduced, as indicated above for similar enones XVI, to the desired starting material 6 8 7

II (R = R aroyloxy, R hydroxy)..

Starting materials of formula II, where Y is a

6 7

ethylene radical and either R and R are both a hydroxy radical and

8 7 6 R is an aroyloxy radical, or R is a hydroxy radical and R and R<8>are both an aroyloxy radical, can be obtained by reducing

respectively an enone XVI or an enone XX with, for example, sodium borohydride, and you get a mixture of 13,14-trans- and 13,14-dihydro-enols, from which you can separate the 13,14--dihydro-enol (II, Y ethylene) by usual methods.

The starting materials of formula II, where A ex* an ethylene radical, can be obtained by hydrogenating a corresponding starting material II, where A is a cis-vinylene radical, or by hydrogenating an intermediate of formula XIV or XVIII, using the hydrogenated intermediate instead of XIV or XVIII 1 the subsequent steps of the syntheses described

above.

In an alternative synthesis, the intermediate XIV used in the above process can be obtained by treating the known compound XXl with an azodicarboxylate ester, as indicated above, and a diester XXII is obtained which is transferred via intermediate analogues to XV and XVI to the desired starting material II "' ( R° v » benzoyloxy, R 7 » hydroxy, R 8 » 4-phenylbenzoyloxy).

In the case of a further, alternative synthesis, the

6 7 starting material of the formula II (R = benzoyloxy, R = hydroxy, R 8 = 4-phenylbenzoyloxy) is obtained by treating a compound of the formula:

with an azodicarboxylate ester as indicated above, and one obtains a

6 7 starting material of the formula II (R = benzoyloxy, R «= hydroxy, R 8 «4-phenylbenzoyloxy).

Compounds of formula XXIII are known values 3 3

for certain meanings of -XR , for example where -XR is 3-chlorophenoxy, and the corresponding compounds for other meanings of -XR<3> can be prepared in a completely analogous way.

Starting materials of formula II, where R1 is a carboxy or hydroxymethyl radical can be obtained from the corresponding compound where R"** is an alkoxycarbonyl radical by respectively saponification or reduction with complex metal hydride, for example lithium aluminum hydride.

Starting materials of the formula II, where R1 is an alkoxycarbonyl radical can be obtained from an 11-epi-prostanic acid derivative according to the invention of formula I, where R<*>is an alkoxycarbonyl radical by reaction with 2,3-dihydropyran, and one obtains a tris(tetrahydropyranyl ether) XXIV which is reduced with lithium aluminum hydride to a hydroxymethyl compound XXV, which is then alkylated to give a starting material II (R"*"

6 7 8

alkoxymethyl, R => R « R = tetrahydropyran-2-yloxy) .

THP »=» tetrahydropyran-2-yl

As indicated above, the compounds according to the invention have luteolytic properties. For example, 16-(3-chlorophenoxy)-9α,118»15α-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienic acid is approx. 500 times as active as natural prostaglandin HE^a in a hamster luteolytic test (oral dosing), but has only 1/12 the smooth muscle stimulatory effect of the natural compound. The compounds according to the invention are therefore more selective than the natural compound when it comes to luteolytic action. No indication of toxicity has been observed in small animals at luteolytically effective doses.

The compounds according to the invention are therefore useful, for example, for inducing labor during childbirth, and for this purpose they are used in the same way as it is known to use the naturally occurring prostaglandins and Ej, i.e. by administering a sterile, mainly aqueous solution containing from 0.01 - 10 ug/ml, preferably 0.01 - 1 ug/itil active compound, by intravenous, extraovular or intra-amniotic administration until labor begins. For this purpose, the compounds according to the invention can also be used in combination, or simultaneously with, a uterine stimulant, for example oxytoxin, in the same way as it is known to use prostaglandin-F2d in combination with, or simultaneously with, oxytoxin for inducing labour.

When a compound according to the invention is used for regulating the estrous cycle in animals, it can be used in combination with, or simultaneously with, a gonadotropin, for example PMSG (pregnant mare serum gonadotropin) or HCG (human chorionic gonadotropin) to accelerate the onset of the next cycle .

A further feature of the present invention thus relates to a pharmaceutical or veterinary medicinal preparation containing an 11-epi-prostanic acid derivative according to the invention, together with a pharmaceutical or veterinary medicine acceptable diluent or carrier.

The preparations may be in a form suitable for oral administration, for example tablets or capsules, in a form suitable for inhalation, for example an aerosol or a solution suitable for spraying, in a form suitable for parenteral administration, for example sterile , injectable aqueous or oily solutions or suspensions, or in the form of a suppository, suitable for anal or vaginal use.

The preparations according to the compound can be prepared according to usual methods and can be added to usual excipients.

The invention is illustrated by means of the following examples.

Example 1

A solution of 16-(3-chlorophenoxy)-9α-hydroxy-113,15α-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-ois,13-trans-prostadioic acid (108 mg ) in 2 ml of a 2:1 mixture of acetic acid and water was stirred at 50°C for 4 hours. The solvents were evaporated, the residue was dissolved in dilute aqueous sodium bicarbonate solution (2 ml), the solution was extracted with ethyl acetate (3 x 2 ml) and the extract was discarded. The aqueous solution was acidified to pH 3-4 with 2N aqueous oxalic acid and the acidified solution was extracted with ethyl acetate (4 x 5 mL). The ethyl acetate extracts were washed with a 1:1 mixture of saturated salt solution and water and then dried. After evaporation of ethyl acetate, the residue consists of 16(3-chlorophenoxy)-9a,118,15a-tri-hydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid. Thin layer chromatography on silica gel plates, (Merck, Darmstadt), using a mixture of 3% acetic acid in ethyl acetate as developer, gives the pure compound, Rp = 0.2. Nuclear magnetic resonance spectrum in deuterated acetone shows the following characteristic bands (6 values): 6.9-7.2, broad multiplet, 4 aromatic protons, 5.2 -6.1, broad multiplet, 4 olefinic and 4 exchangeable protons 3 .95 - 4.5 broad multiplets, 5H, >& E,0 protons The mass spectrum of the tetra(trimethylsilyl) derivative shows (M-CH3)<+>= 697.2990, (calculated for C34H61Cl0GSi4=»697.3001) *

Bis(tetrahydropyranyl ether) used as starting material can be prepared as follows: To a solution of 48-[4-(3-chlorophenoxy)-38-hydroxybut-1-trans-enyl]-2,3,3aB,6a$-tetrahydro- 5a-hydroxy-2-oxocyclopenteno[b]furan (838 mg), triphenylphosphine (1.63 g)

and benzoic acid (758 mg) in tetrahydrofuran (15 ml.) was added dropwise over 10 minutes to diethyl azodicarboxylate (1.06 g). After 45 minutes, the solvent was removed by evaporation and the residue was extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed successively with sodium bicarbonate solution and brine, and dried, and the solvents were evaporated to give the bis-benzoate ester, 56-benzoyloxy-4B-[3a-benzoyloxy-4-(3-chlorophenoxy)but-1 -trans-enyl]-2,3,3a8,6aB-tetrahydro-2-oxocyclopenteno[b]furan,R^, «=■ 0.6 (5% ethyl acetate

in methylene dichloride).

To a solution of the bis-benzoate ester (1.03 g) in a mixture of methanol and methylene dichloride (2:1) was added anhydrous potassium carbonate (578 mg). The mixture was stirred for 6 hours at room temperature, acidified to pH 5 with 1N hydrochloric acid and diluted with ethyl acetate (100 mL). The mixture was washed successively with saturated sodium bicarbonate solution and brine, the organic phase was separated and dried and the solvents were evaporated under reduced pressure. The crude product was chromatographed on MFC silica gel using ethyl acetate in methylene dichloride as eluent, and one obtains the diene, 48-[4-(3-chlorophenoxy)-3a-hydroxybut-1-trans-enyl]-2,3,3a 8,6α3-tetrahydro-5-hydroxy-2-oxocyclopenteno[b]furan, Rp = 0.4 (ethyl acetate).

The nuclear magnetic resonance spectrum (in deuterated chloroform) showed the following characteristic bands (6 values): 6.8 - 7.6, broad multiplets, 4 aromatic protons, 5.8 6.0, 2 olefin protons,

3.7-5.2, broad multiplets, 5H, >CH.O protons To a solution of the diol (215 mg) in methylenedi-

chloride (8ml) in an atmosphere of nitrogen was successively added redistilled 2,3-dihydropyran (0.58ml) and a solution of anhydrous toluene-p-sulfonic acid in tetrahydrofuran (0.6ml of a 1% solution). After 10 minutes, pyridine (3 drops) was added, followed by ethyl acetate (50 ml). The solution was then washed, alternately with saturated sodium bicarbonate solution and saturated salt solution, and was then dried. Evaporation of the solvents gives a bis(tetrahydropyranyl ether) as a clear oil, Rp = 0.6 (ethyl acetate).

To a solution of bis(tetrahydropyranyl ether) (320

mg) in dry toluene (15 ml) in an atmosphere of nitrogen at -78°C

was added 0.86 ml of a 1.95 M solution of diisobutyl hydride in toluene. After 15 minutes the reaction was stopped by the dropwise addition of methanol (3 ml) and after a further 15 minutes at room temperature a mixture of 1:1 saturated salt solution/water (25 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml) ; The extract was washed with saturated saline,

and dried and the solvent evaporated to give the lactol, 43-[4-(3-chlorophenoxy)-3a-(tetrahydropyran-2-yloxy)-1-trans-butenyl]-2,3,3aB,6a8-tetrahydro- 2-hydroxy-5 8-(tetrahydropyran-2-yloxy)cyclopentenoEb] furan, Rp «= 0.3 (25% ethyl acetate in methylene dichloride).

A stirred solution of (4-carboxybutyl)triphenylphosphonium bromide (6.21 g) in dry toluene (125 ml) was treated under argon at 90°C with potassium t-butoxide (3.01 g) to give a solution of the corresponding ylid. The ylide solution (22.3 mL) was then added to a solution of lactol (388 mg) in dry toluene

(5 ml) at room temperature. The mixture was stirred for 40 minutes

and then water (1 ml) was added. The toluene was evaporated and the remaining gum was partitioned between ether (4 x 10 ml) and water (4 ral). The aqueous layer was separated, acidified with 2N oxalic acid to pH 4 and extracted with a 1:1 mixture of ether and pentane (6 x 15 mL). The combined extracts were washed with brine, dried over magnesium sulfate and filtered, and the solvent was evaporated to give the desired bis(tetrahydropyranyl ether), 16-(3-chlorophenoxy)9a-hydroxy-11B715a-bis(tetrahydro-pyran -2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid, Rj = 0.5 (ethyl acetate).

Example 2

The procedure in example 1 was repeated using the corresponding 113,158-bis(tetrahydropyranyl ether) as starting material, and one obtains 16-(3-chlorophenoxy)-9a,118,158-trihydroxy-17,18,19,20-tetranor~5-cis ,13-trans-prdstanoic acid,

Rp = 0.3 (3% acetic acid in ethyl acetate). The nuclear magnetic resonance spectrum (in deuterated acetone) showed the following characteristic bands (6 values): 6.9-7.3, broad multiplets, 4 aromatic protons, 5.2 6.1, broad multiplets, 4 olefinic and 4

exchangeable protons,

4.0-4.6, broad multiplets, 5H, >CH.O- protons.

The mass spectrum of the tetra(trimethylsilyl) derivative showed (M-CH 3 )<+>697.2970, (calcd for C 34 H 61 C 10 g Si 4 ) 697.3001.

The bis(tetrahydropyranyl ether used as starting material can be obtained following the series of steps indicated in the second part of Example 1, starting from 48[4-(3-chlorophenoxy)-3a-(tetrahydropyran-2-yloxy)-1-trans -butenyl]-2,3,3a8,6a8~tetra-hydro-2-oxo-5a-(tetrahydropyran-2-yloxy)-cyclopenteno[b]furan, via the following intermediates: "bis-benzoate esters", Rp «= 0.6 (5% ethyl acetate in methylenedi chloride) "diol", Rp = 0.4 (ethyl acetate). The nuclear magnetic resonance the spectrum in deuterated acetone showed the following characteristic bands (6 values): 6.8 - 7.6, broad multiplet, 4 aromatic protons, 5.8 - 6.0, 2 olefinic protons, 3.7 - 5 ,2, broad multiplet, 5H, >CH,0- protons "bis(tetrahydropyranyl ether)Rp - 0.6 (25% ethyl acetate

in methylene dichloride) "lactol", Rp =0.3 (25% ethyl acetate in methylene dichloride).

Example 3

The procedure in Example 1 was repeated using 16-(3-chlorophenoxy)-9-oxo-113,15a-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13- trans-prostanic acid as starting material, and one obtains 16-(3-chlorophenoxy)-118,15a-dihydroxy-9-oxo-17,18,19,20-tetranor~5-cis,13-trans-prostadienic acid,

Rp «=. 0.4 (2.5% acetic acid in ethyl acetate). The nuclear magnetic resonance spectrum (in deuterated acetone) shows the following characteristic bands (6 values): 6.9 - 7.2, broad multiplets, 4 aromatic protons, 5.2-6.1, broad multiplets, 4 blephinic and 3

exchangeable protons, 3,95- 4,6, 4H, >-CH,0- protons The mass spectrum of the tris(trimethylsilyl) derivative showed M<+>= 667.2936, (calculated for C32H54ClN06Si3»667.2946)*

Bis(tetrahydropyranyl ether) used as starting material can be obtained as follows: A solution of 16-(3-chlorophenoxy)-9a-hydroxy-118, 15a-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor -5-cis,13-. trans-prostadic acid (92 mg) in acetone (5 ml) at 0°C was treated

with 8N chromic acid (50.4 µl) for 25 minutes. Iso-propanol was added and the solution was diluted with ethyl acetate (50 ml),

washed with salt solution and dried. Evaporation of the solvent gave the desired 9-oxo-bis(tetrahydropyranyl ether), Rp =

0.4 (5% methanol in methylene dichloride).

Example 4

The procedure indicated in Example 3 was repeated

using the corresponding 118,158-bis(tetrahydropyranyl ether)

as starting material, and one obtains 16-(3-chlorophenoxy)-118,158-di-hydroxy-9-oxo-17,18,19,20-teér-anor-5-ciS713-trans-prostadienic acid, Rp 0.5 (2 .5% acetic acid in ethyl acetate). The nuclear magnetic resonance spectrum (in deuterated acetone) showed the following characteristic bands (6 values): 5.9 7.2, broad multiplets, 4 aromatic protons,

5.2 - 6.1, broad multiplets, 4 olefinic and 3

exchangeable protons,

3.95- 4.6, 4H, >CH.O- protons

The mass spectrum of the tris(trimethylsilyl) derivative showed M<+>= 667.2928, (calculated for C 32 H 54<C>1NO 6 Si 3 = 667.2946).

Bis(tetrahydropyranyl ether) which is used as starting material can be obtained by oxidation of the corresponding 9α-hydroxy-118,158-bis(tetrahydropyranyl ether) as indicated in example 2, following the procedure described in the second part of example 3, Rp =0.4 (5% ethyl acetate in methylene dichloride).

Example 5"

The procedure indicated in example 1 was repeated using the suitable bis(tetrahydropyranyl ether) as starting material, and the compounds shown in the table below are obtained. Mass spectral data are for the tetra(trimethylsilyl) derivatives. Rp values* for thin layer chromatography on silica gel, eluted with ethyl acetate, are also given for the corresponding diol intermediates of formula VI.

In the preparation of the compound, where Y is a

ethylene radical, the desired starting material is obtained as follows:

A mixture of epimers (epimers with C-3 of the butenyl side chain) of 48-E4-(3-chlorophenoxy)-3-hydroxybut-1-trans-enyl]-2,3,3a8,6aB-tetrahydro-2-oxo -5a-(p-phenylbenzoyloxy)-cyclopenteno[b] furan (1.83 g) was dissolved in ethanol (28 ml)

and the solution was added to nickel boride, which had previously been prepared from nickel acetate (3.5 g) and sodium borohydride (551 mg). The mixture was shaken with hydrogen for 4 h - and then filtered, and the filtrate was evaporated to dryness to give a mixture of epimeric unsaturated alcohols 4B-L4-(3-chlorophenoxy-3-hydroxybutyl]-2,3,3a8 ,6a8-tetrahydro-2-oxo-5-a-(p-phenylbenzoyloxy)cyclopenteno[b]furan, R^, = 0.3 (50% ethyl acetate in toluene). The mixture of epimeric, saturated alcohols (1.47 g ) was stirred vigorously for 12% h with finely powdered anhydrous potassium carbonate (1.02 g) in methanol (40 mL). 1N hydrochloric acid (15 mL) was added, followed by ethyl acetate (200 mL). The organic layer was separated,, washed successively with saturated sodium bicarbonate solution and saline solution and dried, the solvents were

evaporated and the residue chromatographed on "Florisil" (Trade Mark) magnesium silicate (50 g). Elution with ether removed by-products and the subsequent elution with ethyl acetate gives a mixture of the corresponding saturated, epimeric 11a,15-diols, ^=0.3 (ethyl acetate).

Example 6

To a solution of the more polar C-15 epimer of 16-(3-chlorophenoxy)-9α,118,15α-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadioic acid (59 mg) in methanol (1 mL) at 0°C

was added an excess of a solution of diazomethane in ether.

After 10 minutes, the solvents were evaporated, and a single C-15 epimer, methyl-16-(3-chlorophenoxy)-9a,118,15a-tri-hydroxy-17,18,19,20-tetranor-5- cis,13-trans-prostadienoate as a clear oil ^=0.15 (ethyl acetate) (M-CH3)<+>639.2754, (be-

calculated for C31H52C106Si3■ 639.2760).

Example 7

A solution of methyl 16-(3-chlorophenoxy)-9α,118,15α-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate (14 mg) in a mixture of ether ( 1 ml) and tetrahydrofuran (1 ml)

was added to a suspension of lithium aluminum hydride (25 mg)

in ether (3 ml). The mixture was stirred at room temperature for 1

hour, the excess of hydride was destroyed by the addition of water (1 ml) and the mixture was extracted with ethyl acetate. The extract was dried and the solvents evaporated to give 16-(3-chlorophenoxy)-9a,118,15a-trihydroxy-17,18,19,20-tetranor-5-cis,-13-trans-prostadien-1- ol, Rp = 0.5 (10% methanol in ethyl acetate). The mass spectrum of the tetra(trimethylsilyl) derivative showed M+ = 698.3412, (calculated for C34Hg3Cl05Si4698.3441).

Example 8

To a solution of methyl 16-(3-chlorophenoxy)-9α,118r-15α-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate (22 mg) in 1,2- dimethoxyethane (2 ml) was sequentially added methyl iodide (1 ml) and sodium hydride (2.25 mg of a 60% suspension in oil) and the mixture was stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure and the residue was shaken with a mixture of ethyl acetate (3 x 15 ral) and water (3 ml). The organic phases were separated, combined and dried, the solvents were evaporated and the residue was purified by thin-layer chromatography on silica gel plates, using ethyl acetate as developing agent, and methyl 16-(3-chlorophenoxy)-9a,-1187dihydroxy is obtained -15α-methoxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate, Rp = 0.30 (ethyl acetate). The mass spectrum of the bis-(trimethylsilyl) derivative showed (M-CH3)<+>= 581.2490, (calculated for C2gH46Cl06Si2= 581.2521).

Example 9

To a solution of 16-(3-chlorophenoxy)-118,15a-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-prostadioic acid (24 mg) in methanol (3 ml ) was added sodium borohydride (15 mg). After 15 minutes, the reaction was stopped by the addition of aqueous oxalic acid, and the mixtures were extracted with . methylene dichloride (2 x 50 ml). The extracts were combined, washed with brine and dried, and the solvents were evaporated to give an impure product which was purified using an excess of diazomethane in ether (2 ml). The methyl ester was purified by chromatography on 1.5 g of silica gel, using ethyl acetate as eluent, and methyl 16-(3-chlorophenoxy)-96,118,15a-trihydroxy-17,18,19,20-tetranor-5- cis,13-trans-prostadienoate, Rp = 0.30 (50% acetone/methylene dichloride). The mass spectrum of the tris(trimethylsilyl) derivative showed (M-CH3)<+>= 639.2798, (calculated for C31H52C10gSi3=639.2758).

Example 10

The procedure described in example 9 was repeated using the corresponding 11$,158-isomer as starting material/ and one obtains methyl-16-(3-chlorophenoxy)-98,118fl58-tri-hydroxy-17,18,19,20- tetranor-5-cis,13-trans^prostadienoate,

Rp = 0.33 (50% acetone in methylene chloride).

Example 11

A solution of 9α-hydroxy-116,15-bis(1-methoxy-1-methylethoxy)-15-(4-trifluoromethylphenyl)-18,17,18,19,20-pentanor-5-cis,13-trans- prostadic acid (123 mg) in 0.8 ml of pH 3 citric acid buffer and 1.8 ml of acetone was stirred at room temperature in

18 hours. The solvents were evaporated and the residue was extracted

with ethyl acetate (3 x 3 ml). The extracts were pooled, washed with a 1:1 mixture of saturated saline and water and then dried. After evaporation of ethyl acetate, the residue consists of a mixture of C-15 epimers of 9ot,118,15-trihydroxy-15-(4-tri-fluoromethylphenyl)-16,17,18,19,20-;pentanor-5 -cis,13-trans-prostadic acid. Chromatography of this residue on CC4 Malinkrodt silica gel (2 g), eluting with acetone/cyclohexane gave the separated C-15 epimers of 9α,118,15-trihydroxy-15-(4-trifluoromethylphenyl)-16, 17,18, 19,20-pentanor-5-cis,13-trans-prostadienic acid, Rp = 0.15 and

0.20 (2.5% acetic acid in ethyl acetate). The nuclear magnetic resonance spectrum of each epimer (in deuterated acetone) showed the following characteristic bands (6 values): 7.65, 4 aromatic protons 5.4 - 6.1, 5H, 4 olefinic protons and

PhCH(OH).CH^CH-

4.2 - 4.9, 6H, C-9, C-ll and 4 exchangeable protons. The mass spectrum of the tris(trimethylsilyl) derivative showed M<+>o 716.3353, (calculated for c34<H>59<F>3<0>5<Si>4<=>716.3394). The bis-ether used as starting material can be prepared as follows: To a solution of 2,3,3a6,6a8-tetrahydro-5B-hydroxy-48-t3-hydroxy-3-(4-trifluoromethylphenyl)-1-trans-prop- nyl]-2-oxocyclopenteno[b]furan (250 mg) (prepared according to the procedure indicated in the second part of Example 1) in methylene dichloride (4 ml) in an atmosphere of nitrogen, was added in order redistilled 2-methoxypropene (528 mg) and a solution of anhydrous toluene-p-sulfonic acid in tetrahydrofuran (0.073 mL of a 1% solution).

After 25 minutes, pyridine (2 drops) was added, followed by ethyl acetate (30 mL). The solution was washed sequentially with saturated sodium bicarbonate and saturated saline and then dried. Evaporation of the solvents gave a mixture of epimeric 1-methoxy-1-methylethyl ethers as a clear oil, Rp = 0.65 (ethyl acetate).

To a solution of the epimeric ether (260 mg) in dry toluene (17 ml) in a nitrogen atmosphere at -78°C was added 0.75 ml of a 1.95 m mol/ml solution of diisobutylaluminum hydride in toluene. After 30 minutes the reaction was stopped by the dropwise addition of methanol (2 ml), and after a further 15 minutes at room temperature a mixture of 1:1 saturated salt solution/water (15 ml) was added and the mixture was extracted with ethyl acetate (3 x 25 ml). The extract was washed with saturated saline and dried and the solvents evaporated to give a mixture of epimers of lactole, 2,3,3a8,6aB-tetrahydro-2-hydroxy-56-(1-methoxy-1-methylethoxy)-4 £-[3-(1-methoxy-1-methylethoxy)-3-(4-trifluoromethylphenyl)-1-trans-propenyl]-cyclopentenoCb]furan,

Rp = 0.15 (40% ethyl acetate/toluene).

A solution of the lactolene (260 mg) in toluene (7 mL) was added to a solution of potassium 5-triphenyl-phosphoranylidene valerate prepared from 1 mole of (4-carboxybutyl)triphenylphosphonium bromide with 2 moles of potassium t-butoxide in toluene. The solution was stirred for 1 hour as the solvents were removed by evaporation under reduced pressure. The residue was shaken with water (5 ml) and ether (3 ml), the aqueous layer was separated and extracted with ether (4 x 3 ml) and the extracts were discarded. The aqueous solution was acidified to pH 5.5 with oxalic acid and extracted with a mixture of equal parts of ether and petroleum ether (b.p. 40-60°C) (6x4 ml).

The combined extracts were washed with saturated saline and dried, and the evaporation of the solvents in 9α-hydroxy-11,-15-bis-(1-methoxy-1-methylethoxy)-15-(4-trifluoromethylphenyl)-16,-17 ,18,19,20-pentanor-5-cis,13-trans-prostadic acid. Rp = 0.38

(10% methanol in methylene chloride).

Example 12

The procedure indicated in example 1 was repeated using the corresponding 110,15-bis (tetrahydropyranyl ether) as starting material, and one obtains the C-15 epimers of 16-(3-chlorophenoxy)-9a,118>15 -trihydroxy-16,16-dimethyl- 17,18,19,20-tetranor-5-cis, 13-trans-prostadienic acid, Rp = 0.15 and 0.20 (2.5% acetic acid in ethyl acetate). The mass spectrum of the tetra(trimethylsilyl) derivative shows M<+>725.3224, (calculated for C3gH65C106Si4= 725.3312). Bis(tetrahydropyranyl ether) used as starting material can be obtained as follows: To a solution of 48-C4-(3-chlorophenoxy)-3-hydroxy-4,4-dimethylbut-1-trans-enyl3-2,3,3a8 ,6aB-tetrahydro-2-oxo-5a-(4-phenylbenzoyloxy)cyclopenteno[b]-furan (1.97 g)

in methylene dichloride (36 ml) was added in order 2,3-dihydropyran (3.3 ml) and a solution of anhydrous toluene-p-sulfonic acid in tetrahydrofuran (1.8 ml of a 1% solution). After 10 minutes, pyridine (1ml) was added, followed by ethyl acetate (200ml). The solution was washed successively with sodium bicarbonate solution and saline solution and then dried. Evaporation of the solvents gave the epimeric tetrahydropyranyl ether as a clear oil, Rp = 0.5 (20% ethyl acetate in methylene dichloride). To a solution of epimer tetrahydropyranyl ether (2.0 g) in methanol (50 ml) was added finely powdered anhydrous potassium carbonate (648 mg). The mixture was stirred vigorously for 6 hours, then 1N hydrochloric acid (7 mL) was added, followed by ethyl acetate (200 mL). The organic layer was separated, washed successively with saturated sodium bicarbonate solution and brine and dried, and the solvents were evaporated. The residue was chromatographed on "Florisil"

(trademark) magnesium silicate (40 g). Elution with ether removed the byproduct, subsequent elution with ethyl acetate gives a mixture of C-15 epimers of 48-E4-(3-chlorophenoxy)-4,4-dimethyl-3-(tetra-hydropyran-2-yl)but-1 -trans-enyl]-2,3,3a8,6a6-tetrahydro-5a-hydroxy-2-cyclopenteno[b]furan, Rp = 0.25 (40% ethyl acetate in methylene chloride). The procedure in the last part of example 1 is repeated by using the above compound instead of the diol.

Example 13

The procedure indicated in example 3 is repeated using the suitable 9-oxo-bis(tetrahydropyranyl ether) as starting material, and the compounds indicated in the following table are obtained:

Example 14

A solution of 116,15-bis(1^methoxy-1-methyl-ethoxy)-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13- trans-prostadic acid (143 mg) in a mixture of 0.7 ml of pH 3 citric acid buffer and 2.1 ml of acetone was stirred at room temperature for 18 hours. The solvents were evaporated and the residue was extracted with ethyl acetate (3 x 20 mL). The extracts were pooled, washed with a 1:1 mixture of saturated saline and water,

and then dried. After evaporation of ethyl acetate, the residue consists of a mixture of C-15 epimers of 118,15-dihydroxy-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13 -trans-prostadienic acid, Rp = 0.45 (2%% acetic acid in ethyl acetate). The nuclear magnetic resonance spectrum (in deuterated acetone) shown in the following characteristic bands (6 values):

7.67, 4 aromatic protons,

5.3 - 6.3, 4 olefinic protons,

C^g proton and 3 exchangeable protons The mass spectrum of bis(trimethylsilyl)-9-methoxymethyl ester shows

M<+>= 671.3080, (calculated for C32H52<F>3<N>05Si3671.3104).

9-oxo-bis-ether used as starting material. can be obtained as follows: A solution of 9α-hydroxy-118,15-bis-(1-methoxy-1-methylethoxy)-15-(4-trifluoromethylphenyl)-16,17,18,19,20-penta-nor- 5-cis,13-trans-prostadic acid (200 mg) in methylene dichloride (2 ml) was added to a stirred solution of Collins1 reagent, prepared from chromium trioxide (280 mg) and pyridine (0.45 ml) in methylene dichloride (5 ml) . After 15 min at room temperature, the mixture was extracted with ether (2 x 10 mL), and the combined extracts were washed with brine and dried. The evaporation of the solvents gave the desired 9-oxo-bis-ether, R<p>= 0.43 (10% methanol in methylene chloride).

Example 15

Sodium citrate, citric acid and sodium chloride were dissolved in most of the water, 16-(3-chlorophenyl)-9a,118,15a-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid and the solution was diluted to volume with water for injection. The solution is filtered to remove particulate material, filled into neutral glass ampoules and processed in an autoclave, resulting in an injectable pharmaceutical or veterinary preparation.

The prostadic acid derivative can of course be replaced by an equivalent amount of another prostadic acid derivative according to the invention.

Example 16

Sodium phosphate was dissolved in approx. 80% water, then the prostadic acid derivative and after this has dissolved sodium hydrogen phosphate. The solution was diluted to volume with water for injection and the pH was checked so that it was between 6.7 and 7.7. The solution was filtered to remove particulate material sterilized by filtration and filled into pre-sterilized neutral glass vials under aseptic conditions. Immediately before use, the contents of an ampoule were diluted in sodium chloride B.P. for administration by intravenous infusion.

The prostadic acid derivative can of course be replaced by a corresponding amount of another prostanic acid derivative according to the invention.

Claims (1)

1. Method for the preparation of 11-epi-prostanic acid derivative of the formula: where R <1> is a carboxy or hydroxymethyl radical or an alkoxycarbonyl or alkoxymethyl radical with up to 11 carbon atoms, R is a hydroxy radical or an alkoxy radical with 1 - 4 carbon atoms, A is an ethylene or vinylene radical, Y is an ethylene or trans-vinylene radical, X is a direct bond, an alkylideneoxy radical with 1-6 carbon atoms where the alkylidene group is bonded to -CHR 2 and the oxygen atom is bonded to R 3, 3 or an alkylene radical with 1-6 carbon atoms, and R is a phenyl or naphthyl radical which may be unsubstituted or substituted with one or two substituents selected from halogen atoms, nitrogen, hydroxy, phenyl or trifluoromethyl radicals, alkyl, alkenyl or alkoxy radicals each containing 1-5 carbon atoms, or dialkylamino radicals, where each alkyl group contains 1-3 carbon atoms, R 4 is a hydroxy-5 4 5 radical and R is a hydrogen atom, or R and R together form an oxo radical, and for compounds where R* is a carboxy radical, pharmaceutical or veterinary acceptable salts thereof characterized in that one: (a) for compound where R^" is a carboxy radical, and X does not mean a direct bond, hydrolyze a compound else of the formula: 13 ' D where R , R , A and Y have the meanings given above, R is a tetrahydropyran-2-yloxy or C4_1Q -alkoxydialkyl-methoxy radical, R^ is an alkoxy radical with 1-4 carbon atoms or a tetrahydropvran-2-yloxy or C 1 , nalkoxydialkyl- a" 4 methoxy radical and R has the meanings given above for R, or is a tetrahydropyran-2-yloxy radical; or R^ is a hydroxy radical or an aroyloxy radical with up to 15 carbon atoms, R <7> is a hydroxy radical and R <8> is an aroyloxy radical of up to 15 carbon atoms, and optionally for the preparation of a salt reacts the product formed with a base?or (b) for compounds where R 1 is a carboxy radical, A is a vinylene radical and X is a ^.direct bond, reacts a lactol of the formula: where R <2> and R <3> have the meanings given above, with a (4-carboxybutyl)triphenylphosphonium salt, in the presence of a strong base, and to prepare a salt, the product formed reacts a base; or (c) for compounds where B?~ is an alkoxycarbonyl radical,' reacts the corresponding compound of formula I, where R<1> is a carboxy radical, with a diazoalkane of 1-10 carbon atoms, or a salt thereof, with an alkyl halide; or (d) for compounds where R* is a hydroxymethyl radical, reduces a corresponding compound of formula I, where R^" is an alkoxycarbonyl radical; or (e) for compounds where R<2> is an alkoxy radical, reacting the corresponding compound of formula I, where R is a hydroxy radical, with an alkyl halide of 1-4 carbon atoms in the presence of a strong base; or (f) for compounds where A is a trans-vinylene radical, separate a mixture containing the compound where A is a trans-vinylene radical and the corresponding compound where A is a cis-vinylene radical. 2. 11-epi-prostanoic acid derivative of formula I as indicated 12 3 4 in claim 1, characterized in that R,R,R,R, 5 R , A, X and Y have the meanings given in claim 1. 3. 11-epi-prostanic acid derivative as stated in claim 2, characterized in that R is a carboxy-, hydroxymethyl-, methoxy-carbonyl-, ethoxycarbonyl-, butoxycarbonyl-, hexyloxycarbonyl-, decyloxycarbonyl-, methoxymethyl- , ethoxymethyl-, hexylmethyl-, or decyloxymethyl radical, R <2> is a hydroxy-, methoxy-, ethoxy-, propoxy- or butoxy-4 5 radical, A, Y, R and R have the meanings given in claim 1, X is a direct bond or a methyleneoxy-, ethyleneoxy-, isopropylideneoxy-, 1-methylpropylideneoxy-, 1-ethylpropylideneoxy-, methylene-, ethylidene-, isopropylidene-, propylidene-, 1-methylpropylidene-, 1-ethylpropylidene-, ethylene- , 1-methylethyliii-, 1,1-dimethylethylene, 2-methylethylene or trimethylene radical, and R 3 is chloro, bromo, fluoro, nitro, hydroxy, phenyl, tri- fluoromethyl, methyl, ethyl, propyl, allyl, methoxy, ethoxy, propoxy or ddiaethyl-amino-phenyl or -naphthyl radical, and for compounds where R* is a carboxy radical, ammonium, alkylammonium containing 1-4 alkyl substituents each containing 1-4 carbon atoms, alkanol ammonium containing 1-3 2-hydroxyethyl radicals, and alkali metal salts thereof0 4. 11-epi-prostanic acid derivative as specified in the claims 2 and 3, characterized in that R1 is a carboxy, hydroxymethyl or methoxycarbonyl radical, A is a cis-vinylene-4 5 2 radical, R , R and Y have the meanings specified in claim 1, R is a hydroxy or methoxy radical, X is a direct bond or a methyleneoxy or methylene radical, and R is a phenyl, chlorophenyl or trifluoromethylphenyl radical. 5. 11-epi-prostanic acid derivative as stated in claim 2, characterized in that R1 is a carboxy or hydroxymethyl radical, or an alkoxycarbonyl radical with up to 2 3 4 5 11 carbon atoms and R , R , R, R , A, X and Y have the meanings given in claim 1. 6. 11-epi-prostanic acid derivative as stated in any of claims 2-5, characterized in that R1 is a carboxy-, hydroxymethyl-, methoxycarbonyl- or ■ •ethoxycarbonyl radical, R is a hydroxy radical, A is a cis-vinylene radical, Y is a trans-vinylene radical, X is a direct bond or et. methyleneoxy radical where the methylene group is 2 3 3 bound to -CHR - and the oxygen atom is bound to R and R is a chlorophenyl or trifluoromethylphenyl radical. 7. 11-epi-prostanic acid derivative as stated in any one of claims 2-6, characterized in that X is a methyleneoxy radical and R <3> is a 3-chlorophenyl or 3-trifluoromethylphenyl radical. 8. 11-epi-prostanic acid derivative as stated in any one of claims 2-6, characterized in that X is a direct bond and R<3> is a 4-trifluoromethylphenyl radical. 9. 11-epi-prostanic acid derivative as stated in claim 2, characterized in that 16-(3-chlorophenoxy)-9a,118,-15a-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans -prostadic acid, 16-(3-chlorophenoxy)-93,116,15a-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid, methyl-16-(3-chlorophenoxy)-9a,118 ,15α-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate, 16-(3-chlorophenoxy)-17,18,19-20-tetranor-5-cis, 13-trans-prostadien-l, 9a, 118 $ 15a-tetranor,. 16-(3-chlorophenoxy)-118,15-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid and 9a,118,15a-trihydroxy-15-(4 -trifluoromethyl-phenyl)-16,17,18,1972,0-pentanor-5-cis,13-trans-prostadioic acid. 10. 11-epi-prostanic acid derivative as stated in any of claims 2-9, characterized in that it exists in racemic form. 11. 11-epi-prostanic acid derivative as stated in any of claims 2-9, characterized in that it exists in a luteolytically active, optically active form.. 12. Pharmaceutical or veterinary medicinal preparation characterized in that it consists of 11-epi-prostanic acid derivative as stated in claim 1 together with a pharmaceutical or veterinary medicine acceptable diluent or carrier. 13. 11-epi-prostanic acid derivative as stated in claim 2 mainly as described in examples 1-14. 14. 11-epi-prosephenic acid derivative as stated in claim 5 mainly as stated in examples 1 - 4. 15. Preparation as stated in claim 12 mainly as stated in examples 15 or 16.