DE2223365A1 - Cyclopentane derivatives - Google Patents

Description

PATENT LAWYERS

DR.-ING. H. FINOKE DIPL.-INQ. H. BOHR DIPL-ING. S. STAEGER

Fe r η r u f: * 26 60 60

Kappa 2 ^ 87? - Dr. K. Oasö PH 23872/24625

8 MUNICH S, Müllerstra6e 31

1 MAY 2, 1972

Imperial Chemical Industries Ltd. London, UK

Cyc1opsat other derivative

Priorities: May 11, 1971 and January 5, 1972

The invention relates to new cyclopentane derivatives and in particular to new cyclopentane derivatives, which analogs Eggs are naturally occurring tar bindings, which are called Prostaglandin -? 2 & u ^ PzOstaglandin-E «are known» Si © aeigon «in a similar spectrum of pharma & ological properties around yincl usable for similar purposes. The relative effect the new connections as well as the special ones

20985Q / 1256

BAD ORtGtNAL

pharmacological effects are however different. different from the naturally occurring prostaglandins mentioned above? In general, they are much more effective as luteolytic agents than the corresponding natural prostaglandins. In other words, the ProstaglandXn-F ₂ Ou analogs according to the invention are more effective than the natural prostaglandin FpCfc, and the prostaglandin E ₀ analogs according to the invention are more effective than natural prostaglandin Eg * The new compounds are in a similar way as stimulants for the smooth uterine viscule more effectively than the corresponding natural prostaglandins-FgO »and -Sp. The prostaglandin-Ep analogs according to the invention are particularly valuable in this regard. The new compounds have advantages when they are used as contraceptives, for the termination of a pregnancy or for the control of the estrous cycle * as hypotensives or for the helicopter of 3rcnchospa8tnu3. The new compounds according to the invention are also suitable as additives for seeds which are used in the artificial insemination of domestic animals. The success rate of the insemination is increased, especially with pigs.

The Oyclopentanaerivate mentioned in this description are listed below as derivatives of prostanoic acid Formula. The selected numbering is also given in the formula.

13 15 17 19 209850/1256

(in the middle of SrfinduD «; becomes a prostanoic acid derivative of "or & el

(D

A-CH (OH) -IYR ⁴

HO

proposed, where R stands for a hydroxymethyl or carboxy radical, an alkoxycarbonyl radical with 11 carbon atoms or an alkoxycarbonyl radical with 2 or 3 carbon atoms which is a ß- or {■ fe-dialkylamino radical with 1 to 4 carbon atoms in the alkyl radicals or a ß - or! ^ - carries pyrrolidino, piperidino or morpholino radical; either R stands for a hydroxy radical or an alkanoyloxy radical with 1 to b carbon atoms and R ^ stands for a hydrogen atom or R and Br together form the oxo radical; A represents an ethylene or yynylene radical; Σ stands for an alkylene radical with 1 to 3 carbon atoms which carries as substituents 0, 1 or 2 alkyl radicals with between 1 and 3 carbon atoms; T stands for an oxygen or sulfur atom, a sulfinyl radical (-S0-) or an alkyl mirxoradical (-N-Alkyi-) with up to «u M carbon atoms; and R ⁺ radically © represents in aryl, benzyl or Furfury!, which is unsubstituted or the radical by halogen atoms or hydroxy-j nitro or biphenyl, or alkyl, alkenyl _t Halogenoalkyl-, alkoxy, alkenyloxy or Acylamino radicals having 1 to 4 carbon atoms or dialkylamino radicals each having 1 to 3 carbon atoms can be substituted in the alkyl radical oils; would wove the ver ~

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bond O or 1 alkyl radicals with up to 4 carbon atoms on the carbon atoms 2, 3 or 4 contains. Unless R is a Carboxy radical is, if the pharmaceutically acceptable ones as well Salts of these compounds are within the scope of the invention.

1 A suitable value for H when it is for an alkoxycarbonyl radical with up to 11 carbon atoms is, for example, methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical.

A suitable value for H ₁ when it stands for an alkanoyloxy radical having 1 to 4 carbon atoms is, for example, the acetoxy or propionyloxy radical.

A suitable value for X when it is an alkylene radical with 1 to 3 carbon atoms which has 0, 1 or 2 alkyl radicals each with 1 to 3 carbon atoms as substituents is, for example, a methylene, ethylene or trimethylene radical which has 0, 1 or has 2 methyl substituents, such as aB the methylene _% . Ethylidene, isopropylidene and trimethylene radicals.

A suitable value for Y when it is for an alkyleneimino radical Kit up to 4 carbon atoms is, for example, the methylimino radical <

A suitable value for A is the trans-vinylene radical.

A suitable value for R when it is an aryl radical which is optionally substituted is, for example Phenyl or naphthyl radical that is optionally substituted is.

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Suitable halogen atom substituents in R 'are "for example chlorine, bromine or fluorine atoms» Suitable alkyl ₅ alkoxy, alkenyl or alkenylo: xy substituents with 1 to 4 carbon atoms in Ii are, for example, methyl, t-butyl, Allyl, methoxy or allyloxy radicals ♦ Suitable halogenoalkyl substituents with 1 to 4 carbon atoms in R are, for example, the chloroalkyl or fluoroalkyl radicals, such as the trifluoromethyl radical _? are for example dialkylamino radicals in which the two alkyl radicals are the same, such as the dimethylamino radical.

Suitable substituted aryl radicals, for example aind the chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, Tolyl, 2ylyl, methylnaphthyl, t-buty! Phenyl, Methylchlorophenyl-, trifluoromethylphenyl-, hydroxyphenyl-, Methoxyphenyl, methoxynaphthyl, biphenylyl, dirnethylaminophenyl and tetrahydronaphthyl radicals.

Most popular aryl radicals contain no more than two of the substituents defined above. Particularly suitable values for R are therefore phenyl, benzyl, furfuryl, 1-naphthyl, 2-naphthyl, 2-, 3- and 4-chloropheayl, 4-bromophenyl, 2-, 3- and 4 -Fluorophenyl-, 2,3-s 2,4 · -, 2,5-, 2,6-, 3, ^ - and 3 * 5-dichlorophenyl-, 2-, 3- and 4-tolyl-, 2, 3-, 3,4- and 3,5-xylyl-, 4-t-butylphenyl-, 3-AlIy! Phenyl-, 3-trifluoromethylphenyl-, 4-hydroxyphenyl-, 2-, 3- and 4-methoxyphenyl-, 4-biphenylyl, 3-dimethylaminophenyl, 2-chloro-4-methylphenyl, 1-chloro - ^ - naphthyl, 4-chloro-2-naphthyl,. 6-Hethyl-2-naphthyl- ₁ 6-ffethoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl radical.

209850/1256

A suitable value for the alkyl radical with up to 4 carbon atoms, which as a substituent on the carbon atoms 2, 3 or 4, for example, "is that Methyl radical.

Examples of base addition salts are the ammonium salt, the alkylammonium salts with 1 to 4 · alkyl radicals of 1 each hia 6 carbon atoms, the alkanolammonium salts with 1 to 2-hydroxyethyl radicals and alkali metal salts such as the Triethylammonium, ethanolammonium, diethanoiammonium, Sodium and potassium salts *

It is noted that the compounds of formula I at least Contain 5 asymmetric carbon atoms, namely the carbon atoms 8, 9, 11, 12 and 15, with the © configurations of four of these, namely 8, 9, 11 and 12, given in formula I. are. It is also pointed out that the carbon atoms 2, 3 and 4 · are also asymmetrically substituted so that it is clear that these compounds can exist in at least two optically active forms * It should be noted that the useful properties of the fiacemate in the optical isomers in different To the extent that the invention relates to the racemic form of the compounds of formula I and all refers to optically active forms which have the above useful properties. The separation of the optically active Shapes and the determination of their biological properties can be carried out according to known methods.

It should also be noted that the above definition encompasses both C-15 epimers. It is also pointed out that in all the chemical formulas given below the same fixed stereochemistry for the carbon

209850/1256

atoms 8, 9 »11 and 12 as used in formula I.

Both have C-15 epimers of a compound according to the invention the desired pharmacological properties, but the epimer, which is stronger in thin-layer chromatography is polar, is also the more active, e.g. in the luteolytic test. Therefore, the more polar C-15 epiners are preferred .

A preferred group of cyclopentane derivatives according to the invention includes (because of the high luteolytic or stimulating oxide effect on the smooth muscle tissue) such Compound shared in which H is a chlorophenyl, flaorophenyl, Trifluoromethylphenyl or unsubstituted naphthyl radical

is, especially those compounds in which H is the carboxy ₉ methoxycarbonyl or hydroxymethyl radical, and very special those compounds in which R is 3- or ^ -Chlorophenyl-, 2- or 4-Pluorophenyl-, 3-trifluoromethylphenyl or unsubstituted naphthyl radical. A particularly preferred subgroup includes those compounds in which R stands for the carboxy, methoxycarbonyl or hydroxymethyl radical, R stands for the hydroxy radical and R ^ stands for a hydrogen atom, or R and B? together form the oxo radical, A stands for the vinylene radical, X stands for the methylene or isopropylidene radical, Ϊ stands for an oxygen atom and R stands for 3- or 4-chlorophenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2 ~ Haphthyl radical, where a methyl substituent may be present on the 2-carbon atom.

Particularly preferred compounds according to the invention are:

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16- (4-fluorophenoxy) -9ft, 11a »15 ~ trihydroxy-17,18,19,20 ~ tetranor-5-cte-13-trans-prostadienoic acid, 16- (4 ~: εΊλιογο ~ phenoxy) -9α , 11A, 15 ~ trihydroxy-17 »18,19, 20 ~ tetranor-5-cis-13-trans-pro8tadiene-acid methyl ester, 16- (2-fluorophenoxy) -9 Ow 110U15-trihydroxy-17,18» 19 _t 20-tetra? ior-5-cis-15-traneprostadien-acid, 16- (4 ~ chlorophenoxy) -9a »11o> 15-trihydroxy-17» 18,19 »20-tetranor-5-cis-13 -trans-prostadien-acid, 16- (4-dhlorophenoxy) -9flt, 11a * 15-trihydroxy-17 »18,19» 20-tetrauor-5-ois-13-trane-proat / adien-8ä \ ire-methyle8ter , 16- (4-chlorophenyl) -9 «t, 11 a, 15-trihydroxy-17» 18,19,2O-tetranor-5-cis-13-trans-prostadienol _t 16- (3-chlorophenoxy) -9c « 11CU15-trlhydroxy-17 * 18.19 »20-tetranor-5-cis-13-trans-prostadiene acid, 16- (3-chlorophenoxy) ~ 9 ^ 110« 15-trihydroxy ~ 17 »18.19» 20-tetranor- 5-cis-13-trans-prostadien ~ fi acid-metl ^ yle8ter, 16- (5- Chlorophenoxy) -9o »11a» 15-trihydroxy-2-methyl-17 »18,19» 20-tetranor-5-ci s-13-trans-proetadienol _t 9ft ♦ 11öu15-trihydroxy-16- (5-trifluoromethylphenoxy) - 17,18,19,20-tetranor-5-cis-13-trans-proatadien-sä \ ire, 9a »| 11 <V »15-trilydroxy-16- (2-naphthylory) -17,18,19» 20-tetranor-5-cis-13-trane ~ pro8tadienoic acid, 16- (4-chlorophenoxy) -9a »11 OIL» 15 -trihydroxy-16,16-diaethyl-17,18,19,20-tetranor-5-cie-13-tranB-proetadlenic acid and 16- (A-cnilorophenoxy) -11a ·, 15-dihydroxy-9-oxo -17,18,19,20-tetranor-5-cia-i 3-trans-proetadienoic acid.

The erfindungflgemäßen Oyclopentanderi \ ^F ate can be prepared by methods which are known per se for the manufacture of chemically analogous compounds. The following production processes for cyclopentane derivatives of the formula I are proposed as further features of the invention:

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(a) For so-called compounds * in which R is a carboxy radical is the hydrolysis oinex · compound of formula

(CH ₂ ), COOH

(II)

or a mixed anhydride thereof, where A, X, Y, R ² , R * and R have the meanings given and R- * and R each represent a tetrahydropyran-2-yloxy radical or an acyloxy radical having 1 to 6 carbon atoms, whereupon, if a salt is desired, the product is reacted with a base; or

(b) for those compounds in which R is an alkoxycarbonyl radical having 1 to 11 carbon atoms, the reaction of an acid of the formal

(CH ₀ ), COOH

(II)

2 3 4

where A, X ₁ Y, R, Ir and R have the meanings given above

own, with a diazoalkane of the formula R ^. N ₂ , where R ^ is an alkyl radical having 1 to 11 carbon atoms; or

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(c) for those compounds in which H is an alkoxycarbonyl radical with 1 to 3 11 carbon atoms, the conversion of a salt, for example the silver salt, a Acid of formula II with an alkyl halide having 1 to 11 carbon atoms, such as the alkyl iodide; or

(d) for those compounds in which R is the hydroxymethyl radical standS and Y stands for the oxygen or sulfur atom or an alkyl amino radical, the reduction of one Esters of the formula I, in which R is an alkoxycarbonyl radical, for example an alkoxycarbonyl radical with 1 to 11 carbon atoms, with, for example, a complex metal hydride, such as lithium aluminum hydride; or

(e) for those compounds in which I stands for the sulfinyl radical is the oxidation of a thio compound of the formula

A-CH (OH) -X-SR

(IV)

where R ¹ , R ² , R ^, R ^, A and X have the meanings given in claim 1, with, for example, sodium periodate.

A suitable mixture of the anhydride is a mixed anhydride with a lower alkanoic acid, such as a lower alkanoic acid with up to δ carbon atoms, for example acetic acid.

209850/1256

The hydrolysis in process (a) can be carried out under either acidic or basic conditions are executed «for example in aqueous acetic acid or in an aqueous or alcoholic solution of an alkali metal carbonate, such as ζ »B. Potassium carbonate in methanol, and it can also be carried out at room temperature or at an elevated temperature up to 60 ° C.

The starting material of the formula II, in which A is a vinylene radical and Y is an oxygen or sulfur atom which is to be used in the process of the invention can be obtained by using the known Aldehyde IV (Ac = acetyl or p-phenylbenzoyl) with a phosphonate of the formula

(CH ₃ O) ₂ P ⁺ O. "OH.OO.XTE ^ (V)

(which is prepared from dimethyl methylphosphonate and an ester of the formula R ^ .YXCOO-alkyl in the presence of butyllithium) or with a phosphorane of the formula Ph, P: CH.CO.X * YR (which is made from triphenylphosphine and a compound of the formula H .JX COGH ₂ J.) is reacted to produce an unsaturated ketone VI. The ketone VI is reduced with zinc borohydride with the corresponding unsaturated alcohol VII and the protecting acyl group is then removed with potassium carbonate in methanol to give a diol VIII. The diol VIII is protected as bis-tetrahydropyranyl ether and the lactone ring is then reduced with di-isobutylaluminum hydride to give a lactol X. Alternatively, the diol VIII can also be reduced with di-isobutylaluminum hydride, a triol being obtained which can be acylated and selectively hydrolyzed to give the lactol-bis-ester (X, R ^ * R "acyloxy" zn . The Lactol X is combined with the phosphonium

209850/1256

ylid-anion implemented, which aua (4-carboxybutyl) triphenylphosphoniumbroraid and a strong base to produce a carboxylic acid of Formula II.

The starting material of formula II, wherein A is an ethylene radical and Y is an oxygen or sulfur atom eats _v which according to the invention is used can be obtained by reacting an unsaturated ketone VI in the presence of a 5% strength "a palladium, Charcoal catalyst or hydrogenated with nickel borohydride to produce an unsaturated ketone XI, whereupon the above procedure is repeated, but with the saturated ketone XI instead of the unsaturated. Ketone VI is used.

ρ The starting material of formula II, wherein R is an alkanoyloxy radical can be obtained from the corresponding compound in which R is a hydroxy radical, viz by acylation with an acid anhydride in pyridine to give a 9 ~ Est8r-1 mixed anhydride.

2 The starting material of formula I, II or III, wherein R

uni R * together form the oxo radical can be derived from the: corresponding Starting material of the formula II can be obtained in which R is hydroxy and R ^ is hydrogen, namely by oxidation with the Jones reagent (chromic acid in acetone) and, if necessary, subsequent hydrolysis of the Tetrahydropyranyl protective group and esterification of the carboxylic acid group.

209850/1256

+ (MeO) ₂ ^ P-CH. CO.XY

XYE ¹

AcO

AcO

X.Y.H

VII

VIII

OH

.YS ¹

Ac stands for an acyl radical

209850/1256

It is of course pointed out * that an "invention" appropriate optically active compound can thereby be obtained can, that one separates the corresponding racemate or that one the above-mentioned reaction sequences with an optically active one Intermediate product, such as an optically active aldehyde of the formula IV (Ac - acetyl or p-phenylbenzoyl) »

As already stated, the compounds according to the invention have a profile of pharmacological properties which differ from those of the naturally occurring prostaglandins-F- ^ ftund "^ _2. For example, 16- (4-fluorophenoxy) -9a, 110.15- trihydroxy-17,18,19 »20-tetranor ~ 5-cis ~ 15-trans ~ prostadienic acid in a luteolytic test in hamsters (oral dosage approximately 200 times more active than prostaglandin-F ^ o, and shows with regard to the stimulating effect on smooth muscle approximately 10 times the activity of prostaglandin ^ ^ "

As already stated above, the compounds according to the invention are suitable, for example, for inducing childbirth. For this purpose they are used in the same way as the naturally occurring prostaglandins-E ^ and -Ep, ie, by administering a sterile, largely aqueous solution containing 0.01 to 10 / tg / ml, preferably 0.01 to I ^ ig / nil »of the active compound, by intravenous infusion, until labor begins. For this purpose, the compounds according to the invention can also be used in combination or simultaneously with a uterine stimulant, such as, for example, oxytocin, in the same way as prostaglandin F ₂ 4 in combination or simultaneously with oxotooin to induce labor.

209850/1256

When a compound of the invention for. the control of the oestrus cycle is used in animals, then it can be used in Combination or simultaneously with a gonadotrophin, such as e.g. PiBG (pregnant mare serum gonadotrophin) or HOQ (human ohorionic gonadotrophin) can be used to speed up the onset of the next cycle.

So wj> rd also a pharmaceutical according to the invention or veterinary composition proposed which a prostanoic acid derivative according to the invention together with a Contains pharmaceutically or veterinarily acceptable diluents or carriers.

The compositions may be in a form suitable for oral administration (e.g. tablets or Capsules), in a form suitable for inhalation (e.g. as an aerosol or spray solution), in a form suitable for parenteral administration (e.g. sterile injectable aqueous or oily solutions or. Suspensions) or in one suitable for suppositories Form (for example for anal or vaginal use). If, as already stated, the compound of the invention is used to induce labor, then the preferred composition of the invention is a sterile, essentially aqueous, injectable solution.

The inventive compositions can by customary Measures are prepared and the usual excipients contain·

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The invention is illustrated in more detail by the following examples.

example 1

A solution of 120 mg 9a ~ Hjdro: ji ^ -16-ph®noxy-11 <*, 15 "- ^: bie (tetra- · hydropyran-2-yloxy) -17» 18.19 _f 20-tetranor-5- CISS-13 Trane proetadien acid in 1.5 ml of a 2: 1-Geaischa of acetic acid and water was st at 50 ⁰ C for 4 the solvents were evaporated and the residue was dissolved in 2 ml of dilute aqueous sodium bicarbonate. and the solution was extracted 3 times with 2 ml of ethyl acetate each time, and the extracts were discarded. The aqueous solution was acidified to pH 3 to 4 with 2N aqueous oxalic acid, and the acidified solution was extracted 4 times with 5 ml of ethyl acetate each time. The ethyl acetate extracts were washed with a 1: 1 mixture of saturated sodium chloride solution and water and then dried. After the ethyl acetate had evaporated, the residue consisted of a mixture of the C-15 epimers of 9 * 1.11 (1 » 15-Trihydro3cy- 16-phenoxy-17,18,19,20 ~ tetranor-5-ci s-13-transprostadien-acid, thin-layer chromatography on silica gel plates, which is available from M erck in Darmstadt, using a mixture of benzene, dioxane and acetic acid (20: 10: 1) as a developing agent, separated the C-15 epimers, which had Rp values of 0.3 and 0.4 respectively- ( In this example, the Rp values relate to silica gel plates obtained from Merck in Darmstadt, and the stains were also determined either by fluorescence or by spraying the plates with a solution of cerium ammonium nitrate in sulfuric acid The nmr spectrum of each isomer (in deuterated acetone) had the following characteristic bands ($ values):

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5.6-6.1 wide multiplast, 5 arosiatic protons 4.2-4.8 wide ftiltiplete, 4 olefinic protons 2.9-3 * 8 wide fbiltlplete, JH, H-O-O and 4 interchangeable Protons

The bis-tetrahydropyranyl ether used as the starting material can be produced as follows:

69 ml of a 1.2 M solution of n-butyl lithium in hexane were added to a solution of 10 3 S M methoxide methyl phosphonate in dry tetrahydrofuran at -78 ° 0 in a nitrogen atmosphere. Wake up 10 min, wu ^ de © a solution of 4.1 g of phenylacetyl chloride in 20 ml / tetrahydrofuran was added dropwise, and the mixture was 4 h at -78 ⁰ C for "that SeaktioBDsemisch was neutralized with acetic acid and the solvents were removed under reduced pressure. The residue was shaken in a mixture of 100 ml of ether and 20 ml of water, and the organic phase was separated off and washed with brine. The solution was dried, the solvents were evaporated and the residue was distilled in a piston distillation apparatus at an oven temperature of 160 ⁰ C and 0.1 mm pressure to give dimethyl-2-oxo-3-phenoxypropylphosphonat was obtained ·

A solution of 1.01 g of dimethyl 2-oxo ~ 3 ~ phenoxypropylphoaphonate in 20 ml of dry 1,2-dimethoxyethane at -78 ° 0 was mixed with 2.75 ml of a 1.2-m solution of n-butyl-lithium in Treated hexane, and the mixture was stirred for 15 min * To this mixture was a solution of 1.95 g of 4-β-formyl-2, 3, 3eß96ßß-tetrahydro-2-oxo-5Ur (p-phenylbenzoyioxy) opentenojpb ^ jfuran in 10 ml of 1,2-dimethoxyethane were added and after 1 hour the reaction mixture was neutralized with glacial acetic acid, whereupon all solvents were then evaporated

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under vannind-artseiu pressure below 35 ° ß exw? £ reant ww.-f.ii · a * The residue was chromatographed a \\ £ Florisil using a solution of ethyl acetate in ethylene chloride as the solvent, with the unsaturated clay as * jsi.ßdr? eat ~ stoff was obtained Fb _f = 0.6 (1i1 iitbylacstat / Bonaolfj.

To a solution of 500 mg of d <33 unsaturated ketones in 20 ml of dry 1,2-dimethosylethane with ⁰ ° C., 1.5 ml of a 0.5m solution of ZirAk borohydride in 1,2-dimethosylethane were added . The mixture was stirred for 50 min to room temperature and then its saturated sodium hydrogen tartrate solution was added until the foaming stopped. Finally, 100 ml of ethyl acetate were added, the organic layer was separated with a _t-1s1 Gomisch of saturated saline; and water washed and then dried. The solvents were evaporated to give a mixture of splintered unsaturated alcohols. fep * 0.3 (1: 1 ethyl acetate / benzolf}.

500 mg of the mixture of epimeric unsaturated alcohols was stirred vigorously for 2 hours with 140 mg of fainly powdered anhydrous potassium carbonate in 10 ml of methanol. 2.1 ml of 1N hydrochloric acid were then added, followed by the addition of 50 ml of ethyl acetate. The organic layer was separated, washed successively with saturated sodium bicarbonate solution and saturated saline solution and dried, and the solvents were then evaporated. The residue was chromatographed on 20 g of Florisil. Elution with ether removed by-products and a subsequent elution with ethyl acetate gave a mixture of C-15 epimeric diols £ R ^ s "0.2 (Äthylacetat.Q.

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To a solution of 316 ms of the epimeric diols in 3 ml of methylene chloride were slowly added 1 _.; 2 ml of redistilled 2,3-dihydropyran and 0.1 ml of a 1% solution of waesex'-free To.luol ~ p-sulfonic acid in tetrahydrofuran were added.

After 10 minutes, 3 drops of pyridine were added and then 50 ml of ethyl acetate were added «The solution became sequentially with saturated sodium bicarbonate solution and saturated saline solution and dried. Evaporation of the solvents gave a mixture of epimers Bis-tetrahydropyranyl ethers in the form of a clear oil. Rj, * 0 »6 (ethyl acetate}.

To a solution of 420 mg of the epimeric bis-tetrahydropyranyl ethers in 10 ml of dry toluene, 1 ml of a toluene solution was added under a nitrogen atmosphere at −78 ° C., which contained 2 _$ 2 nillimoles of di-isobutylaluminum-nium hydride per ml of Lo ^ - solution contained * After 15 min the reaction was quenched by the dropwise addition of 3 ml of ifethanol, and after a further 15 min at room temperature 25 ml of a 1: 1 mixture of saturated saline and water were added and the mixture was then 3- times extracted with 50 ml of ethyl acetate each time. The extract was washed with saturated sodium chloride solution and dried, and the solvents were evaporated, leaving a mixture of the epimers of 2.3 »3ftl» 6cir ^f i-tetrahydr'O- 2- hydroxy-4S- [jl-phenoxy-3 - (te trahydropyran-2-yloxy) -1 -transbuteziylji -5 «t ~ (te trahydropyraD-2-yloxy) cyclopenteno [VJ furan obtained i <furde. ΓΈ «- 0 _t 4 (1: 1 ethyl acetate / Bsnzol) j |.

1.11 g of finely powdered (4-carboxybutyl) triphenylphosphonium bromide was heated to 100 ° 0 for 1 hour under vacuum. The evacuated

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The reaction vessel was filled with a dry nitrogen atmosphere, the solid was dissolved in 5 ml of methyl sulfoxide! and the solution was cooled to room temperature. 2.55 μl of a 2 "solution of NüthaDsulfinylmethylnodium in dimethylsulfoxide were added dropwise to this solution, whereupon the 2usatz of a solution of 400 mg of the epimer mixture of Cyclopentenojlb ^ furan-bis-tetrahydropyranyl- ether in a mixture of 10 ml of dimethylsulfoxide and 2 ml of benzene connected. The solution was stirred for 3 hours and the solvent was removed under inert pressure at a temperature below 40 °. The residue was shaken with 10 ml of water and 10 parts of ethyl acetate, and the aqueous phase was separated off and extracted twice with 10 ml of ethyl acetate. Ms extracts were discarded. The aqueous solution was acidified with 2N oxalic acid eof pH 3 to 4 and 5-mel with IC ta! a mixture of equal parts of ether and Petro-Uther (Ip 40 to 60 ⁰ G) extracted. The organic phase was burned off, washed with saturated sodium chloride solution and dried. Evaporation of the solvent gave 9 <^ 'Hydrc ^ -1 € pheno3Ey «-1ift ,, 15-bis (tetrahydropyran ~ 2-ylox3r)» 1 ? , 18 «19» 20 «tetranor-5-cis-13-trans-prost adienic acid as a clear 01. {R _? ~ 0.5 (ethyl acetate) !.

Example 2

Dae beeohrieboxie in Example 1 was repeated using dae "steppe afc end Phospb-cnatreagenz have been used and to obtain & i & tu dsr sequence indicated compounds. Uli products were n.aa.r. spectroscopy identical tltizlbTt ^ iCsLcS In de-ϊ 'success © either by the R ^ value of 3U.msCiAiükt3ärft & ategi aphi3 or exact Maseenmeseunget?; through! read & spectroecopy of either the molecular

20S8S0 / 1256

ion or the (M ⁺ methyl) ion (whichever was more appropriate) of the tetra (trimethylsilyl) derivative. This derivative was prepared by adding the compound to be subjected to mass spectroscopy to bis-trimethylsilyl-trifluoroacetamide containing 1% trimethylchlorosilane (ßogisil; registered trademark) and allowing the mixture to stand for 1 hour the unsaturated ketone intermediate characterizes «Corresponding data for these compounds are also given.

OH

GOOH

2098E0 / 12E6

No. Γ Phenyl A. X 1 η -OHrCH- -OH ₂ - 2 Il » -OH OH,)- 3 η dd -0 (0H ₃ ) ₉ - Benzyl I! - (0H ₂ ), - 5 2-caphthyl It -CH ₂ - ' 6th 4-öhlopopheiiyl η Il 4-chlorophenyl Il Ii δ ρ — Ohl ox * opiieny 1 -OH ₂ OH ₂ - 9 S-Oiiloropheiayl -OH: CH- dd 10 Il 11 4-bromoplieny? W η Il 12th Il H -13 4-5olyl I ft
) (I. 3-Iolyi η dd 4.! F-Biitylphenyl H S! 16 phenyl It It 17th
IS 2-KefehOJtypheioyl It
I,.
[ It
U -η; t? λ -; S tr

Ü / Ä

NrJ Isomer * Mass Spectrum calculated Phosphonate _I found 678.3625 Kp CG / mm) 1 mp
Ip M ⁺ -678.3610 677.3545
692
691.3703 178-185 / 0.05 2
3 mp
*
mixed 677.3540
M ⁺ -OH ₅ =
691.3660 706.3938 175 / 0.2
130 / 0.1 4th mp
ip M ⁺ «706.3921
«^ = 706 692.3781 166-16.3 / O ₉ 1 5 mixed M ⁺ = 692.3753 728.3781 170 / 0.1 6th mp ! ^ "» 728.3744 697.3001
712 3 ^ 85-86 * 0 7th mp
Ip 697.2948
if = 712 714.3391 170-173 / 0.1 8th Ip <*> ^ «714.3399 697.3000 17O-173 / O ₉ 1 9 mp 697.2297 712 180 / 0.2 Ip .if «712 712.3235 10 mp M ⁺ = 712.3216 731.2609 174-178 / 0.1 11 mp 731.2599 741.2497
850/1256 j - 12th mixed 741.2485
2OS

Eaon
Fp (

I55-I5B

: -120-122

99-101

185-18? 132-155

.132-135

129-132

«24 -

13th rnp if «696.3468 696.3529 164 / 0.05 162 Ip Ii ⁺ »696 160 / 0.5 14th ge
mixes 1 ^ * 692.3738 692.3701 - 149 15th mp 692 _f 3781 - 140-141 16 ge
mixes ίί ⁴ = 734.4213 754.4251 - 17th mp H ⁺ -746.3467 (b) 746.3499 - 115-117 3P (C) 18th mp if-706,3717 708.5731 -. 19th Hp 708.3731 M ⁺ «70B 20th mp 75 ^, 3938 ->

* mp «more polar, Ip = less polar isomer in SiIicagel-Ditenachochroinatographie

(g) Products synthesized from the more polar or less polar Enolawischer <proaukt®n

(b) By * 0.4J? after 2 Verauehea with Silioagel-Düanschichtchromatof ^ aphie with Seiger Easigsäisr® in ethyl acetate

(c) Κ, «0, ^ 0 c% over 5 experiments on silica gel thin layer chromatography

as with (b)

20S3S0 / 1256

Bsi the preparation of the compound 8, wherein A is an ethylene radical the unsaturated ketone intermediate is reduced to the saturated ketone as follows »

360 mg of the more polar epimer (epimer on the 3-carbon atom of the butenyl side chain) of 4-ß (4 ~ p-0hloropheaoxy-3-hydr oxybut-1-enyl) -2.3 * 3 & ß »6aß ~ te trahydro ~ 2- o3co ~ 5β, - (pphenylbe: azoyloxy) cyclopönteno £ b ^ furan were dissolved in 25 ml of ethanol, and the solution was added to nickel boride which had previously been prepared from 620 mg of nickel acetate and 2.5 ml of a 1m solution of sodium borohydride * Das The mixture was shaken with hydrogen for 3 hours and then filtered, and the filtrate was evaporated to dryness * whereby ^ ß - (^ - p-0hlorophenosy-3 ~ hydroxybutyl) -2.3 »3»% β »6βςβ-tetrahydro-2- o: xo-5A- (p-phanylbenzoyloxy) cyclopent © no J ^ bJ-furan. [Rg ₁ = 0.4 (50% ethyl acetate in toluene ^.

The saturated ketone was then used in place of the unsaturated ketone in the remainder of the procedure described in Example Λ.

Example 3

To a solution of 15 mg of the more polar O-15-epimer of 16- (4 ~ chlorophenoxy) -9flW hay 15-trihydroxy-17 »18.19 ₁ 20-tetranor-5-cis-13-trans-prostadiene acid In 1 ml of methanol, ^{an excess of a solution of diazomethane, ether was added at 0} ° C. After 10 minutes, the solvents were evaporated, with a single Ci ^ -EpiEiQE 'vöa 16 phenoxy) -9 <U 11gt * 15-trihydroxy- 17 »18« 19 »20-cis-13 ~ trans-prostadienic acid ~ methyl ester was obtained as a clear oil. £ Rj, «0,3 (Ät & ylaeetatj]. The n # mr * - Spekfcruia s ^ igte di.-: folgs ^ dsa cka
(J value s) ί

209850/1256

6.8-7ϊ2, 4 aromatic protons
513-5 »7» 4 olefinic protons
5.6, COOC ₁ H ₅

Example 4

The procedure described in Example 1 was repeated using the appropriate phosphonate reagent or the equivalent Phosphoran R CIL, «CO.CH:PPh, was used to make the to establish the connections specified below «The Products were identified by n.m.r. spectroscopy and are subsequently either by their Rp values of Thin-layer chromatography or by precise mass measurements by mass spectroscopy of the molecular ion of the corresponding fully protected (OfeLmethylsilyl) derivative characterized, this derivative having been prepared by adding the compound to be subjected to mass spectroscopy Bia-trimethylsilyl-trifluoroacetaiaid, the 1% Trlmethylchloroailan (Tb-jlsii} registered trademark), was added and the mixture was allowed to stand for 1 hour. In some cases the phosphonate reagent or characterizes the unsaturated ketone intermediate product * Despreeken & e requests of these connections are also specified »

20SS8Q / 1286

Phenyl 4-Ohlorophaayl

-CH ₂ -

37 38 39 40 41 42 43 44 45

3-fluoropb.enyl 2-fluoropheayl 3 ^ -Dichlorophenyl 2,5-dichloropheoyl 2-tolyl

3,5 xyiyi. 2 ~ ghloro-4-methylphenyl 3-dimethylaminophenyX 1-naphthyl 4 ~ chloro-1-naphthyl 2-naphthyl 6-methyl-2-naphthyl 6-Me 13ioxy-2-xiaphthyl 3-chlorophenyl 2,3-dichlorophenyl 2 1 6, Dichlorophenyl 3,5-dichlarophenyl 4-chloro-3-methylphenyl 3-methacyphenyl 1-chloro-2-naphthyl j 5,6 7,8-tetrahydro-2-naphthyl

-CH ₂ -

It Il Il

η η

«Ι ι? ti

Il

ti

K (CH ₃ ) -

—S-

'SncierF'SuSeFr * in the .prostanoic acid

η η st

η η η

2-methyl

209850/1256

ffip

Ip

mp
Ip

mp

24 mp 25th mp 26th mp
Ip 27 mp
Ip 28 mp
Ip 29 mp
ip 30th mp
Ip 31 mp
Ip 32 mp
Ip 33 nip
Ip

mp

No. I isomer ^ f

M ⁺ «69193994

691

9 696

696 {696

746

692

706 * 3971 706

706

M ⁺ = 726 726

7.4020 721

# ■ • «728.3830 728

762

1.

691.3940

725.5313

728,3006

696.3531

696 _t 3531

746.2844

692.3781

706.3935

706.3935

726

721,4047

738.5781

762 _t 3388

Phosphorus i

(b)

15Ο / Ο _? Ο5

p ( ⁰ C)

145-150

(c)

(b) 135-138

(d)

(ε)

154-160 /

0.05

180 / 0.15

Cb)

(10

(i)

138-139

144

(£) 150-152

187-190

165-167

166-168

140-142

113-115

138-145

185-187

(d)

209850/1256

'35 mp
ip ^ 742 * 742.3937 M.p. 85-86 185-187 I. 36 mp
Ip 742 ' 742.3937 M.p. 71-72 153 37 mp
Ip "758 * 758.3887 M.p. 58-59 195 38 mp
Ip "~ 726 * 726.3391 180 / 0.2 00 39 mp
Ip ₊ 731.2644 731.2609 175 / 0.03 153-155 40 mp
Ip if = 746.2844
746 746.2844 M.p. 89-90 140-142 41 mp
Ip if = 746.2829
746 746.2844 80-82 138-139 42 mp
ip iff = 726.3397
726 726.3391 «KB 143 43 mp
Ip V
~ 70δ ' 708.3730 (1) 129-130 44 mixed rf-762.3402 762.3391 M.p. 61-62 195 45 ν ΠΙ j

2098S0 / 12IS

(a) mp - more polar, Ip => less polar

Whether) these compounds, which from phosphoranes (not phosphonates) were synthesized as described below

(c) Eg = 0.5 (50% ethyl acetate in toluene)

(d) Eg, ~ 0.2 (40% ethyl acetate in methylene dichloride)

(e) Hj ₁ ».0.4 (5% acetic acid in ethyl acetate) (f) H _p * 0.3 (50% ethyl acetate in chloroform) (g) Rp * Q523 (50% ethyl acetate in chloroform)

(h) R _F = 0.5 (50% ethyl acetate in methylene dichloride)

(i) ßj, »0.4 (10% methanol in ethyl acetate)

( _t 1) H _p 0.8 (50% ethyl acetate in toluene:

(k) E _F β 0.6 (50% ethyl acetate in toluene)

(1) E _F * 0.4 (50% ethyl acetate in methylene dichloride)

(m) Rp * 0.25 (3% acetic acid in ethyl acetate)

(n) H _p ~ - C30 Op acetic acid in ethyl acetate)

(- / j) and On.}; C 6.8 (1H, aromatic), 6.6 (2H, aromatic), 5, * (2H ₀ olefinic) and 5 * 7 (2H olefinic)

The production of a Phospiiorana _$ which can be used as part of a Pho8phcnata "in the listening position of a cyclopeatanderircit according to the invention, is based on the

Production "<? $ & Fi- (3 ~ i? IffietliylaElnoph © no3 £ y) -acetonylidene] ^ - tripheny 1 · phoBphorane

. - _f i- i * yes ■

; 4 ϋ y. '

3 »85 ml one? 1.3m solution of n-butyl lithium in hexane was added to a solution of 685 mg of 3-dimethylaminophenol in 20 ml of dimethoxyethane at -70 ° under a nitrogen atmosphere. The solution was allowed to warm to room temperature, a solution of 2.22 g of I-iodoacetonylidene triphenylphosphorane in 100 ml of benzene was added, and the mixture was refluxed for 2 hours. The mixture was then diluted with 100 ml of toluene, _{washed twice with (} 50 ml of water and dried, the solvents were evaporated and the residue was treated with Ither gori @ ben «whereby the compound ^ - (3-dimethylaminophenoxy) aeetoE ^ lid © a | - triphenylphosphcran with a melting point of 110 to 115 ° C was obtained «

Similarly, the analogous K-methylaniliiio ^ phospho- * ran (rubber) and 4 ~ chlorophenylthio-phosphorane (melting point 158 to 165 ° G) herge ste11t

Example 5

The procedure described in Example 3 was repeated with the corresponding more polar C-I ^ epimer instead of the strong C-15 polar epimer of 16- (4 ~ chlorophenoxy) ~ 9a »11a» 15 ~ trihydroxy-17 »18» 19,20-tetranor-5-cis »13-trans ~ Prostitutional acid was used. It became the following Methyl esters obtained as the only C-15 epimersί

(a) 16- (4-Fluorophenoxy) -9 «u 11α, 15-trihydroxy-i 7,18,19,20» tetranor ~ 5-cis ~ 13 ~ trans-prostadiene «3 acid methyl ester, R ₁ . * 0.3 (5% methanol in toluene) £ * 6.7-7 * 2 (aromatic) 5 »3-5» 7 (4 olefinic protons), 3 »6 (methyl ester).

209860 / 12B6

M ^f «67O, 55 '! - a (calculated 670.354-1).

(c) 9 Φ, »Ί1 cu 15- ■ trihydrate: 7« 2-methyl-16 ~ (2-naphthophyloxy) 17, 18119, 2G-tötraa.cr-5 ~ öiE-1 S-trans-prostadion methyleetep, ff "-634.3678 (calculated 684.3697).

(d) 9 % 11 iv. » 5-Trihydpojsy-16- (6-aethyl-2-naphthyloxy) 17,18,19 ₁ 2C-tetraiior-5-oi8-13-trans-prost adimmethyl «ater,! ^« 68 ^, 3739 (calculated 684, 3698).

(e) 9cLt11 <fo15-3? riJivd ^ c>: ^ »15- (p

1? / »8.19 t 20-tstraiior-5-is-13 - trans-proste.di2a-8 acid ~ aethyleeteij rf = 700i? 68i (calculated 700 , 3647).

(f) 6 -C I -Ohlorophes oirν). «9δ _Λ 11SL ₁ 13-trib ^ d: eo ^ y» i7,18.19 »20-tf trafio: c ™ ^ -c is-1 3 -trans -protitadi ea methyl acid ester ₄ «.,. - 0.3 (iStfcylacsfcatOs R ⁺ * 65 * |., 2975 (calculated 654.2995)

(g) '? ft * 1' ⁽ ^ U 15-toi3 ^ iPc: ^ - 2-miath5'l- "€ 1 - (i-chlcrophenoaty) -

1 v "* ''& ί ** '3 ■ * £ Q -te tra ^ o ^ -3 ~ cis« ^ 3-trana -pros tadl.sn-acid € r _t % χ ö, 4 (ethyl acetate) » M ⁴ = 668.3133 (be

Appendix 6

Bow of the stäi-lvar polar G-1 "-J0pisiera τοη 16- (4-chloro-

tr ';.-.- v ^ ure vurdea with an excess of

iitejD Asim ^ ivLakbehalc-lt, um the Anmorduasals L.ej?: - nistelle-ri » TmT Asasonlaküberöob \» S ^ ur ^ e ivatsr ver

2 0 & 8SGM2 56

Evaporated under pressure, and the chopping stand was treated with the 3t8cMom9trsicn8a amount of silver nitrate to make the silver salt. The Silbex's salt was filtered through, soaked in water, dissolved in 0.5 ml of n-butylodide and stirred for 1 hour at tree temperature. The solution was extracted with ethyl acetate ?, the ethyl acetate extract was evaporated to dryness, and the residue was chromatographed on 1 g of Florisil using 50% ethyl acetate in toluene as the eluent * 16- (4-chlorophenyl) -9ft, 11 ( & »15-trihydroxy-17,18,19,20-tetranor-5-cis-15-trans-prostadienic acid-n-butyl ester. Μ ⁺ » 696.5Α · 27 (calculated 696.3 ^ 6 ^) , H _p = 0.4 (ethyl acetate).

Similarly, but using ethyl iodide instead of n-butyl iodide, 16- (4-0hlorophenyl) -9d, 11 <1,15-trihydroxy-17,18,19 ■> 20-th tranor-5-ois-13 -trans-proatadienoic acid ethyl ester obtained. M ⁺ »668.3086 (calculated 668.3151).

Example 7

A solution of 73 mg of the mixed anhydride of acetic acid and the more polar σ-15-Bpimer of 90rAcetoxy-16- (4-chlorophenoxy) -1 1 *%, 16-bls (tetrahydropyran-2-ylo3i: y) -17, 18 _s 19, -20-tetranor-5-cis-13-trans-prostadien acid in 2 ml of a 2: 1 mixture of acetic acid and water was 4 st under nitrogen at 47 ° C stirring. The solvents were evaporated, the residue was dissolved in 2 ml of dilute aqueous sodium bicarbonate solution, and the solution was extracted 3 times with ie 2 ml of ethyl acetate. The extracts were discarded, the aqueous solution was acidified to pH 3 to 4 with 2N oxalic acid, and the acidified solution was extracted 4-x & X with 5 ml of ethyl acetate each time. The ethyl acetate extracts were with

209850/1256

washed with a 1; 1 mixture of saturated saline solution and other water and then dried. After evaporation of the ethyl acetate vmvd®, the residue was purified by thin-layer chromatography on silica gel, 3% acetic acid in ethyl acetate being used. It was the more polar E-15-Epiioer of 9 ~ & acetoxy-16- (4-chlorophenoxy) ~ T1 £ l ₁ 15-dihydroxy-17,18,19-tetranor ^ O - ^ - cis-IJ-trans-prostadien Acid obtained »1 ^ * 682-, 294-2 (calculated 682.2944).

The bis-tetrahyciropyranyl ether used as the starting material can be produced as follows:

A solution of 70 mg of the more polar C-15 epimer of 9ftr-hydroxy-16- (4-chlorophenoxy) -11 «,» 15-bis (tetrahydropyran-2-yloxy) -17,18,19120-tetranor-5 -cis-135-trans-prosadienoic acid in 0 _t 15 ml of a 2s1 mixture of pyridine and acetic anhydride was kept at room temperature for 16 hours. The volatile Haterlal was "evaporated" and 10 ml of cyclohexane were added and the residue boiled off (3 times), Vi ..ei da *. * ^ <£ ls3ht8 Asiihydride of acetic acid and 9ÄrAcetoxy- ^Λ - (^ -chiC3: cpi: 6öoxy) * 110. » 15-Ms- (tetrahydropyran-2-yloxy) -1?; IS, I9iiO-tetranor- ^ - cis-i ^ -tiÄas-prostadien.-acid as yellow oil remained. Y max (CHGl,) 1? 20, 1810οβι ~.

Example 8

To a solution of 12 mg of 9ftrAcetoxy-16- (4-chlo2 ^ ophenoae3r) "11 Q _n 15-dihydroxy-17,18,19,20-th tranor-5-ci s-13-transproetadiene acid in 1 ml of methanol O ⁰ O, an excess 9iö "x ^v x-'üauag of Diafcoi & eth & n in Ither 10 aas Worden was added. skilled abgedsapft the LöeungaiRit.tel, the residue was dissolved ia ether, 'and the solution Wirde with 50 mg Litki" m ~ treated aluminum hydride. Bas mixture was

ü 30 ο ü /

Stirred for 1 hour at room temperature, the hydride overlay is destroyed by adding 1 ml of water, and the mixture. extracted with ethyl acetate, whereby 16- (4 ~ chlorophen GKy) -9 it, 11 &. » 15-trihydroxy-17,18,19,20-tetranor-5 ~ cls »13-tsansprostadienol was obtained. M ⁺ = 698 ₅ 3 * 5-39 (calculated R ₁ * 0 * 2 (ethyl acetate}.

In a similar way were obtained:

16- (3 ~ chlorophenoxy) -9 &, 11O * ¹ 5-trihydroxy-2-metalay 1-1?, 18,19,20 »tetranor-5 ~ cis-13-trans-proetadienol _i R ^» 0.15 (l ^ fe.jlsise "öat) _s

Ρί * "" 712.3575 (calculated 712.3597).

90.11 α, 15 ~ iDrihydroxy-16- (6-methy3, -2-naphthyl oxy) -1 ?, 18,19,20-tetranor ~ 5 ~ cis-13-trans ~ prostadienol, E ^ «0.2 (ethyl acetate).

Example 9

The procedure described in Example 1 under of the corresponding phosphoaate reagent repeatedly; tiobsi fol the following was obtained:

tetranor-5 ~ cis-13-trans ~ prostadian-slure _i Ej, ^ 0.2 wiä (3% acetic acid in ethyl acetate), S * 6.82 (4-H ₉ 5 * 3-5.7 (^ H ₅ olefinic), 3 _t 98-5 ₅ 1 (1OH,> GH.O exchangeable protons); biosphonate, E ^ ₁ ^ 0 _t 2 (10% methanol in ethyl acetate); enone, Ip 135-1 ^ 0 ⁰ G.

(b) 16-furfuryl-9a, 110 * 15 ~ trihydroxy-17,18,19 · 20-tetraßor-5-cis-13-trans ~ prostadienoic acid © .. R _1n , * 0.5 (3% acetic acid in £ thylaoetat), £ »7» 5 (1H) and 6 ^ 3 (2E) (Tux ^ l protons) 5 »1-5f6 (4H, olefinic); Riosphate, Ep 200 ° δ / 0.2 mm; Enone, m.p. 92-93 ° 0 *

(c) 16- (3-Allylphenxy) -9 "W 11 € U 15-trihyärescy-17.18 ₀ 19" 20-tetranor-5-cie-13-trans ~ pro8tadie £ L-eäixE> e, H ^! '=? 18 3892 (found 7.18 * 3938); Xtiosphonate, H ^ "O" 32 (ethyl acetate) j enone "mp 110-112 ⁶ C ₂ Q 9 8 SQ / 1 2 S 6

example

The procedure in Example 1 was repeated, except that a 9-0xo-pi ^l ostansävire-deriTat instead of a 9o'-Hydro% y ~
prostanaäuro-äertrats was used. The connections specified below were obtained ».

For the measurement of the 'Kasseaspek'üron the acids were with
Diazomethane converted into methyl ester _t the 9-oxo group was protected by conversion into the ifethoxime with Hetlioxylamia, \ mä ^ wen «. On the other hand, the hydroxy groups at 0-11 and C-15 were protected as Irimefchylsilylaeri'ir & te. The n.i.r. spectroscopy were made in German acetone

COOSS

OH (OH) -X-I-R

208SS0 / 1256

-37 - H ⁴ X Y 2223365 1 I. ■ ι No. Phenyl -OH ₂ - -0- 46 Il
Il -OH (OHj) -
- (0H ₂ ) j- (I.
Il • 47
48 1-naphthyl -OH ₂ - Il • 49 2-naphthyl Il ti 50 4-chlorophenyl Il Il 51 Il It -S- 52 3-chlorophenyl η -0- 53 2-chlorophenyl Il Il 54 4-chlorophenyl ft f f% XX \ H - 55 4-bromophenyl -OH ₂ - Il 56 4-FLUOROPHOHyI It Il 57 3-fluorophenyl ti U 58 2-5 * luorophenyl Il Il 59 2,4-diehlorophenyl Il η 60 2,5 dichlorophenyl It 11 61 3,5-dichlorophenyl Il η 62 4-iolyl It 63 3-tolyl η 64 2-tolyl It Il 65 3,5-lylyl ti 11 66 4-0hloro-3-methyl-
phenyl η η 67

2098S0 / 1256

Mr. 2-chloro - ^ - methyl-
phenyl -CH ₂ - Y 68 3-tri.fluoromethyl-
phenyl Il -0- 69 4-methoxyphenyl «I. Il "70 2-methoxyphenyl It •1 71 4-chloro -1-naphthol ti Il 72 Il

He. l £ 4om «3; · * 46 mixed

48 49

54 55

mp

mixed

sip

mixed

39

R _r , i 0.2 (acetone / öycloheEan / Ätnylaeetat- ¹ 1: 2: 2)

nmr: $ 6.98-7.28 (5H, aromatic), 5, (2H _t cis -OXefi &) _t 5 »7B (2H, trans -olefin), 3.5-4 * 5 (5H,> OH.O - «nd -GOOH)

K ⁺ »5S9,326.7ßerechaet 589,3255 for methyl ester« ·, 9-Meth03cim-, 11 _f 15.-Di- (trinethylsilyl) -derivatl ·% * · 0 ₅ 4 (3% acetic acid in Äthylaceta'c)

Hj ₁ β 0.3 (3% acetic acid in ethyl acetate)

Rgi - ^: 0.4 (3% acetic acid ia ethyl acetate)

n * m «r · t aromatic © protons at ^ 8" 5-8.5 (1H), 7.7-7 · 9 (1H) _? 7.2-7.5 («)« to 6.8-7 * 08 (1E)

g - 0.3 (3% acetic acid in ethyl acetate)

n.m.r.j aromatic protons b @ ii 7 ^ 7-7? S d 7.1-7.5 (4H)

M ⁺ »609.2633 C calculated 609 ^ 2709 for Hetbyl-

ester-, 9 ~ methoxime-. 11.15 - Di (trim © thyl- " eilyl) derivative J. BU «0.4 (3% acetic acid in jithyl acetate)

%. = 0.5 (3% acetic acid in IthyIac®tat) n.m.r.! aromatic protons at 17.3

F acetic acid in ethyl acetate)

n.m.r .: aromatic protons at 7.15 and 6.9 (3H)

0.4 (3% acetic acid in ithylaoetat)

Ep «0.5 (5% acetic acid in ethyl acetate)

n * mr: aromatic protons at 6 7 ₉ 28 (2H) ₅ 7.19 (2H) and 2 methyls at S 1.25 vma 1.30 "(6H) y

2098B0 / 1256

Kr. 56

mixed;

9)

"5 (3% vinegar
? .i'ü 7.03 (2H)

acid χα lth;, 'Xao <? t &t;'

0.3 (2? Δ Efjsigaäw ^ - ia Äthr-lacotat)?.: Aromatiecho Protoairn at $ '/ V * 5 and 6.65 (3H)

0.4 (5% lüsslKss-vre in Ä '£ i: - lacotat) .; aroEiai; ii3Clj.s, »Protons bii S 7? O5

0.4 (0 _{ 2% acetic acid in iithylacetate): a.'i'omatic protons bti. F, 7.12 ('! H). 7.5 (IC) and 7.41 (IC)

.; & λ οmatic protons, hot $ 7 * 5 (7.15 (1H) mid o.9 (IH)

0.34 (5SS Easlgsävffe ic. Itky lace tat) ⁵ .: Aromatic Ρι · οtojien hc.i. S 6.9

0.2 (Cyo

I n.ai.r .: aromatic protons & 6.7 (2H * I ?; I (2H) and HGfchyl hei ^ 2.28

5 V

;; ß.m.r. in l #

a ^ oTaatliiCj.!
d CS..73 (3H)

M ⁺ 569 * 3284 ß) öis., Cli »-3t 589.3 ^ 5 * for methyl

θ st Gr «j Met Jiox Ire-, Di (trii: eth ^ lr? ilylV-

tj

a

209850/1256

8AD ORiGJNAL

JSr *

67 68

69

70 71 72

is?

4-1

Charal "ce rig ie: i

JEL, = 0.2 (Oyclohesane / Acetone / Ätnylaceiiat · -

^J - 4: 1: 2)

r; .m »2?.; aromatic protons up to S6.5 (3H) mid Jfetayle (6H) to 2.28

: = 0.5 (5% acetic acid in ethyl acetate)

j n, m * r «: aromatic protons bai §7» 2 (1H) 6.85 (2H) and methyl at 2.3

E ₀ β 0.4 (Cyclonexaa / ethyl acetate / acetone- ■ '■' 4: 2ί1)

n.Bi.r: aromatic protons at ί 7.18 (IH) and 6.80 (2H) and methyl hot. 2.2

, «■ 0 * 5 (5% Eaaigs & uff © In ethyl acetate)

a * 2i.r .: aromatiacha protons bQi ^ 7 »5 -omd 7.25 (3)

ganisoiit j B ₁₅ , "0-6 (3% Eaaigaäui" in ethyl acetate)

O ₅ 65 ima 0.7 (3% Essigaäires in Ethylacebat)

j n.m.r »: aromatic protons at & 8.4 j 8.15 (1H), 7 * 6 (3H) and 7 * 08 (1H)

^Λ mp = more polar

209850/1256

The 9 ~ O3: ö-proßtGvic.; Ä - '. I: cS "-deriv * ate, dia ale l

can become desolate due to oxidation mo5 will switch as λ «i & which followed voa 9-0x0-16-pb.en.oxy-H ©. » ^ 5 , 18,19,20 »tetraaor-5 ~ ci a ~ 13-uj? Ü exO. is announced;

To a solution of 270 mg 9t
(tetrahydropy3? -aa-2-jXc: 2y) -17.18,19 »20-tetraaör-5-ci s ~ 13-trana prostadiea-eäure in .5 al Acetoa xfurdea feel -10 ⁰ O 0.163 ml Joaea-Rsagsnz (ghromic acid in acetone) 2suggel) ön. After 15 minutes, a drop of isopropenol was added, followed by the addition of 20 n? L of ethylacetac. The solution was washed with an iso mixture of saturated saline and water and dried. Evaporation and chromatography of the Läsungsmittel Ruckstanda on silica gel using 1: 1 ether / Peti oläther (b.p. 40-60 ⁰ C) gave the ElutiierungalösungSEiittQl. desired »9-oxo-bit (tetrahydro-pyranyl ether). H ^ * 0.2 (50% ethyl acetate in toluene).

Example 11

The procedure described in Example 3 was repeated, except that 1 la, 15-üih ^ d: coxy-16 ~ (2-naphthyloxy) -9-0 £ o ~ 17,18,19 ~ 20-tetranor ~ 5 ~ cis ~ 13 -trans-pro3tadienoic acid used instead of 16- (4-chlorophenoxy) - 9'3., 11a'15-trihydroxy-17,18,19'20-tetranor-5-cia-15-trans-pro3tadienoic acid became «It became 11 ^ 15-D5.h7arojr / -» 16 ~ (2-i3.aphthylo3cy) "9-"OXO'-17,18._; 19.20-t8tranor ~ 5-cis ~ 13- · "srans-prostadien-acid-methyleater obtained. Rj, = 0.3 (ithylacstat) *

209850/1256

BAD ORKS <NAL

Example 12

! «■ UM <l> !! ■■■ ΓΜ IXWl I BIIWIIII ■ Il I II

Su a solution of 12 mg

roxy-i ?! 18.19 »20 th

in 0.5 ml of methanol> jurde "at 0 ⁰ C © into LöSsiug - <on 5 fflg Natriuaipei \ iodate in 0.5 nil -water added" the solvents were evaporated st After 18 extracted in the & Riiakstand with acetone vidbsj
11 ft _$ 15 "Grilaydi? O :: 5: y 17,18,19 _H

diene acid was obtained. M "" * 7 ^ 54.2918 (calculated 744.2956), RjP «0.2 (3% acetic acid in ilblaylacetate).

16- (4-FlixorophienoÄy) -9 & »11G * 15-

trih5'drox3r ~ 17.18 «19.2O ~ t © tranor ·" 0, OQJ 5 ~ ci s-13-trans-prystadic acid

sodium phosphate 2.90

Natrixim-hyd jT'Ogsn-pho spliat 0.30

es v / aaser ad 100

The NatP3.Ujapho3phi3.t was dissolved in about 80% of the water, and then, the pro atadienic acid derivative was added. After it had been dissolved, the fiatrium hydrogen was phosplmated added. The solution was injected with Water brought to the desired volume, and the pH was also smoked. It was between 6.7 and 7.7. The solution was filtered to add particulate matter remove, durrih Filtx-aticn ίτϋω.! lined and ib. pre-sterilized ne \ ?. br & .l & Glasempullov :. under aa & pbischen conditions

209850/1256

filled. ft & ititt ^ Ibar before -3. ^ m (t-sb-rauc!?. becomes α οχ- Tjb ^ ll; ο trier Äjapull «. Kd.i. · • oh- ^ iiio.lög.iffcb.-j-. r Eocfr8ala3oe <Aay: vercUan-c, so that he ä, m? oh iatpaveL'fißc lyifuaioa. v-crabrßii ^ r ;; •• ra-o'.i.ow kaiin »

The Prostadiön ^ äxa / Cf-derivö-f; ltar * n aüuiu-Ii «b avicb. by a equivalent Plönge © inos

ii'ats er sot »b Wi

2098S0 / 1256

Claims (1)

Paid claims © 1. Prostanoic acid derivative of the! Formula R ² 'A-OH (OH) -XYR ⁴ where R for sin Hydroxgrcnethyl- or carboxy radical _} an alkaxycarbonyl radical with up to 11 carbon atoms or an alkoxycarbonyl radical with 2 or 3 carbon atoms, which as a substituent ^ a ß- or ^ dialkylamino radical with 1 to 4 carbon atoms in the alkyl radicals or a ß- or ^ -Pyrrolidino, piperidino or morpholino radical carries; either R stands for a Hydroisryradikal or an Alkanoyloxyradikal with 1 to 4 carbon atoms and Br stands for a hydrogen atom or R and Έ? together stand for the oxo radical; A is an ethyl: a or vinylene radical; Σ represents an alkylene radical having 1 to 3 carbon atoms which carries 0, 1 or 2 alkyl radicals each having 1 to 3 carbon atoms; Y represents an oxygen or sulfur atom, a sulfinyl radical (-SO-) or an alkylimino radical (-N-alkyl-) with up to 4 carbon atoms; and R is an aryl, benzyl or Furfurylradikal which is insubstituiert "or obtained by. halogen atoms, hydroxy, or Hitro- Phenylradilsale, alkyl ₅ alkenyl, Halogsnoalkyl" alkoxy ,. alkenyloxy -or- Acylaminora & ical with 1 to 4 carbon atoms odex * dialkylamluoradicals with, in each case 1 to 3 carbon atoms in the alkyl 209850/1256 BAD ORiGINAt is substituted; where the 'compound O cdsr 1 carries alkyl radicals with up to M carbon atoms at atmospheres carbon atoms 2, 3 or 4; as well as the pharmaceutically acceptable Salae of those compounds in which R stands for an arboxy radical. 2. Prostanoic acid derivatives according to claim 1, characterized indicates that R stands for a hydroxymethyl, carboxy, methoxy · carbonyl, ethoxycarbonyl., n ~ But oxy carbonyl or n-decyl oxycarbony! radical; R stands for a hydroxy, acetoxy or propionyloxy radical and Br stands for a hydrogen atom or H and R "^ together stand for the ox radical; A has the meaning given in claim 1; X stands for a methylene, ethylene or trimethylene radical, which bears 0, 1 or 2 methyl substituents; Y stands for an oxygen or sulfur atom or the sulfinyl or methylimino radical; and R stands for a phenyl, naphthyl, eenzyl or furfuryl radical which, as substituents, does not have more than 2 halogen atoms, phenyl -, Hydroxy, methyl, t-butyl, allyl, methoxy or allyloxy radicals, chloroalkyl or fluoroalkyl radicals each with 1 to 4 carbon atoms or dimethylamino radicals; the compound carries 0 or 1 alkyl radicals with up to 4 carbon atoms on the carbon atoms Contains 2, 3 or 4; as well as the ammonium, alkylammonium (with 1 to 4 alkyl radicals of 1 to 6 carbon atoms each), alkanolammonium (with 1 to 3 2-hydroxyethyl radicals) and alkali metal salts of the same. J. Prostanoic acid derivatives of the formula I of claim 1, characterized in that R stands for a hydroxymethyl, carboxy, methoxycarbonyl, ethoxycarbonyl or n-butoxy carbonyl radical; R stands for a hydroxy or acetoxy radical and "Br stands for a hydrogen atom or R unö R- * together 2098S0 / 1256 for the oxo radical s'; - ah.e &: A stands for the Xthjlsn ™ or r'adifcal; X for the Kötnyj.en- «ithjlideD.- ;. den- or sriffisthylenradlkal staht; I for »v \ n S or sulfur atom odoy- the sulfine ricctex. ^; ilöth ^ stands; and R for the furfuryl · or Benaylra & ili & l or - or © r- Kaphthjlradikal, yalcbee as more than 2 chlorine » _s B: eom- or Fluoratoics or Hydrpxy-. Methyl, t »butyl, allyl .. methoxy ~ ₄ trifluoromethyl or dimeth ^ lamlrioradii'.a>bears; the terbiaxümg göbenezifallia on the carbon atom 2 © iaea methyl substitu © aton. ¹ Yu prostanoic acid derivatives according to one of the traditional types Z {. Proverbs "by g © kenni5 © iohnet _t that E represents a Ghlorophenyl- * Ohloronaphthyl-. Bromophea ^ l · -, FluoropheEyl «-. ToIyI-, .Xylyl-, methylnaphthyl- ₁ t-Btatylphansyl-, Methylchloroph9nyl- _i: Trinuoromethylpheayl-j hydroxyphenyl- ". Ksthoxyphesay 1- ₅ Hethoxynaphthyl- «, Biphenylyl-, Dimethylaminophenyl- or Tatrahydronaphthylradikal stands * 5. Prostanaänre.derivate according to one of the toxic claims, by the fact that E "stands for the phenyl--, ben- , Furfuryl, 1-ffaphthyl- _β 2-naphthyl, 2- ₉ 3- or A-chlorophenyl, 4 ~ bromophenyl, 2 ~ ₄ 3- or 4 -]? Luorophenyl-2,3-, 2,4 -, 2.5-, 2.6- _t 3 ^ t- or 3.5 2-, 3- or 4 - ToIyI-, 2 ^ 3-, 3.4 · - or 3 »5-Butylpheiiyl- , 3-ally! Phenyl-, 9 ~ Ψ? if luoiOmethylyhenyl- ₅ 4-Hyäroxypheaiyl-, 2-, 3- or ^ -Metho ^ rphonyl · - * 4-Biphenylyl-, 3-Dimöthylaminophenyl-, 2 ~ chloro-4-methy! phenyl-, 4 ~ 0hloro-3 ~ a'-e'bhylphenyl-, 1-ChICrO-S-SIaPhIaIyI-; 4-Ohloro- 2-naphthyl ₁ 6 ~ Iisthyl-2-naphthyl ₁ 6 - methoxy-2-naphthyl or 5 ~ _{t i} 6.7 8-Tetraiiydpo-2-naphtliylradikal is * 209850/1256 BAOORIGiNAL 6. Prostansäinw: U: '.' I ¥ & rfce dec! Formula I vox. A * inp '£ n & 3 ' ι. " thereby ße.keDx »scj.ch;?. o'l; that Ii? \\ τ an Oaiuo: ny r-adikal <? in Alkoxyctf.rboi ^ ylradifcal with 1 to 6 Eohlönetci'f & toraer or an Alkoxjofcrbouylx & öiteal rait 2 or 3 carbon atoms, which as öubs ^ iuußntei} a ß- odor ^ "- Dj.ialkyJ. Aminoradiks.]. With ^ Ii-CiIs 1 Ms 4 EokleastcffatoiKn ira each alkyl or eisj. Ss ~ or ^ O ^ rrülidijrio- ^ Pi. pe3? idino- p cdei? rio: ppholinoreci.ikal tragi ;, stand * ;; β} 3ΐνί® (5βΓ if "iiu * or an Allcimoylcxiyraaikal laii; Ϊ to E ohiöiistOff atoms and R · ^ stands for a hydrogen off atoia, or S and H- ' g®mex: ui & w form an oxo radical; A is an Ä'tüylen- odor Vinylenradlkal; X stands for a radical with 17 to 5 carbon atoms, ueiuhes bears 0, 1 or 2 alkyl radicals with Jawail's 1 to carbon atoms as substituents; ! and H ⁺ represents a radical Ary "which is unsubstituted or through HalogeBaiorae-, Nitroradikale-- ₁ alkyl, alkoxy or AcyJLaminoradikale with 1" to 3 carbon atoms or dialkylamino: is cadikale each having 1 3 carbon atoms bi3 ira alkyl; as well as the pharmaceutically aulässissa SaJjse the "compounds in which R stands for a Hydro ^ y radical- 7. Prostanoic acid derivats der · Foxmol I from Awiprueh 1, characterized in that B. for a Hydro: xyrasthyl <«or Garboxyradikal _t an Alkoxycarbonyli ^ tdikal with up to 7 carbon atoms or an Alkosiycarbonylradikal with 2 or 3 carbon atoms, wslohes as substituents a ß ~ or li * ^ Ma.lk, ylaminoradikal mxt In each case 1 to 4 carbon atoms in the alkyl or a ß- or ^ -. Pyrrolidino, piperidino or morpholino radical trä ^ t _¥ et ©. ^T .it; e.ntvreder R stands for a Hydro.-xjradical cat ·: '"· an alkanoyloxyridical with 1 to 4 carbon atoms and <! R ^. Stands for a hydrogen atom, or Ή" \ md. R common to form r-jaia dna Oxo radical '; 209850/1256 BAOORIQINAL for an atlsylsn- 'οάΰ.τ? V Injlearadical stands; Σ for e: L & with 1 to 3 carbon atoms, which ala substituents carry 0, 1 or 2 alkyl radicals each with 1 to 3 carbon atoms in the alkyl; -and R stands for an Ar / i- oäex- Banzyiradilcal, which is unsn'bstituisrt or which by Hslogenatoms-, nitro or phenyl radicals "alkyl", Halogönoall ^ lj Alkoscy- or acylamino radicals with 1 "to M- Khllsiistoffatomon or dialkylamiaoradijxale in each case 1 to 3 £ ohlajisto:? fa-öom «a is substituted in the alkyl; as well as the pharmaceutically acceptable Salae derjeaigen Yei'binduugen, in its own R. stands for eia carboxy radical. 8c Prostansäuraderisratö according to ei ».sin the Azi3p: i? ÜGhe 1 _f 2, 3, 6 and 7, by the fact that E stands for aia chloro- FluoropheayA-, Trif luoromethyl- or © r u ^ subetidilial stands. 9. Proatacsänr-säsriv-atw according to one of claims 1, 2, 3 »6 and 7 s by the fact that R stands for ain Oarboxy- 4 or Hethoxycarbonylradikal and R is eia Ohlorophenyl-, Pluorophenyl-, jrifluorojnethyl- or unsubstituted Faphthy! Radically stole ;, 10. Prostanoic acid derivative according to one of claims 1, 2, 3 and 7 »characterized in that R is the hydroxymethyl radical and R stands for sin CJhlorophenyl-, Pluoro- . -t trifluoromethyl »or unsubstituted naphthyl radical.1 ataht. 11. Prostenaäuredsrivate according to one of claims 8, and 10, characterized in that R "" for the 3- or 4-iyl- _? 2- or 4-fluorophenyl- _; 3-Trifluoro-. «Or 2-Nsölithyl3? Adical. 209850/1256 BAD QfHGiNAL 12, ProsüTiisäiirödsrJLvatö of the formula I from Anspi-uch 1, thereby it is understood that E stands for the obobocyte or ifethoxycarbonyl radical stands; R "fits? The Hydroxyradlkal and R ^ for 2 'p a Masseratoffatoin staht or R urad Sr göBieiiLsaa stand for the Oxoradileal; A. For which vinyleax ^ a & ikal stands? Z represents the methylene or isopropylidene radical; Y for ei.a A.
Oxygen a torn stands and P stands for the 3- or 4-Ghlü: eaphe: a 2: - or 4-Fluoroplaenyl- or 2-3üaphth3rlradikal atsht. 15 * ProstsäurederiYate of the formula I of claim 1, that Ί
by 'gekennaelchnetr that R stands for the carboxy-ϊ ülethoxycar- Bonyl ~ or hydroxymethyl radical, j R stands for a hydroxy radical and R stands for a hydrogen atom or R and R ^ gemöiaeam stand for the oxo radical, j A stands for the viaylen radical; J. for the methyl: i ~ or isopropylidene radical, 5 T is an oxygen atom and R is 3- or ^ -chloroplienyl-, 2- or ^ -fluorophenyl-. 3 ~ 'i? I ^% ifluoroiaethylphanyl- or 2-naphthj! Radical. 1 ^. Pro3tansäursd © ri "/ ate according to claim 12 or 13 ·. Thereby marked that 31 © additionally on the carbon atom 2 carry a methyl substituent. 15. The compounds 16 ~ (4 ~ fluorophenoxy) ~ 9 & i1i4,15 ~ trihydroxy-17 »18,19 ♦ 20 ~ tetranor-5-öi s-13 ~ trans-pro, -3 tadienoic acid, 16- (4-fluorophenoxy) -9ä, 11 o "15-tpihydroxj-i 7? 10, 19 »20-tetranor - ^ - cis-IJ-trans-prostadien-acid-mathyloster, 16- (2-fluorophenoxy) -9 ^ 11-4 ·., 15-trihydroxy-17 * ^ 6119 _; 20-tetianor »5-cis ~ 13-trans ~ prostadien - säu: c ©, 16- (4-chlorophenoxy) -9cif 11A, 15-tr jiydr oxy ~ 17» 18,19 * 20-1: e "iüeanop -J-öi s-1 J-trans-proetadiene-acid, 16 ~ (^ -Ghlörophenoxy) "-9 ©., 1 Ία« 15 ~ trihydroxy-17,18,19 «20-t © tranor ~ 5 ™« 3-s ~ 1 ^ 209850/1256 «Βtar, 16- (J-OnIo.?opbes.9xy) -9α _s I%, 1 iM; rihy <3r oa: y ~ 17,18,19 _ε ~ 20-toi'iri? F?.: AD: ^; "-5-ciss" · 1 J-trana-pxOs t; adien - acid _? 1S ™ (3 ~ chlorophenoxy) -9 <V, 11 α, 1! - "faELbyo ro: ay - 17 ν 18 t19» 20-tc-t3? Sno3? ~ 5-cis-13 ~ trans-prosfcaditm « -säm? e -methyle at er _r , 9 ^ 11 Ct »15-Ti? ihy ~ dro3Ey-16- (2-Ä £ piitl3y .lossy) -1? - _; 18,19,20 - feötTaiior-5" -ois - 1? - iiss.isi ^ e urd 16- (4 ~ -0hloroph.Qno3cy) -9 «^ Hr ^ ₅ 15 ™ ie, 16 ~ aimethyi" 17i '' 8,19 ₉ 20-tet3? aaÄr ~ 5-ois-13- 1; 3? Ajii3-prof5i; e.ai0a · acid » 16 · The Verbiadungea 16- (4 ~ Chlo3? Op! Ienyl) ~ 9e * i11 ^ _Ä 15 · - trihycb? Oxy ~ 17,18,19 ₉ 2O-teüranur-5-ci s-13-trans-prostaaieixo 1 LU1 & 9i ?. " 11 <* - i 15 "lVclh; rdro: £ y ~ 16 ™ (5-trifluoromstliyl- 17. _i hydro3cy-2-methyl-17 »" ¹ O »Ί9 ο 2O-tatranor-5 ~ cis ~ -13 ~ transproetadienol · 18, The connection 16 »(4-Gtilorophej3LOxy) -11fli _l , 15-diliy dro3ry ~ 9-O3CO» 17? 18.19 ₅ 2 acid. 19 · compounds of vorliergeh, ends claims "characterized gekennsseicduaet according to one that it is the stronger pol & ä at 0-1i> - 'epimer" n _t aisnittelt through. Thin-layer chromatography, acts " 20. Compounds Jiacfc one of the preceding claims, thereby gelcönnaeichnet; that they have a racemic Porm. 21. Compounds according to one of claims 1 to 19, dadtuyih giikfis ^ saichftsi;,. that she is a lutaolj-rfeiscb active, 209850/1256 BAD ORKSdNAL optically active form bsGltit- Procedure on core division of According to claim 1, thereby germinating "needless" that one: (ß) for the ^ ejiigen compounds, in'den B for a carb oxyradical stands for “eiu © connection of the Forrael .COOK IJ A-CH-X-Y-R ^ or a mixed anhydride of the type Ib © n hydrolysiart, A, X, Y, R »R ^ uKfi R the abovementioned terms. be ,, gg p sit and Ir and R each for a tetrahydropj3? an-2-yl oxy radical i ^ which is an acyloxy radical with 1 to 6 carbon atoms stand on what if a salt; desired iut, the product reacted with a base i * ir £; or (b) for the oneo. Connections ^ in which R for? an alkoxycarbonyl radical with 1 to 11 foal atoms, an acid represents Foruisl COOH III where A, X * I, E ^, IV * and K ^ the obsn fangeßebeu-an meaning- 209850/1 256 SADORfGlNAL & ζώ "besitaeiu niit © inain" Oiaaoalkan dor formula R '„NUi worl.i R ^{7 represents} an alkyl radical having 1 to 11 carbon atoms; or (c) for those connections? in which H is an alkoxycarbonyl radical with 1 to 11 carbon atoms is a Salsa of the formula II with an alkyl halide from 1 to 11 coal & stoj *. £ atoia © n converts; or (d) for that ». Connections _{ in which E stands for the hy- and Y stands for an oxygen or sulfur atom or sin AlJäir / limi & oradikal, a Esters of the formula I, in which .R is an alkoxy carbonyl radical has 1 to 11 carbon atoms, reduced; or (e) for ciiQ, those compounds in denon I for the SuI-finyl radical oteht _} a thio compound of the formula IV 'A-OH (OH) -X-SH ⁴ HO 12-54
in which R, R, E, S »A and X have the meanings given in claim 1 , oxidized. 23. The method according to claim 22, characterized in that the hydrolysis is carried out in an aqueous or alcoholic solution eiiuäs alkali metal carbonate. 2Ü9850 / 1256 24-. Method according to claim 22, characterized in that that it is carried out with a solution of potassium carbonate in methanol * 25 · Method according to claim 22, characterized in that the salt of the acid de ?. ¹ Formula II is the silver salt. 26. The method according to claim 22 *, characterized in that that the alkyl halide is an alkyl iodide, 2? » "Method according to claim 22, characterized in that that the reduction is carried out with a complex metal hydride. 28 «Method according to claim 27 *, characterized in that the complex metal hydride is LithiumBi-aluminiutu-hydride. 29 »The method according to claim 22, characterized in that that the oxidation is carried out with sodium pariodate. 30c pharmaceutical or veterinary compositions, characterized in that they contain a prostanoic acid derivative according to claim 1 together with a pharmaceutical or Contains veterinary approved diluents or carriers. 31 «Compositions according to claim 30, characterized in that that they are for oral administration, for inhalation, for parenteral administration or for anal or shape suitable for vaginal use. 32. Composition according to claim 31, characterized in that that they take the form of tablets, capsules, aerosols, Solutions suitable for syringes, sterile injectables aqueous or oily solutions or susx> enaionen or of suppositories. 209850/1256 fc'aiiiseai according to isji3agh JO, thereby zeictmei; that it is a © ieterile in the weaentlieisen Wi.sämige LftsuBC hand "lt _t 6i.e. · O ₁ CI" to 10 / & y / m'J. From your I'rostaasüuroß erivat c 20985 0/1256 - BAD ORIQitiAL