DE2322142A1 - CYCLOPENTAN DERIVATIVES - Google Patents

Description

PATENTANWÄLTE D R. ■ IN GH F! NCK E

DiPL -Ίr: G. H. bo ;: i

DIPL ■ IMG. S. STAZGIri _L MAY 2, 1975

8 MUNICH 5 MÜLLERSTRASSE 31

2322H2

Folder 23184 - Dr. K.
Case PH 25001

Imperial Chemical Industries Ltd. London, UK

Cyclopentane derivatives

Priority: May 3, 1972 - Great Britain

The invention relates to new prostanoic acid derivatives and in particular to new prostanoic acid derivatives, which are analogues of the naturally occurring compounds, those known as Prostaglandin F ^ fiu and Prostaglandin ^ have a similar spectrum of pharmacological properties and are useful for similar purposes. The relative effectiveness of the new compounds, however, is related to the particular pharmacological effects shown from that of the naturally occurring ones mentioned above

309847/1125

Prostaglandins different. In particular, they are more effective as luteolytic agents than their natural counterparts Prostaglandins. That means, the prostaglandin FpC * analog of the present invention are more powerful than the natural prostaglandin Fpß, and the prostaglandin Ep · analogues of the present invention are more powerful than the natural prostaglandin Ep. The new compounds are similarly more powerful than uterine smooth muscle stimulants than the corresponding natural prostaglandins-PpO- and -Ep. The prostaglandin Ep analog of the The present invention are particularly of value in this regard. The new compounds therefore show advantages when used as a contraceptive, to terminate a pregnancy or to control the oestrus cycle and they are also suitable for adding to semen, which are used for artificial insemination of domestic animals can be used, increasing the success rate of insemination, especially in pigs. Some of the compounds are useful as vasodilators and bronchodilators and as inhibitors of platelet aggregation and gastric secretion.

The cyclopentane derivatives mentioned in this description are used as derivatives of prostanoic acid of the following formula, which also shows the selected numbering, denotes:

COOH

309 * 47/1128

According to the invention, prostanoic acid derivatives of the formula

1
suggested, wherein R stands for a hydroxymethyl or carboxy radical, an alkoxycarbonyl radical with up to 11 carbon atoms or an alkoxycarbonyl radical with 2 or 3 carbon atoms, which carries a ß- or ^ "- dialkylamino radical as a substituent, in which each alkyl radical has ^Λ to 4 carbon atoms, or a ß- or y-Ci-pyrrolidinyl) -, piperidino or morpholino radical, A stands for an ethylene or vinylene radical; R stands for an aryl, furyl or thienyl radical, which is unsubstituted, or which is replaced by halogen atoms or nitro , Phenyl or halophenyl radicals, alkyl, alkoxyalkyl, haloalkyl, alkoxy or acylamino radicals each having 1 to 4 carbon atoms or dialkylamino radicals, in which each alkyl has 1 to 3 carbon atoms, is substituted; and

2
R for a hydroxy radical or an alkanoyloxy radical with

1 to 4 carbon atoms and R ^ is a water

2 3
atom or R and R ^ together form the oxo radical; wherein the compound has 0, 1 or 2 alkyl radicals with up to 4 carbon atoms as substituents on carbon atoms 2, 3 or 4; and wherein the invention, in the case that R is a carboxy radical, also includes the pharmaceutically and veterinarily acceptable salts thereof.

309847/1125

2322H2

A suitable value for R when it stands for an alkoxycarbonyl radical is, for example, such a radical, that contains up to 11 carbon atoms, such as the Methoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl

p radical. A suitable value for R 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 A is, for example, the trans-vinylene or ethylene radical. A suitable value for R is a phenyl, naphthyl, 2- or 3-I ¹ UTyI or 2-thienyl radical which, if it is substituted, preferably contains no more than 2 of the substituents defined above

4 Suitable substituents in the radical R are: as halogen substituents: fluorine, chlorine, bromine or iodine atoms; as alkyl substituents: methyl, ethyl or propyl radicals; as alkoxyalkyl substituents: methoxymethyl, ethoxymethyl or 2-ethoxyethyl radicals; as Haiοgenoalkylradikalische: Halo genome thylrad ika le;. and as alkoxy, acylamino and dialkylamino radicals: methoxy, ethoxy, acetamido and dimethylamino radicals. Thus, suitable values for R ^{4 are} : phenyl, 1-naphthyl, 2-naphthyl, 2-puryl, 3-puryl, 2-thienyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, nitrophenyl -, biphenylyl, ghlorophenyl-2-furyl, tolyl, ethylphenyl, propylphenyl, methoxymethylphenyl, ethoxymethylphenyl, (2-ethoxyethyl) phenyl, methoxyphenyl, ethoxyphenyl, halomethylphenyl, acetyletamidethylphenyl and dimethylphenyl.

Especially ^

suitable values for R are phenyl _v 2-haphthyl, 2-furyl, 3-furyl, 2-thienyl, 4-fluorophenyl, 3- and 4-ChI or ophenyl, 3,4-dichlorophenyl, M- nitrophenyl , 4-biphenylyl, 5- (4-chlorophenyl) -2-furyl, 4-tolyl, 4-methoxymethylphenyl and 3- and 4-3? Ri fluorome thy lphe nyl.

3Q9847 / 112S

A suitable value for an alkyl substituent on the For example, carbon atoms 2, 3 or 4 is a Methyl radical.

Examples of pharmaceutically and veterinarily acceptable Salts are the salts of 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 metals, e.g. the triethylammonium, ethanolammonium, diethanoiammonium, sodium and potassium salts.

It should be noted that the compounds of formula I have at least four asymmetric carbon atoms contain, namely the carbon atoms 8, 11, 12 and 15, the relative configurations of three of them, namely 8, 11 and 12, are given in Formula I. It it can also be seen that the carbon atoms 2, 3 » 4- and 9 can also be asymmetrically substituted, so that it is clear that such compounds exist in one racemic form and at least two optically active Forms can exist. It should be noted that the useful properties of the racemates in various Extent may exist in the optical isomers and that the invention applies to both the racemic Form of the compounds of formula I as well as the optically active forms which the above useful Properties show extends, it being a matter of common knowledge how the optically active forms and their biological properties can be determined.

It should also be noted that the above definition encompasses both C-15 epiners and that in all in the chemical formulas shown in this description have the same fixed stereochemistry on the carbon

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material atoms 8, 11, and 12 occurs as it does in the Formula I is shown.

A "preferred group of prostanoic acid derivatives of the Er-

4 invention includes those compounds in which R is selected from 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl or 4-methoxymethylphenyl radical consists. These are particularly preferred

4th
Nigen compounds in which R is the 4-chlorophenyl, 4-nitrophenyl or 4-trifluoromethylphenyl radical.

Of the C-15 epimers, those epimers become one each pair preferred that on silica gel thin layer chromatography are more polar.

Particularly preferred prostanoic acid derivatives of the invention are described in the examples. The following are particularly preferred: 9a>1'a ^ ' ¹ 5-' £ rihydroxy- '' ¹ 5- (4-trifluoromethylphenyl) -16,17,13,19,20-pentanor-5-cis, 13- trans-prostadienoic acid, 15- (4-chlorophenyl) -9a, " ¹ I α, ^ 5-trihydroxy-16,17,18,19,20-pentanor-5-cis, ι3-trans-prostadienoic acid, 15- (4-Chlorophenyl) -9 cl, 11 ex, 15-trihydroxy-16, i7,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid methyl ester, 9 ^, 1 - "α., 15 -Trihydroxy-15- (4-nitrophenyl) -16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienic acid, .15- (3-chlorophenyl) -9o-, 1 ^ a -, 15-trihydroxy-16,17, -18,19,20-pentanor-5-cis, 1'3-trans-prostadienoic acid, 15- (3,4-dichlorophenyl) -9o-, 1Ί «-, 15- trihydroxy-16,17,18, 19,20-pentanor-5-cis, 13-trans-p'rostadienoic acid and 9a, 1 "a, 15-trihydroxy-15 ~ (4-methoxymethyl phenyl) -16.17, 18,19,20-pentanor-5-cis, 13-trans-prostadic acid.

309847/1125

The cyclopentane derivatives according to the invention can by Processes are produced which are known for the production of chemically analogous compounds themselves. the The following processes for the preparation of the cyclopentane derivatives of the formula I represent further aspects of the invention dar:

(a) for those compounds in which R stands for the

■■ """2
Is carboxy radical, R is the hydroxy radical and Ir is the hydrogen atom; Implementation of a lactol of the formula

OH

II

A-CH (OH) -R ⁴

4th
wherein A and R have the meanings given above, with a (4-carboxybutyl) triphenylphosphonium salt, which optionally carries 0, 1 or 2 alkyl radicals with 1 to 4 carbon atoms on carbon atoms 2, 3 or 4, in the presence of a strong base, whereupon, if a salt is desired, reacting the product with a base; or

(b) for those compounds in which R is an alkoxycarbonyl radical having 1 to 11 carbon atoms stands: implementation of an acid of the formula

, 2 _Ώ 3

^v ' ^{rnu s} .COOH

III

A-CH (OH) -R ⁴

30 98 47/1126

2322H2

2 '3 4
in which A, R, Ir and R have the meanings given above, with a diazoalkane of the formula R .ITp, in which R is an alkylidene radical having 1 to 11 carbon atoms; or

(c) for those compounds: in which R stands for a Alkoxycarbonyl radical with 1 to 11 carbon atoms: conversion of a salt, such as the silver salt, an acid of formula III with an alkyl halide having 1 to 11 carbon atoms, such as an alkyl iodide; or

(d) for those compounds in which R stands for the Hydrοxymethylradikal: reduction of an ester of 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) Reduction of a compound of the formula

R ⁶

IV

1 ⁷ I 4
wherein R, R and R have the meanings given above and R and R 'each represent a hydroxy radical or a protected hydroxy radical, the compound carrying 0, 1 or 2 alkyl radicals on carbon atoms 2, 3 or 4, with, for example, zinc borohydride, Aluminum tri-isopropoxide or di-isobornyloxyaluminum isopropoxide, whereupon when R and R 'each represent a

309847/1 125

2322H2

protected hydroxy radical, the protective groups are removed and, if a salt is desired, one obtained carboxylic acid is reacted with a base; or

(f) for those compounds in which A stands for the vinylene radical: hydrolysis of a compound of formula

COOH

,8th

0.R ¹

2-5 4-where R, R and R have the meanings given above

sit and R for an alkoxy-dialkylmethyl radical with 4 to 8 carbon atoms, for example the "I-methoxy-1-methylethyl radical stands; or (g) for those compounds in which A represents the ethylene radical: hydrolysis of a compound of

2-5 4-Formula V, in which A, R, R ^ and R have the meanings given above and R stands for the tetrahydropyranyl radical, for example with aqueous acetic acid or in an aqueous or alcoholic solution of an alkali metal carbonate, such as potassium carbonate in methanol a temperature between room temperature and approximately 60 ⁰ C.

A suitably protected hydroxy radical in process Ce) is for example an \ alkanoyloxy radical with up to carbon atoms, such as an acetoxy radical, or a Aroyloxy radical with up to 12 carbon atoms, such as e.g., a p-phenylbenzoyloxy radical.

3098A7 / 112S

The starting material in the formula II, in which A stands for the trans-vinylene radical and that of the invention Process can be used can be obtained by using an aldehyde VI (Ac = p-phenyl-

benzoyl) with a compound (CH ^ O) _Q P ® 0. ⁰ CH.COR ⁴

j? * - or a phosphorane PIwPrCH.COR converts, where a Unsaturated ketone VII is obtained, which is then reduced to enol VIII and hydrolyzed to diol IX will. The lactone ring is then reduced with diisobutylaluminum hydride to produce the desired lactone starting material II is obtained.

The starting material of the formula II, in which A is an ethylene radical, and that in the case of the invention Method used can be obtained by using an unsaturated ketone YII in the presence of a ie2 ran 5% palladium-on-charcoal catalyst in a saturated Hydrogenated ketone and followed the above procedure using the saturated ketone instead of the unsaturated ketone VII repeated.

ρ The starting material of the formula III, in which R stands for an alkanoyloxy radical can be selected from the corresponding

2 compound can be obtained in which R is a hydroxy radical by acylation with an acid anhydride in pyridine, a 9-ester-i-mixed anhydride being obtained which can be hydrolyzed into the desired starting material.

The starting material of the formula IV can be obtained from the known Compound 4-ß-Dimethoxymethyl-2,3, 3ass, 6ass-tetrahydro-5ouhydroxy-6ß-iodo-2-oxocyclopenteno] [br] furan (X) can be obtained by treatment with tributyltin hydride, wherein the deiodinated lactone XI is formed.

3Q9847 / 112 &

2322H2

AcO

C0.R

TL VII

AcO

CH (OH).

CH (OH) .R

VIII IX

II

Ac represents an acyl radical 1

309847/1125

2322U2

The ^ -hydroxy group is protected as tetrahydropyran-2-yl ether XII, the lactone is reduced to lactol XIII, using di-isobutylaluminum hydride, and the lactol is reacted with (4-carboxybutyl) -triphenylphosphonium bromide, with the cyclopentanol derivative XIII arises that after. "Esterification, protection of the two hydroxyl groups as p-phenylbenzoate ester, hydrolysis of the acetal, reaction with a phosphonate of the formula (CH-JO) ₀ PO.CHpCOR in the presence of a strong base and methanolysis of the tetrahydropyranyl group a starting point

Ί 6 7

material of the formula IV (R = ffethoxycarbonyl, R = R = Hydroxy).

The starting material of the formula. V can be obtained from the corresponding intermediate of formula IX, and by reacting this compound with 2-methoxypropene, whereby a bis-ketal is formed which is reduced by diisobutylaluminum hydride and reaction with (4-carboxybutyl) triphenylphosphonium bromide as above

2 described, in a starting material V (R = hydroxy, R ^ = hydrogen) is converted, which in turn can be oxidized with chromium trioxide into the corresponding starting material V (R and R ^ are together oxo).

The starting material of formula V, wherein R is the tetrahydropyranyl radical and used in process (g) can be obtained by reacting the diol IX with 2,3-dihydropyran in the bis-ether, this reduced to lactol and this with (4-carboxybutyl) triphenylphosphonium bromide in the presence of a strong base, as described above, reacted.

309847/1 12S

I.
HO

1 /

CH (OCH _x ),

THP.

XII

ι I.

HO

XI

OH

i
I.

THP. O

XIII

COOH

IV

THP. O

XIV

THP = tetrahydropyran-2-yl

309847/1125

As indicated above, the compounds according to the invention have a profile of pharmacological properties which differs from that of the naturally occurring prostaglandins-F ₂ ^ and E-. Thus the more polar C- "5-epimer of 1- (4- chlorophenyl) -9 ⁱ l ₅ ^^ 0 ', 15-" fcrihydroxy-16,17i ^ 8> ^ 9,20-pentanor ~ 5-ci s, ^Λ J-trans-prostadienoic acid as a luteolytic agent at least 50 times as active

which like Prostaglandin-FoCfc, although it is only approximately | same has otimulierungsaktivitat on the smooth muscles such as prostaglandin-FpO-.

For example, if a compound of the invention is used to induce work, then it will used in the same way as the known naturally occurring prostaglandin Ep or -F.cu ", i.e. by Administration of a sterile, essentially aqueous solution containing up to 1 mg / ml active compound, namely by intravenous infusion, by transcervical extra-ammotic injection or by intra-ammotic Injection until work starts.

Thus, according to the invention, a pharmaceutical or veterinary composition is also proposed, which together form a prostanoic acid derivative according to the invention with a pharmaceutically or veterinarily acceptable diluent or carrier.

The compositions may take the following forms: a form suitable for oral administration suitable, such as tablets or capsules, a form suitable for inhalation, such as an aerosol or a solution suitable for syringes, a form suitable for intrauterine infusion or parenteral administration suitable, such as a sterile, essentially aqueous solution or the form of a suppository, the

309847/1125

.suitable for anal or vaginal use. As already a preferred composition of the invention is stated to be sterile, essentially aqueous Solution when the compound of the invention is used to induce labor in childbirth.

The compositions according to the invention can be prepared by conventional means and converted into conventional excipients be incorporated.

The invention is illustrated in more detail by the following examples. The R “- ¥ values relate to thin-layer chromatography on Merck silica gel unless otherwise noted.

example 1

0.532 g of finely powdered (4-carboxybutyl) triphenylphosphonium bromide were under vacuum for 1 st to 100 ⁰ C heated. The evacuated reaction vessel was filled with a dry nitrogen atmosphere, the solid was dissolved in 2 ml of dimethyl sulfoxide, and the solution was cooled to room temperature. 1.1 ml of a 2M solution of kethanesulfinylmethylsodium in dimethylsulfoxide were added dropwise to this solution, followed by the addition of a solution of 72 mg of a mixture of the epimers of 4-β- (5-p-chlorophenyl-3-hydroxy-1-trans -propenyl) -2,3, 3ass, 6ass-tetrahydro-2,5 <* dihydroxycyclopenteno [V \ f ^uran in a mixture of 2 ml of dimethyl sulfoxide and 0.3 nil benzene. The solution was stirred for 3 hours and the solvent was removed by evaporation under reduced pressure at a

309847/1 1 25

Temperature below 40 ⁰ C removed. The residue was shaken with 10 ml of water and 10 ml of ethyl acetate, and the aqueous phase was separated off and extracted twice with 10 ml of ethyl acetate, and the extracts were discarded. The aqueous solution was acidified with / 2n 'oxalic acid to pH 3 to 4 and extracted with 5x ^ O mL of a mixture of equal parts of ether and petroleum ether (b.p. 40 to 6O ⁰ C). The organic phase was separated off, washed with saturated sodium chloride solution and dried. Evaporation of the solvent gave a mixture of C-15 epimers of 9 ^, ^'1 1os15-trihydroxy-15- ^(/ <-chlorophenyl) -16,17,18,19,20-pentanor-5-cis, 13-trans -prostadienic acid. Thin layer chromatography using 3% acetic acid in ethyl acetate separated the 0-15 epimers, which had R- ^ values of 0.3 and 0.4, respectively. The NMR spectrum of each isomer (in deuterated acetone) showed the following characteristic bands (£ values): 7.35, doublet, 4 aromatic protons 5.1 to 5 _? 6, 4 olefinic protons.

The mass spectrum of the tetra (trimethylsilyl) derivative showed an M ⁺ = 682.3410 (calculated 682.3129).

The cyclopenteno [V] furan used as the starting material was obtained as follows:

39 ml of a 2.2m solution of η-butyl-lithium in hexane were added to a solution of 1 '', 3 g of dimethyl methylphosphonate in dry tetrahydrofuran mit.-78 ⁰ C in a Stickstof fatmosphäre added. To ^"1 O min, a solution of 8.0 g of 4-Chlorobenzoesäureäthylester in 20 ml of tetrahydrofuran was dropwise added, and the mixture was 4 h at -78 ⁰ C for the reaction mixture was neutralized with acetic acid., And the solvents were

30.98 47/1 125

~ ¹⁷ ~ 2322H2

removed under reduced pressure. The residue was shaken with a mixture of 100 ml of ethyl acetate and 20 ml of water, and the organic phase was separated 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 210 ⁰ C and 0.1 mm pressure to give 2- -2-oxoäthylphosphonsäuredimethylester was obtained (4- Chlorophenyl).

A solution of 2.36 g of 2- (4 ~ chlorophenyl) -2-oxoäthylphosphonsäure-dimethylesfers in 4-0 ml of dry 1,2-dimethoxyethane at -78 ° C was with 5.6 ml of a 1.4m n-butyl lithium solution in hexane and the mixture was stirred for 15 minutes. A solution of 2.1 g of 4β-formyl-2,3,3ass, 6ass-tetrahydro-2-oxo-5a- (4-phenyIbenzoyloxy) cyclopenteno [b3furan in 10 ml of ^Λ , 2-dimethoxyethane was added to this mixture, and After ^Λ st, the reaction mixture was neutralized with glacial acetic acid, and all of the solvents were removed by evaporation

and under
reduced pressure / 35 ° C removed. The residue was rubbed with ether to give the unsaturated ketone product as a white solid. R, -, = 0.6, (50% ethyl acetate in toluene).

1.5 g of the unsaturated ketone were in 50 ml of dry Benzene dissolved, and 11 ml of a 0.515 M solution of aluminum propoxide in benzene were added to this solution admitted. The mixture was stirred under reflux for 2 hours and then became a saturated sodium hydrogen tartrate solution admitted. 200 ml of ethyl acetate were then added and the organic layer was separated, with a 1: 1 mixture of saturated saline solution and water washed and then dried. The solvents

309847 / 112S

were evaporated, leaving a mixture of the epimers unsaturated Alcohols, Rp = 0.2 (50% ethyl acetate in toluene).

1.5 g of the mixture of the epimeric unsaturated alcohols was violently 2 st with 427 mg of finely powdered anhydrous potassium carbonate stirred in 20 ml of methanol. Then 6.08 ml of 1N hydrochloric acid were added, whereupon the addition of 100 ml of ethyl acetate followed. The organic layer was separated sequentially with saturated Sodium bicarbonate solution and saturated saline solution washed and then dried, and the solvents were then evaporated. The residue was added to 20 g of Florisil chromatographed. Elution with ether removed the by-products. Subsequent elution with ethyl acetate gave a mixture of the C-15 epimeric diols. R ^ = 0.3 (ethyl acetate) .

To a solution of 369 mg of the epimeric diols in 5 ml of dry toluene under a nitrogen atmosphere at -78 ⁰ C a 2.2 millimole was added per ml of solution containing diisobutylaluminum hydride in toluene 0.5 ml. After 30 min, the reaction was quenched by the dropwise addition of 3 ml of methanol, and after a further 15 min at room temperature, 25 ml of a 1r ^ mixture of saturated saline and water were added and the mixture was then extracted 3 times with 50 ml of ethyl acetate each time. The extract was washed with saturated saline and dried, and the solvents were evaporated, leaving a mixture of the epimers of 4-ß- (3 ~ p-chlorophenyl-3-hydroxy-1-trans-propenyl) -2,3 ^ 3, 6ass-tetrahydro-2,5 * »- dihydroxycyclopenteno (VJfuran was obtained. R ^ ₁ = 0.3 (2% methanol in ethyl acetate).

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2322H2

Example 2

The procedure described in Example 1 was repeated using the appropriate cyclopentene [b} furan to give the compounds shown in the table below. Mass spectrum measurements refer to the tetra (trimethylsilyl) derivatives. Characterization data for the phosphonate _{reagents (CH 3} O) _{2 PCCH 2} COR ⁴ and for the enones VII (Ac = p-PhenyTbenzoyl) are also given:

HO

COOH

CH (OH) - // Vs

No. R ⁹ 3-chloro other substituents
in prosranic acid 1 4-chloro 2 4-pluoro - 3 4-methyl - - 4th 3-trifluoromethyl - VJl 4-trifluoromethyl - 6th Il - 7th 2-methyl

30 9847/1 125

2322H2

No. Mass spectrum calculated Phosphonate Pp Enone ° c 1 found 682.3129 Kp ⁰ C / mm Hg K _F 2 M ⁺ = 682.3095 682.3129 Rp - 0.2 ^a) i'P 163-164 ° c 3 M ⁺ = 682.3 "140 666.3425 210 / 0.1 = 0.65 ⁰ C 4th M ⁺ = 666.3387 662.3670 Rp = o, 3 ^c) % 129-130 ^} 5 M ⁺ = 662.3669 701.3159 210/0, " 170- ^ 76 6th (M-CH) ⁺ =
701.3126 701.3159 Rp - 0.3 ^a)
I. = 0.6 ^b (M-CH ₃ ) ⁺ = 140 / 0.4 178 ° C 7th 701.3133 1,730.3549 M ⁺ = 730.351 11 Il

a) in 50% ethyl acetate / chloroform

b) in 50% ethyl acetate / toluene

c) in 75% ithyl acetate / methylene dichloride

For ¹ No. 2 the mass spectrum data relate to each C-15 epimer, for numbers 1 and 3 to 8 the data relate to the mixed C-15 epimers.

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2322H2

3 example 3

110 mg 15- (4-methoxymethylphenyl) -15-oxo-9 ^ 1ic ^ -d.i - (^ - phenyl "benzoyloxy) -5-cis, 13-trans-prostadienoic acid methyl ester were added to 5 »0 ml of dry toluene under argon Stirred at room temperature and with 2.0 ml of a 0.323m solution of di-isobornyloxyaluminum isopropoxide in Treated toluene. After 1 1/4 st the mixture became Distributed between 0.5 ml of water and 1.0 ml of ethyl acetate and filtered through "Hyflo", whereupon the filter pad Was washed twice with 4ml ethyl acetate. The organic layer was separated. washed with 4 ml of saline solution, dried over magnesium sulfate, filtered, and the solvent was evaporated to give a crude oily product remained, which was added to 2 g of "Florisil" was chromatographed. Elution with 5 to 1C% Ethyl acetate in toluene gave the enol, namely 15-hydroxy-15- (4-methoxyniethylphenyl) -9 α, 11 <x-di- (4-phenyl benzoyloxy) -5-cis, 13-trans-prostadienoic acid-methyl- ester as a viscous oil, R "= 0.4 (20% ethyl acetate in methylene dichloride).

69 mg of the crude enol were stirred under argon in a mixture of 4 ml of methanol, C, 7 ml of water / water and 0.9 ml of potassium hydroxide IS for st long. The mixture was acidified to pH 5 with oxalic acid and then extracted with ethyl acetate, and the extracts were finally ^{washed / dried with a ^ t "1} mixture of saturated sodium chloride solution and water. Evaporation of the solvents gave a residue from which the two G -15 epimers were separated by thin layer chromatography using 3% acetic acid in ethyl acetate, R ^ = 0.3 and 0.4, respectively, The NMR spectrum of each epimer in deuterated acetone showed the following characteristics

309847/1125

Peaks (S values):

7.2 to 7.4, 4H, aromatic

5.1 to 5.6, 5H, 4 olefinic protons and -CH (OH) -CH = CII-

4,4, 2H, -CH ₂ .OMe

3.32, 3H, -CH ₂ -OMe

The checkout spectrum showed (M-CH,) = 677.3493. The calculated value for C ₃₅ Hg ₄ O ₆ Si ₄ = 677.354-7 (for the T-etra-trimethylsilyl derivative).

The 15- (4-methoxymethylphenyl) - "5-οχο-9α, ^Λ " α., Di- (4-phenylbenzoyloxy) -5-cis, 13-trans-prostadienoic acid methyl ester used as the starting material in the above process was made as is made as follows:

4.0 g 4SS-dimethoxymethyl-2,3,3aß, 6aß-tetrahydro-5o - hydroxy-6ß-iodo-2-oxocyclopenteno (V] furan in 4-0 ml of dry toluene at 8O ⁰ C under argon for 18 st stirred with 6.6 g of tri-n-butyltin hydride. the solvent was evaporated under reduced pressure, the residue was stirred with 100 ml of petroleum ether (b.p. 40 to 60 ⁰ C) for 30 minutes. the solvent was decanted and the residual oil was chromatographed on 50 g of "Florisil" rt. Elution with mixtures containing 25% ethyl acetate in toluene and finally with ethyl acetate gave 4β-dimethoxyme'thyl-2,3,3ass, 6ass-tetrahydro-5'-hydroxy -2-oxocyclopentenojV ^ furan as oil, R- = 0.3 (2C% acetone in chloroform). The NMR spectrum in deuteriochloroform showed the following characteristic peaks (ά values): 3.4C and 3.42.6H, 2 singlets, methoxy 4.04 to 4.36 MH, multiplet 5 [beta] proton

f IH, doublet, -CH (OMe) ₂

VJH ₁ multiplet, 6ass proton

309847/1 126

2322H2

4.01 g of 4β-dimethoxymethyl-2,3,3ass, 6ass-tetrahydro-5ö ^ hydroxy-2-oxocyclopenteno [irj ^iuran were stirred with 30 ml of dry toluene under argon, and the resulting solution was mixed with an excess of 17 ml of freshly distilled dihydropyran treated, followed by treatment with 2.0 ml of a 0.1% (w / v) solution of toluene-p-sulfonic acid in dry tetrahydrofuran. After 3/4 st the mixture was treated with 0.50 ml of pyridine and then partitioned between 150 ml of ethyl acetate and 75 ml of saturated sodium bicarbonate. The organic layer was separated, washed with 50 ml of saturated saline, dried over magnesium sulfate, filtered, and the solvent was evaporated to give a crude lactone, 4β-dimethoxymethyl-2,3,3ass, 6assetrahydro-2-oxo-5o ^ - (tetrahydropyran -2-yloxy) -cyclopenteno-Cb) furan. R ™ = 0.70 (20% acetone in chloroform).

6.2 g of crude lactone were mixed by stirring in 120 ml of dry dimethoxyethane under argon at about -60 ⁰ C (chloroform - "Drikold" -Kühlbad) dissolved, and then 11.2 ml of diisobutylaluminum hydride was added. After 30 minutes, 3 ml of methanol were added and the mixture was allowed to warm to room temperature and partitioned between 600 ml of ethyl acetate and 300 ml of a 1: 1 mixture of saturated saline and water. The entire mixture was filtered through "Hyflo" and the two phases were separated. The aqueous phase was extracted again with 300 ml of ethyl acetate and the combined organic layers were washed with 100 ml of water, dried over magnesium sulfate and filtered and the solvents were evaporated to give the crude lactol (VI), namely 4β-dimethoxymethyl-2, 3,3ass, 6assetrahydro ^ -hydroxy ^^ itetrahydropyran ^ -yloxy) -cyclopentenols! furan when obtained as an oil. R "= 0.4 (20% acetone in chloroform).

309847/1125

2322U2

A stirred solution of 24.8 g of (4-carboxybutyl) -trip'henylphosphoniumbromid in 50 ml of dimethyl sulfoxide (DMSO) was slowly under argon and with cooling in an ice / water bath with 5.5 ml of 2M methanesulfinylmethyl sodium in DMSO ( 2.5 equivalents) to prepare a solution of the corresponding ylide. 6.3 g of the crude lactol in 150 ml of dry DMSO was then added to the ylide solution at room temperature. The mixture was stirred for 11/4 st and then "· ml of water was added. The DMSO was then ^{removed under high vacuum at a temperature not above 50 °} C. The remaining gum was distributed between 4x 225 ml of ether and 150 ml of water. The aqueous layer was separated off, acidified to approximately pH 4 with 2N oxalic acid and then extracted 3 times with 300 ml each of a 1: 1 mixture of ether and pentane. The extracts were washed with 150 ml of saturated sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent was evaporated to give the crude acid, 2ß-dimethoxymethyl-5o- ~ hydroxy-3o - (tetrahydropyran-2-yloxy) cyclopent-1ö-ylhept-5-cis-enoic acid, which was obtained as an oil for use in the next step of the synthesis A sample was purified by chromatography on silica (70: 1), the product being eluted as an oil with 2% methanol in toluene, R ^ ₁ = 0.4 (5% methanol The NMR spectrum in deuteriochloroform, e.g. showed the following characteristic peaks (J values):

3.35. until , Singlet, -IH, Methoxy ) ^ CH-O- , 6H until 3.65, IH, 3.3 to until 4.0, 2H, Y multiplets, 3.68 4.6 to 4.19, 1H, 4.00 4.38, 1H, J 4.19 4.8,

5.09 to 5.78, 2H, multiplet, olefinic protons

309847/1 125

4.48 g of the crude acid in 45 ml of methanol were stirred under argon at room temperature for 2 3/4 hours with 240 mg of toluene-sulfonic acid. The solution was then partitioned between 300 ml of ethyl acetate and 60 ml of saturated sodium bicarbonate solution and then 60 ml of saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and filtered, and the solvent was evaporated off, leaving a crude ester diol, namely 2β-dimethoxymethyl-3β, 5β-dihydroxycyclopent-iQ.-ylhept-5-cis-enoic acid methyl ester, as an oil. R _p = 0.65 (10% methanol in methylene chloride). The NMR spectrum in deuteriochloroform showed the following main peaks (& values): 3.39, 6H, singlet ") 3 _methyl g _rU pp _en 3.64, 3H, singlet J

4.03 to 4.3, 3H (multiplet, ^ CH-O-

t.Doublet, ^ CH (OMe) ₂ 5.1 to 5.7, 2H, multiplet, olefinic protons

3.3 g of the crude ester diol were dissolved in 50 ml under argon dissolved dry pyridine and mixed with 9.2 g of p-phenylbenzoyl chloride and the mixture was stirred for 17 st. Then 0.8 ml of water was introduced and stirring was continued for 3 to 4 hours. The mixture was under evaporated in vacuo and toluene was added to aid in the azeotropic removal of the pyridine. The residue was partitioned between 300 ml of toluene and 150 ml of saturated sodium bicarbonate solution. The whole mixture was filtered through "Hyflo" and the organic phase was separated off. The aqueous layer was extracted with 150 ml of toluene and the organic Extracts were combined, washed with 100 ml of sodium chloride solution, dried over magnesium sulfate and filtered,

309847/1125

and the solvent was evaporated leaving a solid crystalline residue. This was carefully rubbed with 70 ml of methanol, the mixture was filtered, and the product was washed a further 3 times with 10 ml of methanol, the dimethylacetal, namely 2β-dimethoxymethyl-3a., 50 ^ <3.i- (4- phenylbenzoyloxy) cyclopent-1a-ylhept-5-cis-enoic acid methylester was obtained as a white solid with a Pp 104.5 to 106.5 ⁰ C. R ₅₁ = 0.5 (5% acetone in toluene). The NMR spectrum in deuteriochloroform showed the following characteristic signals (& values):

3.41, 3H, singlet Ϊ

3.47, 3H, "> Methyl 3.52, 3H, ")

4.59 to 4.61, IH doublet, - ^ GH (OMe) ₂ 5.17 to 5.70, 4H, multiplet, 2 χ> GH-O- and 2 olefinic protons

7.80 to 8.00, 2H, 1

T doublet, 8.00 to 8.20, 2H, J

An analytical sample that recrystallizes 3x from ethanol had an mp of 105-1C7 ° C.

500 mg of 2β-dimethoxymethyl-3cs5ö-di- (4-phenyl-benzoyloxy) -cyclopent-10L-ylhept-5-cis-enoic acid methyl ester were vigorously stirred for 10 min under argon in a two-phase system that from 20 ml of 2% isopropanol in chloroform and 10 ml of concentrated Hydrochloric acid. The chloroform layer was separated and the aqueous layer was extracted with 20 ml of chloroform. The organic layers were combined successively with 20 ml of aqueous "saturated sodium bicarbonate solution" and 10 ml of saturated saline solution

3 09847/1126

wash, dried over magnesium sulfate, filtered and the solvent evaporated. The oily residue crystallized on drying under high vacuum, the 2fi-formyl-3iX, 5 ^a --di- (4-phenylbenzoyloxy) cyclopent - was obtained 'a-ylhept-5-cis-enoic acid methylester!. R "on Merck silica gel G _F- 254 plates was 0.4 (5% ethyl acetate in toluene). The NMR spectrum in deuteriochloroform agreed with the required structure and showed the following main signals (i values):

3.5% 3H, singlet, methyl ester

5.3 to 5.6 4H, multiplet, ^ CH-O- and olefinic protons

7.8 to 8.0, 2H, "\

Y doublets, - «, ·> - _{rn o} 8.0 to 8.2, 2H, J. ^ = ' ^υυ ' ^υ "

7.22 to 7 »73? 14H, multiplet, residue of natural protons 10.01 to 10/4, 1H, doublet, -CHO

An analytical sample, FP 93 to 97 ⁰ C, was obtained by rubbing the above product with ether.

A solution of 104 mg of 2- (4-methoxymethylphenyl) -2-oxophosphonic acid dimethyl ester (1.5 equivalents) in 3.0 ml of tetrahydrofuran was stirred under argon and cooled in a chloroform / "Drikold" bath and with 148 / ti 2.2m butyllithium treated in hexane, whereupon after a few minutes the treatment of a solution of 175 mg of 2ß-dimethoxymethyl-3cL, 5a-di- (4-phenylbenzoyloxy) cyclopent-iG-yl-hept-5- cis-enoic acid methyl ester in 2.0 ml of tetrahydrofuran connected. The cooling bath was then removed, and after 2 hours a few drops of acetic acid and then 200 / tl of water were added

3 0 9 8 4 7/1125

~ ²⁸ ~ 2322H2

added to adjust the pH to about 6. The solvent was evaporated under reduced pressure, and the residue was between 15 ml of water and once 30 ml and once 15 ml of ethyl acetate distributed. The organic, Layer was separated, washed with 10 ml of water, then dried over magnesium sulfate and filtered, and the solvent was evaporated to give a viscous oil. This oil was through Chromatography on 2 g "Florisil" 'purified, one Elution was carried out with 10% ethyl acetate in toluene to give the desired enone starting material, namely 15- (4-methoxymethylphenyl) -15-oxo-9iL, 11 "- di- (4-phenylbenzoyloxy) -5-cis, 13-trans-prostadienoic acid methyl ester to get what was an oil. Rp = 0.4 (20% ethyl acetate in methylene dichloride). That. NMR spectrum in deuteriochloroform showed the following main peaks (i-values):

3.35, 3H, singlet, methoxy 3.50, 3H, singlet, -COOCH ₅ x 4.45, 2H, -CH ₂ OCH ₅

5.4 to 5.6, 4H, multiplet, olefinic cis-pfotons and

> CH-O-

6.12 to 7.1, 1H, doublet, = CH.CO-

7.86 to 8.02, 2H, doublet ') π ~ ζ ~

L - // y__ Q ₀₀ -

8.02 to 8.23, 2H, doublets) ^ = S,

7.3 to 7.7, 15H, multiplet, remainder of aromatic

Protons, + -CH = CH.CO-

309847 / 112S

Example 4

The procedure described in Example 3 was repeated, where the corresponding enone was used and where the compounds given in the following table were obtained. Mass spectrum measurements are based on tetra- (trimethylsilyl) derivatives. Characterization data are also used for the phosphonate reagents, Naalicn (CH, O) pPO.CHpCOR, and for the enone starting materials are also given:

OH (OH) .E

No. R * Phenyl Mass spectrum 667.2895 2-chlorophenyl • found! Calculated 716.2746 2 3,4-dichlorophenyl M ⁺ = 64-8.3462 648.3462 3 (M-CH ₅ ) ⁺ = 667.2829 678.3136 4-nitrophenyl τη.μ, Μ ⁺ = 716.2722 724.3832 4th 4-biphenylyl Lp., M ⁺ = 716 698.3676 5 2-naphthyl (M-CH,) ⁺ = 678.3144 638.3312 6th 2-FuryI Μ ⁺ = 724, 3831 748.3235 7th 5-p-chlorophenyl-2-furyl M ⁺ = 698.3620 638.3312 8th 3-furyl M ⁺ = 638.3252 654,3084 9 2-thienyl M ⁺ = 748.3201 10 • M ⁺ = 638.3303 m.p ^ 654,3045 Ip ^ 654

309847/1125

No. Ph.osph.onate Enone I. 1 Bp 162 ° C / 0.1 mm Hg Rp = 0.7, ethyl acetate / toluene I.
Mp 107 to 109 ⁰ C. 2 ' Kp 185 ⁰ O / 0.05 mm Hg ' Rp = 0.8, 50% allyl acetate /
. toluene
Rp * 0.77, ether 3 Rp = 0.3, ethyl acetate Rp »0.93, 4th
5 Mp 73 to 75 ° C
ITp 85 to 87 ⁰ C Rp = 0.76, 6th Kp 240 ⁰ C / 0.5 mm Hg Rp = 0.81, 7th Kp 150 ⁰ C / 0.1 mm Hg Rp = 0.82, 8th Rp = 0.22, ethyl acetate Rp = 0.79, '9 Kp 150 ⁰ C / 0.1 mm Hg 10 Rp = 0.19, 50% ethyl
acetate / methylenedi-
chloride

a) The mass spectrum gave (M-phenylbenzoyl) ⁺ = 568.1973 _v the calculated value for CJ ₁ -H ₂₂ O ₁ -Cl = 568.2016

35 33 5

309847/1125

Example 5

To a solution of 12 mg of a mixture of the C-15 epimers of 15 ~ (4-chlorophenyl) -9ä, 11o05-trihydroxy-16, 17 * 18,19 »20-pentanor-5-cis, 13-trans-pros tadienoic acid in 1 ml of methanol, an excess of a solution of diazomethane in ether was added ^{at 0 ° C.} After 10 min, the solvents were evaporated off, a mixture of the C-15 epimers of 15- (4-chlorophenyl) -9 °> -, 11o, 15-trihydroxy-16.17 » ^y1 8,19,20-pentanor -5-cis, 13-trans-prostadienoic acid methyl ester was obtained as a clear oil. R ^ = 0.3 and 0.4 (ethyl acetate). For the more polar epimer, the tris (trimethylsilyl) derivative showed a value for M ⁺ = 624.2840. The calculated value for C, .Hc _x ClO ₁ -Si, = 624.2889.

Example 6

A solution of 270 mg of 15- (4-chlorophenyl) -9 <irhydroxy-11 uL, 15-bis (tetrahydropyran-2-yloxy) -16,17,18,19,20-pentanor-5-cis-prostenic acid in 3 ml a 2: 1 mixture of acetic acid and water was ^{stirred at 50 °} C. for 4 hours. The solvents were evaporated, the residue dissolved in 2 ml of dilute aqueous sodium bicarbonate solution and the solution extracted 3x with 2 ml of ethyl acetate and the extracts 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 selected with a 1: i mixture of saturated saline solution and water and then dried. After the ethyl acetate had evaporated, the residue consisted of a mixture of the C-15 epimers of 15- (4-chlorophenyl) -9gl, 11 oil, 15-trihydroxy-16, ^ 7,18,19,20-pentanor-5- cis-

309847/1125

prostenic acid. The mass spectrum of the tetra (trimethylsilyl) derivative found (M-CH,) " ¹ " -.669.3031. The calculated value for C ₃₂ H ₅₈ ClO ₅ Si ₄ »669.3051.

The bis-tetrahydropyranyl ether used as starting material in the above ration was obtained as follows: -

300 mg of 5% palladium-on-charcoal were added to a solution of 97 ^ mg of 4-β- £ 3- (4-chlorophenyl) -3-oxo-1-transpropenyl} -2,3,3ass, 6ass-tetrahydro -2 ~ oxo-5 <5 ¹ - (4-phenylbenzoyloxy) cyclopenteno £ b3furan (aas unsaturated ketone, which is described in the second part of Example 1) in 15 ml of chloroform, and the mixture was shaken in a nitrogen atmosphere for 20 min. The mixture was filtered and the filtrate was evaporated to dryness giving the saturated ketone 4β- £ 3- (4- chlorophenyl) -3-oxopropyl] -2,3,3afi, 6ass-tetrahydro-2-oxo-5- ( 4- phenylbenzoyloxy) cyclopentene ^! furan was obtained. Rp = 0.3 (50% ethyl acetate in toluene).

The rest of that described in the second part of Example 1 The procedure was repeated using this saturated ketone in place of the unsaturated ketone and wherein mixed epimeric alcohols and mixed epimeric diols were successively obtained which are conventionally used Way in the presence of toluene-p-sulfonic acid with 2,3-Dihydropyran in tetrahydrofuran into the epimeric bis (tetrahydropyran-2-yl) ether were converted. The lactone ring in the bis-ether was reduced to the corresponding lactol in the usual manner, with di-isobutylaluminum hydride in toluene was used, and the lactol was in the usual manner with (^ -Carboxybutyl ^ triphe'nylphosphonium bromide reacted in dimethyl sulfoxide and in the presence of MethanesulfinylmethyInatrium, the desired Bls- (tetrahydropyranyl) ether starting material,

309847/1125

namely 15- (4- chlorophenyl) -9 ^ hydr oxy-11 et, 15 ~ bis (tetrahydropyran-2-yloxy) -16,17,18,19,20-pentanor-5-cis-prostenic acid, was obtained.

Example 7

The procedure described in Example 6 was repeated using 15- (4- chlorophenyl) -9-oxo-11a-, 15-bis- (tetrahydropyran-2-yloxy) -16,17,18,19,20-pentanor-5 -cis-prostanoic acid was used in place of the corresponding 9ci-hydroxy compound to give 15- (4-chlorophenyl) -11oc, 15-dihydroxy-9-oxo-16,17i18,19i20-pentanor-5-cis-prostenic acid. R = 0.4- (3% acetic acid in ethyl acetate). The mass spectrum of the bis-trimethylsilyl-9-methoxime-methyl ester showed M ⁺ = 581.274-5. The calculated value for C ₂ QH ₄₈ ClNO ₅ Si ₂ 581.2759.

The bis (tetrahydropyranyl ether used as starting material was by oxidation of the corresponding 9 & -hydroxy-bis-ether, which in the second part of Example 6 is obtained as follows:

To a solution of 10 mg of 15- (4- chlorophenyl) -9Ä.-hydroxy- "1α, 15-bis- (tetrahydropyran-2-yloxy) -16 ^ (7,18,19,20-pentanor-5 -cis-prostenoic acid in 2 ml of acetone was added at -10 ⁰ C 0.06 ml of Jones reagent After 15 min, 1 drop of isopropanol was added, followed iSich joined the addition of 10 ml of ethyl acetate the solution was washed with a 1:.. 1 washed mixture of brine and water and then dried evaporation of the solvents and chromatography of the residue on silica gel, using a 1:. 1 mixture of ether / petroleum ether was used (Kp 4-0 to 6O ⁰ C) as the eluting solvent gave the ge -

309847/1125

wished 9-oxo-bis-ether-starting material. "IL ₁ = 0.2 (50% ethyl acetate in toluene) *

Example 8

A solution of 50 mg of 15- (4 ~ chlorophenyl> 11a., 15-bi3- (1 ~ methoxy-1-methylethoxy) -9-oxo-16,17,18,19,20-pentanor-5-cis, 13 -trans-prostadic acid in'0.25 ml of citric acid buffer of ρΈΓ 3 and 0.75 ml of acetone was at room temperature 18 st stirred. The solvents were evaporated and the residue was extracted 3x with 2 ml of ethyl acetate. . The 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 15- (4-chlorophenyl) -11 α ,, 15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadic acid. Chromatography of this residue on 2 g of CC4 - Malinkrodt silica gel and elution with Ethyl acetate / cyclohexane gave the separated C-15 epimers from 15- (4 ~ chlorophenyl) -1V, 15- <lihydroxy-9-oxo-16,17,18,19, 20-pentanor-5-cis, 13-trans-prostadic acid. R ™ = 0.2 and 0.3 (10% methanol in methylene chloride). The NMR spectrum of each epimer (in deuterated acetone) showed the the following characteristic bands (J "values):

7.25 to 7> 4-5, 4 aromatic protons

5.0 to 5.9, 8H, 4 olefinic protons, 3 interchangeable Protons and PhCH (OH) .CH = CH-

4.1, 1H, 11 [beta] proton

309847/1125

The mass spectrum of the bis-trimethylsilyl-9-methoxymethyl ester showed M ⁺ = '579.2603. ^The calculated value for C ₂₉ H ₄₆ GlNO ₅ Si ₂ = 579> 2603. The 9-0xo-bisester used as the starting material was prepared as follows:

To a solution of "165 mg of 4-β- (3- (4-chlorophenyl) -2,3,3ass, 6ass-tetrahyd2X> -3 ~ hydroxy-1-trans-propenyl} -50tf-hydroxy-2-oxocyclopentenotb ^ furan in 5 ml of methylene chloride were slowly added under a nitrogen atmosphere, 0.4-5 ml of redistilled IMethoxypropene and 0.2 ml of a 1% solution of anhydrous toluene-p-sulfonic acid in tetrahydrofuran. After 25 min, 2 drops of pyridine were added, 30 ml of ethyl acetate were then added. The solution was washed successively with saturated sodium bicarbonate solution and with saturated sodium chloride solution and dried. Evaporation of the solvents gave a mixture of the epirers 1-methoxy-1-methylethyl ether as a clear oil. Rj ₁ = 0 , 3 or 0,4-ethyl acetate in toluene).

To a solution of 228 mg of the epimeric ether in 10 ml dry toluene were under a nitrogen atmosphere at -78 ° C 0.4 ml of a 1.66 millimole per ml Solution of di-isobutylaluminum hydride in Toluene added. After 30 min the reaction was quenched by the dropwise addition of -2 ml of methanol, and after a further 15 min at room temperature 15 ml of a 1: 1 mixture of saturated saline solution / Water was added, and the mixture was 3x with 25 ml Ethyl acetate extracted. The extract was washed with saturated saline and dried, and the solvents were evaporated, leaving a mixture of the epimers

309847/1 125

of lactol, namely 4ß-Q5- (4 ~ chlorophenyl) -3 - ('1-methoxy- Λ -methylethoxy) -1-trans-propenyl} -2,3,3ass, 6aß-tetrahydro - 2ß-hydroxy- 5ou-C1-methoxy-1-methylethoxy) -eyelopenteno [b} furan, was obtained. Rj ₁ = 0.3 ('' see ethyl acetate / toluene).

A solution of 243 mg of the lactol in 5 nil dimethyl sulfoxide was added to a solution of sodium 5-triphenylphosphoranylidene valerate obtained from 1 mole (4-carboxybutyl) triphenylphosphonium bromide and 2 moles methanesulfinylmethyl sodium in dimethyl sulfoxide. The solution was stirred for 1 hour and the solvent was removed by evaporation under reduced pressure. The residue was shaken with 5 ml of water and 3 ml of ether, the aqueous layer was separated and extracted 4 times with 3 ml of ether, and the extracts were discarded. The aqueous solution was acidified to pH 5 »5 with oxalic acid and extracted 6 times with 4 ml of a mixture of equal parts of ether and petroleum ether (boiling point 40 to 60 ° C.). The combined extracts were washed with saturated sodium chloride solution and dried, and evaporation of the solvents gave 15- (4-chlorophenyl) -9 ^c i.-hydroxy-11S ¹ 5-bis- (1-methoxy-1-methylethoxy) -16, 17,18, 19,20-pentanor-5-cis, 13-trans-prostadienoic acid. Rj ₁ = 0.5 420% methanol in methylene chloride).

A solution of 98 mg of this prostatic acid derivative in 1 ml of methylene chloride was added to a stirred solution of 145 mg of chromium trioxide in 3 ml of methylene chloride. After 15 minutes at room temperature the mixture became

309847/1125

2x mil; 10 ml of ether were extracted and the extracts were made washed with saturated saline solution and dried. Evaporation of the solvents gave the desired 9-oxo-bis-fold. Rp = 0.6 (10% methanol in methylene chloride).

Example 9

% (W / v) 15- (4-Trifluoromethylpheny1) -

ie.i ^^ e, 0.1 19,20-pentanor-5-cis, 13-transprostadiensaure

Sodium phosphate. * 2.9

Sodium hydrogen phosphate 0.3

ad 100 water suitable for injection

The sodium phosphate was dissolved in approximately 80% of the water, followed by the addition of the pro-stadienoic acid derivative followed, and after this was dissolved, the sodium hydrogen phosphate was added. The solution was made up to volume with injectable water and the pH became between 6.7 and 7.7 set. The solution was filtered to remove particulate matter by filtration

309847/1125

-38- 2322H2

sterilized and filled into pre-sterilized neutral glass ampoules under aseptic conditions.

The Prostadiensaederivat can of course by a equivalent amount of another according to the invention. Prostanoic acid derivative can be replaced.

3098U / 1125

Claims (1)

-39- 2322H2 Claims 1. Prostadiensaederivat of the formula A-CH (OH) -R ⁴ 1
wherein R is a hydroxymethyl or carboxy radical, an alkoxycarbonyl radical with up to 11 carbon atoms or an alkoxycarbonyl radical with 2 or 3 carbon atoms, which is a sub stitute. ß- or} f-dialkylamino radical carries, in which each alkyl radical has 1 to 4 carbon atoms, -oder.ein B- or} T- (1-pyrrolidinyl) -, piperidino- ■ or morpholino radical, A stands for an ethylene or vinylene radical ; R represents an aryl, furyl or thienyl radical which is unsubstituted or which is substituted by halogen atoms or nitro, phenyl or halogenophenyl radicals, alkyl, alkoxyalkyl, haloalkyl, alkoxy or acylamino radicals each having 1 to 4 carbon atoms or dialkylamino radicals, wherein each alkyl is 1 to -5 carbon Has 2 atoms, can be substituted; and R stands for a hydroxy radical or an alkanoyloxy radical with 1 to carbon atoms and Ή ~ stands for hydrogen or R and R ^ together stand for the oxo radical; wherein the compound 0, 1 or 2 alkyl radicals with up to 30 98 47/1126 2322H2 Carbon atoms as substituents on the carbon atoms 2, 3 or 4 carries' and where also for the case, that R stands for a carboxy radical, including the pharmaceutically and veterinarily acceptable salts thereof, are. 2. Prostanoic acid derivatives according to claim 1, characterized in that R is a hydroxymethyl, carboxy, Methoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical stands, A stands for an ethylene or trans - 4th
Vinylene radical, R stands for a phenyl, naphthyl, furyl or thienyl radical, which optionally bears no more than two substituents consisting of fluorine, chlorine, bromine and iodine atoms and nitro, phenyl, chlorophenyl, methyl -, ethyl, propyl, methoxymethyl, ethoxymethyl, 2-ethoxyethyl, halogenomethyl, methoxy, ethoxy, acetamido and dimethylamino radicals are selected 2 3
and R and R have the meanings given above, the compound containing 0, 1 or 2 methyl substituents on the carbon atoms 2, 3 or 4, and also in the event that R 'is a carboxy radical, the ammonium or alkylammonium - (which have 1 to 4 alkyl radicals each having 1 to 6 carbon atoms), alkanolammonium (which have 1 to 3 (2-hydroxyethyl) radicals) and alkali metal salts thereof are included. 3. · Prostanoic acid derivatives according to one of the claims 4 1 or 2, characterized in that R stands for phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl or 2-thienyl radicals or a fluorophenyl, chlorophenyl, bromophenyl, Iodophenyl, nitrophenyl, biphenylyl, chlorophenyl-2-furyl, tolyl, ethylphenyl, propylphenyl, Methoxymethyl phenyl, ethoxymethylphenyl, 309847/1125 (2-Ethoxyethyl) phenyl, methoxyphenyl, ethoxyphenyl, halogenomethylphenyl, acetamidophenyl or dimethylaminophenyl radical stands. 4. Prostanoic acid derivatives according to one of the claims 1, 2 or 3, characterized in that R stands for phenyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl-4-fluorophenyl, 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 4-nitrophenyl-, 4-biphenylyl-, 5- (4-chlorophenyl) -2-furyl-, 4-tolyl-, 4-methoxymethylphenyl- or 3- or 4-trifluoromethyl radical. 5. Prostanoic acid derivatives of the formula I of claim 1, characterized in that R represents a hydroxymethyl or carboxy radical, an alkoxycarbonyl radical with up to 11 carbon atoms or an alkoxycarbonyl radical with 2 or 3 carbon atoms which carries a ß- or if-D-alkylamino radical as a substituent, wherein each alkyl radical has 1 to 4 carbon atoms, or is a β- or] r- (1-pyrrolidinyl), piperidino or morpholino radical; R stands for an aryl radical which is unsubstituted or which is substituted by halogen atoms, nitro or phenyl radicals, alkyl, haloalkyl, alkoxy or acylamino radicals each with up to 4 carbon atoms or dialkylamino radicals , in which each alkyl has 1 to 3 carbon atoms exhibits, - substi- 2
is tuiert, R stands for a hydroxy radical or an alkanoyloxy radical with 1 to 4 carbon atoms, and R stands for a hydrogen atom, the compound 0, 1 or 2 alkyl radicals each having up to 4 carbon atoms as substituents on the carbon atoms 2, 3 or 4, with the case that R 'for a Carboxy radical stands, even the pharmaceutically acceptable ones Salts thereof are included. 309847/1125 2322H2 6. Prostanoic acid derivatives of the formula I of claim 1, characterized in that S is the carboxy or 2
Methoxycarbonyl radical, R stands for a hydroxy radical, and Br stands for a hydrogen atom or R 'and R together form the oxo radical, A for an ethylene or Zj. trans-vinylene radical and R is the 3- or 4- Chlorophenyl-, 3,4- Die hl or ο phenyl-., 4-nitrophenyl-, 4 - Methoxymeth.ylph.enyl, or 4-Trifluoromethy! Phenylradikal stands, where, in the event that R 'stands for the carboxy radical, also the pharmaceutical and veterinary permissible salts thereof are included. 7 · Prostanoic acid derivatives according to claim 6, characterized 4th
characterized in that R stands for the 4-chlorophenyl, 4-nitrophenyl or 4-trifluoromethylphenyl radical. δ. 9 α, 11α., 15-Trihydroxy- ^ 5- (4-trif Iu or omethylphenyl) -16,17,18,19,20-pentanor-5-cis, 13-t-rans-prostadiene, acid, 15 - (4-Chlorophenyl) -9 a, 1 lot, 15-trihydroxy-16,17,18, 19,20-pentanor-5-cis, 13-trans-prostadienoic acid, 15- (4- chlorophenyl) -9a, 11 α, 15 ~ trihydroxy-16,17, ^ 8,19,20-pentanor-5-cis, 13-trans-prostadienoic acid methyl ester, 9 o, 11 ei, 15-trihydroxy-15- (4-nitrophenyl) -16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid, 15- (3-chloro-phenyl) -9 ° -, 11 cl, 1 5-trihydroxy-16.17 , 18,19,20-pentanor-5-cis, 13-trans-prosadienoic acid, 15- (3,4-dichlorophenyl) -9o-, 11ou, 15-trihydroxy-16, -17,18,19,20 -pentanor-5-cis, 13-trans-prostadienoic acid and 9 ^, 11Ou, 15-trihydroxy-15- ( ^Z <-methoxymethylphenyl) -16,17, ^ 8,19,20-pentanor-5-cis, -13 -trans-prostadic acid. 3098.47 / 1126 9 · Prostanoic acid derivatives according to one of the preceding claims, characterized in that it is the more polar of the two C-15 epimers in silica gel thin layer chromatography. 10. Prostanoic acid derivative according to one of the preceding claims, characterized in that it is racemic. 11. Prostanoic acid derivative according to one of the claims 1 to 9, characterized in that it is a luteolytically effective, optically active form. 12. .Process for the preparation of prostanoic acid derivatives according to claim 1, characterized in that that he a) for those compounds in which R stands for the ρ
Carboxy radical, R stands for the hydroxy radical and R represents the hydrogen atom, a lactol the formula 0. II A-CH (OH) -R ⁴ • in which A and R have the meanings given above, with a (4-carboxybutyl) triphenylphosphonium salt, which optionally contains 0, 1 or 2 alkyl radicals with 1 to 4 carbon atoms on carbon atoms 2, 3 or 309847/1125 2322H2 carries, reacts in the presence of a strong base, whereupon, if a salt is desired, the product with a base is implemented; or b) for those compounds in which R is an alkoxycarbonyl radical with 1 to 11 carbon atoms is an acid of the formula .COOH 2 3 4
in which A, R, R and R have the meanings given above with a diazoalkane of the formula R .N ~, in which R ^ is an alkylidene radical having 1 to 11 carbon atoms; or c) for those compounds in which R is an alkoxycarbonyl radical having 1 to 11 carbon atoms is a salt of an acid of the formula III with an alkyl halide reacts with 1 to 11 carbon atoms; d) for those compounds in which R represents the hydroxymethyl radical, an ester of the formula I, wherein R is an alkoxycarbonyl radical, reduced; or e) a compound of the formula 847/1 1 2B 2322H2 Ί 3 4
wherein R, R and R have the meanings given above 6 7
and R and R each represent a hydroxy radical or a protected hydroxy radical, the compound. 0, 1 or 2 alkyl radicals on carbon atoms 2, 3 or 4, reduced, whereupon 6 1 if R and R 'each represent a protected hydroxy radical are standing, the protective groups are removed and, if a salt is desired, the carboxylic acid obtained in this way reacts with a base; or f) for those compounds in which A represents the vinylene radical, a compound of the formula COOH 2 3 4
wherein R _1, R and R have the meanings given above have and R is an alkoxy-dialkylmethyl radical with 4 to 8 carbon atoms, hydrolyzed, whereupon, if a salt is desired, the product is reacted with a base; or g) for those compounds in which A represents the ethylene radical, a compound of the formula V, 2 3 4
wherein A ₁ R, R ^ and R have the meanings given above have and R stands for the tetrahydropyranyl radical, hydrolyzed, whereupon, if a salt is desired, the product reacts with a base. 309847/1125 "J. Method according to claim ^ 2C), characterized in that that the salt of the acid of formula III is the silver salt. 14-. Method according to claim 12c), characterized in that that the alkyl halide is an alkyl iodide. 15 · The method according to claim 12d), characterized in that the reduction with a complex .Metallhydrid is performed.- 16. The method according to claim 15, characterized in that that the complex metal hydride consists of lithium aluminum hydride. 17 · The method according to claim 12e), characterized in that the reduction by zinc borohydride, aluminum tri-isopropoxide or di-isobornyloxy-aluminum-isopropoxide is carried out. 18. The method according to claim 17 *, characterized in that that in the starting material the protected hydroxy radical from an alkanoyloxy radical with up to 6 carbon atoms or consists of an aroyloxy radical of up to 12 carbon atoms. 19 · The method according to claim 12f), characterized in that that in the starting material the alkoxydialkylmethyl radical which is 1-methoxy-1-methylethyl radical. 20. The method according to claim 12g), characterized in that the hydrolysis with aqueous acetic acid or with an aqueous or alcoholic solution of one 309847/1 125 ~ ⁴⁷ ~ 2322 U Alkali metal carbonate is carried out. 21. The method according to claim 20, characterized in that that potassium carbonate is used as the alkali metal carbonate. 22. The method of claim 20 or 21, characterized in that it is carried out at a temperature between room temperature and about 60 ⁰ C. 23. ^ Pharmaceutical or veterinary compositions, characterized in that it contains a prostane acid derivative according to claim 1- together with a pharmaceutical or veterinary approved diluents or carriers. 24. Compositions according to claim 23, characterized characterized in that they have a shape suitable for oral administration, for inhalation, for parenteral Administration or suitable for anal or vaginal use. 25- A composition according to claim 24, characterized in that they have the form of tablets, capsules, aerosol, suitable for spraying solutions, _sterile} essentially aqueous solutions or suppositories. 26. 'Compositions according to claim 25, characterized characterized in that they are in the form of a sterile, substantially aqueous solution containing up to 1 mg / ml of the prostanoic acid derivative according to claim 1. -Mi · 309847/1125