DE2554760A1 - NEW PROSTAGLANDIN ANALOGS AND METHODS FOR THEIR PRODUCTION - Google Patents

Description

NEW PROSTAGLANDIN ANALOGS AND METHODS FOR THEIR PRODUCTION

Prostaglandins are a group of natural substances made up of various Animal tissues were isolated. In mammals they are responsible for a variety of physiological effects. The natural prostaglandins have a carbon structure of generally 20 carbon atoms and are different primarily due to the excess or minor content of hydroxyl groups or double bonds in the cyclopentane ring (M. F. Cuthbert "The Prostaglandins, Pharmacological and Therapeutic Advances", William Heinemann Medical Books LTD, London 1975)

909844 / ftAtt

^{/ 2}

FOLLOWED UP ^ 5 5 A 7 6

The synthesis of non-naturally occurring analogs of prostanoic acids, in which the multitude of pharmacological Effects of natural prostanoic acids are differentiated, is becoming increasingly important.

The present invention relates to new, non-naturally occurring ones Analogs of prostanoic acids of the general formula I

CO ₂ H

which includes both the optically active compounds of the natural configuration and the racemic compounds and in which mean:

X is a trans-vinylene group or an ethylene group, Y is a cis-vinylene group or an ethylene group Z is an alkylidene group having 1-4 carbon atoms

R is an alkyl group with 1-4 carbon atoms or, if X and Y are trans or cis vinylene groups, also one Vinyl group, an ethynyl group or an allyl group,

R is a cycloalkyl group with 4-8 carbon atoms, the in turn can be substituted up to three times by alkyl or alkoxy groups each with 1-6 carbon atoms, by halogen or by fluorinated alkyl groups with 1-4 carbon atoms,

as well as their physiologically compatible salts with organic and inorganic bases and their esters with aliphatic, cycloaliphatic or araliphatic alcohols with 1-8 carbon atoms.

709844/001

ORIGINAL INSPECTED

The invention further relates to a process for the preparation of the new analogs of prostanoic acids of the formula I, their physiological compatible salts with organic and inorganic bases and their esters »as well as pharmaceutical preparations containing them contained as active ingredients.

The process is characterized in that a) the aldehyde of the formula II

TI

with a phosphonate of the formula TII O O

CH ₃ O

P - CH ₂ - C - Z - O - R ² III

wherein R and Z have the same meaning as in formula I, to a <* ',, ß-unsaturated ketone of the formula IV-converts

IV

b) the ketone of the formula IV with an organometallic compound of the formula R Met, where R is the formula I given Has meaning and Met means a metal atom

709844/0011 Λ

554760

converts to a mixture of the epimeric alcohols of the formula V.

ZOR

R OH

1 2

in which R, R and Z have the same meaning as in formula I, and the epimeric geniic obtained is optionally separated into the tA> - and ß-epimers by means of column chromatography,

c) the alcohol of the formula V either as a pure d ^ - or ß-form or as a mixture of epimers by treatment with an excess of a complex aluminum hydride in a lactol of the formula VI

OH

VI

ZOR

HO

HO R

1 ρ
wherein R, R and Z have the same meaning as in formula I, converted

d) the lactol of the formula VI with an excess of 4-carboxybutylidene triphenylphosphorane in an aprotic, dipolar solvent under an inert gas atmosphere to an acid of formula VII

709844/001

VII

converts, and this acid is optionally converted into a physiologically acceptable salt or an ester

e) and optionally the acid of the formula VII or optionally their esters catalytically hydrogenated to give a compound of the formula I in which Y and / or X is an ethylene group, and, if desired, the acid into a physiologically acceptable one Salt transferred.

Of the substituents mentioned for Z, the methylene, ethylidene and the isopropylidene group is preferred.

-1

Of the substituents mentioned for R are in addition to those listed unsaturated alkyl groups, the methyl, ethyl, propyl and isopropyl groups are preferred.

Of the substituents mentioned under R, in addition to the unsubstituted Cycloalkyl radicals with 4 - 8 carbon atoms their substituted derivatives are particularly suitable. Preferred substituents are: alkyl groups with 1-4 carbon atoms, fluorinated alkyl groups with 1-2 carbon atoms, especially the trifluoromethyl group, Alkoxy groups with 1 - 4 carbon atoms, as well as fluorine.

ρ
In particular, the following radicals are suitable for R:

Cyclobutyl, jJ-methoxy-cyclobutyl, 3-methylcyclobutyl, cyclopentyl, 2-methylcyclopentyl, 2-methoxycyclopentyl, 3-methylcyclopentyl, 3-methoxycyclopentyl, cyclohexyl, 3-methylcyclohexyl, J-methoxycyclohexyl, 3-fluyclohexyl, 3-fluyclohexyl, 3-fluoro-hexyl Methylcyclohexyl, ^ -Methoxycyclohexyl, k -trifluoromethylcyclohexyl, 4-fluorocyclehexyl, cycloheptyl, 3-methylcycloheptyl, J-methoxycycloheptyl, 5-trifluoromethylcycloheptyl, 3-fluorocycloheptyl ^ 4-methylcycloheptyl,

Oaf / 6

4-methoxycycloheptyl, 4-trifluoromethylcycloheptyl, 4-fluorocyeloheptyl, Cyclooctyl, 2-methoxycyclooctyl, 3-methoxycyclooctyl, 4-methoxycyclooctyl

Of the ^{radicals mentioned for R 2} , the following are particularly preferred:

Cyclopentyl, cyclohexyl, 3-methoxycyclohexyl, 5-methylcyclohexyl, 3-trifluoromethylcyclohexyl, 3-fluorocyclohexyl, 4-methoxycyelohexyl, 4-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-fluorocyclohexyl and cycloheptyl.

In the case of the substituted cycloalkyl radicals, both stereochemically uniform and mixtures of cis- and trans isomers. Is the cycloalkyl radical used chiral, either the pure enantiomers or the racemic mixtures of the corresponding phosphonates can be used III can be used.

The process according to the invention is based on the aldehyde of the formula II, which according to DT-OS 24 16 195 from the primary bicyclic Alcohol of formula VIII

«A

durch'Oxydation with an oxidizing agent, such as with a complex of thioanisole and chlorine or the complex compound of CrO., and pyridine in an aprotic solvent at temperatures between -50 ⁰ C and room temperature, preferably between -30 ⁰ C and -5 ° C is produced in an inert atmosphere. Possible solvents are, for example, aromatic hydrocarbons such as benzene or toluene or, for example, chlorinated aliphatic hydrocarbons such as carbon tetrachloride.

709844 / Qttte / 7

The aldehyde of the formula II is reacted according to Horner, Wittig and Emmons with a phosphonic acid ester of the formula III to give an unsaturated ketone of the formula IV, a preferred embodiment of the reaction being that the sodium salt of the phosphonic acid ester with sodium hydride in an inert solvent, such as eg Glykoldimethyläther or tetrahydrofuran at room temperature produces, are then added an aldehyde of formula II and at -10 to +50 ⁰ C, preferably allowed to react at room temperature for 2 to 6 hours.

The phosphonic acid esters of the formula III can be reacted

of an ester of the formula R QZCOp-alkyl in the presence of excess Butyllithium and methylphosphonic acid dimethyl ester (e.g. according to Corey, J. Am. Chem. Soc. 88 5654 (1966)) will.

The ketone of the formula IV is obtained by reacting with an equimolar amount of an organometallic compound, for example a Grignard compound or an organolithium Compound of the type R Met at temperatures preferably between -20 ° and -70 ° C, the epimeric mixture of alcohols V. Preferred solvents are ethers such as diethyl ether, monoglyme, tetrahydrofuran or dioxane.

The compound of formula V obtained in this way is reduced with a complex aluminum hydride in an aprotic solvent to a mixture of lactol VI with p-phenylbenzyl alcohol. Is preferably carried out with diisobutylaluminium hydride in toluene at temperatures between -50 ° and -70 ⁰ C.

The product mixture obtained in this way can be used without further purification or after separating off the p-phenylbenzyl alcohol formed can be used in the subsequent Wittig reaction with 4-carboxybutylidene triphenylphosphorane. This ylide is preferably made from the corresponding phosphonium bromide with the Na salt of dimethyl sulfoxide is produced in dimethyl sulfoxide.

709844/001

The reaction is advantageously ^{carried out between 20 and 50 °} C., for example in DMSO or hexamethylphosphoric acid triamide. After the non-acidic components of the reaction mixture thus obtained have been separated off and chromatographed on silica gel with CHCl., / CH-ZOH mixtures, the pure carboxylic acids of the formula VII are obtained as a mixture of their C-15 epimers.

These carboxylic acids can be converted into the corresponding esters by the customary methods. The methyl ester is preserved it is preferred to react with diazomethane in aprotic solvents.

The separation of the 15-C epimers by chromatographic means is advantageous in analogy to the method described by EW Yankee, U. Axen, and GL Bundy (J-. Amer. Chem. Soc. 96: 18 , 5865 (197 ^)) possible at the lower alkyl ester stage, especially the methyl ester.

The compounds of formula I.

(ι)

¹ OH '.

in which Y and / or X are ethylene groups, are hydrogenated of the corresponding compounds with Pd / C in protic solvents such as ethanol obtained at normal pressure.

If desired, all compounds of the formula I can be converted into physiologically acceptable esters or by the customary methods Salts are transferred.

In addition to the in the examples also mentioned in particular the following

7Q98U / 001S / 9

make bonds:

9S, 11S, iS

13-trans-tetranorprostadienoic acid

9S, 11S, 15-trihydroxy ~ 1 5τ1 6-dimethyl-1 6-cyclopentyloxy 5-CXS-1 3-trans-tetranorpi-ostadienoic acid

9S, 11S, iS

9S, 11S, iS norprostanoic acid

9S _t 11 S, 15-trihydroxy-1 5-

1 3-trans-tetraiaorprostadienoic acid

9S, 11S, t ^ 5-cis-13-trans-tetranorprostadienoic acid

9S, 11S, iS

13-trans-tetranorprostadienoic acid 9S, 11 S, 1 5-trihydroxy-1 5-metlayl-1 ß-cyclohexyloxy-t etra

• ■

nor-prostanoic acid

9098.44 / öatt

9S, 11S, iS-trihydroxy-IS-methyl-io - ^ - methyl oxy) -5-cis-13-trans-tetranorprόstadienoic acid

9S, 11S, iS

i.e., exyloxy) -5-cis-13-trans-tetranorprostadienoic acid

9S, 11S, 15-trihydroxy-15-ethyl-1 6- {k- methyl-cyclohexyloxy) -5-cis-1 3-trans-tetranorprostadienoic acid

9S, 11 S, 1 5 ~ trihydroxy-1 5-methyl-1 o-i ^ - 5-cis-1 3 ~ trans-tetranorprostane acid

9S, 11S, 15-trihydroxy-15-methyl-16- (4-methoxy-cyclohexyl oxy) -5-cis-13-trans-tetranorprostadienoic acid

9S, 11S ₁ 15-trihydroxy-15 »16-dimethyl-16 - (^ - methoxycyclohexyloxy) -5-cis-13-trans-tetranorprostadienoic acid

9S, IIS, 15-trilydroxy-1 5-ethyl-1 6 ~ (^ -mettioxycyclohexi'-loxy) S-cis - ^ - trans-tetranor-prostadienoic acid

9S, 11S, 1 5-trihydroxy-1 5-metliyl-i 6- (4 ~ ^r methox3 cyclohexyloxy) -tetranorprostansäure

9S, 11S ,. 1 5-trinydroxy-1 5-methyl-1 ö-C ^ - hexyloxy) -5 ~ cis-13-trans-tetranorprostadienoic acid

7098U / 001I

9S, 11S, 15-trihydroxy-15, i6-dimethyl »i6- (4-tri: fluoromethylcyclohexyloxy) -5-cis-13-trans-tetranorprostadien-

9S _t 11S, IS

hexyloxy) -5-c ± s-13-trans-tetranorprostadienoic acid

9S, 11S, IS cyclohexyloxy) tetranorprostalic acid

₁ 11 S, i5-trihydroxy-i5 ~ niethyl-I6 (4 ~ fluorc5xiohexyloxy) -5-CXS-13-trans-tetranorprostadiensäure

9S, 11S ₁ IS hexyloxy) -5-ciε-13-trans-tetranorprostadienoic acid

9S, 11S, i ^ 5-cis-13-trans-tetranorprostadienoic acid

9S, 11 S, 15-trihydroxy-1 5-methyl-1 o-X ^ - tetranorprostanoic acid

9S, 11S, 15-trilydroxy-15 ~ aethyl-16-cyclolieptyloxy-5 cis-13-trans-tetranorprostadienoic acid

9S, 11S, ^ 5-cis «13-trans ~ tetranorprostadiensi | ii: re

13-trans-tetranorprostadienoic acid

9S, 11S, 15-trihydroxy-15-methyl-16-cycloheptyloxy-tetra ~ norprostanoic acid

9S, 11S ₁ 1 5-triliy droxy-1 5-niethyl-1 6 -cyclooctyloxy-5-cis- »13-trans-tetranorprostadienoic acid

9S, 11 S, 1 5 ~ trihydroxy-1 5-ethyl-1 6-cycloliexyloxy-1 3-trans tetranorprostenic acid methyl ester

9S, 11S, 15-trihydroxy-15-methyl-16 - (^ - £ luoro-cyclohexyloxy) -1 3 ~ trans-tetranorprostenic acid methyl ester

11 S, 1 5-trihydroxy-1 5-raethyl ~ 1 6- (4 ~ 13-trans-tetranorprostenic acid methyl ester

9S, 11S, iSi hexyloxy) ~ 1 3-trans-tetranorprostenic acid ethyl ester

2.5 5476 Q

The compounds of the formula I according to the invention are non-naturally occurring analogs of prostanoic acids which are based on Can be used as medicinal products because of their pharmacological effects.

The natural prostaglandins PGE .., ^PGE ? * ^PGF 20 ^ ^or PGAp have the disadvantage that they are deactivated so quickly in the living body that they cannot maintain their pharmacological effect during the time required for the therapy.

In contrast, the compounds according to the invention stand out by a longer duration of action and a stronger effect.

The compounds according to the invention also show a more differentiated one Effect. Experiments on cattle have shown that the luteolytic effect of these preparations is that of the outperforms natural prostaglandins. χ_η vitro experiments showed that the spasmogenic effects of these compounds were against it is weakened compared to the natural prostaglandins.

The compounds according to the invention can be used as medicaments with antihypertensive and diuretic, prophylactic effects and therapeutic effect in thrombosis, induction of labor, as abortive drugs, contraceptives, as inhibitors the gastric juice secretion and as an agent against gastric ulcers and against asthma. Particularly suitable the compounds according to the invention as contraceptives for use in humans and also for synchronizing oestrus in different animal species.

They can be used as free acids, in the form of their physiologically harmless ones inorganic or organic salts or as esters

709844 / ÖOii

-Χ;

of aliphatic, cycloaliphatic or araliphatic alcohols are used. The salts come, for example into consideration benzylammonium, triethylammonium or morpholine salts as well as alkali salts, as esters preferably the esters of saturated branched or unbranched lower aliphatic Alcohols such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters and the benzyl ester.

Acids such as salts or esters can be used in the form of their aqueous solutions or suspensions or as solutions in pharmacologically harmless organic solvents such as or polyhydric alcohols, dimethyl sulfoxide or dimethyl formiamide, can also be used in the presence of pharmacologically safe polymer carriers such as polyethylene glycol.

The usual galenic infusion or injection solutions and tablets, as well as locally applicable ones, are used as preparations Preparations such as creams, emulsions, suppositories or aerosols in question.

The connections can be for sir ^ 'Heine or together with other pharmacological agents such as diurectics, antidiabitics or hormones are used.

The compounds of the formula IV, V and VI are valuable intermediates for the synthesis of the compounds of the formula I according to the invention.

• / 15

7093AWQ01

Preparation of the starting compound:

Synthesis of 2-oxa-3-oxo-6syn-formyl-7-anti-p-biphenyl-carboxy-

(II)

In a 2 l four-necked flask, 1.354 l of a solution of 21.3 g of CIp in 1.5 l of abs. CCl ^ presented under argon and cooled to −10 ° C., to this, 3.5.3 g of thioanisole are added dropwise, a white precipitate being formed. Upon complete addition, is cooled to -20 ⁰ C and stirred for 30 minutes. In the meantime, a solution is prepared from 30 g of lactone alcohol (II) in a maximum of 300 ml of CHgCl ₂ abs.

This solution is rapidly added dropwise at -20 ⁰ C and then stirred for 2-3 hours at -20 ⁰ C.

54.3 ml of triethylamine, dissolved in 50 ml of CHgCl ₂ (absolute), are then slowly added dropwise over the course of 1 hour, the temperature being allowed to rise to -5 ° C. towards the end of the dropping.

The reaction mixture is then poured into an ice-cold solution of 600 ml of 1 HCl and 1.5 liters of diisopropyl ether. The resulting white precipitate (24 g) is filtered off with suction on a suction filter and washed with ether. The filtrate is placed in a separating funnel and the organic phase is separated off, dried and concentrated at a maximum of + 15 ° C. to a volume of approx. 750 ml. The precipitated crystals are filtered off with suction after good cooling (5 g) and cleaned with the filter residue. Yield: 29 g of white crystals (98 %) thin layer chromatogram (solvent chloroform-methanol 15: 1).

R _f "= 0.63

709844/0011

Nuclear magnetic resonance spectrum (in CDCl ^) <f values: 1.9 - 4, O: multiplet 6 H (-CH ₂ -,> CH-), 5.0 - 5.3 * '- triplet 1 H (-CH- OCO), 5.65 - 5.9 multiplet JH (-CH-OCO), 7.3 - 8.2 multiplet 9 H (aromatic protons) 9.8 singlet 1 H (CH = 0)

? 09844 / Qüii

Example 1 » S * λ

a) Synthesis of. Dimeth.yl-2-oxo-3-cyclohexyioxy-propylph.osph.onate

21 g of dimethyl methanephosphonate in 100 ml of tetrahydrofuran are mixed with 100 ml of a 20% butyllithium solution under argon to 50%. The mixture is stirred JO min. And then add 25 g of 2-Cyclohexyloxyessigsäuremethylester in 100 al tetrahydrofuran au. The mixture is stirred for a further 3 hours at - 50 °, then allowed to come to - 20 and neutralized with acetic acid. It is then poured into ice water and the aqueous phase is extracted several times with chloroform. The combined chloroform phases are washed with water, dried and evaporated.

After purification by column chromatography on silica gel with Essigeeter-toluene (l / l) gives 10.2 g of phosphonate.

NMR (60 MHa ₁ CDCI-) singlet at 4.1 ppm (2H, g

Doublet at 3.8 ppm (6H, (CH ^ o) _2. Xtv 13 Η «)

Doublet at 3.2 ppm (2H, CH "P, 1 ^ 22 Hat)

• .,. "Λ

Multiplet by 3. Λ ppm (1H, CH-OCH «) Multiplet from 1.0 to "2.2 pp" (lOH, 5 alicyclic 0Η_-

Groups)

b) Dimethyl 2-oxo-3-cycl ⁰ Pe ⁿ * yloxy-propylphosphonate is prepared accordingly.

909844/01111 / 18

Example 2j «ι ^

Synthesis of 2-oxa-3-keto-6- (3-keto-4-cyclohexyloxy-buten-1-yl) -7- (4-phenylbenzoyloxy) -bicyclo (3 »3 * O) octane

It is added to a slurry of 250 mg SO ^ igem NaH in 15 ml of ethylene glycol dimethyl ether at room temperature below Argon dropwise a solution of 2.7 g of the phosphonate from Example 1 a in 30 ml of abs. Ethylene glycol dimethyl ether. The mixture is then stirred for a further 1 hour at room temperature and then a solution of 3 g of 2-0xa ~ 3-oxo-6syn-formyl-7-anti- ■ p-phenylbenzoyloxy-cis-bicyclo [3f3 »o] octane in 50 ml of dimethoxyethane added. The mixture is stirred for 5 hours at room temperature, then brought to pH 6 with a few drops of glacial acetic acid. It is clarified with a little Animal charcoal and evaporated to dryness. In the chromatography of the material obtained in this way on silica gel with toluene / ethyl acetate (l / l) is obtained as the first fraction 1.45 g of the sought Materials.

NMR (60 MHz, CDCl)

Multiplet from 7 $ 2 to 8.3 ppm, (9 aromatic protons) Double doublet (7fO5l 7.15; 6.77; 6.87J)

Doublet (6.43? 6.70) Jtogether 2 olef. H

Multiplet from 4.9 - 5 | 6 ppm (2H, CH-OC)

Singlet at 4.2 ppm (2H, C-CHg-O

Multiplet from 0.9 ppm to 3 »6 ppm residual protons

709844/0018 / 19

Example 3s

Synthesis of 2-oxa-3-keto-6- (3-hydroxy-3-methyl-4-cyclohexyloxy-buten-1-yl) -7- (4-phenylbenzoyloxy) -bicyclo (3,3,0) octane

To a solution of 1.05 g of the α, ß-unsaturated ketone from Example 2 in 30 ml of abs. Tetrahydrofuran is added dropwise - 78 under argon 10 ml of a 0.86 molar solution of methylmagnesium iodide in ether. The mixture is stirred for a further 5 hours at -78 ° and 20 ml of a saturated ammonium chloride solution are then added dropwise. You come out loud to 0, dilute with 50 ml of water and extracted 3 χ with ethyl acetate / ether (lsi). After working up by column chromatography (silica gel) ethyl acetate er / toluene l / l) 930 mg of the desired end product are obtained TLC (toluene / ethyl acetate 1/1) R - / ^ 0.27

NMR (60 MHz, CDCl)

Multiplet from 8.3 - 7.1 ppm (9 aromatic H) Narrow multiplet at 5.7 ppm (2 olefinic H) Broad multiplet from 5.4 to 4.9 ppm (2 χ CH-O-C-)

- S.

remaining protons from 4.3 to 0.9 ppm, the signals for the CHgO group (3.3 ppm) and the newly introduced methyl group (approx. 1.3 ppm) all appear clearly singlets.

* l · - ■

/ 20

Synthesis of 9S, 11S, 1 5-trihydroxy-1 5-diethyl-1 6-cyclohexyloxy-5-cis-13-trans-17 »18,19,20-tetranorprostadienoic acid

2 ^ 0 mg 2 ~ oxa-3-keto-6 (3-hydroxy-3-methyl-4-cyclohexyloxybuten-1-yl) -7 - (^ - phenylbenzoyloxy) -bicyclo (3 »3» O) octane white dissolved in 10 ml of absolute toluene and treated with 2 ml of a 1.2 molar solution of diisobutylaluminum hydride at -60 under Ar. The mixture is stirred kO min at -60, 1 ml of isopropanol is added and the mixture is allowed to come to 0 * 20 ml of ice water are then carefully added and the mixture is again stirred for 15 min. The organic phase is separated off and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed 1 with saturated NaCl solution and dried with magnesium sulfate.

After evaporation of this solution, 2 ** 2 mg of one are obtained Mixture of 2-oxa-3-hydroxy-6- (3-hydroxy-3-methyl- ^ ~ cyclohexyloxy-buten-1-yl) -7-hydroxy-bicyclo (3.3.0) octane (A) and p-phenylbenzyl alcohol (B), which can be added to the Wittig reaction can be used.

DG (silica gel, CHCl / MeOH 10 / i) R _f ^ 0.16 (a) <v 0.6 (b).

41O mg of 55 # iges sodium hydride are under Ar at 70 ° in 5 ml dissolved in absolute dimethyl sulfoxide. The solution obtained in this way is cooled to room temperature and treated with 2.1 g of 4-carboxybutyltriphenylphosphonium bromide offset. The red solution of 4-carboxybutyltriphenylphosphorane is made with the above obtained mixture of A and B in 3 ml of abs. DMSO offset

° stirred. .,

709844/0018

and stirred for 3 hours at 50 °.

255476Q

The mixture is then cooled to room temperature and 50 ml of ice water are added to the reaction solution. The non-acidic parts are removed the reaction mixture by extracting twice with ether and acidifying the aqueous phase with 10% citric acid solution at.

The acidic aqueous solution is extracted 5 times with a l / l device of ether and pentane. The crude product obtained after drying and evaporation of the solution is purified by chromatography on silica gel (chloroform / methanol 10/1). 71 mg of 9S, 11S, 15-trihydroxy-15-methyl-16-cyclohexyloxy-5-cis-13-trans-1 7,18,19-20-tetranorprostadienic acid, TLC (silica gel, CHCl / CH ₃ OH 10/1) R _f ~ O, 092 TLC (silica gel, ACOEt / ACOH 97.5 / 2.5) R ^ O, 28

NMR (CDCl / 60 MHz)

Multiplet of 5 »0 - 5» 6 ppm (4 olefinic protons) Multiplet from 3.5 - 4.4 "ppm (2 χ CH-OH, 3 χ OH, 1 χ COgH)

Multiplet from 3.0 to 3.5 ppm J.

Singlet at 3.3 ppm J) Multiplet from 0.9 ppm to 2.5 ppm residual protons.

The methyl group at C-15 appears as a singlet at 1.3 ppm.

together 3H (-CH-O-CH)

7098U / ÖÖ.16 / 22

Synthesis of 9S, 11IS, 1S-

oxy-5-cis-13-trans-17 »18.19» 20-tetranorprostadienoic acid methyl ester

65 mg of 9S, 11S, 15-trihydroxy-15-methyl-1o-cyclohexyloxy-S-cis-13-trans-tetranorprostadienoic acid are dissolved in 5 οΊ abs ether and mixed with 10 ml of a molar solution of diazomethane in ether Stand at room temperature for 2 hours and then evaporate. 58 mg of the desired ester are obtained.

TLC R * ^ 0.42 (ethyl acetate)

NMR (CDC1_ / 6O MHz)

Multiplet of 5 _f 0 - 5 »6 ppm (4 olefinic H) doublet (l ~ 6 Hz) together with multiplet from 4.25 to 3» 70 ppm <2H, CH-OH) singlet beirsj 3.6 ppm) singlet at 3 »3 PF ^m

together 3H (CH_-O-CH) multiplet at 3 »O - 3t5 ppm ^λ multiplet from 0.9 ppm to 2.7 ppm for the remaining protons with a distinct singlet at 1.25 ppm for the C-15 methyl group ·

709844 / Ö016

Example 6: * ^

Synthesis of 9S, 11S, 15-trihydroxy-i5-methyl-16-cyclohexyloxy-13-trans-17 »18 »19,20-tetranorprostenic acid methyl ester

ο Jt - r \ r »-« - ir * * t?

«■ τ mg 7 \ J , ι ιο, IJ

1 3-trans-1711.8, 19,20-tetranorprostadienoic acid methyl ester are dissolved in 10 ml of absolute methanol and hydrogenated for 1 hour with 25 mg of 10bigem Pd on animal charcoal at room temperature and atmospheric pressure. The catalyst is filtered off with suction and washed with absolute methanol . After evaporation of the filtrate obtained 19 mg 9S, 11S, 15-trihydroxy-15-methyl-16-cyclohexylox3 ^r -1 3-trans-17ti8 he i9,20-tetranorprostensäuremethylest

NMR (60 MHz, CDC1_)

Doublet-like signal at 5.6 to 5.5 ppm (2 olef. H) multiplet of h, 3 to 3.8 PP «0 _{add 5H (2 χ CH-0H)} with doublet ( ^{1-6 Hz) J 3} alcoholic protons

Singlet with oa. 3.6 ppm (CO CH) singlet at approx. 3.3 ppm j

r ~ together 3H (CH ₂ -OOH) multiplet of 3.0-3.5 ppm) "" ^

Multiplet from 0.9 to 2.7 ppm for the remaining protons, CH group on C-15i singlet at 1.25 ppm.

70984A / Ö016

Λ *

Claims (8)

PATENT CLAIMS: "--- 'Compounds of the formula I. CO ₂ H which include both the optically active compounds of the natural configuration and the racemic compounds includes and in which mean: X is a trans-vinylene group or an ethylene group Y is a cis-vinylene group or an ethylene group, Z is an alkylidene group with 1-4 carbon atoms R is an alkyl group with 1-4 carbon atoms or, if X and Y are trans or cis vinylene groups, also one Vinyl group, an ethynyl group or an allyl group, R is a cycloalkyl group with 4-8 carbon atoms, the in turn can be substituted up to three times by alkyl or alkoxy groups each with 1-6 carbon atoms, by halogen or by fluorinated alkyl groups with 1-4 carbon atoms, as well as their physiologically compatible salts with organic and inorganic bases and their esters with aliphatic, cycloaliphatic or araliphatic alcohols with 1-8 carbon atoms. 2) Process for the preparation of the compounds according to claim 1, characterized in that one 709844/0018 _{/ 25} HOE 75 / P 305 a) the aldehyde of formula II = O II with a phosphonate of the formula III II P - CH ₂ - C - Z - O - III where R and Z have the same meaning as in formula I, converts to an αθ, β-unsaturated ketone of the formula TV IV / VVa-I b) the ketone of the formula IV "with an organometallic compound" bond of the formula R Met, in which R has the meaning given for formula I and Met is a metal atom, converts to a mixture of the epimeric alcohols of the formula V. 0 / 26 HOE 75 / P 305 wherein R, R and Z have the same meaning as in formula I, and the epimer mixture obtained, optionally by means of Column chromatography separates into the oO- and ß-epimers, c) the alcohol of the formula V either as a pure ch - or ß-form or as a mixture of epimers by treatment with an excess of a complex aluminum hydride in a lactol of the formula VI OH VI 1 2
wherein R, R and Z have the same meaning as in formula I, converted d) the lactol of the formula VI with an excess of 4-carboxybutylidene triphenylphosphorane in an aprotic, dipolar solvent under an inert gas atmosphere to form an acid of the formula VII ² VII HO R ¹ OH converts, and this acid is optionally converted into a physiologically acceptable salt or an ester e) and optionally the acid of the formula VII or optionally their esters catalytically hydrogenated to give a compound of the formula I in which Y and / or X is an ethylene group, and, if desired, the acid into a physiologically compatible one Salt transferred. 709844/0016 / 27 3) compounds of formula IV HOE 75 / F 305 IV ZOR wherein Z and R have the meaning given for formula I in claim 1 to have. 4) compounds of formula V O. ZOR R 'OH 1 2 wherein Z, R and R are those mentioned for formula I in claim 1 Have meaning. 5) compounds of formula VI OH VI 12th
wherein Z, R and R are those mentioned for formula I in claim 1 Have meaning. 6) Process for the production of pharmaceuticals, characterized in that that a compound of the named in claim 1 709844/001/28 HOE ^ / - ^ ₇ gQ ten formula I, optionally with conventional pharmaceutical Brings carriers and / or stabilizers into a therapeutically suitable application form. 7) Medicines characterized by a content of one A compound of the formula I mentioned in claim 1 or consisting of such a compound. 8) Use of a compound of the formula I mentioned in claim 1 in medicaments or as medicaments. 700844/0011 ORIGINAL INSPECTED