DE2355324A1 - NEW PROSTAGLAND INDIREVATIVES AND METHODS FOR THEIR PRODUCTION - Google Patents

Description

PATENT LAWYERS

Dipl.-Ing. P. WIRTH ■ Dr. V. SCHMIED-KOWARZIK

Dipl.-Ing. G. DANNENBERG -Dr. P. WEINHOLD Dr. D. GUDEL

281134 β FRANKFURT AM MAIN

TELEPHONE (0611) _28γ0Η CR ESCHENHEIMER STRASSE

SK / SK

PA-606

Syntex Corporation Apartado Postal 7386 Panama / Panama

New prostaglandin derivatives and processes for their Manufacturing

( Additional registration to registration Case PA-579)

The present invention relates to certain new prostaglandin derivatives, on processes for their production and on certain new intermediate products obtained by this process "

In particular, the present invention relates to prostate-4,5,13-transtrienoic acid derivatives with oxygenated functions in the C-9 and C-15 or C-9, C-II and C-15 positions of the molecule that continues at C-4, C-6, and / or C-15 by a methyl, ethyl or propyl group substituted serine C-20 nor and bis-nor derivatives thereof, or the C-20 alkyl derivatives thereof, wherein the alkyl group is straight-chain and has 1-5 carbon atoms contains. The present invention also includes the corresponding, pharmaceutically acceptable, non-toxic esters, ethers and salts.

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Prostaglandins are members of "a new hormonal system with a notable one Range of biological and pharmaceutical properties. These compounds belong to a group of chemically related hydroxy fatty acids with 20 Carbon atoms in the chain, a five-membered ring in the structure and varying degrees of unsaturation; a number of these compounds have already been described in the literature. Regarding an overview on prostaglandins and the definition of primary prostaglandins see ».Β. S. Bergström, "Recent Progress in Hormone Research", 22, pp. 153-175 (1960) and Science 157, page 382 (1967) by the same author.

Prostaglandins are largely distributed in human and mammalian tissues and have been isolated in very small quantities from natural sources. Furthermore, some of the naturally occurring prostaglandins were produced by chemical syntheses (cf., for example, J. Am. Chem. Soc., 91, page 5675 (1969); J. Am. Chem. Soc. _T 92, page 2586 (1970) and J .Am.Chem.Soc., 93, pages 14-89-14-93 (1971) and the literature references cited therein; WP Schneider et al J Jlm.Chern.Soc. _R 90 _t page 5895 (1968); U. Axen et al., Chem. Cominun., p. 303 (1969) and WP Schneider, Chem. Commun., p. 304- (1969)).

Due to the remarkable range of biological and pharmacological properties, shown by this family of compounds has attracted much interest in them and the preparation of analogs of these compounds; according to the invention, processes and intermediates for production have now been established modified prostaglandins and their derivatives found.

The novel prostaglandic rates of the present invention can be obtained by the following Formulas are represented:

409821/1132

COOE

CA)

COOE

(B)

COOR

(G)

, 3

oor '

in which R and R ^ each represent hydrogen, methyl, ethyl or propyl; R is hydrogen, hydroxy or a customary hydrolyzable ester or ether

the same means; ■ ■

Z 3 R and R each represent hydroxy or a customary hydrolyzable ester

~ "40982 17 1132

or ethers of the same;

R is methyl, ethyl or propyl;

R for hydrogen, a lower alkyl group with 1-3 carbon atoms stands, or the pharmaceutically acceptable, non-toxic salts of the

k
bonds in which R is hydrogen: and η is an integer from 2 to 9;

with the prerequisite that - if R is in the d position, the to the same ·. Carbon atom such as the hydroxyl group bonded to R is in the ß-position; and, if · R is in the β-position, the hydroxyl group bonded to the same carbon atom as R is in the <K -position.

The dashed lines in the above and the following formulas mean that the substituents are in the e <configuration, i.e. below the level of the Cyclopentane ring.

The wavy line (<) means the oC or ß configuration or mixtures thereof.

The double bond; at C-13 of the compounds according to the invention has the same configuration as in the natural prostaglandin of the PGE ₁ , PGE ₂ , PGF ₁ , or series, ie the trans configuration.

The preferred meaning of / is k, ie according to the invention those compounds are preferred which have the usual structural unit with C-20 carbon atoms of natural prostaglandins.

These new compounds have asymmetric centers and can thus be called racemic mixtures can be prepared. The racemic mixtures can, if appropriate, be separated at the appropriate stages by known processes thereby obtaining the corresponding individual antimers. The present invention naturally includes the individual 8R antimers

409821/1132.

as well as mixtures of the two antimers.

Thus, the compounds of the formula (A) are mixtures of the same proportions Compounds of the specified structure and their mirror image according to the following Formula A-I

COOR

(A-I)

The compounds of the formula (B) are mixtures of compounds of the formulas

B-I and B-2 in equal proportions

COOR ⁴ . ,

(BI)

COOR

(B-2)

'or mixtures of the compounds of the formulas B-3 and Bk in the same proportions;

.3 '■: ■ ·

COOR

and 3

COOR

(B-4)

The compounds of the formula (C) are mixtures of the associations of formulas CI and C-2 in the same proportions _β

4,99821/1132

or mixtures of compounds of the formulas C-3 and C-4 in equal proportions

nits;
0

COOR

COOR

and

and the compounds of the formulas (D) are mixtures of the compounds of Formulas D-I and D-2 in equal proportions

i> c-c «c <£ v /

COOR

R ¹ HO

and

COOR

or mixtures of the compounds of formulas D-3 and D-4 in equal proportions

COOR

(D-3)

(D-4)

409821/1132

- 7 - or mixtures of the compounds of the formulas D-5 and D-6 in the same proportions

COOR ⁴ _R 3

(D-5)

COOR

or also mixtures of compounds of the formulas D-7 and D-8 in the same Conditions »

R-

COOR

COOR

(D-7)

and-

= C = C

^^ - ^ (CH ₂ O _n -CH ₃ HO ' ^X R ⁶

(D-8)

If the compounds according to the invention are racemic disorders, then there will be they are made from Raceraaten as starting materials; are the invention Compounds, on the other hand, are single antimers, then they are preferably obtained, by starting from the corresponding individual antimers.

For the sake of simplicity, in the description of the present application only one antimer of each pair is shown; it will be taken for granted, however also the mirror images for the racemic mixtures and the individual antimers includes.

The use of the symbol ¹¹ R "as a prefix of a substituent denotes the absolute stereochemistry of this substituent according to the Cahn-Ingold-Prelog rules (cf. Cahn et al., Angew.Chem.Inter.Edit., · ■ -

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Vol. 5, page 385 (1966), errata page 511; Cahn et al., Angew. Chem., Vol. 78, p. 413 (1966); Cahn and Ingold, J. Chem. Soc. (London), 1951, p. 612; Cahn et al., Experientia, Vol. 12, p.81 (1956); Cahn, J. Chem. Educ, Vol. 41, Seitell6 (1964)). Due to the mutual relationships of the designated substituent with the other substituents in the compound with q (- or ß-prefixes, the designation of the absolute configuration of a substituent fixes the absolute configuration of all substituents in the compound and thus the absolute configuration of the compound as a whole.

The term "common hydrolyzable esters or ethers" as used herein refers to the physiologically acceptable hydrolyzable ester and ether groups used in pharmaceutical technology which do not appreciably adversely affect the pharmaceutical properties of the base compound. The term "hydrocarbon carboxylic acid" refers to substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be fully saturated or have varying degrees of unsaturation (including aromatic unsaturation); they can be straight-chain or cyclic and preferably contain 1-12 carbon atoms. Furthermore, they can be substituted by functional groups, such as hydroxyl, alkoxy groups with up to 12 carbon atoms, nitro, amino, halogen, etc., which are bonded to the main hydrocarbon chain. Typical common hydrolyzable esters of this definition are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenyl acetate, diphenyl acetate, diethyl acetate, trimethyl acetate, tert-butyl acetate, trimethylhexanoate, cyclohexyl acetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, Hemiadipat, Hemi-ß, ß-dimethylglutarate, Acetoxyacetat, 2-chloro-4-nitrobenzoate, amino acetate, Diäthylaminoacetat, Piperidinoacetat, ß-chloropropionate, trichloroacetate, ß-chlorobutyrate, B ± ayclo- {2.2 _m z] -

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octane-1-carboxylate, ^ -Methyl-bicyclo- ^. 2. ^ -oct ^ -en-l-carboxy lat, etc., of preferred, the usual hydrolyzable ester is acetate.

The term "common hydrolyzable ethers" includes the tetrahydrofuran-2-yl, Tetrahydropyran-2-yl and ^ -Methcxytetrahydxpyran- ^ - yl ethers.

The addition salts are made from pharmaceutically acceptable basic salts including metal salts such as sodium, potassium, calcium, magnesium, aluminum etc., as well as organic amine salts such as ammonium, triethylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine ₈ arginine, caffeine, pro * ; cain; · N-ethylpiperidine, hydrabamine, etc. The term "pharmaceutically acceptable" refers to salts that do not appreciably adversely affect the properties of the base compound.

The new prostaglandin derivatives according to the invention with the exception of those which is further substituted at C-15 by a methyl, ethyl or propyl group can be obtained by a method according to the following reaction scheme

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ο -

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ο-

- (Z

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- X C /

CO

> H

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In the above formulas

R, R and η have the meaning already given} R stands for hydrogen or tetrahydropyranyloxyj

1"
R is hydrogen or hydroxy;

R ^ 'represents methyl, ethyl or propyl;

Ac means a lower acyl group with 1-A carbon atoms, especially acetyl; and
THP stands for tetrahydropyranyl.

In carrying out the method illustrated above, the starting materials of the formula I (racemates or individual Antimere) with excess dilithium salt of pent-4-yn-l-ol in a-geeigneten- liierten organic * _LÖ _ • ^ solvents to form the corresponding trihydroxyacetylenischen Treated compound of formula II. ■ '

The dilithium salt of the pent-4-yn-1-ol reagent is used in amounts between about 5-15 molar equivalents per molar equivalent of starting hemiacetal, preferably in an amount of about 10 molar equivalents. This reagent is prepared by reaction of pent-4-yn-l-ol and methyl lithium in ether solution at a temperature of about -78 C. to -50 ⁰ C. under an inert atmosphere, such as the central bus station. Nitrogen or argon for a period between 15-24 hours, preferably about 18 hours. The reagent prepared in this way is combined with a solution of the hemiacetal of the formula I in an ethereal solvent, the reaction mixture being kept at a temperature between 10-30 ° C. for about 4-10 hours; the reaction time depends in turn on the temperature used. In the preferred embodiments, the reaction is carried out at room temperature (about 25 ° C.) for about 6 hours.

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Suitable solvents for this reaction are diethyl ether, diethyl ether, Dipropyl ether, dimethoxyethane, etc., especially diethy lather.

The product is obtained by dilution with Vfasser, extraction with an organic, water-immiscible solvent and evaporation of the solvent isolated under reduced pressure, whereby it is checked that the temperature not above 20 ° C. increases. To separate the unwanted, non-polar The trihydroxylated compound becomes by-products by column chromatography cleaned. A mixture of the 6jf- and 6ß-hydroxy isomers is obtained, which, if necessary, by thin layer chromatography in the individual Isomers can be separated.

The compound of formula II is then under conventional conditions, i.e. under Use of a carboxylic acid chloride or additive in pyridine solution for formation esterified of the corresponding triest of the formula III. The preferred esterifying agent is acetyl chloride, with the reaction taking about 6 hours Room temperature is carried out. When using a carboxylic acid anhydride, like acetic anhydride, esterification is slower and requires reaction times by 12-18 hours or higher temperatures to achieve complete esterification.

After selective oxidation of trihydroxyacetylenischen compound of formula H with manganese dioxide or 2,3-dichloro-5,6-dicyano-l _t 4-benzoquinone in a suitable inert organic solvent such as chloroform or tetrahydrofuran, to give the corresponding dihydroxy-keto-acetylene compound of formula IV. ' This reaction occurs at room temperature for about 4-6 hours with vigorous stirring and with the use of a large excess of oxidizing agent. Then the oxidizing agent is filtered off and the reaction

409821/1132

by conventional methods, such as evaporation of the solvent and purification of the Back tande s by thin-layer chromatography, isolated.

The compounds of the formula IV are converted into the corresponding 6-alkylated derivatives of the formula V "by reaction with methyl, ethyl or propyllithium or the corresponding alkyl magnesium halides. The reaction takes place at a temperature between 10-30 C ₀ , preferably at room temperature using an excess of about 2-10 molar equivalents of alkylating agent per mole of starting material, preferably about h molar equivalents, in a suitable inert organic solvent, * especially an ethereal solvent such as diethyl ether, tetrahydrofuran, etc., _f for a period between about 30 Minutes to 2 hours, depending on the temperature used. The course of the reaction can be followed by thin-layer chromatography. The product is added in the usual way, for example by diluting with water, extraction with an organic, water-immiscible solvent and evaporation of the latter under vacuum low temperature r, be isolated from the reaction mixture; this is followed by purification by thin-layer chromatography and yields a mixture of the 6 [alpha] -hydroxy-6 [beta] -alkyl and 6 [beta] -hydroxy-6g (-alkyl compounds of the formula V.

Then the compounds of formula V via the formation of the lithium salts and subsequent reaction with a carboxylic acid chloride in pyridine solution to form the corresponding triester of the formula VI in admixture with the diveresterified Compound of formula VII esterified, which are separated by chromatographic methods. The compounds of the formula V are thus left in Room temperature with at least 3 molar equivalents of methyl lithium in Diethyl ether solution for a period between 1-5 hours, preferably about 3 Hours, react, whereupon you get excess acyl chloride, especially acetyl chloride and pyridine, adds; the reaction mixture becomes the 'achievement

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the esterification for a few hours, preferably about 12-18 hours, at room temperature held. Then the esterified products in the usual way, preferably by diluting with water, extraction with a water-not miscible solvents, evaporation and separation of the tri- and diesterified compounds of the formula VI and VII by chromatography, isolated from the reaction mixture.

Those substituted or unsubstituted at C- ^ t- and unsubstituted at C-6 Allen compounds of the formula VIII (R = H, Me, Et or Pr; R = H) can by reacting a triacyloxyacetylenic compound of formula III with a lithium dialkyl copper reagent. The reaction takes place under an inert atmosphere, i.e. under argon or nitrogen, in an ethereal solvent. Dialkyl copper reagents are used in which the alkyl parts are the same, each alkyl group having 1-3 carbon atoms contains, such as lithium dimethyl copper, lithium diethyl copper and lithium dipropyl copper, especially lithium dimethyl copper. These reagents can be obtained by reacting cuproiodide with an alkyllithium in diethyl ether Solvents are prepared (see e.g. J. Am. Chem. Soc., 91, 3289 (1969)).

In this conversion, the reaction conditions and the amount of lithium dialkyl copper used determine the product obtained. The reaction therefore takes place at very low temperatures, ie around -50 ° C. down to -78 ° C. for about 3-7 hours using k molar equivalents of dialkyl copper reagent, in particular lithium dimethyl copper as reagent, then the alienic compound unsubstituted at C-4 and C-6 is obtained (VIII; R and B? = H). The reaction can be followed by thin layer chromatography; at temperatures around -70 ° C. it is complete within about 5 hours. If the reaction takes place at about 0 ° C. for the same duration, but using only about one molar equivalent of the organocopper reagent, then the 4-alkyl-

409821/1132

substituted allenes (VIII; R = Me, Et, Pr; R * = H) in which the alkyl group corresponds to the alkyl group of the reagent.

In any case, the allenic compounds are made according to the usual methods, e.g. dilution with ammonium chloride solution, extraction, evaporation of the solvent and purification by chromatography, isolated from the reaction mixture, avoiding a temperature above room temperature.

If the reactions described above take place with a lithium dialkyl copper on the 6-alkyl triesters of the formula VI, the corresponding 6-alkyl- or 4-, 6-dialkylallenes of the formula VIII (R = H, Me, Et, Pr; R ⁵ =) are obtained Me, Et, Pr), the 6-monoalkylated compounds being formed when the reaction with about K molar equivalents of dimethyl copper as a reagent takes place at about -70 ° C .; the dialkyl derivatives are obtained by using about 1 molar equivalent of the organocopper reagent at about 0 ° C., as has already been described for the 6-unsubstituted compounds.

Then the acyloxy groups in all allenic compounds of the formula VIII under alkaline conditions using a dilute solution of an alkali metal hydroxide or carbonate in a lower aliphatic Alcohol is hydrolyzed at room temperature or below for a time sufficient to complete the reaction, which is between about 12-24 hours. The preferred reagent used is anhydrous (calcined) potassium carbonate using methanol as a solvent at a reaction time from about 6-18 hours, after which the corresponding dihydroxy compound of Formula IX.

After oxidation of a dihydroxy compound of the formula IX with chromium trioxide, being in particular the stoichiometric amount of an 8N solution of chromic acid is used in acetone solution in the presence of sulfuric acid (Jones' reagent), the corresponding keto acid derivative of the formula X is obtained, whose

4Q982171132

Tetrahydropyranyioxy groups under mild acidic conditions to form the prostrienoic acid compounds of the formula XI, e.g. racemic or individual antimers ^ keto-lia ^ iSJt-dihydro ^ prosta ^. SflS-trans-trienoic acid and 9-ketol ^ f-hydroxyprosta- ^ f. SilS-trans-trienoic acid, are hydrolyzed; Furthermore, the 4- or 6-methyl, ethyl or propyl and 4-, 6-dialkyl derivatives of the same can be obtained in which the alkyl groups are identical or different, and the C-20 nor- or bis-nor- compounds' or the C-20 alkylated derivatives thereof. This hydrolysis is carried out using a weak acid such as acetic acid, oxalic acid, tartaric acid, etc., in the presence of water. Usually the crude compound of Formula X is dissolved in an organic water-miscible solvent such as tetrahydrofuran, dioxane, etc., prior to adding the acid reagent. The reaction takes place at a temperature between 20-50 ° C. for a period of about 4-18 hours, depending on the temperature used. The preferred reagent is aqueous acetic acid at a concentration of $ 40-80. It is particularly useful to use a 65 * 35 mixture of acetic acid and water; however, other concentrations can also be used.

By reacting the alien diacyloxy compounds of the formula VIII with 1.1 molar equivalents of anhydrous potassium carbonate in methanol solution about OC. the primary acyloxy group is selectively saponified. This selective Hydrolysis can be followed by thin layer chromatography. Usually it is completed in about 90 minutes to about 2 hours. The compounds of the formula XII thus obtained are in the already for the dihydroxylated Allene described manner oxidized with 8N chromic acid and provide the corresponding Carboxylic acid, i.e. the compound of formula XIII. "The protecting groups are in turn hydrolyzed in the manner described above, i. the acyloxy group is formed under alkaline conditions using preferably anhydrous potassium carbonate in methanol at room temperature

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or below hydrolyzed and yield the compounds of the formula XIV in which the tetrahydropyranyloxy groups are cleaved off by simple acid treatment using, in particular, 65% aqueous acetic acid. We get the Trihydroxjrprostatriensäurederivate the formula XV, for example 9ei, IU, 15A ^T rihydroxyprosta- ⁱ i- _{1 5)} 13-trans-trie acid and ° Wi> 15 <(- Dihydroxyprosta- ^/ + 5 "13-trans-trie acid , the k- or 6-methyl-, -ethyl- or -propyl- and the ^, 6-dialkyl derivatives thereof, in which the alkyl group can be the same or different, ₉ as well as the C-20-nor or -bis-nor compounds or the C-20 alkylated derivatives thereof.

To achieve the 9ß-hydroxy isomers of the compounds of formula XIi is a Compound of formula XI esterified in the usual way with ethereal diazomethane, and the methyl ester thus obtained is combined with sodium borohydride in one lower aliphatic alcohol, such as ifebhanol or ethanol, at around room temperature Reduced for a duration of about 30 minutes to an hour, whereby a mixture of the corresponding 9 @ C ~ wd 9ß-hydroxy compounds obtained which are separated by chromatography on silica gel. So one obtains about the same amount of each isomer o the methyl ester group can by chemical or enzymatic processes, as described in more detail below are described, are hydrolyzed.

The new prostaglandin derivatives, which are further substituted at C-15 by a methyl, ethyl or Proßrl group, can be prepared by a process illustrated by the following reaction scheme:

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235532A

O -

(M

409821/1132

(XXIV)

' ₅ > C = C = C

(XXV)

_ 22 -

(XXIII)

235532A

.COOCH

(XXVI)

COOH

(XXVII)

The above formulas have R, R, R, R _1, R and η as already stated

Meaning;

R represents hydrogen or methyl;

R means hydrogen or trimethylsilyloxyj

R 'represents hydrogen or trimethylsilyl; and TMS means trimethylsilyl (i, with the proviso that when R "j in <is (position, bonded to the same carbon atom as R hydroxy group in .beta.-position, and when R is in .beta.-position, to dassel dene Hydroxyl group in ((position.

when R is in the ß-position, which is bonded to the same carbon atom as R

4 0 9 8 2 1/113 2

In carrying out the above method, a compound of the formula XIVA (racemic mixture or individual antimers) in which the. Hydroxyl group in the C-15 position in the ^ (- and / or ß-configuration, the ß-isomer according to the above process (I to VIII - ^ XII -> ■ XIV), but starting from the corresponding 3 "ß- Tetrahydropyranyloxyisomers of the compound of formula I had been prepared, converted into an alkyl ester, preferably the methyl ester, by reaction with diazomethane in ether solution, whereupon the tetrahydropyranyloxy groups present with 65 % aqueous acetic acid in the manner described above to give the corresponding compound of formula XVI (fi = Me), in which the hydroxy group at C-9 is in the "C configuration". The 9β-Hydroxy isomers of the compounds of the formula XVI are obtained from compounds of the formula XI or the 15β-hydroxy isomers thereof via esterification with diazomethane and reduction of the 9-keto group in the manner described above A compound of the formula XVI is then selectively treated at C-15 with excess manganese dioxide or 2g3-dichloro-5 ₉ 6-dicy an-l ₉ 4-benzoquinone in a suitable inert organic solvent such as chloroform, tetrahydrofuran, dioxane, etc ", oxidized to form the corresponding 15-Ket © compound of formula XVII. If manganese dioxide is used as the reagent, this reaction takes place at room temperature for a period of about 18-40 hours with vigorous stirring, chloroform or tetrahydrofuran being preferably used as the solvent. The oxidizing agent is added in batches at intervals of 4-6 hours. If the oxidation using 2 _t 3-dichloro-59 6-dicyano-l, 4-benzoquinone as a reagent, the reaction is preferably performed at a temperature above room temperature, ie, at about 40-50 C _{e 9} particular with dioxane as solvent for a period of around 14-20 hours, preferably about 18 hours. In each case, the course of the reaction can be determined by thin-layer chromatography or periodic determination

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of the UV spectrum can be monitored. When the reaction is complete, it becomes the oxidizing agent filtered off and the reaction product in the usual manner, e.g. by evaporating the solvent and purifying the residue by thin layer chromatography or chromatography on Florisil, isolated.

The compounds XVII are then converted into the corresponding Mono- or ditrimethylsilyl ethers of the formula XVIII converted (cf. e.g.

"Silylation of Organic Compounds", Pierce Chemical Co., Rockford, 111. (I96B)). This reaction is expediently carried out using a mixture of hexamethyldisilazane and triraethylchlorosilane or N-triraethylsilyl diethylamine as the etherifying agent.

"After" reaction of the trimethylsilyloxy compound with a slight molar excess an alkylltihiuras or alkylmagnesium halide, in particular Methyl, ethyl or propyllithium or methyl, ethyl or propy! Magnesium bromide are used as reagents, the corresponding 15? -alkyl-15 I -hydroxy compounds of the formula XIX are obtained. In the preferred

■ c
Execution forms the reaction is carried out using preferably 1.1-1.2 molar equivalents of alkyl lithium or 6-12 molar equivalents of the alkyl magnesium halide per molar equivalent of starting compound with ether or tetrahydrofuran as solvent at a temperature between -78 ° C. and room temperature for a period of around 2-10 hours under an inert atmosphere, preferably argon. The silyloxy groups of the crude mixture of alkylated compounds are instantly hydrolyzed to yield the compounds of Formula XX. This hydrolysis is carried out according to known processes for converting silyl ethers into alcohols, preferably by dissolving the compound of the formula XIX in a mixture of a lower aliphatic alcohol and water, for example 5O- 8O # aqueous methanol or ethanol, the solution for a period of about ^{Is kept at a temperature between 0 °} C. and room temperature for 18 hours to a few days; the response time depends on the

409821/1 132

Temperature at which the hydrolysis takes place. This hydrolysis can optionally can also be carried out in the presence of a small amount of an organic or inorganic acid or in the presence of carbon dioxide, which accelerates the cleavage of the trimethylsilyloxy groups.

The mixture of 15 ^ r-hydroxy-15ß-alkyl and 15ß-hydroxy-15p (-alkyl compounds the formula XX "is separated in this stage by thin layer chromatography, and the methyl ester group in the individual isomers is in turn through chemical or enitymatic process saponifies and delivers the appropriate 15 ^ -hydroxy-15ß-alkyi- and 15ß-hydroxy-15e (-alkyl-prostatrienoic acid of the formula XXI :.

If this hydrolysis is done chemically, then the alkyl ester compound will be of the formula XX in a lower aliphatic alcohol such as methanol or. Ethanol, dissolved and.with an aqueous solution of an alkali metal carbonate, such as sodium or potassium carbonate, at a temperature above room temperature, e.g. by about 30-50 ° C., preferably at about * tO C, for the duration of treated for about 12-20 hours, preferably about 16 hours, and so after acidification provides the corresponding prostrienoic acid compound of the formula XXI. This hydrolysis is preferably carried out under an inert atmosphere, i.e. nitrogen or argon.

The compound XX can also be obtained by using enzymes in aqueous solutions be hydrolyzed. A commercially available raw pancreatic hydrolysis is preferably used for this enzymatic hydrolysis. Lipase ("Sigma Steapsin") » however, other enzyme systems can also be used which are suitable for the hydrolysis of compounds which are unstable to alkaline or acidic conditions are known. Other lipases from bacterial sources can also be used can be used, e.g., those from the supernatant fluid of a Corynebacterium acnes culture, or a lipase known to be

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it acts on water-insoluble esters of long-chain fatty acids (cf. L.Sarda et al. _r "Biochem.Biophys. Acta" 23-264 (1957) or baker's yeast (cf. CJ. Sih et al, JCSChem.Somm. 2 ^ K) (1972) ).

The hydrolysis of the compound XX with the crude pancreatic lipase can be carried out in a buffered aqueous solution containing sodium and calcium chloride at a neutral or almost neutral pH value at a temperature between 22-30 C, preferably about 25-27 ° C, be carried out, the pH of the reaction being adjusted to 7 _t 2-? t ^ by adding, for example, a dilute sodium hydroxide solution at intervals. The compound of the formula XX is dissolved in the previously prepared, buffered aqueous lipase solution by sonication at about 37 ° C., about 0.5-1 ecm of lipase solution per mg of substrate being used. The methyl ester group is easily hydrolyzed in a short time, that is, from 5 minutes to an hour. The course of the reaction can be followed by thin-layer chromatography; After the hydrolysis has ended, the free acid can be removed by conventional methods, e.g. acidification with a dilute acid solution, e.g. with dilute hydrochloric acid, extraction with a water-immiscible solvent such as diethyl ether, ethyl acetate, chloroform, methylene chloride, etc., evaporation of the solvent and purification of the residue by column, thin layer or liquid chromatography, can be isolated from the reaction mixture. Good results in the separation of the acid XXI from the lipase have been achieved by column chromatography on Florisil.

By using the carboxylic acid function of the compounds of formula X or of 15β-Tetrahydrop5rrany "loxyepimeren (both represented by Formula XA) with an ethereal solution of diazomethane and subsequent hydrolysis of the tetrahydropyranyloxy functions present in the molecule with aqueous acetic acid in in the manner described above and protection of the 9-keto group as an oxime according to known methods Process, i.e. by reaction with hydroxylamine hydrochloride in aqueous Methanol and in the presence of sodium acetate at room temperature for about

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The corresponding compound of the formula XXlI is obtained for 16-2A hours. This compound is then oxidized with manganese dioxide or 2 _f 3-dichloro-5,6-dicyan-l, * J-benzoquinone in the manner described above (cf. preparation of compound XVII) and gives the corresponding 15-keto compound of formula XXIII .

By reacting a compound of the formula XXIII (R = hydroxy) with a Silylating agents, especially using a mixture of hexamethyldisilazane and trimethylchlorosilane or N-trimethylsilyldiethylamine as Reagent, the corresponding trimethylsilyloxy derivative of the formula is obtained XXIV.

1"

Treatment of compound XXIII (R = H) or compound XXIV with a slight molar excess of alkyl (e.g. methyl, ethyl or propyl) lithium or the corresponding alkyl magnesium halide, the corresponding 15 | -alkyl-15 4-hydroxy compound of the formula XXV is obtained. This reaction is preferably carried out in ether or tetrahydrofuran solution, preferably using of 1.1-1.2 molar equivalents of the alkyl or 6-12 molar equivalents n of the alkyl magnesium halide per molar equivalent of starting compound. The reaction takes place at a temperature between -78 ° C. and room temperature for a period of 2-10 hours under an inert atmosphere »

The mixture of 15o6-hydroxy-15ß-alkyl and 15ß-hydroxy-15oC-alkyl compounds is separated into the individual isomers by thin layer chromatography (with prior hydrolysis of the trimethylsiüyloxy group, if present, with aqueous methanol), whereupon the oxime to form the 9-keto function hydroüy ^ is sated; in this way the separated 9-keto-15o (-hydroxy-15β-alkyl- and 9-keto-15β-hydroxy-15 _i ^ -alkylprostatrienoic acid ester compounds of the formula XXVI are obtained. Deoximation takes place under mild conditions, for example by the method in J. Am . Chem. Soc, 92, 5276 (1970) or J. Am. Chem. Soc, 93, 4-918 (1971) and the literatures cited there.

409821/1132

"The first-mentioned process takes place with conversion of the oxime into the O-acetate derivative and subsequent reaction with excess chromoacetate in 90% aqueous tetrahydrofuran, at least 2 molar equivalents being used, at a temperature around 25-65 ° C. for about 10-24 hours.

The second method involves treating the oxime with thallium (III) nitrate using about 1-1.1 molar equivalents of the reagent per mole of starting compound. The reaction takes place at room temperature or below for a short time around 5-30 minutes in an inert organic solvent? then the precipitated thallium (l) nitrate is filtered off and the fiI-tat is briefly treated with dilute acid to decompose the nitrosocompound. According to the invention, this reaction is carried out in methanol solution at about 20 ⁰ C. using aqueous acetic acid to decompose the Nitrosozwischenpröduktes. ..

The hydrolysis of the oxime can also be carried out using titanium trichloride according to "Tetrahedron Letters" 195, (1971).

1 "The compounds of formula XXVI (in which R = H) are also made by Oxidation of the compounds of formula XX (in which R = H) with chromium trioxide-dipyridine complex (manufactured according to "Tetrahedron Letters, 3363 (I968)) obtain.

1 "The compounds of formula XXVI (in which R = hydroxyl) are also by treating the compounds of formula XX (R = hydroxyl) according to the method in J.Am.Chem.Soc, 9 ^, 3651 (1972), namely by selective silyly

1 ″ on the H position of the compound XX (R = hydroxyl), oxidation with Collins ¹ reagent and subsequent hydrolysis with aqueous methanol containing a sparing acetic acid; in the compounds of the formula XXVI obtained, R ¹ ″ stands for Hydroxyl.

409821/1132

The hydrolysis of the oxime can also be carried out with a mixture of the 15 "(- and 15 [beta] -hydroxy isomers take place, the individual isomers then being separated by thin layer chromatography.

The alkyl ester group in the compounds of formula XXVI is chemical or enzymatic processes, e.g. by reaction with potassium carbonate in aqueous Methanol or hydrolyzed with a crude pancreatic lipase, as already described in detail for the ° V- 'hydroxylated compounds Wuräe; in this way the free acids of the formula XXVII are obtained.

The hydroxyl groups in compounds of formulas XI and XV and the secondary ones Hydroxyl groups in compounds of the formulas XXI and XXVII can be used in the customary Wise esterified or etherified and produce mono-, di- or tri-esters or mono-, di- or tri-ethers, depending on the particular prostaglandin derivatives. The esterification takes place by reacting the hydrolyzed compound with a carboxylic acid anhydride or a? -Chloride with less than 12 carbon atoms in pyridine solution.

The etherification can also be carried out by customary methods, such as, for example, reaction with dihydropyran, dihydrofuran or ^ -methoxy-5,6-dihydro-2H-pyran in an inert solvent such as methylene chloride or benzene, and in the presence of an acid catalyst, for example p -Toluenesulfonic acid, p-toluenesulfonyl chloride, to form the tetrahydropyran-2 ^l -yloxy, tetrahydrofuran-2 ¹ -yloxy or 4 × ¹ -methoxytetrahydropyran-V-yloxy derivatives.

Although the esterification and etherification reactions usually occur with one An excess of esterifying or etherifying agent is preferred at least 1 molar equivalent of this reagent is used per hydroxyl group present in the starting compound.

4 0 9 8 21/113 2

The alkyl esters of the carboxylic acid function can be prepared in a conventional manner by treating the free acid with excess diazoalkane, such as diazomethane, diazoethane or diazopropane, in ether or methylene chloride solution or by reaction with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature.

The salt derivatives of the prostanoic acids of the invention can be prepared by treating the corresponding free acids with about one molar equivalent of a pharmaceutically acceptable base per molar equivalent of free acid. Suitable pharmaceutically acceptable bases include, for example, sodium hydroxide, trimethylamine, triethylandn, tripropylamine, β- (dimethylamino) ethanol, B- (diethylamino) ethanol, arginine, lysine, caffeine, procaine, etc. The reaction is usually carried out in aqueous solution, alone or in combination with an inert, water-miscible organic solvent at a temperature of about 0-3O ⁰ C, preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, dioxane, etc. In the production of divalent metal salts, for example the calcium or magnesium salts, the free acid as starting material is treated with at least half a molar equivalent of the pharmaceutically acceptable base.

If the above procedures are successful using racemic mixtures as starting materials, then each intermediate and final product is a racemate; on the other hand, if one assumes an R-antimer, then every intermediate and end product is an R-antimer.

The compounds of the formula I which are used as starting materials in the above processes can be obtained according to the following sequence scheme :

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£ 355 324

409821/1132

CO

Oil

CMI St.

CO

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- Vf-

ml

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In the above formulas

R represents methyl or benzyl;

IT means hydrogen or p-phenylbenzoyl; .

R ^ ¹ represents p-phenylbenzoyl;

M means sodium or thallium; and

η has the meaning already given.

In the above reaction scheme, the compounds of the formula (Q) to ( IA ) ind (^ A) to (BB) in the form of racemates or as the corresponding individual

Antimers, in particular R-Atimers, are present. The l'R antimers of 7A (R = benzyl) and (8) were described in J.Am.Chem.Soc., 93, 1 ^ 91 (1971), while the l'R antimers of TA (R ⁸ = Methyl) in J. Am. Chem. Soc, 92, 397 (1970).

In short, the process for preparing the starting materials comprises the reaction of cyclopentadienyl sodium or cyclopentadienyl thallium

(1) (obtained by reaction of cyclopentadiene with sodium hydride or in the presence of aqueous Thallosulf at van potassium hydroxide /j.Am.Chem.Soc., 93 1489 (19? 3) 7) with a slight excess of chloromethyl methyl ether or in tetrahydrofuran at about Ghlormethylbenzyläther -55 C., whereby one * - g

5-methoxymethyl-1,3-cyclopentadiene (25 (R = methyl) or 5-benzyloxymethyl- ! ^ - cyclopentadiene ^), (R = benzyl) obtained with excess 2-chloroacrylonitrile (about 5 molar equivalents) in the presence of cuprifluoroborate were subjected to a Diels-Alder reaction as a catalyst and a mi

The endo-exo cyanonitriles of the formulas (J) and (W) (R = methyl or benzyl) were obtained. This mixture of the sterically isomeric nitriles was treated with potassium hydroxide in diethyl sulfoxide and gave the anti-bicyclic ketones of the formula (J5), ie 7-syn-methoxymethyl-2-norbornen-5-one (R ⁸ = methyl) or 7-syn-benzylo : jqmethyl-2-norbornen-5-one (R ^{8 =} benzyl), the

409821/1132

after reaction with a slight molar excess of ra-chloroperbenzoic acid a selective in methylene chloride in the presence of sodium bicarbonate Baeyer-Villiger oxidation with formation of the corresponding lactone (6), namely

K ft

borrowed 2-0xa-3-oxo-A -8-syn-methoxymethylbicyelo- (3.2.1) -octene (R = methyl) and 2-0xa-3-oxo-Ar-8-syn-benzyloxymethylbicyclo- (3.2.1 ') -octane (R = benzyl) resulted. The saponification of the above lactones of the formula (6) with 2.5 equivalents of sodium hydroxide in aqueous methanol, 'subsequent neutralization with carbon dioxide and treatment with 2.5 equivalents of aqueous potassium triiodide solution at 0-5 ° C gave the corresponding hydroxy-iodolactones of the formula ( £}., Namely (2 ' _e i, 4 ^l oi-dihydroxy-3 ^l ß-iodo-5'ß-methoxymethylcycopent-l ^| efyl) -acetic acid-l _t 2'-lactone (R ⁸ = methyl; R ⁹ = H) and (2 ' _oi , if' _e <-dihydroxy-3 ^r ßjodo ^ 'ß ^ benzyloxymethylcyclopent-l' ^ - ylj-acetic acid-i, 2'-lactone (R - benzyl; R = H), the were esterified under customary conditions with p-biphenylcarboxylic acid in pyridine and gave the corresponding p-phenylbenzoates (Z 'R ⁼ p-phenylbenzoyl).

These compounds were made using tri-n-butyltin hydride in the presence catalytic amounts of azobisisobutyrbnitrile in a benzene solution Subjected to diiodination and after cleavage of the 5'ß-benzyloxymethyl or 5'ß-methoxymethyl group the hydroxymethyl compound (8),

The benzyloxymethyl group was split off by hydrogenolysis in the presence of palladium-on-charcoal and perchloric acid as a catalyst in a suitable organic solvent; the methoxymethyl group was formed by reaction with boron tribromide in methylene chloride at a temperature between about -78 ° C. hydrolyzed to O ^{0 C.} - ·

409021/1132

As mentioned, the I ¹ R antimer of (8), ie l'R- (2 '" ^{(-hydroxy-4 l} _e (-pphenylbenzoyloxy-SVß-bydroxymethylcyclopent-l' eC-ylJ-acetic acid-l _f 2 · -Lactone, according to the method in J.Am.Chem.Soc., 93. 1A-91 (1971) by basic cataly-

R.
Sated hydrolysis of the lactone (6) (R = benzyl) to the corresponding hydroxy acid, separation of the hydroxy acid as (+) - amphetamine salt and subsequent iodolactonization of the separated l'R-antimer, esterification with p-phenylbenzpyl chloride, deiodination with tri-n-butyltin hydride and Hydrolysis of the benzyloxymethyl group obtained.

The oxidation of a raceric hydroxymethyl compound (8) or the l'R-antimer with chromium trioxide-dipyridine complex (prepared according to "Tetrahedron Letters" 3363 (1968)) in methylene chloride at about 0 ° C. provides the aldehyde (j?), (racemic mixture or R-antimers), which is converted stereospecifically into the corresponding trans-enone lactone of the formula (IQ) without purification. This conversion takes place by a modified Wittig reaction with treatment of the aldehyde of the formula (9) with the sodium anion of a dimethyl-2-, oxo-n-alkyl phosphonate from Foiroel:

CH (CH _? ) -C-CH ₉ -P- (OCHJ ₉ .

in which m stands for an integer with a value from 2 to 9, in dimethoxyethane solution. The following reagents are used: dimethyl 2-oxopentylphosphonate, dimethyl 2-oxohexylphosphonate, dimethyl 2-oxo-heptylphosphonate, dimethyl-2-oxo-octylphosphonate, dimethyl-2-oxononylphosphonate, dimethyl-2-oxodecylphosphonate, dimethyl-2-oxodecylphosphonate, and dimethyl 2-oxododecyl phosphonate. These reagents are expediently prepared according to the method described in J.Am.Chem.Soc., 88 565 ^ (1966) from dimethyl-öt-läthioraethanphosphonat and a methyl _r or ethyl ester of an n-alkanoic acid with ^ - 10 carbon atoms, such as uryl n-butanoate, methyl n-hexanoate and ethyl n-deeanoate, produced, The reaction takes place at temperatures around 0-40 ° C, preferably at

A09821 / 1132

- - 37 -

at room temperature or below, for about 1-Λ hours under an inert Atmosphere with at least one molar equivalent of reagent per mole of aldehyde, preferably 1.2-2 moles.

The treatment of the racemic enone (10) or the 1'R-antimer with excess zinc borohydride in dimethoxyethane at room temperature for about 1 hour gives a mixture of the corresponding ei- and ß-hydroxy compounds, which can be separated by thin layer chromatography on silica and the desired ^ -hydroxylated compound give in pure form (11, R = p-phenylbenzoyl), the p-phenylbenzoyloxy group is then. hydrolyzed under alkaline conditions, preferably with anhydrous potassium carbonate in methanol, and the diol is etherified with dihydropyran in methylene chloride solution and in the presence of p-toluenesulphonic acid and gives the bis-tetrahydropyranyloxy compound (J ₁ E) (racemic mixture or l'R- Antimers), which after reduction with diisobutylaluminum hydride in toluene at about -60 ° C. the lactol of the formula IA) gives, for example ^ '^ - hydroxy-Λ'ίί-tetrahydropyranyloxy-5 ¹ ß- (3 "e (-tetrahydropyranyloxyoct-1" (t) -en-1 "-yl) -cyclopent-10i -y ^ -acetaldehyde-l ^ '- hemiacetal (IAj η - k) _t / ^' af-Hydroxy- ^ ytetrahydropyranyloxy-5 ¹ ß- (3 "« i-tetrahydropyranyloxyhex-l "(t) -en-1" -yl) -cyclopent-l'ei-ylj-acefaldehyd-l ^ '- hemiacetal (IA, η = 2) and / ^ y-hydroxy- ^ V -.-. tetrahydropyranyloxy-5' ß- (3 "* - tetrahydropyrany loxytridec-1 "(t) -en-1" -yl) cyclopent-l'ji-ylJ-acetaldehyde-l.Z'-hemiacetal (IA; η = 9) or the l'R-antimers thereof.

By reacting a racemic hydroxyiodolactone of the formula (^ A) or the Ϊ'R antimers of the same with freshly distilled phosphorus oxychloride in Pyridine solution, first at £> ° C. and then at room temperature the corresponding dehydrolactone compound (racemic mixture or l'R-antimers) of the formula (1/3).

409821/1132

The l'R antimers (TA.), Namely l'R

8 oxymethylcyclopent-l'ei-yD-acetic acid-.l.a'-lactone (ΤΑχ R = benzyl) and 1 "R- (2 '^ Λ' X-dihydroxy-3 ¹ ß ~ jado-5 ^! Ss-methoxymethylcyclopent -l ■, (- yl) -acetic acid-

1,2 "-IaCtOn (^ A; R = methyl) is obtained by the processes described in J.Am.Chera.Soc. 93t 1 ^ 91 (1971) and ibid. 92, 397 (1970) by base-catalyzed hydrolysis of the corresponding lactones (6) into the hydroxy acid, separation of the hydroxy acid as (+) - amphetamine salt for the benzyloxymethyl compound or as (-) - ephedrine salt for the methoxymethyl compound and iodolactonization of the corresponding l'R-antimeric acid. To avoid hydrogenolysis of the allylic hydroxyl group During the reduction of the double bond, the lactone group in a compound of formula (13) is opened by treatment with 2N methanolic sodium hydroxide, before being carefully neutralized to pH 6 with 3N hydrochloric acid in ethyl acetate; this gives the hydroxy acid (14 ) (Racemic mixture or l'R-Antimerea). The catalytic reduction of this hydroxy acid with Raney nickel in methanol solution and subsequent brief treatment with acid yields the corresponding lactone (1J5), i As according to the process described above, ie hydrogenolysis in the case of the benzyäoxymethyl compound (ij5; R = benzyl) or by reaction with boron tribromide for the methoxymethyl derivative (JJJ; R = methyl), is hydrolyzed into the corresponding hydroxymethyl compound (16) (racemic mixture or l'R-antimers).

Then the hydroxymethyl compound of formula (16) is converted into the desired lactol

-Dipyridinium complex of formula (JEB) converted 'by oxidizing with chromium trioxide / to the aldehyde, the aldehyde with the sodium anion of a dimethyl-2-oxo-n-alkylphosphonate condensed of the type mentioned above to the corresponding trans-enone lactone, the Keto group selectively reduced with zinc borohydride and fine mixture of e (- and ß-hydroxy isomers obtained; these are determined by thin layer chromatography

A09821 / 1132

■ - 39 -

separates, the 3 "cl-hydroxy compound is etherified with dihydropyran and the Lactone ring reduced with diisobutyl aluminum hydride, as already mentioned above for converting a compound (8) into a compound (IA). described has been,

. The compounds, esters and salts according to the invention exhibited pwstaglandin-like properties biological activities and are therefore suitable for the treatment of "'Humans and animals in all cases where the use of prostaglandins is indicated is. The compounds, esters and salts of the invention are bronchodilators; they are therefore suitable for the treatment of bronchial spasms in humans and animals or in all cases where strong bronchodilators are indicated. These compounds are also useful for combating or attenuating of hypertension in humans and animals, they continue to have a dampening effect on the central nervous system and are valuable as sedatives » Furthermore, the compounds can cause labor during pregnancy initiate and induce the menses to correct or reduce menstrual abnormalities.

The compounds and / or salts according to the invention can be used in many different ways. which dosage forms, alone or in combination with other pharmaceutically acceptable drugs, in the form of pharmaceutical, oral or parenteral Administration or inhalation administered in the case of bronchodilators will. Usually the compounds are administered as pharmaceutical preparations, which essentially consist of the compounds according to the invention and / or Salts and a pharmaceutical carrier. The pharmaceutical carrier can be a solid or liquid material or an aerosol in which the Compound and / or the salt is dissolved, dispersed or suspended, and it can optionally contain small amounts of preservatives and / or pH buffering agents contain. Suitable preservatives include, for example, benzyl alcohol

409821/1132

- «ο - 235532Λ

etc., while suitable buffering agents include sodium acetate and pharmaceutical Are phosphate salts, etc.

The liquid preparations can e.g. in the form of solutions, emulsions, suspensions, Syrups or elixirs are present. The solid preparations may be in the form of tablets, powders, capsules, pills, etc., preferably in a unit dosage form for easy administration or in precise doses. Suitable solid carriers include, for example, pharmaceutical starches, lactose, sodium saccharin, Sodium bisulfite, etc.

For administration by inhalation, the compounds and / or salts can be used as Aersosol composed of the compounds or salts in an inert propellant with a cosolvent (such as ethanol) and, if necessary, with preservatives Buffer agents are administered. More general information on the administration of aerosols by inhalation can be found in the U.S. Patents 2,868,691 and 3,095,355. '

The compounds of the invention are usually used in doses of about 0, Oi-: 10 mg administered per kg of body weight. The exact effective dose will vary depending, of course, on the mode of administration, the treated Disease and the patient.

The following experiments and examples illustrate the present invention without restricting it. The starting materials and products in experiment 8, Part C, to 18 and Example 1 to 40 are racemates, while the starting materials in Experiment 8 'to 18' and Example IA to kok are the corresponding individual antimeres. All mixing ratios used in relation to liquids are volume ratios. Experiments and examples were repeated where necessary to provide sufficient starting material for the subsequent examples.

409821/1132

V e r s u oh

A. To a solution of 125 g of thallium sulfate and 50 g of potassium hydroxide in 750 1 cc water was freshly distilled with stirring under an argon atmosphere 43 cc Cyclopentadiene was added and the mixture was stirred vigorously for 10 minutes was} the yellow precipitate formed was filtered off, with ice water, Washed methanol and ether and yielded 32 g of cyclopentadienylthallium ml.

B. A mixture of 216.28 g of benzyl alcohol, 61.44 g of paraformaldehyde, 481.6 g of anhydrous Mangesiumsulfat and 1200 cc of methylene chloride was cooled in a dry ice-acetonitrile bath to a temperature between -50 ⁰ C to -55 ° C and the cold solution was saturated with anhydrous gaseous hydrogen chloride while stirring. The reaction mixture was further held for 10 minutes at -5o C. ⁰ to -55 ° C, then the excess hydrogen chloride was eliminated by introducing a stream of nitrogen for 30 minutes. The reaction mixture was filtered and the solid material was washed thoroughly with pentane; the combined filtrates were evaporated at a temperature below 30 ⁰ C. to dryness and yielded an oil which afforded the Chlormethylbenzyläther by distillation under reduced pressure.

£. A suspension of 132 g of cyclopentadienylthallium in 200 ecm of anhydrous ether was heated to -20 ° C. in a dry ice-carbon tetrachloride bath. cooled down. To the cooled mixture, 90 g of chloromethylbenzyl ether were added in 15 minutes with stirring and under an argon atmosphere. The reaction mixture was left at -20 ° C. for 3.5 hours. stirred, then filtered into a cooled previously to -78 ° C filtration flask and washed the solid precipitate with "cold pentane (-78 ⁰ C.).

The filtered solution immediately became a mixture of 216 g of anhydrous »{-chloroacrylonitrile and 30 g of anhydrous cuprifluoroborate, which was previously heated to -78 ° C. had been cooled. The reaction mixture was reduced to half of its original volume at a temperature not above ^{0 ° C.!}

409821/1132

. evaporated and the concentrate was stirred at ⁰ ° C. for k8 hours. The reaction mixture was then poured into 200 ecm saturated sodium chloride solution and extracted 3 times with ether. The combined extracts were washed twice with 200 ecm saturated sodium carbonate solution each time and twice with 200 ecm saturated sodium chloride solution each time, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained was purified by filtering through 100 g of silica gel using benzene as the eluent ; this gave pure 2-chloro-2-cyano-ör-7-syn-benzylox3rmethylbicyclo- (2 _e 2.1) -heptane (mixture of (JJ) and (jj); R ⁸ = benzyl).
Attempt 2

To a slurry of 7 ^ »1 g cyclopentadienes! Thallium in 100 cc of anhydrous ether under an argon atmosphere in a Troekeneis-Tfefcrachlorkohlenstoff bath on. 2O ⁰ C. to-22 ⁰ C. (internal temperature) was, were within was 15 minutes was added 20.13 g of chloromethyl methyl ether, followed by stirring the slurry for 7 hours at -2O ⁰ C to -22 ⁰ C.. Then the reaction mixture into a precooled flask (-70 ⁰ C, Trockenein-acetone) was filtered and the residue washed from thallium chloride 3 times with 100 cc of cold ether (-7O ⁰ C.). The combined filtrate was taken from a dropping funnel with a dry ice jacket to a suspension of 29.65 g of cuprite tetrafluoroborate in 87.5 g of anhydrous o-chloroacrylonitrile, which on OC. was held, added dropwise. After the addition was complete, the mixture was left in the dark at 0 ° C. for 18 hours. touched. Then 100 ecm of saturated sodium chloride solution were added and the reaction mixture was extracted with ether. The ether extracts were washed in succession twice with 100 ecm saturated sodium bicarbonate each time and twice with 100 ecm sodium chloride each time and dried over magnesium sulfate. After evaporation under reduced pressure at room temperature, 2-chloro-2-cyano- 7-synmethoxymethylbicyclo- (2.2.1) -heptane (mixture of Q) and (k) was obtained; R ⁸ ₌ methyl) as a clear, pale yellow oil.

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Attempt 2_ '

To a solution of 100 g of 2-chloro-2-cyano- £ ^ -syn-benzyloxymethylbicyclo- (2.2.1) -heptane in 368 ecm of dimethyl sulfoxide under stirring within 15 minutes under an argon atmosphere, a hot solution of 105 »2 g Potassium hydroxide dripped into 52.6 ecm of water. The reaction mixture was stirred at room temperature for 28 hours, diluted with twice its volume in ice water, and extracted several times with ether. The united organic ex-. tract was washed twice with saturated sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was purified by high vacuum distillation (0.6 mm) and gave 7-syn-benzyloxymethyl-2-norbornen-5-one (J5, R ⁸ = benzyl), which was homogeneous on thin-layer chromatography.

In the above procedure, if 2-chloro-2-cyano-A ^ -7-syn-methoxymethylbicyclo- (2.2.1) -heptane was used instead of 2-chloro-2-cyano-A ^ -7-syn-benzyloxymethylbicyclo- (2.2 , l) -heptane was used, then 7-syn41ethoxymethyl-2-norbornen-5-one (j>, R ⁸ = methyl) was obtained. '

Attempt 4

To a suspension of 55 g of m-chloroperbenzoic acid and 43.5 g of sodium bicarbonate in 57Ω ecm of anhydrous methylene chloride, 57 g of 7-syn-benzyloxymethyl-2-norbornen-5-one were added over the course of 15 minutes with stirring, the temperature increasing to about 25 C. was held. The reaction mixture was stirred for an additional 3 hours and diluted with methylene chloride. The mixture obtained was stirred vigorously with 470 ecm of saturated aqueous sodium sulfite solution, and the organic layer of Tfurde was separated off and washed with saturated sodium sulfite solution. The aqueous phase was extracted with methylene chloride and the combined organic methylene chloride extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure; thus obtained 2-0xa-3-oxo-

& -S-syn-benzyloxymethylbicycio-OelJ-octane as a homogeneous oil (6, R ⁸ = benzyl).

409821/1132

If? -Syn-MethcKyraethyl-2-norbornen-5-one was used instead of 7_syn-Benzyloxyraeü5a-2-norbornen-5-one in the above process, 2-0xa-3-oxo- ₄ ^ ⁵ -8-syn was obtained -methoxymethylbicyclo- (3.2.1) -octane (6, R = methyl).

V e r s- .u. c It 5

To a solution of 60 g 2-0xa-3-oxo - ^ - 8-syn-benzyloxymethylbipjrclo- (3.2.i) -octane in 7® ecm ⁰ C. Methanol was added at O, a solution of 30 g of sodium hydroxide in water 2V7 ecm added and the mixture obtained was stirred at room temperature for 3 hours. Then the methanol was under vacuum at a temperature below 30 ° C. evaporated, it was at 0 ° C. cooled and extracted with ether to eliminate unsaponifiable products. The aqueous pliase was neutralized with carbon dioxide and immediately treated with a solution of 188.1 g of iodine and 369 g of potassium iodide in 275 ecm of water. The reaction mixture was ^{stirred at 0} ° C. for 48 hours and diluted with sodium sulfite solution until it was completely decolorized. The mixture was then saturated with sodium potassium tartrate and extracted with methylene chloride. The organic extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue was crystallized from ßr-methylene chloride and yielded

read pure (2 ^l ^, 4 ^l j { _i -dihydroxy-3 ^l ß-iodo-5 ^l ß-benzyloxymethylcyclopent-l '_< (-yl) -acetic acid-1,2'-lactone (£, R ⁸ = benzyl , R ⁹ = H). '

Starting from 2-0xa-3-oxo-Δ-8-syn-methoxymethylbicyclo- (3.2.1) -octane one obtained (2 ^l ^, 4 '^ - dihydroxy-3'ß-iodo-5'ß-methoxymethylcyclopent- l '^ - yl) .- acetic acid-1,2'-IaCtOi (2, R ⁸ = methyl, R ⁹ = H).
Trial 6

To a solution of 39-5 g (2 ' ₄ f, 4' _l {-Dihydro _X y-3-ß-iodo-5'ß-benzyloxymethylcyclopent-l'.C-yD-acetic acid-l ^ '- lactone in I52 ecm 32.8 g of P-biphenylcarboxylic acid chloride were added to anhydrous pyridine, and the resulting solution was stirred at room temperature for 1 hour, then 9 ecm of water was added and the

409821/113

Mixture stirred for 1 hour to destroy excess reagent. The solvents were eliminated under reduced pressure and the residue was dissolved in 3: 2 methylene chloride-cyclqhexane. The organic solution was washed successively with 10% hydrochloric acid solution, saturated sodium bicaronate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated; so received to '{2' _c ^l-hydroxy-i <- 'e ^{(p-phenylbenzoyloxy-3-iodo-l} ß-5'ss benzyloxymethylcyclopent-l ^ ^l-yl) acetic acid-l, 2 ^I-lactone (£, R = benzyl, R ^ = p-phenylbenzoyl), which can be purified by recrystallization.

Using the same procedure, 2 ^l _e (, 4 ^l ^ -dihydroxy-3 ^l ß-iodo-5 ^l ß-methoxymethylcyclopent-1 '^ -yl) -acetic acid, 1,2-lactone in (2 V -hydroxy-4 '^ -p-phenylbenzoyloxy-3'ß-iodo-5 ^l ß-methoxymethylcyclopent-l ^t U-yl) -acetic acid- ^{1,2 l} -lactone (£,

8 9

R = methyl, R = p-phenylbenzoyl).

Trial 7

To a solution of 61 g (2'et-Hydroxy- ⁱ l- ^l | {-p-phenylbenzoyloxy-3 ^I ß-iodo-5 ^l -ßbenzyloxymethylcyclopent-1 ^ yI) -acetic acid-1,2'-IaCtOn in 610 1 cm of benzene (dried over molecular sieves) 45.25 g of tri-n-butyltin hydride, prepared by the method in iJ.Am.Chem.Soc., 83, 1246 (196I), and 211 mg of azobisisobutyronitrile were added. The mixture was left for 30 minutes, at 50 ° C. stirred, the benzene was removed by evaporation under reduced pressure, the oily residue was dissolved in 1.5 liters of ether and the ethereal solution was washed a few times with 5% aqueous sodium hydroxide solution and then with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo . The residue was chromatographed on 915 g of silica gel, 1: 1 ether-hexane being used as the first eluent to remove non-polar tin by-products. The eluted with ethyl acetate fractions afforded the desired ^(2! El-hydroxy-4 ^I ^ _r p-phenylbenzoyloxy-5 ßbenzyloxymethylcycopent ^l-1 'rf-yl) -acetic acid, 1,2'-lactone.

40 9821 / -1-1 3 2

Similarly, (2 ' _e (-hydroxy-4 ^l _e j; -p-phenylbenzoyloxy-3 ^l ß-iodo-5 ^l -ßmethoxymethylcyelopent-1 ^l ₀ ^ -yl) -acetic acid ~ l _l 2 ^l -lactone in (2'oC-Hydroxy-VQf-pphenylbenzoyloxy-5 ¹ ß-methoxymethylcyclopent-l'oC-yl) -acetic acid-1,2 "-lactone converted.

Trial 8

A. To a pre-hydrated? A suspension of 1 g of 10 # palladium-on-charcoal catalyst in 200 ecm of anhydrous dimethoxyethane was 10 g of (2 · ^ -Ηνατοχν- k. Ι ^ -p-phenylbenzoyloxy-5 'ß-benzyloxymethylcyclopent-l' ef-yl ) -acetic acid-1, 2 'lactone and 1 ecm perchloric acid were added and the mixture was stirred under a hydrogen atmosphere until absorption ceased. Then the catalyst was filtered off and washed with ether. The combined organic filtrates were washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The crystallization of the residue from chloroform gave (2 ^! O (-Hydroxy-4 ^! ^ -P-phenylbenzoyl- axy-5 * β-hydroxymethylcyclopent-1 '^ - yl) -acetic acid, 1-2 ¹ -lactone (JJ).

B ₁ A solution of 15 g (2 ^l _i (-hydroxy-4 ^l Qj-p-phenylbenzoyloxy-5 ^I ß-methoxymethylcyclopent-l '^ - was YLJ-acetic acid-l, 2 · lactone in 190 cc of anhydrous methylene chloride while stirring in a dry ice-acetone bath, cooled to -8 ° C. and treated with 25 ecm boron tribromide. The mixture was allowed to quickly come to 0 ° C. with stirring and kept at this temperature for 50 minutes ecm of ether was added to decompose the excess tribromide, the reaction mixture being kept at 0 ° C. It was then poured into a vigorously stirred slurry of 95 g of sodium bicarbonate in 500 ecm of a saturated solution of sodium potassium tartrate; the organic layer was separated and the aqueous Phase extracted with methylene chloride, the combined organic extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure delivered

409821/1132

(2 'gi-Hydroxy-Λ ty-p-phenylbenzoyloxy-5' ß-hydroxymethylcyc opent-1 'ctf-yl) -acetic acid-! , 2'_lacton which was identical to the product obtained in Part A.

£. To a suspension of 300 g Gelite diatomaceous earth ( dried for 2 hours at 105 ° C.) and 61.5 g chromium trioxide-dipyridine complex (produced according to "Tetrahedron Letters" 3363 (1968)) in 610 ecm anhydrous methylene chloride, which is heated to -5 ° C. Was cooled, 10 g of (2 '^ Hydroxy-V ^ -p-phenylbenzoyloxy-5' ß-hydroxymethylcyclopent-1 'i (-yl) ~ acetic acid-1,2' -.! acton-, in 60 ecm Dissolved methylene chloride, added and the mixture was stirred for a further 10 minutes, the temperature being kept between -5 ° C. and ⁰ ° C. "Then 100 g of sodium bisulfite monohydrate were added and the mixture was stirred for a further 10 minutes, filtered through magnesium sulfate and the solid with Wash methylene chloride, the filtrate being taken up in a flask which had been cooled to -60 ° C. in an ice-cream acetoribath. The combined filtrates were evaporated to dryness under reduced pressure (at a temperature below ⁰ ° C.) and yielded (2 ¹ ^ -hydroxy ^ ¹ e (p-phenylbenzoyloxy-5 ^l-ß formylcyclopent-l '^ - yl). -acetic acid l, 2'-lactone ■ (_ £) as a homogeneous oil experiment 8'

After this. Oxidation process vexi Part C of Experiment 8 xirde, starting from the 1'R-antimer of (8), namely l'Ri ^ '^ - Hydroxy - ^' gg-p-phenylbenzoyloxy ^ 'ßhydroxymethylcyclopent-l'e ^ -yl) - acetic acid - !, 2-lactone (obtained according to J.Ahio Chem. Soc. 93, 1 ^ 91 (1971)), the 1 «R- (2 ' _s (-hydroxy-4 ^! ^ p-phenylbenzoyloxy-5 ¹ i3 -formylcyclopent-l ^ -ylj-acetic acid-l ^ -lactone (l'R-antimers of 2) obtained ^

Attempt 9

A solution of 22 g (2 ^l _i |, ^ ^l _e (-dihydroxy-3 ^l ß-iodo-5 ¹ ß-benzyloxymethylcyclopent- ¹ '^ -yl) -acetic acid-1,2'-IaCtOn in 60 ecm anhydrous pyridine was cooled to 0 ° C. and treated dropwise with stirring with a mixture of 8 ecm phosphoray chloride and 20 ecm pyridine After the addition had ended, the reaction was stirred for 30 minutes at room temperature and the solvent was reduced under reduced pressure

409821/1132

Eliminates pressure. The oily residue was dissolved in methylene chloride and the organic solution washed with 10- $ iger hydrochloric acid solution, again the aqueous phases were extracted with methylene chloride.

Then the combined organic extracts were washed with saturated sodium sulfite solution washed until completely discolored over magnesium sulfate dried and evaporated to dryness under reduced pressure; thus obtained (2 ^ l -hydroxy-5'ß-benzyloxymethylcyclopent-3 '- "- en-l'" <-yl) -acetic acid-1,2 '-

8th
lactone (l ^ _t R = benzyl) as a colorless oil.

If (2Ό (, ^ • ^l efc-dihydroxy-3 ^f ß-iodo-5'ß-methoxymethylcyelopent-1 V-acetic acid-1,2'-laetone, then the (2 '* { -Hydroxy-5 ^l ß-methoxymethylcyclopent-3 ^f -en-l ^l _e ^ -yl) -acetic acid- ^{1,2 I} -lactone (1 ^, R ⁸ = methyl).
Attempt 9 ^l

By using 1'R- (2 ¹ ^, 4 ' ₀ (-dihydroxy-3 ^I ß-iodo-5'ß-benzyloxymethylcyclo pent-l' ^ - yl) -acetic acid-1,2 "-lactone (obtained according to J. Am. Chem. Soc, 93, 14-91 (I97I)) instead of (2 ^l _Q (, ^ ^l _e {-dihydro3qy-3 ^l ß-iodo-5'ß-benzyloxymethylcyclopentl'el-yl) acetic acid ~ 1,2-lactone in the process of Experiment 9, 1'R-hydroxy-5'ß-benzyloxymethylcyclopent-3'-en-1 'cC-yl) -acetic acid-1,2-lactone was obtained

(1'R-atoms of J / 3, R == benzyl),

By using the obtained according to J.Am.Chem.Soc, 92, 397 (I970) l'R- (2 ^f "t, 4 '''-dihydroxy-3'ß-iodo-5' ß-methoxymethyleyclopent-1 ¹ O ^ yI) -acetic acid-1,2 'lactons in experiment 9 one received 1' R- (2 'o (-hydroxy-5 ¹ ß-methoxyme thy Icy clo pent-3'-en-lO (-yl) - acetic acid-1,2'-lactone (l'R-antimers vcn 1 ^, R ⁸ = methyl).

409821/1132

Attempt 10,

A solution of 13 g of (2y-hydroxy-5'ß-benzyloxyraethylcyclopent-3 ^l -en-l ^l «(-yl) -acetic acid-1,2'-lactone in 20 ecm of methanol was cooled to 0.degree. C. and added dropwise treated with a solution of 6.5 g of sodium hydroxide in 63 ecm of water; after the addition was complete, the reaction mixture was stirred for 1 hour at room temperature. The methanol was then eliminated under reduced pressure at a temperature below 30 ° C. and the resulting solution was reduced to 0 ° C. The aqueous phase was carefully acidified with 3N hydrochloric acid at 0 ° C. to a pH of 5-6, then 100 ecm of ethyl acetate were added and the reaction mixture was then added The organic phase was separated off, and the aqueous phase was saturated with sodium chloride, extraction being carried out 6 times with 50 ecm of ethyl acetate each time. The combined extracts were washed with saturated sodium chloride solution, washed over M dried agnesiumsulfat and evaporated to dryness in vacuo. The crystallization of the residue from hexane-methylene chloride gave the pure (2 '_< ^ -hydroxy-5 ^l ß-benzyloxymethylcyclopent-3'-en-l ^l oi-yl) acetic acid (JA, R = benzyl).

Similarly, the (2 ^l ^ -hydroxy-5'ß-methoxymethylcyclopent-3 ^l -enl'K-ylJ-acetic acid-l ^ '-lactone in (2' _e (-hydroxy-5 ^l ß-methoxyme.thylcyclopent -3 ^l -

en-1 '^ - yl) acetic acid (JA, R = methyl).

Experiment 10 »·

According to the procedure of Experiment 10, 1'R- (2 ^l _i (-hydroxy-5 ^l ß-benzyloxymethylcyclopent-3 ¹ -en-1 '^ -yl) -acetic acid-1,2 «-lactone and 1' ^ - (2 ^ -Hydroxy-5'ßmethoxymethylcyclopent ^ '- en-l'ei-ylj-acetic acid-l ^' - lactone in VR- (Z ^ - Hydroxy-5 ¹ ß-benzyloxymethylcyclopent-3 ¹ -en-1 · g (-yl) -acetic acid (1 "R-antimers of JA _,. R = benzyl) or l ^l R- (2 ' ₀ (-hydroxy-5 ^t ß-methoxymethylcVclopent-3 ^l -en-. -acetic acid (l 'R-An.timeres of JA, r8 = methyl) converted.

40982 1/1132

Attempt 11

^{13 g (2'ol-hydroxy-5 l} ß-benzyloxyinethylcyclopent-3 ^l -en-l ^l ei-yl) -acetic acid were added to a prehydrated suspension of 10 g Raney nickel in 200 ecm methanol and the mixture under a Stirring hydrogen atmosphere until hydrogen uptake ceased; then the catalyst was filtered off and washed thoroughly with water. The combined organic filtrates were evaporated to dryness under reduced pressure and the oily residue was dissolved in 200 ecm of ethyl acetate. The resulting solution was treated with 3N hydrochloric acid up to a pH of 2-3, whereupon the reaction mixture was stirred for a further 30 minutes. became. Then it was neutralized with sodium bicarbonate, dried over magnesium sulfate and. evaporated to dryness in vacuo; This gave (2 ^l ^ -hydroxy-5 ^l ß-benzyloxymethylcyclopent-l'c <-yl) -acetic acid-1,2'-lactone (I ^, R = benzyl), which was homogeneous according to thin layer chromatography.

In a similar way, the (2 ^l oC-hydroxy-5'ß-methoxymethylcyclopent- ⁱ 4 -'-enl'ct-yl) acetic acid was converted into the (2 OC -hydroxy-5'fi-methoxymethylcyclopent-l'tf-yl ) -

ο
acetic acid-1,2'-lactone (Ij5, R -methyl) converted.

Attempt 11 '

Following the procedure of Experiment 11, l'R- (2fc (-hydroxy-5 ^l i3-benzyloxymethylcyclopent-3 ¹ -en-1'ef-yl) -acetic acid and l'R- (2 ^l o (-hydroxy-5 ^l ß-methoxymethylcyclopent-3'-en-l OC-yl) acetic acid in 1 '5- (2 ¹ Oi-HyOIrOXy-S ¹ ß-benzyloxymethylcyclopent-l'ol-ylj-acetic acid-l ^' - lactone (1 'R-antimers of £, R = benzyl) or 1' R- (2 '«(-hydroxy-5' ß-methoxymethylcyclopen t-1 ^! O (-yl) - acetic acid -

1,2'-IaCtOn (1'R-antimers of ! £., R = methyl) converted.

09821/1132

Attempt 12

According to the procedure of Experiment 8, Part A and B, (2 ^{l of} rt-hydroxy-5 ^t -benzyloxymethylcyclopent-1'el-yl) -acetic acid-1,2'-lactone and {2 ^! et-Hydroxy-5'ßmethoxymethylcyclopent-l ^l ei-yl) -acetic acid-1,2 ^l -lactone converted into (2VC-Hydroxy-5'ßhydroxymethylcyclopent-l'el-yll-acetic acid-1,2'-lactone, the after oxidation with chromium trioxide-olipyridine complex, according to the method of Experiment 8, Part C, which gave (Z'xjt-Hydroxy-S'ß-formylcyclopent-1 '^' - ylJ-acetic acid-1,2 "-lactone.

Experiment 12 | _ · ·

Following the procedure of Experiment x 8, ^{Parts A and B, respectively, 1'H- (2 t} 4-hydroxy-5'ß-3 benzyloxymethylcyclopent-1'el-yl) -acetic acid-1,2'-lactone and 1 'R-5 ^l ß-methoxymethylcyclopent-l'elt'-yl) -acetic acid - !, 2' -lactone converted into l'R ^ S'ß-hydroxymethylcyclopent-l '^ - ylJ-acetic acid-l ^' - lactone , which after oxidation'with chromium trioxide-dipyridine complex according to the method of Experiment 8, Part C, the l ^l R- (2 ' _e i-Hydroxy-5 ^l ß-formylcyclopent-l ^l ^ -yl) -acetic acid-l, 2'-IaCtOn delivered.

Try 1/3

A. A solution of 100 g of dimethyl methylphosphonate in 6? 0 ecm of anhydrous tetrahydrofuran was cooled to -78 ° C. under an argon atmosphere. 495 ecm of a 0.1M solution of n-butyllithium in tetrahydrofuran were added dropwise to the cold solution with stirring and an argon atmosphere, the temperature being kept at -70 Co. After complete addition, the Reakticnsmisehung uwede another 10 minutes under the same conditions retained ^ then a solution aus.58 ecm methyl caproate, dissolved in 187 cc of tetrahydrofuran, was added cautiously pre-, the temperature was maintained at -78 ⁰ C.. The reaction mixture was at -78 ° C for 2 hours. and then stirred for 4 hours at room temperature. The excess base was neutralized with acetic acid and the solvent evaporated under high vacuum. The residue was made up in a 1: 1 mixture

409821 / Π32

950 ecm each of ether and water dissolved, the ethereal phase separated, with Washed waters and dried over magnesium sulfate. The ether was evaporated and the residue is purified by vacuum distillation. So you got the pure dimethyl 2-oxoheptylphosphonate.

If methyl n-butanoate, methyl n-pentanoate, ethyl n-heptanot, Ethyl n-oetanoate and methyl n-undecanoate used then received one the following connections

Dimethyl 2-oxopentyl phosphonate

Dimethyl 2-oxohexyl phosphonate

Dimethyl 2-oxooctyl phosphonate
Diine thyl-2-oxononylphosphonate and
Dimethyl 2-oxododecyl phosphonate.

B. A solution of 7.1 g of dimethyl 2-oxoheptylphosphonate in 150 ecm of dimethoxyethane was added to a suspension of 1.55 g of sodium hydride (previously washed with pentane under argon) in 355 ecm of dimethoxyethane freshly distilled from lithium aluminum hydride added. The reaction mixture was stirred for 30 minutes at room temperature, then 10 g (2 »gI-hydroxy-4 '^ -p-phenylbenzoyloxy-5'β-formylcyclopent-1'W-yl) -acetic acid-1,2-lactone were added . The reaction mixture was stirred at room temperature for a further 2 hours, then it was carefully neutralized with acetic acid to a pH of 7 and evaporated to dryness at a temperature below 30 ° C. under reduced pressure. The solid residue was purified by chromatography on Florisil using methylene chloride as the eluent; So one obtained / ^ 'cl-Hydroxy - ^^ - p-phenylbenzoyloxy ^ BO ^ -oxo-oct-l ¹¹ Ct) -en-r'-ylj-cyclopent-l' ^ - y ^ -acetic acid-1,2 '-IaCtCn (JLO, η = 4) and a small amount of 2-oxoheptylphosphonate.

409821/1132

In the above process, when diraethyl 2-oxoheptylphosphonate, dimethyl 1-2-oxohexylphosphonate, dimethyl-2-οχό-octylphosphonate, dimethyl-2-oxononylphosphonate and dimethyl-2-oxododecylphosphonate were used instead of dimethyl 2-oxoheptylphosphonate, the following were obtained Compounds j / ^ 'it-Hydroxy-Vtf-p-phenylbenzoyloxy-S ¹ ß- (3 "-oxohex-1" (t) -en-l "-yl) -cyclopent-1' 4, -yy -acetic acid- 1,2'-lactone

/ 2 '^ -Hydroxy- ^' ^ ip-phenylbenzoyloxy- ^ 'ß- (3 "-oxohept- ^ll (t) -en-1 ^w yl) -cyclo-pent-1 ¹ aryy- acetic acid-1,2 ^l -lactone

/ 2 '^ - Hydroxy-4 ^l _e (-p-phenylbenzoyloxy-5 ^l ß- (3 "-oxonon-1" (t) -en-l "-yl) -cyclo ~ pent-1 ^l JL-yi} -acetic acid-1,2'-lactone

/ 2 ^l ^ -hydroxy-4-V (p-phenylbenzoyloxy - 5 ^I .beta. (3 "-oxodec-1" (t) -en-l '-yl) -cyclopent-1'et-yy-acetic acid -l, 2'-lactbn and

/ ^ '^ -Hydroxy-Λ' öt-p-phenylbenzoyloxy-5 'ß- (3 «-oxotridec-l" (t) -en4 "-yl) -cyclopent-l'i (-yy-acetic acid-1 , 2'-lactone. .

Similarly, (^ '^ - Hydroxy-S'ß-formylcyclopent-l' ^ - ylJ-acetic acid-1,2 '-lactone in / 2 « _- l-hydroxy-5 ^l ß- (3" -oxo- oct-1 "(t) -en-l" -yl) -cyclopent-1 ^ -yl7-acetic acid-1,2 · -lactone and / 2 ^l _e f-hydroxy-5'ß- (3 "-oxodec- l "(t) -en-l" -yl) -cyclopent-1 'ef-y3 / -acetic acid-1,2 · lactone converted.

Attempt 13 '

Following the procedure of Experiment 13, Part B, I'R- (2 ^l _e ^ -hydroxy- ^ ^l _e (-p-phenylbenzoyloxy-5 ^l ß-formylcyclopent-l ^l »C-yl) -acetic acid-l _t 2 ^l _lacton in l'R - / ^ ¹ ^ -

Hydroxy - ^ '/ - p-phenylbenzoyloxy-5 ¹ ß- (3 "-oxo-oct-1" (t) -en-1 "-yl) -cyclopent-1 ^ y ^ -acetic acid-1,2'- lactone (1 "" fi-antimers of 10, η = 4).

By using dimethyl 2-oxopentyl phosphonate, dimethyl 2-oxohexyl phosphonate, Dimethyl 2-oxooctyl phosphonate, dimethyl 2-oxononyl phosphonate and dimethyl 2-oxododecyl phosphonate instead of dimethyl 2-oxoheptylphosphonate, the following compounds were obtained

409821/1132

l'RZ ^ -Hydroxy- ^ 'ol-p-pheriylbenzoyloxy-5'ß- (3 -oxohex-1 "(t) -en-l" -yl) -cyclopent-1 'd-y'jj-es slgsäwe-1 , 2'-lactone

i 'R- / 2' «f-Hydroxy-4 V -p-phenylbenzoyloxy-5 'β- (3" -oxohept-1 "(t) -en-1" -y 1) cyclopent-1' «l -ylj-acetic acid-l, 2 ' -lactone

1'R- / 2 · JL-Hydroxy-4 · «Up-phenylbenzoyloxy-5 '-β- (3" -oxonon-1 "(t) -en-1" -yl) -cyclopent-1 'rf-ylj-acetic acid-1,2' -lactone

1 · R-ß Ot-Hydroxy - ^ 'Ap-phenylbenzoyloxy-5' -ß- (3 "-oxodec-1" (t) -en-l "-yl) -cyclopent-1 '^ -yl7-acetic acid- 1,2'-lactone or 1 «R- ^ gi -hydroxy- ^ 'e (-p-phenylbenzoyloxy-5' -β- (3" -oxotridec-1 "(t) -en-l'tyl) cyclopent -l'eif-y37-acetic acid-1,2 · lactone.

Similarly, l ^l R was (2 _'s ^{t-Hydroxy-5-l} ß formylcyclopent-lH-.yl) vinegar acid-1,2' lactone in l ^l R £ S ^I _e (-hydroxy-5 ^l ß- (3 "-OXO-OCt-I" (t) -en-l "-yl) -cyclo pent-l '« l-yl7-acetic acid-1,2' -lactone and 1 'R - ^^ -Hydroxy ^^ - iT-oxo en - l "-yl) -cyclopent-l ' _e t-yi7-acetic acid- ^{1,2 l} -lactone converted by using the appropriate reagent.

attempt V *

To a solution of 5.3 g ^ / 2 _'e ^(4-hydroxy-l i (p-phenylbenzoyloxy-5 ^I .beta. ^{(3! L} -oxooct> -l "Ct) -en-1" ^1-yl ) -cyclopent-1 ¹ ^ -yü ^ -acetic acid-1,2'-lactone in 36 ecm diraethoxyethane (freshly distilled from lithium aluminum hydride) were 9 ecm

Zinc borohydride reagent added in anhydrous dimethoxyethane. The reaction mixture was stirred for an additional hour at room temperature and then treated with saturated sodium bitartrate solution until the evolution of gas ceased. It was then diluted with methylene chloride, dried over magnesium sulfate and under vacuum at a temperature below 30 ° C. evaporated to dryness; thus obtained ^ '«{- Hydroxy - ^'et-p-phenylbenzoyloxy-S'ß-i ^ '^ oct-1" (t) -en-l "-yl) -cyclopent-l'eC-yl / -acetic acid-1,2'-lactone (Ij ,, R ⁹ ^ ppheylbenzoyl; η = 4) in a mixture with the 3 "ß-hydroxy isomer.

40982-1 / 1132

The oily mixture was broken down into the individual, Isomers separated, a 2: 1 mixture of benzene and methyl isobutyl ketone being used as the eluent.

In a similar manner, the remaining 3 "-oxo compounds from Experiment 13 were converted into the corresponding 3" -hydroxy compounds, namely in / ^ 'flt-hydroxy- ² i- ^l ei-p-phenylbenzoylo-xy-5 ^l ß- (3 "s <-hydroxyhex-1 "(t) -en-1" -yl) -cyclopent-1 '{Ky ^ -acetic acid-1,2' -lactone β ' _e | ^ hydroxy-4U-P-phenylbenzolyoxy-5' ß - (3 "o (-hydroxyhept-l" (t) -en-1 "-yl) cyclopent-1 ¹ ^ -yy-acetic acid-!, 2 '-lactone / ^', (- Hydroxy - ^ '^ - p-phenylbenzoykBör- ^ ¹ ß- (3 ^b ef-hydroxynon-1 "(-t) -en-1" -yl) -cyclopent-1 '^ t-y3 ^ -acetic acid-1,2 · -lactone / 2 '^ -Hydroxy-4 # -p-phenylbenzoyloxy-5' ß- ( 3'bC -hydroxydec -1 "(t) -en-1" -yl) cyclopent-1 'et-ylj-acetic acid e-1,2 '-lactone 3 ' pi-hydroxy - ^ 'ci-P-phenylbenzoyloxy-S' ß- (3 "ei-hydroxytridec-1" (t) -en-1 "-yl) -cyclopent-1 ^f ei-y ^ -acetic acid e-1 _f 2 '-lactone ^' oC-hydroxy-5 ¹ ß- (3 "oi-hydroxyoct-1" (t) -en-1 "-yl) -cyclopent-1 ^ -ylacetic acid-1 _f 2 '-lactone and fc y- ^ droxy-5 ^f ß- ( 3 "^ - hydraxydeo-1 " (t) -en-1 "-yl) -cyclopent-1' ^ -y ^ -acetic acid-i _f 2 · lactone

in mixture with the corresponding 3 "ß-hydroxy isomers determined by thin layer chromatography were separated,

The zinc borohydride reagent was made from 0.025 moles of molten Zinc chloride, 0.050 mol of sodium borohydride and 50 ecm of dimethylethane, the Mixture stirred for 16 hours and the insoluble material under an argon atmosphere. Sphere was filtered off.

40982 1/1132

Experiment ^{1 for 1}

According to the procedure of Experiment 1fr, 1'R- / 2 «rf-Hydroxy-frty-p-phenylbenzoy: bxy-5'ß- (3" -oxo-oct-1 "(t) -en-1" -yl) -cyclopent ~ ly-yl7acetic acid-1,2 «_lactone in 1 ¹ R- ^ 'el -Hydroxy-fr tf-p-phenylbenzoy loxy-5' ß- ( 3" ef-hydroxyoct-l · »(t) - en-1 "-yl) cyclopent-1'J-ylJ-acetic acid-l, 2 · -lactone (l'R-antimers of 11, R = p-phenylbenzoyl, η = fr) in a mixture with the corresponding 3" Converted ß-hydroxy isomers.

The remaining 3 "oxo compounds from Experiment 13 'in

converted the corresponding ^ '- hydroxy compounds, namely 1' R- ^ 2 '^ -hydroxy-fr' «(- p-phenylbenzoy loxy-5 'ß- (3" e ( ^L -hydroxyhex-1 "(t) -en -1 "-yl) cyclopent-1 '^ - yl / acetic acid-ljE ¹ -lactone

1 'R - ^' ^ - Hydroxy-fr'oi-p-phenylbenzoyloxy-5 'ß- (3V-hydroxyhept-1 "(t) -en-1" -yl) cyclopent-1'of-yl ^ -acetic acid -l, 2-lactone

¹¹ EZ ^ 'ef-Hydroxy-fr ¹ ^ -p-phenylbenzoyloxy-5' ß- (3V-hydroxynon-l ^ft (t) -en-1 »-yl) cyclopsnt-1 'ei-y ^ J-acetic acid- 1,2'-lactone

¹ % - & ^! e (-hydroxy-fr y ^ .p-phenylbenzoyloxy-5 'ß- (3 "i (-hydroxydec-1" (t) -en-1 "-cyclopent-1' ei-yjj-acetic acid-1,2 '-lactone

cyclopent-1 Of-ylJ-acetic acid-1 ", 2 '-lactone

1 'R- / 2 «4-hydroxy-5' ß- (3" o (-hydroxyoct-l ¹¹ (t) -en-1 "-yl) -cyclopent-1 'of-3 acetic acid-1,2' -lactone and

¹¹ S-ZF 'et -Hydroxy-5' ß- (3'bf-hydroxydec-1 "(t) -en-1" -yl) -cyclopent-1 ^ acetic acid-1 _f Z ^l lactone

in a mixture with the corresponding 3 "ß-hydroxy isomers determined by thin-layer chromatography were separated.

4 0 9 8 2 1/113 2

Attempt 15.

A solution of 3.7 g of fz ^ -Byäroxy - ^ - p-pheTiyl ^ nzoyloxy ^ 'ß-iJM-hyaroxy oct-1 "(t) -en-l" -yl) -cyclopent-l ^l et-yl7- acetic acid - !, 2-lactone in J? 1 cm of anhydrous methanol was treated with 1.1 g of anhydrous potassium carbonate and the reaction mixture was stirred for 2.5 hours at room temperature. It was then ^{cooled to 0} ° C. and adjusted to a pH of 2-3 with ION aqueous hydrochloric acid . Ethyl acetate was added and the organic solution was washed with saturated sodium bicarbonate solution and saturated sodium potassium bitrate solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was obtained by filtering through a Florisil column (130 g). cleaned. The fractions eluted with methylene chloride-ethyl acetate gave methyl p-biphenyl carbonylate and the fractions eluted with ethyl acetate / ^ • _o (. _> 4 ^l _< ^ -dihydroxy-5 ^l ß- (3 " ₀ l-hydroxyoct-l" (t) -en-l "-yl) -cyclopent-l'af-y ^ -acetic acid-l ^ '- lactone (1_1, R = Η, · η = h) .

The corresponding 4'e ^ -p-phenylbsnzoyloxy compounds were obtained by the same procedure, namely

& ^l oi, ^ 'Ä-Dihydroxy-5' ß- ( Td-hydroxyhexy-1 »(t) -en-1» -yl) -cyclopsnt-1 V-yl? acetic acid-1,2 · lactone

β ^! ((L, ⁱ «- ^l eC-Dihydroxy-5 · ß- (3" _i (-hydroxyhept-l "(t) -en-i» -yl) -cyclopent-1 "g (-y ^ - acetic acid- 1,2'-lactone

i ^ 'etA'el-Dihydroxy ^ ¹ ß- ( yef-hydroxynon-1 » (t) -en-1» -yl) -cyclopent-1 frytf eesigsäure-1,2'-lactone

iJ ^I o (. ^{i <} - ^l o <-dihydroxy-5 <ß- (3'V-hydroxydec-l »(t) -en-l ^II -yl) -cyclopent-l ^ -yl7-acetic acid-1, 2 ¹ -lactone and

/ P'oit ^ bC -Dihydroxy-5 'ß- (3'W-hyaroxytridec _r l »(t) -en-1" -yl) -cyclopent-1' acetic acid-1,2'-lactone.

409821/1 132

attempt 1 £ _

Following the procedure of Experiment 15, 1 'R - ^' ot-Hydroxy- ^ VP-Phenylbenzoyl oxy-5'ß- (3 "« {- hydroxy-oct-1 "(t) -en-1" -yl) -cyclopent-l'ec-y37-acetic acid-l, 2 'lactone in 1 "R- / 2'cl.Vol-Dihydroxy-S ¹ ß- (3" i (-hydroxyoct-l "(t) -en- l "-yl) -cyclopent-l'ot-yjj- ⁶³³ ^ ³ ^ ⁶ - ¹ » ² '"- ^ ⁰ * ⁰¹¹ (l'R-antimers ναι 11,' R = H, η = 4).

Using the same procedure, the following compounds were obtained from the corresponding l'R-benzoyloxy compounds from Experiment IV: 1 'R_ £ * ¹ ^ l Λ ^! <) {-Dihydroxy-5 'ß- (3 "<< - hydroxyhex-1" (t) -en-1 "-yl) -eye lopentl' ^ - y ^ -acetic acid-1,2 '-lactone

1 ' dryi / acetic acid-1,2'-lac ton 1 ■ R- / 2 ^, 4'il-dihydroxy-5' β- (3 "e (-hydroxynon-1" (t) -en-1 "-yl) -cyclopent-1 * e (-yi7-acetic acid-1,2'-lactone l ^l R- ^ l6 ^ ^l el-dihydroxy-5 ^! ß- (3 ^ll « C-hydroxydec-l »(t ) -en-l "-yl) -cyclopentl '^ - y ^ -acetic acid-1, 2' -lactone and 1 ¹ R-./2 ^I ₀ i, 4« o (-dihydroxy-5 ¹ ß- (3 "e (-hydroxytridec-l ^tl (t) -en-l ^I1 -yl) -cyclopent-1V-ylI-acetic acid-1,2'-lactone.

Try 16

To a solution of 2.3 g / 2 ' ₀ (, ^' _e i-dihydroxy-5 ^l ß- (3 "oi-hydroxyoct-l ^ll (t) -en-!" - ylj-cyclopent-l'et -ylj-acetic acid-1,2'-lactone in 23 ecm methylene chloride, 2.3 ecm freshly distilled dihydropyran and 23 mg anhydrous p-toluenesulfanic acid were added.The reaction mixture was stirred for 15 minutes at room temperature, then a few drops of pyridine were added and ether was added The ethereal solution was washed with 100 ml of 50% aqueous sodium chloride solution and then with saturated sodium chloride solution The organic phase was separated off and washed over magnesium sulfate

409821/1132

and evaporated to dryness under reduced pressure at about 0 ° C .; thus obtained β> V-hydroxy-Vd-tetrahydropyranylaxy-S'ß-C 3'tf-tetrahydropyranyloxy oxyoct-1 "(t) -en-1" -yl) -cyclopent-1 ^f _e ^ -y ] ^ - acetic acid- ^{1,2 l} -lactone (.12, η = 4) as an oil.

Similarly, the usual compounds obtained in Experiment 15 were converted into the following compounds: ■

22 ^l ^ -hydroxy-4y-tetrahydropyranylöxy-5'ß- (3 ^ll c (-tetrahydropyranyloxyhex-1 "(t) -en-l" -yl) -cyelopent-l ^ -yiy-acetic acid-1,2'- lacton ^ 'a-Iiydro ^ y - ^'ei-tetrahydropyranyloxy-S'ß- (3 "e / -tetrahydropyranyloxyheptl" (t) -en-l "-yl) -cyclopent-l ^l _e / -yl7-acetic acid- i, 2 '-lactone / 2' ^ -hydroxy - ^ '^ - tetraiiydropyranyloxy-Sfß-i 3 "flf-tetrahydropyranyloxynon-1" (t) -en-1 "-yl) -cyclopent-1' e (-y ^ -acetic acid-1,2'-lactone Jj. 'flt-iftrdroxy- ^' e (-tetrahydropyranyloxy-5 'ß- (3'i (-tetrahydropyranyloxydeci "(t) -en-l ^ll -yl) -cyclopent- l ^l öi-yi? -acetic acid-1,2'-lactone and ^ '^ [- Hydroxy - ^' ei-tetrahydropyranyloxy-S 'ß- (3 "^ - tetrahydropyranyloxytrMecl' ^l (t) -en-l ^II - yl) -cyclopent-l '^ -ylj-acetic acid-1,2' -lactone.

Similarly, the / 2 «g (-hydroxy-5'ß- (3" ^ - hydroxy-oct-l "(t) -enl" -yl) -cyclopent-1 ty-ylj-acetic acid-l ', 2 '-lactone and ^ 2 ^ -hydroxy-5'ß- (3 "^ - hydroxydec-l" (t) -en-l "-yJ-acetic acid-l _! 2'-lactone in / 2 V-hydroxy- 5'ß- (3 "ii-tetrahydropyranyloxyoct-1» (t) -en-1 »-yl) -cyclopent-1 '^ -y ^ -acetic acid-I ₀ 2'-lactone or / z ^ -hydroxy- S'ß-i ^ -tetrahydropyranyloxydec-l '^ tJ-en-! "- ylJ-cyclopent-l'eC-yJ ^ acetic acid-l ^« -lactone converted.

Attempt 16 '

According to the procedure of Experiment 16, I'R- / 2 ^, 4'c (-dihydroxy-5 »ß- (3» _ä / _ hydroxyoct-1 "(t) -en-1» -yl) -cyclopent- 1 yy ^ -acetic acid-1,2-lactone in

l »(t) -en-l» -yl) -eyclopent-l '^ - y ^ acetic acid-1,2'-lactone in the form of an oil (l'R-antimer of 12, η = k) .

409821/1132

- 6ο -

In a similar way, the other l'R-Verbm-

compounds converted into the following compounds · 1 'R- / 2 ¹ J-Hydroxy- ^' ^T o (-tetrahydropyranyloxy-5 ^l ß- (3 ^l b ^ -tetrahydropyranyloxyhex-1 »■ (t) -en-1" ~ yl) -cyclopent-1 V-yl / -acetic acid-1,2'-lactone 1 'R- _i ^ ^r ef-hydroxy - ^ - ^l ii-tetrahydropyranyloxy-5' ß- (3 "o (~ tetrahydropyranyloxyhept-1 "(t) -en-1" -yl) -eyclopent-1 '(K-yi7-acetic acid-1,2 "-lactone 1« R - ^^ - Hydroxy- ^ y -tetrahydropyranyloxy-5 ¹ i3- (3 "E (-tetrahydropyranyloxynon-1" (t) -en-1 "-yl) -cyclopent-1 ¹ ^ -ylj-acetic acid-1,2'-lactone 11 R-J2 'jt-hydroxy- ^' ei-tetrahydropyranyloxy -5 'ß- (3 "* C- te trahydropyranyloxydec-1" (t) -en-l "-yl) -cyclopent-1 ^! O (-y ^' - acetic acid-1,2 '-lactone and l' R- / 2y-Hydroxy-i ^ ^l β ^ tetrahydropyranyloxy-5 ^t ß- (3 "o (-tetrahydIΌpyranyloxy ..

tridec-1 "(t) -en-1" -yl) -cyclopent-1 '^ -y tj -acetic acid-1,2'-lactone.

Similarly, I ^l R- ^ ^l _e l _> -hydroxy-5 ^l β- (3 " ₀ ( ^{-hydroxyoct-l M} (t) -en-l" -yl) -cyclopent-1 'J ^ -y ^ -acetic acid ~ 1,2'-lactone and l'R- ^ JpC-hydroxy-S'ß- (3 "^ - hydroxydec-l" (t) -en-l ^ll -yl) -cyclopent-l ^! _e ( -yl7-acetic acid- ^{1,2 l} -lactone in 1 ■ R- £? 'e (-hydroxy-5' ß- (3 "(^ - tetrahydropyranyloxyoct-l" (t) -en-1 "-yl) - cyclopent-iy-y ^ -acetic acid-1,2'-lactone or l ^l R- _< ^ ¹ ^ t-hydroxy-5 ¹ ß- (3 "-tetrahydropyranyloxydec-1" (t) -en-1 "- yl) -cyclopent-1 OZ-yl / acetic acid-1,2'-lactone.

Attempt I ^

¹ gi / ' ^l ^ - ^H y ^ ^{o ;?} 3 ^r - ^{i |} ' ^t ^ -tetrahydropyranyloxy-5 ^t ß- (3 ^1I e (-tetrahydropyranyloxyoct-1 "(t) -en-1" -yl) -cyclopent-1 ifylj-acetic acid-1,2 · -lactone was in 20 ecm anhydrous The solution was cooled to -60 ° C., and 3Λ3 ecm of a mixture of 1 ecm diisobutylaluminum hydride and 3 ecm anhydrous toluene were added to the cold solution, whereupon the reaction mixture was stirred for 15 minutes at -6 ° C. Then was they were diluted with methanol until the evolution of gas ceased, the mixture was left for a further 15 minutes

409821/1132

• " ⁶¹ " 235532 ".

stirred at room temperature and diluted with ether. The organic phase was separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate and at about 0 ° G. evaporated to dryness; so one obtained Jz Ol-Hydroxy- ² * ¹ e (-tetrahydropyranyloxy-5 'ß- (S'Oi-tetrahydropyranylo ^ yoctl »(t) -en-l" -yl) -cyclopent-l ^l _e i-yl7- acetaldehyde-1,2'-hemiacetal (, IA, η = 4).

Similarly, the remaining compounds obtained in Experiment 16 were made converted into the corresponding lactols, namely in

1 "(t) -en-1" -yl) -cyclopent-1 ', fy 3 ^ acetaldehyde-1, 2' _hexmiacetal ^ ^l ₀ (-hydroxy- ^ ^I _i (-tetrahydropyranyloxy-5 ^t ß- ( 3 " c l "(t) -en-l '-yl) -cyclopenf-l' ((-y] J-acetaldehyde-l, 2'-hemiacetal Π ^{1 l} _e (- ^H y ^DROX y ^{2 <} '' e (- ^tetri ^ ^dl1 ° pyranyloxy-5 'ß- (3 " _e f-tetrahydropyranyloxynonl" (t) -en-l "-yl) -cyclopent-l' _c (-yl7'-acetaldehyde-1,2 ^{l -hemiacetal} J2 '^ -Hydroxy - ^' ^ t-tetrahydropyranyloxy-S 'ß- (3'y-tetrahydropyranyloxydecl "Ct) -en-l" -yl) -cyclopnt-l' ^ -ylJ-acetaMehyd-l, 2 «- hemiacetal Jz ^l ₀ ^(l -hydroxy- ^ ei-tetrahydropyranyloxy-5 'ß (3 "</ - tetrahydropyranyloxytr idec-1" (t) -en-1 "-yl) -cyclopent-1' ^ -yoj-acetaldehyde -l, 2 '-hemiacetal / 2' _e (-hydroxy-5'ß- (3 ^l ^ -tetrahydropyranyloxyoct-l ^ll (t) -en-l ^II -yl) -cyclopent-1 'flil-yij-acetaldehyde- l, 2 '-hemiacetal and

-Hydroxy-5 ¹ ß- (3 "o (-tetrahydropyranyloxydec-l" (t) -en-1 "-yl) -cy clopent-

yp -acetaldehyde-1,2-hemiacetal.
Experiment 17 ¹ . .

Following the procedure of Experiment 17, I'Rj ^ 'oi-hydroxy - ^'oi-tetrahydropyranyloxy-5'ß- (3 » _e j (-tetrahydropyranyloxyoct-l ^ll (t) -en-i ^ll _T yl) -cyclopent -lV-yl? - acetic acid-1,2 "-lactone into the l'R - ^ '^ - hydroxy- ^ y-tetrahydropyranyloxy ^' ß- (3" o ^ -tetrahydropyranyloxy oct-1 "(t) -en -1 »-yl) -cyclopent-1 Of-y ^ f -acetaldehyde-1,2'-hemiacetal (l'R-Antmeres of IA, η = 4).

409821/1132

•. 62 -

In a similar way, the other I ¹ R compounds obtained in Experiment 16 gave the corresponding lactols, namely 1 ^! R / 2 · ^ -hydroxy - *) - ¹ ^ -tetrahydropyrane- loxy-5 'SS (T4 - tet r rahydropyranyloxy-hex-1 "(t) -en-1" -yl) -cyclopent-1 ¹ UY] J-zcetaldehyd-1,2 '-hemiacetal 1' R- / 2 '/ -hydroxy- · ^' ^ [- tetrahydro parany loxy-5 'ß- (3'y-tetrahydropyranyloxyhept-1 "(t) - en-1 "-yl) -cyclopent-1 y -ylj-a.ee taldehyd-1,2 · -hemiacetal 1 · R- ^ y-hydroxy - ^ 'iC-tetrahydropyrany loxy-5' ß- (3", (-tetrahydropyranyloxynon-1 "(t) -en-1 ^ir -yl) -cyclopent-1 'ef-y ^ -acetaldehyde-1 _r 2' -hemiacetal

I R-ß 'aJ-Hydroxy- ^ ¹ 4-tetrahydropyrany loxy-5' ß- (3 "i (-tetrahydropyranyloxydec-1 ⁿ (t) -en-1" -yl) -cyclopent-1 V-yl / -acetkldehyd-1,2 '-hemiacetal 1' R- / 2 '^ -hydroxy- ^ ¹ ^ C-tet rahydr opyrany loxy-5' ß- ( 3 "ti- te trahydr opyranyloxytridec-1" (t) -en -l "-yl) -cyclopent-IV-yl / acetaldehyde-1,2'-hemiacetal

I ^I R- ^ 2 ' _e (-Hydroxy-5 ^t ß- (3'b (-tetrahydropyranyloxyoct-l "(t) -en-1" -yl) -cyclopent-1 Vy! LJ- ^ace t, aldehyde- l, 2 '-hemiacetal and 1' R- / 2 '/ -hydroxy-5' ß- (3'y-tetrahydropyranyloxydec-l "(t) -en-1 ■■ -yl) -cyclopent-1 'it- ylj-ace taldehyde-1,2'-hemiacetal.

Attempt 18

Following the procedures described in Run 15, 16 and 17, 2 g ^ • ^ -Hydroxy ^^ - p-phenylbenzoy loxy-5 'ß- (3 "ß-hydroxyoct-1" (t) -en-1 "-yl) -cyclopent-l'oi-yl ^ -acetic acid-l ^ '- lactone one after the other into the

i * '»i-Dihydroxy-5 ¹ ß- (3" ß-hydroxyoct-l ¹¹ (t) -en-l "-yl) -cyclopent- -y! / - acetic acid, 1-2« -lactone,
[2 ', (- Hydroxy- ^ · «(- te trahydropyrany loxy-5' ß- (3" ß-te trahydropyranyloxyoct-1 "(t) -en-1" -yl) -cyclopent-1 '^ -ylj -acetic acid-1,2'-lactone and / 2 ^ -hydroxy-il · ¹ ^ -tetrahydropyranyloxy-5 'ß- (3 "ß-tetrahydropyranyloxyoct-1" (t) -en-1 "-yl) -cyclopent- 1 '^ -y ^ -acetaldehyde-1,2' -hemiacetal (3 ^u ß-isomer of IA )
converted.

409821/1132

e r s u c h

According to the ancestors of Experiment 15, 16 and 17 1 'R- / 2 ¹ ^ -hydroxy - ** · VP-phenylbenzoylöxy-5 ¹ ß- (3 "ß-hydroxyoct-1" (t) -en-4 " -yl) -cyclopent-1 * / - ylJ-

acetic acid-1,2'-lactone one after the other in.

1 · R- / 2 ¹ ^, A'rf-Dinydroxy-S ¹ ß- (3 "ß-rhydroxyoct-1" (t) -en-1 "-yl) -cyclopent- 1 ¹ ^ -yy -acetic acid- 1,2'-lactone

1 ' R-ß. ¹ ^ -Hydroxy- ^ · fet -tetrahydropyranyloxy-5 'ß- (3 "ß-te trahydropyranyloxyoct-1" (t) -en-1 "-yl) -cyclopent-1 yy ^ -acetic acid-1,2' - lactone and ¹ 'R- ^ Oi- ^ dr ^ y- ^ Oi-tetrahydropyranyloxy-S ¹ ß- (3 "ß-tetrahydropyranyloxyoct-1" (t) -en-1 "-ylj-cyelopent-l j ^ -ylj -acetaldehyde-1,2 «-hemiacetal (3" ß-isomer of the 1 «R-antirera of _1A) converted.

Be is ρ ie 1 1 '

A mixture of 2.1 * l · g of Fent - ^ - in-l-ol and 250 ecm of anhydrous ether was heated to -70 ° C. under an argon atmosphere. cooled (in a Troekeine acetone bath). 26.2 ecm 2M4iethyllithium in ether were added dropwise to the cold mixture with stirring. After this reagent had been added, the reaction mixture was allowed to come to room temperature while stirring was continued for a further 18 hours. A solution of 380 mg of I2 '^ -hydroxy- *! · Ty-tetrahydropyranyloxy-5 · ß- (3 "et-tetrahydropyranyloxyoct- 1 »(t) -en-1" -yl) -cyclopent-1 V-acetaldehyde-1,2 «-hemiacetal (I, R '= tetrahydropyranyloxy ₅ η = k) in 5 ecm of anhydrous ether was added and the mixture was added for 6 hours stirred at room temperature. Then it was poured into ice water and extracted several times with ether. The combined organic extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate and under reduced pressure at a temperature not above 20 ° C. evaporated to dryness. The residue was purified by chromatography on Florisil. The eluted with ethyl acetate ^ iethanol (90:10) fractions afforded 1.6 |, 9af.Trihydroxy-H _"{s 15ei-Mstetrahydropyr anyloxyprost- _i * f-in-13rtrans-ene (II, R ¹ '= tetrahydropyranyloxy; η = 4).

409821/1132

The 6d- and 6ß-hydroxy isoprene can be separated by thin layer chromatography on silica gel using a 1: 1 mixture of methylene chloride / ether as the eluent.

Similarly, the ^ ' _e (-H, ydroxy-5 ^l ß- (3 ^II e (-tetrahydropyranyloxyoct-1 "(t) -en-1" -yl) -cyclopent-1 L (-y £ P-acetaldehyde -l, 2'-hemiacetal in 1,6 |, ^. Trihydroxy-15flt-tetrahydropyranyloxyprost- ^/ f-in-13-trans-ene (II, R =

Hj η = 4).
They continued in this way

1 "(t) -en-1" -yl) -cyelopent-1 '«(-yllj-acetaldehyde-1,2' -hemiacetal / 2 ^l ^ -hydroxy- ⁱ l ^l * (- tetrahydropyranyloxy-5 ^l ß- ^(3-i y tetrahydropyranyloxyhept-1 "(t) -en-l '-yl) -cyclopent-1y-yl7-acetaldehyde-l, 2'-hemiacetal Z?' ^ -hydroxy-M '' (tetrahydro pyranyloxy -5 ¹ ß- (3 V-tetrahydro pryranyloxynon-1 "(t) -en-1" -yl) -cyclopent-1 V-ylJ-acetaldehyde-1,2 '-heraiacetal and Z2 ¹ _c i -hydroxy- ^ 'e (-tetrahydrop5rranyloxy-5 ^l ß- (3 "^ - tetrahydropyranyloxytridec 1" (t) -en-l "-yl) -cyclopent-1 V-ylJ-acetaldehyde-1,2' -hemiacetal converted into:

1.61, 9 "(- trihydroxy-ll ^, 15 ^ -bistetrahydroFryranyloxy-20 bisnorprost-4-in-13-trans-en '

¹ A ! »Pei-Trihydroxy-ll ^ .li ^ -bisistrahydropyranyloxy ^ O-norprost- ^ - in-13-trans-en

116 |, 9 ^ -Trihydroxy-l 1 ^, 15 <-toistrahydropyranyloxy-20-methylprost - ^ - in 13-trans-ene and

1.6 |, 9 ^ -trihydroxy-ll | (, l ^ -bis-tetrahydropyranyloxy-20-pentylprost-4-yne 13-trans-ene.

409821/1132

Example l ^ Ä

Following the procedure of Example 1, i'R - ^ '^ - hydroxy- ^ lrf-tetrahydropyranyloxy-5 ¹ i3- (3 "X-tetrahydropyranyloxyoct-1" (t) -en-1 "-yl) -. Cyclopejit- l V-

ylj-acetaldehyde 1,2 '-hemiaoetal in 8R-1,6 \ , 94 "trihydroxy-1 U (> * 5ef-bis-

I ¹ tetrahydropyranyloxyprost - ^ - in-13-trans-en (8R-antimers of II, R = tetra-

hydropyranyloxy; η = k) converted. _t

The 6Jg- and 6ß-hydroxy isomers can be separated by thin layer chromatography on silica gel using a 1: 1 mixture of methylene chloride / ether as the eluent

Similarly, l'R- ^ ' _e (-Hydroxy-5 ^l ß- (3 "« (-' tetrahydropyranyloxyo.ctl '»(t) -en-l" -yl) -cyclopent-l ^l _e (-yl7 ^> _T acetaldehyde-1,2'-hemiacetal in 8R-1.6 %, <% - trihydroxy-15 -tetrahydropyranyloxyprost - ^ - converted into-13-trans-ene (8R-antimers of II, R = H, η = k) .

Similarly, were

1 'R - ^' ei-Hydroxy- ^ y-tetrahydropyranyloxy-S ¹ ß- (3 "(/ - tetrahydropyranyloxyhex-1" (t) -en-1 "-yl) -cyclopent-1 '^ -ylj-acetaldehyde -l, 2 · -hemiacetal ¹¹ R - / ^ 'el-Hydroxy - ^' of-tetrahydropyranyloxy-S ¹ ß- (3 "rf-tetrahydropyranyloxyhept-1" (t) -en-r'-ylj-cyclopentwl ^ - y ^ -acetaldehyde-l, 2 '-hemiacetal' 1 'R - ^' ol-Hydroxy - ^ 'rf -tetrahydro pyranyloxy-S'ß-i ^' of-tetrahydropyranyloxynon-1 "(t) -en-1" -yl) -cyclopent-1 '«i-yiZ-acetaldehyde-1,2'-hemiacetal and ¹ 'S" /? 'ol-HydrcÄy - ^ - tetrahydropyranyloxy-5' ß- (3 "o (-tetrahydropyranyloxytridec-1 "(t) -en-l" -yl) -cyclopent-l '© (-ylj-acetaldehyde-1,2 · -hemiacetal-converted into the following compounds:

8R-11 6 1, 9 ^ -Trihydroxy-lI ₀ ^, 15e (-bis-tetrahydropyranyloxy-20-bisnorprost-4-yn-13-trans-en

8R-If 6 1,9 _e f-Tfihydroxy-ll _e (, 15 ₀ (. Bis-tetrahydropyranyloxy-20-norprost-4-yn-13-trans-en

8R-If 6 f i9ol-Trihydroxy-llo {, 15o (-bisetrahydropyranyloxy-20-methylprost- '' 4-in-13-trans-ene and

8R-1,6 J, o ^ -Xrihydroxy-ll ^, l ^ bistetrahydropyranyloxy - ^ - pentylprost- - »- in-13-trans-an. _409821/1132

Example 2

A mixture of 300 mg 1.6 I ^ X-Trihyo ^ oxy-ll ^ l ^ -bis-tetrahydropyranyloxyprost- ¹ f-in-13-trans-ene, 2 ecm pyridine and 0.2 ecm acetyl chloride was at room temperature for 6 hours stirred, then poured into water and sprinkled with ether

extracted. The organic extract was saturated with sodium chloride solution washed, dried over magnesium sulphate and evaporated to dryness in vacuo; so one got!, ol. ^ - Tri

prost-4-in-13-trans-ene (III, R = tetrahydropyranyloxy; n = b) , which can be purified by filtration through Florisil.

Using the same procedure, 1.6 | , 9a (-Trihydroxy-1-4 -tetrahydroEyranyloxyprost-Vin-13-trans-ene in 1.6 1.9 <(- Triacetoxy-15o (-tetrahydropyranyloxypro3t-

I ¹
4-into-13-trans-ene (III, R = H; η = 4) converted.

In a similar manner, the usual 1,6 Z, ^ - ^! Hydroxy compounds "from Example 1 were converted into the corresponding 1,6 i , 9 ^ -triacetoxy derivatives.

Example 2-A

Following the procedure of Example 2, 8R-1,6 <, 9 ^ {- trihydroxy-II | (, 15 ^ -bis-tetrahydropyranyloxyprost-4-yn-13-trans-ene in ^ «1,6 \ , 9i / -triacetoxy -llc (, 15tAr bistetrahydrohyranyloxyprost- ⁱ 4-yn-13-trans-en (& ^ - antimers of III, R ¹ '= tetrahydropyranyloxy; η = 4).

If the same procedure was based on 8R-1,6, 9 "(- trihydroxy-1 ^ (- tetrahydropyranyloxy prost-4-yn-13-trans-ene, then 8R-1,6% oxy-1 was obtained ^ -tetrahydropyranyloxyprost-4-yn-13-trans-en (£ R-antimers of III,

R ¹ '= Hj η =

Similarly, the remaining 8R-1,6 C, ^ - ^! Hydroxy compounds of Example 1-A were converted into the corresponding 8R-1,6 \ , 9 ^ -triacetoxy derivatives

from converted

40982 1/1132

Example 3_

A suspension of 117.5 mg cuproiodide in 2 ecm anhydrous ether was brought to about −10 ° C. with stirring. cooled under an argon atmosphere and with
Treated 2 molar equivalents of eaner 2M solution of methyllithium in ether.
The colorless solution obtained was heated to -75 ° C. in a dry is-acetone bath.

cooled, then a solution of 100 mg 1.6!, ^, (- Tri
tetrahydropyranyloxyprost-Λ-yn-13-trans-ene. in 3 ecm of anhydrous ether was added and the reaction mixture was stirred at -75 ° C. for 5 hours. The temperature of the mixture was increased to -10 ° C., a saturated ammonium chloride solution was added and the mixture was stirred for 1 hour and extracted with ether. The organic extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure
Evaporated to dryness. The residue was purified by chromatography on Florisil
cleaned. The fractions eluted with 80; 20 methylene chloride / ether yielded the pure 1, 9rf-diacetoxy-Hs (, 15d (-bis tetrahydropyranyloxyprosta-Λ, 5,13-transtriene (VIII, R = tetrahydropyranyloxy; R and R ⁵ = H;, η = 4).

In the above procedure, the following compounds were used as starting materials used:

1,6 I, 9pί-triacetoxy-15dl-tetrahydropy "ranyloxyprost-4-yn-13-trans-ene

1 ₉ 6 I, 94-Triacetoxy-llei, lS ^ -bis-tetrahydropyranyloxy ^ O-bisnorprost-

4-in-i3-trans-ene

1} 6 |, Pei-Triacetoxy-ll ^, i5e (-bisetrahydropyranyloxy-20-norprost-4 ~ in

13-trans-ene

19 6 I "^ -Triaceto ^ y-ll ^, 15 ^ -bis-tetrahydropyranyloxy-20-methylprost-4-yn-13-trans-en and

1.6 |., 9ii-Triacetoxy-ll _e ( _s 15 _l i-bistetrahydropyranyloxy-20-pentylprost-
4-yn-13-trans-ene

then one got the following compounds:

1 ₅ 9 ^ -Diacetoxy-15 ^ -tetrahydropyranyloxyprosta-4 _s 543-trans-triene.

409821/1132

l _t 94-diacetoxy-lleC, 15 "<- l3istetrahydropyranyloxy-20 bisnorprosta-4,5 ₁ 13- • fcrans-triene

1 _f 9dUDiacetoxy-II "(, IS ^ bistetrahydropyranyloxy-ao-norprosta- ^, 5,13-trans-triene

1,9 ^ -Diacetoxy-lJ ^, 15 ^ bistetrahydropyranyioxy-20-me thy lprosta-Λ, 5,13-trans-trien and

1, 9 ^ -Diacetσxy-llβ (, i5 _β ^ bistetΓahyciroϊyrarιyloxy-.20-pentylpΓosta-Λ, 5 ^ 13 - trans-triene.

example

Following the procedure of Example 3, 8R-JL, 6 I, Stf-'Tri bistetrahydrppyranyloxyprost- ⁱ 4-.in-13-trans-ene in 8R-1, ^ f-diacetoxy-.lle { _? 15g (-bisistrahydropyrarörloxyprosta-4,5 »13-trans-triene (^ -antimer of VIII, R = tetrahydropyranyloxyj R and R- * = H, η = k) .

In the above procedure, "the following compounds were used as starting materials used

8R-1,6 I »^ 5-friacetoxy-15e (-tetrahydropyranyloxyprost-4-yn-13-trans-ene

St-1 , 61, 9e £ -triacetoxy-lle (, 15o (-bis-tetrahydropyranyloxy-20-bis-norprost-4-yn-13-trans-en

^ -1,6 K9iit-Triacetoxy-lloi, 15j (-bisistrahydropyranyloxy-20-norprost-4-yn-13-trans-ene

8R-1 »6c, 9 <j (-Triacetoxy-ll ^, l ^ -bisistrahydropyranyloxy - ^ - methylprost-4-yn-13-traa $ -en wnd.

4-yn-13-trans-ene

then one got the following compounds:

8R-1, 9e (-diacetoxy-l ^ -tetrahydropyranyloxyprosta-ii ·, 5,13-trans-triene 8R-1, 9 ^ -Diacetoxy-11 ^, 15 ^ -bis-tetrahydrQpyranyloxy-20-bisnorpΓoata-4,5,13-trans-triene

⁸ I- ¹ »9i £ -Diacetoxy-ll _c (, l ^ -bisistrahydropyranyloxy ^ G-norprosta- ^, 5» 13-trans-triene

40 9 821/1132

8R-1, Stf-Diacetoxy-llei, 15e (-bisetrahydropyranyloxy-20-rae thylprosta-4,5,13-trans-triene and

8R-1, 9 ^ -diacetoxy-ilot, 15ot-bistetrahydropyranyloxy-20-pentylprosta ~ 4,5,13-trans-triene.

Example k_

A mixture of 110 rag !, ^ - Diacetoxy-ll ^ jl ^ -bisistrahydropyranyloxyprosta-4,5,13-trans-triene, 50 mg anhydrous potassium carbonate and 2 ecm anhydrous Methanol was stirred under an argon atmosphere at room temperature for 18 hours. Then the solvent was eliminated under reduced pressure, water was added and the product extracted with ether. The ether extract was washed with saturated sodium chloride solution over magnesium sulfate dried and evaporated to dryness in vacuo; so you got 1, 9eV-dihydroxy-lle (, l ^ -bis-tetrahydropyranyloxyprosta - ^ -, 5,13-trans-triene (IX, R = tetrahydropyranyloxy; R and R * = H) 'η = 4).

Similarly, the remaining 1.9 # C-diacetoxo compounds of Example 3 converted into the following compounds

1,9ot-dihydroxy-15 ^ -tetrahydropyranyloxvpros ta-4,5,13-trans-triene 1,9 ^ -dihydroxy-llfli, ^ c ^ bistetrahydropyranyloxy-EO-bisnorprosta-4 · ι 5113- trans- trien

1, 9 | f-Dihydroxy-1 I ₀ ^, 15ei-bistetrahydropyranylo3q> r-20-norpros ta- ^ i5t13-trans-trien

1, 9e | -dihydroxy-ll "(, ^ e ^ bistetrahydropyranyloxy-gOHmethylprosta- ² S 5113-trans-triene and

1, 9o (-dihydroxy-llcf, 15e <! - bistetrahydropyranyloxy-20-pentylprosta- ^ »5i13-trans-trien.

Example 4-A

When the procedure of Example 4 was repeated using 8R-l, 9o (-diacetoxy-ll ^, 15 ^ .bis tetrahydropyranyloxyprosta-4,5,13-trans-triene as starting material, SR-lo ^ -dihydroxy-lloC. ^ - bistrahydropyranyloxyprosta- '4,5,13-trans-triene (8R-An time res of IX, R ¹ ' = tetrahydropyranyloxy; R and R ^

409821/1132

- 70 η = k) .

Similarly, the remaining 8R ~ l, 9o (-diacetoxy compounds obtained in Example 3-A converted into the following compounds:

8R-1, 9 "(-dihydroxy-15eC-tetrahydropyranyloxypros ta-Λ, 5 _r 13-trans-triene 8R-1, 9 _e (-dihydroxy-i: Le (, 15c (-bisistrahydrop; yTaiiyloxy-20-bisnorprosta - ^ »5» 13-trans-trien

8R-1, 9 ^ -dihydroxy-llo ( _t lSfll-bistetrahydroRjrranyloxy - ^ - norprosta- ^ f 5113-trans-trien

8R-1, ^ dihydroxy-lltf, l ^ l-bistetrahydropyranyloxy-20-methylprosta-4,5,13-trans-troen and

Sl-119el-dihydroxy-l 1β (, 15e (-bisetrahydropyranyloxy-20-pentylpro sta-

^ t5t13-trans-trien.
. Example £

A solution of 300 mg l, 5W-dihydroxy-ll ^ (, l ^ (- bistetrahydropyranyloxyprosta-A, 5 »13-trans-triene in 10 ecm acetone was cooled to -10 ° C. and under a nitrogen atmosphere with stirring with 0, 8 ecm of an 8N solution of chromic acid (prepared by mixing 26 g of chromium trioxide with 23 ecm of conc. Sulfuric acid and diluting with water to 100 ecm). The reaction mixture was stirred for a further 90 minutes at -10 ° C., then was destroyed of the excess reagent was added a few drops of isopropanol and the mixture was diluted with ethyl acetate. The solution was immediately washed 3 times with sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. 2J \ ecm

a 65:35 mixture of acetic acid and water was added and the reaction mixture was stirred at room temperature for 18 hours. Then she was under vacuum

evaporated to dryness and the residue purified by thin layer chromatography using ethyl acetate as the eluent; in this way the pure 9-keto-11rf, 15 _fl (-dihydroxyprosta-4,5,13-trans-trienoic acid (XI, R and r5 = H; R ¹ ″ = hydroxy, η = h) was obtained.

A 0 9 8 2 1/1 1 3 2

Similarly, were

1, ^ -Dihydrojqjr-iioi-tetrahydrQpyranyloxyprosta- ^, 5,13-trans-triene

1 _f 9 ^ -Dihydro ^ -lloΓ ^ ^ i 5 * 13-trans-trien

trans-trien

1 _f 9rf-dihydroxy-lle (, 15a (-bisetrahydropyranyloxy-20-methylprosta-

4-, 5,13-trans-triene and

1, ^ -Dihydroxy-l l "o £, lScC-bistetrahydropy ranyloxy-20 -pentylprosta- ^ t5» 13-trans-.triene converted into the following compounds-9-keto-15ei-hydroxyprosta- ^, 5 »13- trans-ftienoic acid 9-keto-l let, 15oi (-dihydroxy-2lp -bisnorprosta- ^, 5,13-trans-trienoic acid 9-keto-ll "(v 15if-dihydroxy-20-norpros t a - ^ -, 5 '13-t rans - trienoic acid 9-keto-ll4,15 ^ -dihydroxy-20 raetlTylprosta- ⁱ i-, 5' 13-traHs-trienoic acid, and 9-keto-lloi, 15 ^ -dihydroxy-20 pentylprosta- ^, 5 »13-trans-triene acid, Example 5-A

Repeating the procedure of Example 5 using ^ ₁ -1, ^ - dihydroxy-lleClSct-bistetrahydropyranyloxyprosta - ^, S ,, 13-trans-triene as starting material gave ^ -9-keto-11 ^, 15e (-dihydroxypropsta - ⁱ i- _r 5.13-traiis-

6 1 "

trienoic acid (8H-antimers of XI; R and Ir = H; R = hydroxy; η - k-).

Similarly, were

8R-1 "9" (- Dihydr oxy-15e (-t etrahydropyranyloxypros ta- ^, 5,13-trans-triene

8R - 1, 9ef-dihydroxy-lloe, ^ »5113-trans-trien

4 ^ 5,13-trarts-trien 8R-1 s ^ K-Dihy ^, 5113-trans-trien and

^ -1 »^ rf-Dihydroxy-lleC, l ^ -bisteträhyidropyransrloxy-ZO-peiitylproata

^ »5s13-trans-trien

409821/1132.

converted into the following compounds:

^ -9-Keto-l ^ -hydroxyprosta-4,5,13-trans-trienoic acid 8R-9-keto-ll ^ 15c ^ dihydiOxy-20-bisnorprosta- ^, 5i 13-trans-trienoic acid Sl-9-keto- lla, l ^ -dihydroxy ^ O-norprosta- ^ ·, 5.13-trans-trienoic acid 8R-9-keto-llel, 15 flt-dihydroxy-20-methylprosta- ¹ »-, 5 , 13-trans-trienoic acid o ^ - 9-keto-ll "(, 15oi-dihydroxy-20-pentyiirostä- ^, 5il3-trans-trienoic acid.

Example 6

A ₁ . A mixture of 100 mg l ^^ diacetoxy-ll ^ lftf-bistetrahydropyranyloxyprosta- ^ J- ^ jlS-trans-triene, 27.5 mg (1.1 molar equivalents) anhydrous potassium carbonate and 2 ecm anhydrous methanol was for 2 hours under a

Stirred in an argon atmosphere. Then the solvent was eliminated under reduced pressure, water was added and the product was extracted with ether. The ether extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by thin-layer chromatography and gave the kine 9e (-A-cetoxy-li ^ _t 15eC-bistetrahydropyranyloxyprosta- ⁱ l-, 5-13-trans-trien-l-ol (XII, R and R ^J = H ; R == -Tetrahydropyranyloxy; η = W) .

Oxidation of the above compound with 8N-chromic acid according to the procedure of Example 5 gave S ^ -acetoxy-lty, l ^ -bis tetrahydropyranyloxyprosta- ^ i5i13-trans-trienoic acid. This compound was then treated with 25 mg of anhydrous potassium carbonate in methanol according to Example k and then with oxalic acid

acidified and delivered the 9 <(- hydroxy-llfl (, 15oi-bistetrahydropyranyloxyprosta- ^ t5tl3-trans-trienoic acid (XIV, R and R ^ = H; R ¹ '= tetrahydropyranyloxy; ή. "= 4).

B _1- A solution of 50 mg of 9rf-hydroxy-11ft (, 15 _e (-bisetrahydropyranyloxyprosta- ^, 5,13-trans-trienoic acid in 0.15 ecm of tetrahydrofuran was treated with 1.3 ecm of 65% aqueous acetic acid The reaction mixture was stirred for 4 hours at kS ^{C., cooled to 0} ° C. and evaporated to dryness under reduced pressure; the oily residue was purified by thin-layer chromatography

409821/1132

purified using a 9: 1 mixture of chloroform / methanol as the solvent and delivered the pure 9i £ ₉ ll ^ »15 $ trihydroxyprosta-4,5,13-trans-trienoic acid (XV ₅ R and R ⁵ = H; R = hydroxy? Η = ty.

Similarly, using ij ^ hydropyranylo3? Yprosta-4 ₁₎ 5 ₉ 13-trans-triene as the starting compound was obtained in succession

9g | -Acetoxy-154-tetrah3rdropyranylo3grprosta- ^ ₉ 5 * 13-trans-trien-acid S ^ -H, ydroxy-15 ^ rtetrahydropyran3rloxyprosta-Aj5 »i3-trans» trienoic acid and 9βί »15d-dihydrox3 & .pro5sta- ^ _t 5 ₉ 13-trans-trienoic acid (XV ₅ R, R ¹ "and R ^5. = H | η = ^ ·) _β

If you are from

1j 9g (-diacetoxy-ll ^, 15 ^ -bistedrahydrOF & ^r i'anylo3 ^ -20 "bisnorprosta-

1 "9 ^, - Diacetoxy-llg (, 15 ^ -bis-tetrahydropyranyloxy-20-norporsta = ^ ■ o 5 j 13-trans-trien

1 "94-Diace toxy-11 ^, 15 ^ bistetrabydropyranyloxy-20" Biethylprosta- ^ ■ o 5s 13-trans-trien and

1.9g £ -diacetoxy-llo ( _f 15et-bistetrahydropyranyloxy-20-p3ntylprρsta- ^ s5s13-trans-triene.

the following end products were obtained:

9 ^, 11C ("15eC-Trihydroxy-20-bisnorprosta-4 ₉ 5, i3-trans -trienoic acid ,, 154-trihydroxy-20-norprosta- ^ _t 5 _i> 13-trans-trienoic acid" 15 ^ -Trihydroxy- 20-methylprosta- ^, 5 _t 13-trans »trienoic acid and

[-Trihydroxy ^ O-pentylprosta- ^, 13-trans-trienoic acid. Example '6-A

By repeating the procedure of Example 6, Parts A and B, but using ^ -l ^ ei-diacetoxy-llei.l ^ -bis tetrahydropyranyloxyprosta- ^, 5,13-trans-triene as the starting material, the end product 8f Hot, 156 «-Trihydroxyprosta- ^, 5,13-trans-trienoic acid (at-antämeres of XV, R and R ⁵ = H; R" = hydroxy, η = ty.

409821/1132

The starting material used was gRLl ^ -Diaceto ^ -lSof-tetrahydroForranyloxyprosta-4,5,13-trans-triene used, then one received one after the other

Sl-9IT-acetoxy-15el-tetrahydropyranylo3qsrprosta-4 _e 5 _i 13-trans-trienoic acid 8R-9 (| (hydroxy-15oJ-tetrahydropyranyloxyprosta- ⁱ i ₉ 5 '13-trans-trienoic acid, 8R-9d, 15 £ ßihydroxyprosta-4,5, lj-trans-trienoic acid.

Was used in the above procedure by

8R-1, c ^ -diacetoxy-llei, l ^ -bis-tetrahydropyranyioxy. ^ O-bisnorprosta-4,5,13-trans-triene

8r_1, cy_Diacetoxy-lle (, 15A-bistetrahydropyranyloxy-20-norpros'ta- ^ - «5ι13-trans-trien

ER-I, Sbt-diacetoxy-lleC, 15of-bistetrahydropyranylo3iy-20-ynethylprosta-

hfStVi-trans-trlen and -. .

^ -1,9dl-diacetoxy-llo {, lidl-bistetrahydropyranyloxy - ^ - pentylprosta-4,5,13-trans-triene

proceeded, the following end products were obtained:

8R-9oit 11 * < »15d T ^r ihydr ^oxy--20 bisnorpros ta-4.5" 13-trans-trie acid j, l ^ trihydroxy-20 norprosta-4,5,13- trans-trie acid trihydroxy -20-methylprosta-4,5,13-trans-trisic acid and

tl ^ -Trihydroxy-ZO-pentylprosta- ^, 5 ₁ 13-trans-trienoic acid.

Example 7

A ^ To a suspension of 10.4 g Guprojodid in 200 cc of diethyl ether, which was cooled to 0 ⁰ C., was added dropwise with vigorous stirring, a 2M solution of Methyllihtium in ether under an argon atom sphere, received until a colorless solution of Lithiumdimethylkupferreagenz .

Were used in place of methyllithium in a similar way Äthyllithiun and Propyllithium used, then one got the lithium diethy! Copper and L ithium-di-n-propyl copper reagent ζ.

IL A solution of 100 mg 1.6 I, 9 <lttriacetoxy-11of, 15o ^ -bisistrahydropyranyl oxyprost-4-yn-13-trans-ene in 3 ecm anhydrous ether was brought to 0 ° C. departed

409821/1132

cools and under an argon atmosphere with one molar equivalent of lithium dimethyl copper (prepared according to Part A). The reaction became 5th Hours at 0 ° C. stirred, a saturated ammonium chloride solution was added and the mixture was stirred for 1 hour and extracted with ether. The organic one Extract was washed over with saturated sodium chloride solution

Magnesium sulfate dried and evaporated to dryness under reduced pressure. The residue was purified by chromatography on Florisil. ! With 8o 2O methylene chloride / ether eluted fractions afforded the pure l, 9 ^ diacetoxy-il ^, 15 ^ ^ ~ -bistetrahydropyrajiyloxy- methylprosta-4,5,13-trans triene (VIII, R = methyl; R ⁵ = H ?, R ¹ '= tetrahydropyranyloxyj η = 4).

In the above procedure, instead of lithium dimethyl copper, a molar Equivalent lithium diethyl copper and lithium dipropyl copper used, then one received. ·

1, 9e (~ diacetoxy-llol, l ^ -bisetrahydropyranyloxy- ^ f-ethylprosta-Λ , 5A3- trans-triene and

1 »Stt-Diacetoxy-llel,! ^ (- bistetrahydropyranyloxy-4-propylprosta-4-» 5 »13-trans-trien.

By using 1.6 | , ^ - Triacetoxy-l ^ -tetrahydropyranyloxyprost - ^ - in 13-trans-ene instead of 1,6 ί, ^ triacetoxy-llefil ^ -bisistrahydropjTanyloxyprost-4-in-13-trans-ene was obtained
1, 9 ^ -Diacet oxy-15e (-tetrahydropyranyloxy-4-methylprosta- ² 4 ·, 5,13-trans-trisn

l, 9EL-diacetoxy-15 ₀ (-tetrahydropyranyloxy - ^ - äthylprosta - ^, 5,13-trien-trans and l, 9c (diacetoxy-15cί-tetrahydropyranyloxy-i ^ - ^ ⁱ · propylprosta- _J 5.13 -trans-trien.

Following the same procedure were

1.6 I, ^ - Triacetoxy-llotjlSiC-bistetrahydropyranyloxy-eO-bisnorprost-

^ -in-13-trans-ene.

1.6 J, 9 ^ -Triacetoxy-lle (, lScf-bistetrahydropyranyloxy-aO-norprost- ^ -in-13-trans-ene

1,6 J, 9rfrTriaceto _X yl I ^ 1 ^ -bisistrahydropyranyloxy-20-methylprost- ^ -in-13-trans-en and · "

40982 1/1132

4- yn-13-trans-ene

into the corresponding .4-methyl - (- ethyl- or -propyl) -prosta-4,5,13-transtrienes converted into

1, 9 ^ -Diaeetoxy-llel, 15 "t-bistetrahydnjpyranylo3qsr- ¹ i-methyl-20-bisnorprosta- ^ 15113-trans-triene

1, 9dt-diacetoxy-l 1 * 1, l ^ -bis tetrahydropyranyloxy - ^ - ethyl-ao-norprosta k, 5, 13-trans-triene

1,9ol-Diacetoxy-II | {, 15o (-bisetrahydropyranyloxy-4-propyl-20-raethylprosta-4,5,13-trans-triene .and

1, Stf-Diacetoxy-lltf, ^^ - bistetrahydropyranyloxy - ^ - methyl ^ O-pentylprosta- ^ f5t13-trans-triene.
Example 7-A

By repeating the procedure of Example 7, Part B, using ER-1,6 X , 9 ^ -triaceto3cy-llol, 15ot-bistetrahydΓopyranyloxyprost-4-yn-13-trans-ene as starting materials and lithium dimethyl copper as reagent, one obtained ER-I, Sb (-Diacetoxy-llc ( _f 15o ^ -bisistrahydropyranyloxy-4-methylprosta-4,5,13-trans-triene (8R-antimers of VIII, R = methyl; ' B? = H; R = tetrahydropyranyloxy Η = k),

In the above procedure, instead of lithium dimethyl copper, a molar Equivalent lithium diethyl copper and lithium dipropyl copper used, then one received

8R-1, 9i (-Diaceto * y-l lif, 15e (-bisetrahydropyranyloiy-4-ethylprosta- ^ t5t13-trans-trien or

8R-11 ^ t-diacetoxy-lle (, lSef-feistrahydropyranylojqr - ^ - propylprosta- ^ 15f13-trans-trien.

By using 8R-1,6 T, ^ - triacetoxy-lSoi-tetrahydropyranyloxyprost-4-yn-13-trans-ene instead of δΈ-1,6 |, 9 * C-triacetoxy-11 ^, 15 ^ -bis-tetrahydropyranyloxyprost-4 ~ in-13-trans-ene the following compounds were obtained:

409821/1132

8R-1,94-Diacet oxy-15g5-tetrahydro-pyranyloxy-4-methylprosta-4

Γ5.1 3-tran5-trien

8R-1, ^ diacetoxy- ^{15e ^ tetrahydropyranyloxy- i} i'-propylprosta-4 "5,13-trans-triene.

Using the same procedure, _ ■. ;

BR-1,6 I, 9 ^ f-Tr iacetoxy-11 ^, 1 ^ -bis-tetrahydropyranyloxy-20-bisnorprost-If-in-l 3-trans-en £ §-1,6 C ^^ - triacetosy-ll ^ jli ^ -bisistrahydropyranyioxy ^ O-norprost- ^ -in-13-trans-en 8R-I ₈ 6f ^ sf-Triacetoxy-llgCslS ^ -bisistrahydropyranyloxy-EO-inethylprost- ^ • -in-13-trans-en and 8R- 1,6 1, 9g (-Triacetoxy-l 1 ^, 1 ^ -bis tetrahydropyranyloxy ^ O-pentyiprost- _ 4-yn-13-trans-ene into the corresponding 8R-methyl- (-ethyl- or -propyl) -prosta - ⁱ <-, 5.13-transtriene converted.

Example _8 '- ·,

Examples k and 5 were prepared using tetrahydropyranyoxy - ^ - methylprosta- ^ j5s 13-trans-triene as the starting material

repeated, whereby one after the other 1 "9 ^ -Dihydrosy-llö £, 15cJ-bis tetrahydro Kjcranyloxy-A-me t hy lpro s ta-4,5,13-transtrien,

^ • -Me thyl-9-keto-l I ^, 155 ^ -bist et rahydropyranylo ^ prosta-Λ, 5 ₀ 13-transtrienoic acid and

4-methyl-9-ke to-11 rf, 15efc-dihydroxyprosta- ^, 5,13-trans-trienoic acid (XI, R = methyl; R ⁵ * H; R ¹ V = Hydroxyj η = 4).

Similarly, starting from

1, 9ofc-Macetoxy-l Itf, 15öf-bistetrahydropyranyloxy-4-ethylprosta-

4 »5.13-trans-triene

1, 9a-diacetoxy-l 1 «<, 15§ (-bisetrahydr opyranyloxy - ^ - propylprosta- ^ »5,13-trans-trien

1190ί-diacetoxy-15 ^ .tetrahydropyranyloxy ^ -methylprosta-4t5tl3-trans-triene

1,9-diacetoxy-15gf-tetrahyd / dpyranyloxy-4-ethylprosta-4,5,13-trans-triene 4 0 9 8 2 1/113

119dl-Diacetoxy-lloi, 15eJ-bistetrahydrcpyranyloxy- ¹ f-methyl-20-bisnorprosta-4-, 5,13-trans-triene ί,% ii) iacetoxy-lloi, l ^ -bis-tetrahydropyranylo ^ r - ^ - ethyl-SO -riorprosta k , 5,13-trans-triene 1, 9 ^ -diacetoxy-lloC, 15 ^ -bisetrahydropyrany lo ^ - ^ - propyl ^ O-methylprosta-4,5,13-trans-triene 1, 9 ^ -D £ acetoxy-ll5 < _f 15 ^ -bisetrahydropyrarQTlo3i3r-ii-methyl-20-pentylpro sta-4,5,13-trans-triene the following end products

^ -Ethyl-9-keto-l 5 »(- hydroxy pro s ta- ^ J-, 5,13-trans-trienoic acid 4-methyl-9-keto-ll | ( _r 15j ^ dihydroxy-20-bisnorprf3Sta ~ 4 , 5,13-trans-trienoic acid 4-ethyl-9-keto-lle (, lSot-dihydroxy ^ O-norprosta- ^, 5t 13-trans-trienoic acid ^ -propyl-9-keto-llrf, 15ef-dihydroxy-20 -raethylprosta _4-f 5 '13-tia.ns-trienoic acid, and • ^ -methyl-9-keto-l Itf, 15et-dihydroxy-20-pentylprosta- ² f, 5' 13-trans- trienoic acid. example

Example k and 5 were _{repeated using ^ -l t} 9 _e f-diacetoxy-lle ^ l5ef-bistetrahydropyranyloay - ^ - methylprosta - ^, 5 _e 13-trans-triene as starting material, whereby 8R-1, <fci -Dihydroxy-llot, 15e (-bisistrahydropyranyloxy-4-methylprosta- ^ "5113-trans-triene, 8R-4-methjrl-9-keto-lei, 15" (- bistetrahydropyranyloxypros ta-4,5,13-transtriene acid and

a-4,5,13_trans-trienoic acid (& l-antimers of XI; R = methyl; R ^ = H; R ¹ "= hydroxy; η = k) .

In a similar way, starting from 8R-1-, 9 (^ - diacetoxy-llo {, l ^ -bisetrahydropyranyloxy - ^ - ethylprosta- ^ * 5ι13-trans-trien

40982 1/1132

8R-1 _s 9 ^ -Diacetoi} qy - llÄ, 15e ^ bistetrahydropyranyloxy- ⁱ f-propörlpro sta k, 5 _v 13-trans-trien
8R-l, 94-Diaceto ^ -15 ^ -tetrahydropyranylöxy-4 - metl ^ lprosta-4,5 ₉ 13-trans-triene 8R-19 9 # -Diacetoxy-15 ^ tetrahydropyranyloxy - ^ - äthylpros ta-4 ·, 5,13-trans-triene 8R-1,9 ^ -Diacetaxy-llfli, 154-bistetrahydropyranyloxy- ⁱ <.- methyl-20-

bisnorprosta - ^, 5 »13-trans-trien.

8R-1 «9o (-Diacetoiy-ileC _J lSgg-bistetrahydropyranyloxy - ^ - ethyl-ZO-norprosta k , 5,13-trans-triene

£ R-1, ^ (- Diacetoxy-lleC, 15 _fi (-bisetrahydropyranyloxy- ² f-propyl-20-methyiprosta-

^, 5,13-trans-trien and ■

^ -1, 9fli-diacetoxy-llet, 15fl ^ -bisistrahydΓoρyΓanyloxy- ^ί ^ -methyl-20-pentylpΓOsta- ^ »5» 13-trans-triene

the following compounds as final products

8R-4- Hhyl-9-keto-l lo (i 15ai-dihydroxyprosta-^, 5-13-trans-trienoic acid ^ -A-propyl ^ -keto-11 ^, 15 (4-dihydroxyprosta-4,5 "13-trans- trienoic acid% -4-41ethyl-9-keto-l ^ 5 -hydroxypros ta- ^, 5 _(13-trans-tr iens äure ^ - ² 4-ethyl-9-keto-15EC-hydroxyprosta-4 , 5,13-trans-trienoic acid ^ - ^ - Methy 1-9-keto-lliÄ, 15o (-dihydraxy-2G -bisnorpros ta- ^, 5,13-trans-trienoic acid 8R- * 4-ethyl-9-keto -il (! l _f 150tdihydroxy-2O-horprosta- ⁱ <·, 5; 13-trans-trienoic acid 8R-4-propyl-9-keto-110t, 15ol-d.ihydroxy-20-methylprosta- ^, 5.13 -trans-trienoic acid and

^ _44.iethyl-9-keto-llöl, 15fl ( _r dihydroxy-20-pentylprosta- ^, 5,13-trans-trienoic acid. Example 9

Following the procedure of Example 6,!, QeC-diacetoxy-lletjlSfll-bistetrahydro-. pyranyloxy - ^ - methylprosta-Λ, 5,13-trans-triene one after the other in l-hydroxy-9cfc-acetoxy-lle (, lSd-bistetrahydropyranyloxy - ^ - methylprosta- ^ »5 t 13-trans-triene,

4-methyl-9oi-acetoxy-ll e4 IS ^ -bisetrahydrppyranyloxirprosta- ^, 5,13-transtrienoic acid

409821/1 132

4-methyl-SK-hydroxy-1 l "f, 15" (- biste trahydropyranyloxypros ta-4, 5.13-trans-trienoic acid and

^ -JMethyl-9 ^ 1,1 IgI ₁ 1 5 & - tr ihydroxypro s ta-Λ, 5,13-t rans-triensäur e (XV; R = methyl; R ^ = H; R '= hydroxy; η = 4) converted.

Similarly, were
l, 9 ₀ <diacetoxy-llol, 15β ^ bistetrahydropyranyloxy-4-äthylprosta- ⁱ ^ _'f 5,13-trans-triene
l, 9el-diacetoxy-llcl, 15el-bistetrahydropyranyloxy- ⁱ ) -propylprosta- ** ·, 5,13-trans-trien

1 _f '9EC-diacetoxy-15 _e (-tetrahydrop! Yranylo3y- ⁱ f _i inethylprosta 4-5,13-trans-trien 1, 9ot-diacetoxy-llol, 15 »ί-bistetrahydropyranyloxy-4-methyl-20-bisnorprosta - ^, 5,13-trans-trien and

1, 9 ^ -Diacetoxy-lloi, 15e (-bisetrahydropyranyloxy- ⁱ <-propyl-20-methylprosta-4,5113-trans-triene ... ·

converted into the following compounds 4-ethyl-9o (, lle (, lSol-trihydroxyprosta- ^, 5,13-trans-trienoic acid 4-propyl-9 | (, 11 "<, 15el-trihydroxyprosta-4,5,13-trans-trienoic acid l-SW, lSei-dihydroxyprosta- ^, 5,13-trans-trienoic acid

lloi.l ^ -trihydroxy-ZO-bisnorprosta- ^ -, 5,13-trans-trienoic acid and 4-propyl-9oi, lle (, 15j (-trihydroxy-20-methylprosta-4 _f 5,13-trans-trienoic acid.

Example 9-A

Following the procedure of Example 6, SR-l ^ oc-diacetoxy-ll ^ l ^ -bisetrahydropyranyloxy - ^ - methylprosta - ^, 5,13-trans-triene one after the other in fiR-l-Hydroxy-grf-acetoxy-llei.l ^ -bisetrahydropyranyloxy - ^ - methylprosta- ^ »5,13-trans-trien

8E-4-methyl-9ef-acetoxy-llo (, 15 _e {-bis-bistrahydropyranylo ^ rprosta- ^ i5i13-trans-trienoic acid.

& ^ - 4-Methyl-9 _i i-nydroxy-ll ^, ^ ej-bistetrahydropyranyloxyprosta- ^, 5 «13-trans-trienoic acid and

l-9e (, lle (, 15e (-trihydroxyprosta-4,5,13-trans-trienoic acid

4 0 9 8 2 1/113 2

- 81 (8R-antimers of XV; R = methyl; R ⁵ = H; R ¹ "= hydroxy; η = h) .

Similarly, were

St'-l, 9eC-Macetoxy-liy, 1 ^ bistetrahydropyranyloxy - ^ - äthylprosta- ^ »5» 13-trans-trien

8R_1 ₁ 9g (-Diacetoxy-lle (, l ^ -bis tetrahydropyranyloxy - ^ - propylprosta- ^ ι5913-trans-triene

8R-1, ^ -Diacetojqy-lioi-tetrahydropyranyloxy - ^ - methylprosta- ^ »5» 13-trans-trien

iR-1 »9el-Diacetoxy-llg (, 15rf-bistetrahydropy ranyloxy-4-methyl-20-bisnorρrosta-45,13-trans-triene and

8R-1, Sdi-Dia-cetoxy-ll ^ t, l ^ -bisistrahydropyranyloxy - ^ - propyl - ^ - methylprosta-Ψ, 5 »13-trans-triene

converted into the following compounds -Sfe (, ll «(t 15e <-tr ihydrojcypro sta-Λ, 5 , 13-träns- triens äure 1-9βί» 1 let »15 ^ -trihydroxyprosta- ^, 5 » 13-trans- 1 rienoic acid

^ -4-methyl-9oi »ISef-dihydroxyprosta- ^, 5,13-trans-trienoic acid 8R - * {.- iiethyl-90 (t 11« (»15ei-trihydroxy-20-bisnorprosta-4 _i 5.13-trans- trienic acid

and ■

SR - ^ - Propyl-9rf, llo (, 15e (-tr ify-droxy-ao-methylprosta- ^, 5113-trans-trienoic acid.

Example 10

Following the procedures of Example I ₁ 2, 3, 4 and 5, tetrahydropyranyloxydec-l »(t) -en-l ^ir -yi) -cyclopent-l ^f ₀ i-yl7-acetaldehyde _T ^{1.2 l} hemiacetal was successively added to the converted to the following compounds:

1.6 J, 9 ^ -Trihydroxy-, 11 ^, 15c (-bis tetrahydropyranyloxy-20-ethylprost-4-yn-13-trans-ene

Ί 1.6, 9 "t-triacetoxy-llo _(f 15bί-bistetrahydrΌpyxanyloxy-20 äthylprost-4-in-13-trans-ene

1, 9ci-Diacetoxy-ll ^, lSoC-bistetrahydropyranyloxy ^ O-ethylprosta- ^ i5 »13-trans-trien

Α09821 / 1Ί32

1, ^ -Dihydroxy-lltf, 1 Stf-bistetrahydropyranyloxy ^ -äthylprosta- ^, 5,13-

trans-trien and

'9-Keto-Iloi, 15öt-aihydroxy-20-ethylprosta-4j513-trans-trisic acid (XI; R and R ^ = H; R "= hydroxy; η = 6).

Similarly, from ^ '^ - Hydroxy ^' ß-O ^ -tetrahydropyranyloxydec-1 ⁿ (t) -en-1 "-yl) -cyclopent-1 '| (-yl7-es'setic acid, 1-2 ^l -lactone as the end product the 9-keto-15o ^ -hydroxy-20-ethylprosta- ⁱ ^ _t 5,13-trans-trienoic acid (ΧΊ; R, R ⁵ and R ¹ "= H; η = 6).

Example IQ-A

Following the procedures of Example 1, 2, 3, ^ and 5, 1'R- ^ 2ty-Hydroxy- ^ •, (- tetrahydropyranylojqy-S ¹ ß- (3 "oi-tetrahydropyranyloxydec-l" (t) -en- 1 "-yl) cyclopent-1 Ό (-y ^ -acetaldehyde-1,2-hemiacetal in succession in SR-1, 6 \ , 9 | ( _i -Trihydroxv-lle (, 15e (-bis tetrahydropyranyloxy-20-ethylprost-

^ -1,6>, ° i (-Triacetoxy-llfl ^, 15 _i (-bisetrahydrcpyranyloxy-20-ethylprost _r ^ -in-13-trans-en

fiR-1, 9 ^ -Diacetoxy-llei, lSgf-bistetrahydropyranyloxy-ZO-ethylpro sta- ^ t5i13-trans-trien

6R-1 ^ -dihydroxy-lliC, 15 * (- bistetrahydropyranyloxy-20-ethylprosta- ^ »5ι13-trans-trien and

m-9-keto-llo (, l ^ t-dihydroxy-20-ethylprosta- ^, 5,13-trans-trienoic acid (^ -antimer of XI; R and R ⁵ = H; R "= hydroxy; η = 6 ) converted.

Similarly, one received from

psyranyloxydec-1 "(t) -en-1" -yl) -cyclpent-1 '"f-ylj-acetic acid-1,2" -lactone as the end product the ^ -9-keto-15oi-hydroxy-20- äthylprosta- ^ _t 5 _t 13-trans-trienoic acid (% antimer of XI; R, R ^ and R ¹ "= H; η = 6).

409821/1132

Example 11

Example 6 was made using i ^
pyranylo3! y-20-äthylprosta-4,5 »13-träns-triene repeated as starting material and delivered successively '

■ 9, J-acetoxy-1 V "15c (-bistetrahydropyranyloxy-20 äthylprosta- f ^1, 5" 13-trans trien-1-ol

trienoic acid

9e (-Hydroxy-llo (, 15o (-bisetrahydrop5rranyloxy-20-ethylprosta-4,5,13-transtrienoic acid and

9 ^, 1 lot, i 5d ^ Trihydro3ςy-20-äthylprost a. -k , 5,13-trans-trienoic acid (XV, R and R ⁵ = H; R ¹ "= hydroxy} η = 6).

In a similar manner, 1.9 <(- Diacetaxy-15gt-tetrahydropyranylo: xy-20-ethyl prostate, 5,13-trans-triene as the end product 9rf, 15ot-dihydroxy-20-ethylprosta- ^, 5,13-trans-trienoic acid (XV, R, R ^ and BE = H; η = 6).

Example H-A

Example 6 was repeated using% -l, S ^ -diacetoxy-llef, l5o (-Mstetrahydropyranyloxy-20-äthylprosta- ⁱ f, 5,13-trans-triene as starting material and gave successively

8R-9a (-Acetoxy-llot, 15 _e (-bisetrahydropyranyloxy-20-ethylprosta-4,5 _f 13-trans-trien-1-ol

5 ^ - 9i (-Acetoxy-ll _e l, 15 ^. Bistrahydropyranyloxy-20-ethylprosta- ^, 5 _f l3-trans-trienoic acid

^ -Soi-Hydroxy-llek lSei-bistetrahydropyranyloxy - ^ - äliiylprosta-ii -, ^, 13-trienoic acid and

^ -9rf, ll ₀ l, 15oC-trihydroxy-20-äthylprosta-i ^, 5,13-trans-trienoic acid (m-antimers of XV, R and R ⁵ = H} R ¹ "= hydroxy; π = 6) .

409821/1132

- 8k -

Similarly, eR-l ^ -diacetoxy-l ^ -tetrahydropyranyloxy-20-ethylprosta-4,5,13-trans-triene was obtained as the end product the 8R-9cftl5öt-dihydroxy

1 1 "5

20-ethylprosta-4,5 _f 13-trans-trienoic acid (8R-antimers of XV, R, R and R ^ = H; η = 6).
Example 12

'Following the procedure of Example 7, Part B, 1,6 S, 9 ^ -triacetoxy-11 ^, 15j ^ -bis tetrahydropyranyloxy-20-ethylprost- ⁱ 4-yn-13-trans-ene in 1,9 ^ - Diacetoxy-llflC, l ^ -bisistrahydropyranyloxy ^ -methyl- ^ O-äthylprosta- ^ i-, 5,13-trans-triene converted, which after saponification and subsequent oxidation and hydrolysis of tetrahydropyranyloxy groups according to the method of Example 4 and 5, the 4- Methyl-9-keto-ll _t (, l ^ (- dihydroxy-20 ^ äthylprosta-4,5,13-transtrienoic acid yielded (XI; R = methyl; R = H; R = hydroxy; η = 6).

Example 12-A

Following the procedure of Example 7, Part B, 8R-1.6 i , 9gl-triacetoxy-

- lM, l ^ -bisistrahydropyranyloxy-20-ethylprost-4-yn-13-trans-ene in 8R-l, 9e (-diacetoxy-1 lc (, 1 ^ -bisistrahydropyrany loxy-4-methyl-20-ethylpros t a -4, ^ L 3-trans-triene converted, which after saponification and subsequent oxidation and hydrolysis of the tetrahydropyranyloxy group according to the method of Example 4 and 5, the 8R-441ethyl-9-keto-II (< _f l ^ -dihydroxy-20- ethyl prosta-4,5,13-trans-trienoic acid gave (8R-antimers of XI, R = methyl; R ^ = H;

1"
R = hydroxy; η = 6).

Example I3

•. To a solution of 2 g 1,6 », ^ oC-Trihydroxy-ll ^ l ^ jf-bistetrahydropyranyloxyprost-4-yn-13-trans-en in 60 ecm of anhydrous tetrahydrofuran, 4.6 g of activated manganese dioxide were added and the reaction mixture at 90 minutes Stirred at room temperature; the manganese dioxide was filtered off and washed with acetone washed and the combined filtrates evaporated to dryness in vacuo. The residue was redissolved in 60 ecm anhydrous tetrahydrofuran, then 4.6 g of manganese dioxide was added and the mixture among them

409821/1132

Conditions stirred for a further 90 minutes. The manganese dioxide was filtered off and washed with hot acetone. The combined organic filtrates were evaporated to dryness under reduced pressure and the residue was purified by thin layer chromatography using a 1: 1 mixture of methylene chloride / diethyl ether _{containing .0 8} % methanol as the eluent ; we l _t ^ S-dihydroxy-6-keto-ll $ received, l5 ^ -bistetrahydropyranyloxyprost - * - in-13-trans ~ s in pure formula (IV; R = tetrahydropyranyloxy; n ~ ^) *

Similarly, were

1.6%, 9 ^ -trihydroxy-15o | -tetrahydropyranyloxyprost - ^ - in - 13-trans-ene 1,6 l, 9 @ J-trihydroxy-llS, l ^ -bis-tetrahydiOpyranyloxy-20-bisnorprost-4-yn 13-trans-ene

1 f 6] |, 9 <4-trihydroxy-ll ^, 15e (-bisetrahydropyranyloxy-20-norprost-4-yn-13-trans-ene .

1.6 ι, 9 | j (-Trihydroxy-II§ (, 15ίt ■ bistetrahydropyranyloxy-20- · methylprost-4-yn-13-trans-en

i » ⁶ |» 9e (-Trihydroxy-ll ^, 15gl-bistetrahydropyranyloxy-20-ethylprost k- in-13-trans-en and

1,6>, 9 || -Trihydroxy-1 Itf, 15 ^ ■ bistetrahydropyranyloxy-20-pentylprost- ^ -in-13-trans-ene

converted into the corresponding 6-keto compounds. Example- 13-A

Following the procedure of Example I3, 8R-1,6 C, Q ^ -Trihydroxy-11 (1,1 5Λ- bistetrahydropyranyloxyprost-Λ-yn-13-trans-ene in SR-l ^ ef-dihydroxy-o-keto- 1Id ₉ 15 oV-bistetrahydropyranyloxyprost-A · -in-13-trans-ene converted in pure form (8R-antimers of IVj R = tetrahydropyranyloxy; η = ^).

0 9 8 2 1/1 132

Similarly, were

8 & -lf6 \ _r Sgt-Trihydroxy-15ei-tetrahydropyranylo2cyprost- ⁱ <-in-13-trans-en

8R-1 · ⁶ \ iSH-TrihydrGjgr-llit, 15et ^bistetrah y ^drc P ^{yranyloxy '20} " ^to " ^norprost "

4-in-13-trans-ene

8R-1,6 £, Q - ^ - Trihydroxy-ll ^, ISet-bistetrahydropyranyloxy ^ O-norprost-

4-yn-13-trans-ene

8R-1 Λ \ , 9 ^ -Trihydroxy-ll ^, 15 ^ -bisistrahydrcpyranyloxy-20-methylprost-

4-yn-13-trans-ene

8R-1.6 ί, 9 ^ (- Trihydroxy-llo (, iSjt-bistetrahydropyranyloxy - ^ - äthylprost-

^ f- in-13-trans-en and

8R-1,6 *, ^ jf-Trihydro3iy-lle (, 15 ^ -bis-tetrahydrcpyranyloxy-20-pentylprost-

4-yn-13-trans-ene

converted into the corresponding 8R-6-keto compounds.

Example 1Λ

To a solution of 275 mg l _t 9 t-dihydroxy-6-keto-ll (, 15ol-bistetrahydropyranylcBcyprost- ^ - in-l3-trans-ene in 69 ecm anhydrous diethyl ether wui ^ the with stirring at room temperature and below 0.96 cen of a 2.2M solution of methyllithium in ether (4 molar equivalents) was added dropwise to an argon atmosphere. The reaction mixture was kept at room temperature for 1 hour and then poured into a saturated aqueous ammonium chloride solution. The organic phase was separated off and the aqueous phase with The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure.The residue was purified twice by thin layer chromatography, a 4-9: 49: 2 mixture of methylene chloride-diethyl ether in the first pass Methanol and then a 6O; 39: 1 mixture of the same solvents were used for the second chromatography to give 6 l-methyl-1,6 », ^ (- trihydroxy-llii, 15β-bistetrahydropyranyloxyprost-4-yn-13-trans-ene in pure form (V, * R ¹ '=

409 82 1/1 1 32

- 8th? - tetrahydropyranyloxy; R ⁵ = ■ methyl; n = 4). ^

In a similar way, starting from 1 _e 9 _i (_Dihydroxy-6-keto-15ef-tetrahydropyranyloxyprost- ^z i-in-13-trans-ene 1, 9el-dihydro: xy-6-keto-ll "i, l ^ -bis tetrahydropyranyloxy ^ Q-bisnorprost-

4-in-13-trans-en -

1 _f o, i-dihydroxy-6-keto-lli <, 15el-bistetrahydropyranyloxy-20-norprost-

^ ■ -in-13-trans-ene.

1,9 ^ -dihydroxy-6-keto-llgC _t 15 | (-bisetrahydroFöTanyloxy-20-methylprost-4-yn-13-trans-ene ■

1, o ^ -dihydroxy-o-keto-lleii 15o {-bis-bis-tetrahydropyranyloxy-20-ethylpist-4-yn-13-trans-ene

and 1, 9fl (-dihydroxy-6-keto-i lfl (, 15e (-bisetrahydropyranyloxy-20-pentylprost-

4-in-13-trans-en '

the following connections:

6 i-methyl-1,6 ^ _t Sb (-trihydroxy-i ^ (- tetrahydropyranyloxyprost k- in-13-trans-en

6 | ^ ethyl-1,6 | , OfC-trihydroxy-ll ^ .l ^ -bis-tetrahydropyranyloxy ^ O-bisnorprost - ^ - in-13-trans-en

6 l-methyl-1,6 ^ _t 9iC-trihydroxy-ll _e (, 15 _e (-bisetrahydroiyranyloxy-20-norprost- ^ f-in-13-tans-en

6 ί, 20-dimethyl-l, 6? , Si <-trihydroxy-ll ^, l ^ j (_bistedrahydropyranyloxyprost 4-in-i3-trans-ene

1.6Λ, 9 / -Trihydroxy-llo (, ISet-bistetrahydropyranyloxy-SO-methylprost k- in-13-trans-en

¹ I ⁶ \ f9o (-Trihydroxy-11 ₀ ( _J l ^ -bis tetrahydropyranyloxy-20-ethylprost-4-yn-13-trans-ene and

116 \ 191-Trihydroxjr-llei, l ^ -bistetrabydropyranyloxy ^ O-pentylprost-4-yn-13-trans-en. :

409821 / 1132- "

Following the same procedure, using equivalent amounts of ethyl lithium and propyllithium instead of methyllithium the corresponding 6 f -ethyl and 6 c -propyl derivatives obtained.

Example IA-A

Example was lh using & ft ^ l, 9tl-dihydroergotamine ^d roxy-6-keto-lle <, 15o (-bistetrahydropyranyloxy-prost - ^ - in Tian-13-ene as the starting material, and gave% -6 i -methyl -1,6!, O ^ t-trihydro ^ y-ll ^ .l ^ -bisistrahydropyranyloxyprost- ⁱ »-in-13-trans-en (8R-antimers of V; R = tetrahydropyranyloxy; ^ r = methyl; η = 4).

In a similar way, starting from 8R-1, 9e (-dihydro ^ -6-keto-15cl-tetrahydropyranyloxyprost - ^ - in-13-trans-ene 8R-1,94-dihydroxy-6-keto-lletf 15 <{- t> is tetrahydropyranyloxy-20-bisnorprost-4-yn-13-trans-ene

Sa ^ l, ^ i-Dihydroxy-6-keto-llei, l ^ -bistetraliydropyrajiyloxy ^ O-norprostii-in-13-trans-en

8a-l, 9e (-dihydroxy-6-keto-llci,

8R-1,9 "i-Dihydroxy-6-ket ol l <rf, 15tf-bistetrahydropyranyloxy-20-ethylprost ⁱ * -in-13-trans-en and

^ R-I. ^ - Dihydroxy-o-keto-i let, l ^ f-bistetrahydroFE / Tanyloxy-20-pentylprost 4-yn-13-trans-ene

the following connections

k- in-13-trans-ene
% -6? -Methyl-l,
bisnorprost - ^ - in-13-trans-en

norprost-4-yn-13 ~ trans-en

409821/1132

• - 89 -

8R-6 |, 20-dimethyl- !, 6 | , 9 ₀ f-trihydro3q7-llo _{f {15i -bistetrahydropyranyloxyprost- ^z t-in-13-trans-ene

8R-1,6 ί ^^ - Trihydroxy-lloLlSsf-bistetrahydropyranyloxy ^ O-methylprost - 4-yn-13-trans-en

8R-1,6 *, 9e (-Trihydroxy-ll'gf, 1 ^ -bisistrahydropyranyloxy ^ O-ethylprost-4-yn-13-trans-en and

8R-1,6 I ^^ - Trihydroxy-lle ^ l ^ -bisistrahydropyranyloxy ^ O-pentylprost- ^ in-13-trans-en.
Example ' . 1 £ _

To a solution of 200 mg of 6 $ -methyl-l, 6-s ^ gf trihydraxy-iloJ, 15 ^ ⁱ i -bistetrahydropyranyloxyprost--in-13-trans-ene in 20 cc of anhydrous ether was added 1 cc of a 2,2M- Solution aus'Methyllithium in ether was added and the reaction mixture was stirred at room temperature for 3.5 hours. Then she was in an ice bath on OC. cooled and treated dropwise with stirring with 0.62 ecm acetyl chloride, whereupon 1.22 ecm pyridine was added. The resulting mixture was stirred at room temperature for 18 hours, then water was added and the product extracted with ether. The organic extracts were washed 3 times with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by thin layer chromatography using an 80:20 mixture of methylene chloride and ether; This gave Si- 41ethyl-1,6 S, ^ - triacetoxy-llet .l ^ -bis-tetrahydropyranyloxyprost-4-yn-13-trans-ene (VI; R = tetrahydropyranyloxy; R ^ = methyl; η = k) and 6 I -Methyl-1, 9of-diaeetoxy-6 C-hydroxy-11 tf, ^ -bisistraJiydropyranyloxyprost-4 ~ in-13-trans-en (VII; R = tetrahydropyranyloxy; R ^ = * methyl; η = * 0.

409821/1132

In a similar manner, starting from 6 f -methyl-1,6 i , S ^ -trihyd.roxy-15e (-tetrahydropirranyloxyprost - ^ - in-13-trans-ene

-l, 6i, 9 ^ (-trihydroxy-ll | ( _f ^ -bis-tetrahydropyranyloxyprost-4-yn-13-trans-ene
_6 j-Propyl-1,6 ϊ, 9j [-trihydiOxy-lltf, l ^ -bis-tetrahydropyranyloxyprost-

6 f -Methyl-1,6 £, 9 ^ -trihydroxy-lle (, 15 ^ -bis tetrahydropyranvloxy-20- -üsnorprost-4-in-l 3-trans-en
.. "6 l-methyl-1,6 l ^" (- tri

norprost-4-in-13-trans-en
- ~ 6i _t 20-dimethyl-l, 6 \ , ^ - tri

4 ~ in-13-trans-ene

6 * -Methyl-1,6>, 9e (-trihydroxy-1 1 ^ 15o (-bisistrahydrq3yranyloxy-20-methylprost- ^z i-yn-13-trans-ene

6 f -Methyl-1,6 ί, 9 /, - trihydroxy-lloC, 15o (-bisetrahydrcpyranyloxy-20-ethylprost- ^ i- in-13-trans-en and

6-methyl-1,6 1.9T (trihydroxy-ll | (15e (-bistetrahydropyranyloxy-20 pentylprost- ² * -in-13-trans-en

the following connections

6> -Methyl-1,6 j, 9 ^ -triaceto3qy-15 ^ -tetrahydroFörraiiyloxyprost-4-yn-13-

trans-ene and 6 | -i-lethyl-1, 9rf-diacetoxy-6 f-hydroxy-15 ^ -tetrahydro pyranyloxyprost-A-in-13-trans-ene

6 j-ithyl-1,6 ", 9 ^ -triacetoxy-llei, 15D <-bis-tetrahydropyranyloxyprost-

4-yn-13-trans-ene and 6 l-ethyl-1,9 «i-diacetQxy-6 i-hydroxy-ll ^, l ^ (- bistetrahydropyraiiyloxyprost-4-yn-l 3-trans-ene 6 J - Propyl-1,6 ^, 9 ^ -triacetoxy-lle ( _f l ^ iJ-bistetrahydropyranyloxyprost-

4-yn-13-trans-ene and 6 S-propyl-l, 9tt-diacetoxy-6 | -hydroxy-ll # <, 15A-

bistet rahydropyranyloxypro s ΙΛ- in-13- trans-en

409821/1132

6 I -methyl-1,6 1,9 ^ -triacetoxy-lltf »lM-distrahydropyranyloxy-20-

bisnorprost - ^ - in-13-trans-en and 6 i-methyl-l ^ -diacetoxy-o f-hydro ^ - ll ^, 15dt-bistetrahydroFryranyloxy-2G-bisnorprost-4-yn-13-trans-en 61 -Methyl-1,6 f, 94-triacet oxy-11 Jt, Ι ^ ζ, -bisetrahydropyrany loxy-20-

norprost - ^ - in - ^ - trans-en and 6 T-methyl-l, 9j £ -diacetoxy-6 \ -hydroxy-.

11 ^, 1 ^ -bis-tetrahydrop5yτanyloxy-20-norprόst- ² ^ -in-l 3-trans-en

6 \, 20-Dimethyl-l, 6 % ^^ - triacetoxy-H ^ slSeC-bistetrahydropyranyloxypropst-4-yn-13-trans-2 · and 6 1,20-diraethyl- "l, 9oi-diacetoxy-6 C- hydroxy-ll ^, 15 <bistetrahydropyranyloxyprost - ^ - in-13-trans-en 6 <-Methji-l _t 6 ", 9 ^ -triacetoxy-ll | (, l ^ -bisistrahydroRyranyloxy-20-äthylprost-4-in 13-trans-ene and 6 <-Methyl-1,9rf-diacetoxy-6 | -hydroxyll <(, 15i (-bis (-bis-tetrahydropyranyloxy-20-ethylprost - ^ - in-13-tPans-2n and 6> -Methyl-1, 6c, 9 ^ -triacetoxy-lljfe 15g ^ -bis-tetrahydropyranyloxy-20-pentylprost- ^/ l-yn-13-trans-ene and oi-methyl-l ^ af-diacetoxy-o l-hydroxylldt, 15 ^ -bis-tetrahydropyranyloxy-20 -pentylprost- ² 4-in-l 3-trans-ene.

Example 15-A

Following the procedure of Example 15 using 8R-6 J-methyl-1,6 c, ^ - trihydroxy-ll ^, 15 | (-bisetrahydropyranyloxy-prost-4-yn-13-trans-ene as starting material 8R-6 $ «methyl-1,6 f, ^ gZ-triacetoxy-llii, 15 ^ -

bistetrahydropyranyloxyprost- ² f-in-13-trans-en (8R-antimers of VI; R ^ '=

I ¹ C

Methyl; R = tetrahydropyranyloxy; η = k) and 8R-6 1 -Methyl-1, ^ f-diacetoxy-

ς ~ ■ ~ * f

6 \ -hydroxy-llst, 15ot-l> istetrahydropyranyloxyprost-4-yn-13-trans-en (8R-

Antimers of VII, R ⁵ '= methyl, R ¹ ' = tetrahydropyranyloxy; η = ^ J-).

Similarly, starting from 8R-6 J -Methyl-1,6 |, ^ -trihydroxy-l ^^ tetrahydropyranyloxyprost-ii-in-l ^ - trans-en

8R-6 | -Ethyl-1,61,9 ^ -trihydroxy-llite, 15e (-bisetrahydropyranyloxyprQst-4-yn-13-trans-en '

409-02.1 /.KtS? , ν

8R-6 \ -P ropyl-1,6 1, 9 «(- trihydroxy-.l lei, 15A-bistetrahydropyranyloxyprost-4 ~ yn-13-trans-ene
8R * 6 ί-methyl-1,6

bisnorpro ^s t - * 4-in-13-trans-en

norprost-ij-in-13-trans-en

®-6 J, 20-diraetlyl-l, 6 ί, 9 ^ -trihydroxy · - lldt.l5A-bistetrahydropyranyIoxyprost- ⁱ l-yn-13-trans-en

aft-6 | -Methyl-1,6 ί _f ^ -trihydiOxy-llo {, 15e (-toistrahydropVTanylo3Qr-20.-roethylpropst-4-yn-13-trans-ene

8R-6 ^ -Methyl-1,6 | _f 9 ^ -trihydro3qr-llet, 15 (| -t> istetrahydropyranylO3Qr-20- _äthylprost-4-yn-13-trans-en and
& L-6 $ -Methyl-1.6 $
pentylprost - ^ - in-l3-trans-en
the following connections
8R-6> - * lethyl-1,6 <, ^ K-

13-trans-ene and ^ -6> -ilethyl-1, 9y (-diacetoxy-6 j -hydroxy-15fl (-tetrahydro Tpyranyloxyprost-A- in-13-trans-ene

& L-6 c-ethyl-1,6!, ^ - triacetoxy-llif ^^ - bistetrahydropyranyioxyprost-4-yn-13-trans-ene and 8R-6 i-ethyl-l,% f-diacetaxy-6 $ -hydro3qr -lle / _t l ^ (- bistetrahydropyranyloxyprost- ⁱ f-in-13-trans-en 8R-61 -propyl-1,6 I. ^ C-tri

4-yn-13-trans-ene and 8R «-6i -propyl-l _# 9e (-diacetoxy_6 F-bistetrahydi'opyranyloxypfost-4-yn-13-trans-ene ^ -6 | -Methyl-1,6 |, ^ (- triaeetoxy-lleltl ^ rbisternrahydropyranyloxy-ao-

bisnorprost-4-yn-13-trans-ene and% -6 J -methyl-1, 9g-diacetoxy-6 l ^ mt.l5Ä-bistetrahydropyranyioxy-20-bisnorprost-ij- in-13-trans-ene 8R-6ί ^! ethyl-1,6 ί, 9 ^ -triacetoxy-ll ^, lä (-bisetrahydropyranyloxy-20-

norprost-4-yn-13-trans-en and% * - 6 {^ lethyl-l _f 9it-diacetoxy-6f-hydroxy-

-T- 409821/1132

, 15 ^ -bis-tetrahydropyranyloxy-20-norprost- ⁱ f-in-13-trans-en 8R-6 ί, 20-dimethyl-1,6 | , S ^ -triacetoxy-llei.lSot-bistetrahydropyranyloxyprost - ^ - in-13-trans-en. and 8R-6 ί, 20-dimethyl-l, 9 "t-diacetoxy-6 f -hydroxy-1Ü 1 15et-bistetrahydropyranyloxypropst- ¹ » ^ in-l3-trans-en 8R-6i-methyl-1,6 ί, ^ t-triacetoxy-lliijl ^ -bisistrahydrc ^ yranyloxy ^ O-äthylprost- ² <-in-13-trans-en and 8R-6 X -Methyl-1, 9rf-diacetoxy-6 C-hydroxy-H ^ Li 15frt » istetrahydropyrarisrloxy-20-äthylprosti4'-in-13-trans-en and% -6 ii-lethyl-1,6 ^, 9 / _r triacetoxy-lle (, 15 ^ - ^{bistetr £} ^ ^c ^ ^o P! y ^ran y ^{lo : x} y- ²⁰ -pentylprost- ^J 4-yn-13-trans-ene and 8R-6 € -methyl-1,9 ^ (- diacetoxy-6 f ^ -hydroxyllot, 15 ^, - bis trahydropyranyloxy-20-pentylprost - ⁱ l-in-'13-trans-en.Example 16

• A suspension of 117.5 mg cuproiodide in 2 ecm anhydrous Xther was brought to about -10 ° C with stirring and under an argon atmosphere. cooled and treated with 2 molar equivalents of a 2M solution of methyllithium in ether. The colorless solution was cooled in a dry ice bath to -70 ⁰ C., then a solution of 100 mg of 6-methyl-1,6 Z {, o ° (-triacetoxy-ll '(15 ^ ⁱ i -bistetrahydropyranyloxyprpst- -in-13-trans-ene in 3 ecm of anhydrous ether was added and the reaction mixture was stirred for 5 hours at -70 ° C. The temperature of the mixture was increased to −10 ° C., a saturated ammonium chloride solution was added and the mixture . stirred for 1 hour and extracted with ether The organic extract was washed with saturated sodium chloride solution, evaporated, dried over magnesium sulfate and concentrated under reduced pressure to dryness, then one received 6-ilethyl-l 9j (diacetoxy-ll _l (, 15y _(k - bistetrahydropyranyloxyprosta-i> -, 5,13-trans-triene (VIII;

5 Ii -

R = H; R- '= methyl; R = tetrahydropyranyloxy; η = k) .

Similarly, by using 6> -Methy1-1.6 C, 9 ^ -triacetoxy-15 ^ -tetrahydropyranyloxyprost-4-yn-13- ' trans-en ■ "-

409821/1132

61 -ethyl-1,6 l, 9 ^ -triacetoxy-llei, lSd-bistetrahydropyranyloxyprost- k- in-13-1 ran s-en

6 $ -Proparl-'l, 6 {^ -triacetoxy-lltf. ^ - bistetrahydropyranyloxyprost- ^ -in-13-trans-ene

6 J -Methyl-1,6 ί, 9 * i-triacetoxy-lle (, 15d-bistetΓahydΓopyΓanyloxy-20-bisnorprost- ^ - in-13-trans-en

61 methyl-1,6 | , 9 /, - triacetoxy-llei, ^ ol-bistetrahydropyranyloxy ^ O-norprost-4-yn-13-trans-en

6 f, 20-Dimethyl-1 | 6 f, Q ^ -triacetoxy-Hd »15 ^ rbistrahydrop5rranyloxyprostn-13-trans-en

-Methyl-1,6 ί, ^ - triacetoxy-llel, 15j (-bisetrahydropyranyloxy-20-ethyl-

prost-4-in-13-trans-ene and

6c -Methyl-1,6 c, ^ fc-triacetoxy-ll ^, 15 ^ -bisetrahydropyranyloxy-20- " pentylprost - ^ - in-13-trans-en

instead of ναι 67-methyl-1,6 {, ^ - triacetoxy-llet.lSel-bistetrahydropy.ranyltHcyprost- ^ · -in-13-trans-en the following connections

6-methyl-l, 9i (-diacetoxy-15 _< (-tetrahydro-pyranyloxyprost-4 _f 5 _f 13-trans-triene 6-ethyl-l, 9i (-diace toxy-1 let, 15 / f-bistetrahydropyranyloxyprosta- ^ , 5,13-trans-triene

6-Propgrl-l, 9 ^, - diacetoxy-llei, 15rf-bistetrahydropyranyloxypropsta-4,5,13-trans-triene

6-methyl-l, 9 "i-diacetoxy-ll _l (, 15dl-bistetrahydropyranyloxy-20-bisnorprosta ⁱ * 't5il3-trans-triene

6-ilethyl-l, 9 * (- diacetoxy-ll »c, 15 * t-bistetrahydropyranylQxy-20-norprosta-

6,20-dimethyl-l, 9ii-diacetoxy-ll ti, l ^ -bis-tetrahydropyranyloxyprosta- ^ 5 »13-trans-triene

6 ^ ethyl-l, 9i (-diacetoxy-lle (, 15flt-bistetrahydro-p3rranyloxy-20-ethylprosta- ^, 5 »13-trans-trien and

4 0 9 8 2 1/113 2

641ethyl-1,4-diacetoxy-Hoi, 15o (-bisetrahydropyranyloxy-20-pentylprt> sta-4,5,13-trans-triene.

Example 16 ~ A ...

Following the procedure of Example 16 it becomes 8R-6 | -Methyl-1,6 | ₁ 9o (-triacet-

oxy-llei. 15 ^ -bis tetrahydropyranyloxyprost- ¹ i - in-13-trans-ene in 8R-6-methyl-1, 9 ^ -diacetoxy-l 1 «(, lS ^ -bis-bis-tetrahydropyranyioxyprosta- ^, 5,13-trans-triene

ς

converted (8R-antimers of VIII; R = H; ψ - methyl; R - tetraliydropyranylöxyj η = k) »

Similarly, starting from the corresponding 8R-6 «- alkyl-1,6? ^^ - triacetoxyprost - ^ - in-lS-trans-ene-compounds the following compounds 8R-641ethyl-1 _t 9 _c (-diacetoxy-15 ^ -tetrahydropyranylöxyprosta - ^, 5ii3-ti * äns- trien 8R-6-Ä thyl-1, Syt-diaeetöxy-lii ( _f i ^ -bisetrahydropyranyloxyprosta- ^ i5t13-trans-trien ^ -orPropyl-l, 9i (-diacetoxy-lli (, l ^ -bistedrahydropyranyloxyprosta- ^ »5,13-trans-trien 8Ä-6-4iethyl-l _# 9eC-diacetoxy'-lle (* l ^ (- bistetrahydropyranyloxy-20-bisnorprosta- ² ! -, 5,13-trans-triene 8R-6-methyl-l, 9 ^ diacetoxy-llj (, lS ^ f-bistetrahydropyranyloxy-ZO-norprosta b , 5,13-trans-triene ^ -o ^ -Dimethyl-l ^^ diacetoxy-lleClSef-bistetrahydropyranyloxyprosta- ^, 5 »13 ^ trans-triene ^ -6-methyl -l, 9 / -diacetoxy-ll J, l ^ f-bistetrahydropyraiiylöxy-20-äthyl ^ prosta-Λ, 5,13-trans-triene and

, 9 <-diacetoxy-ll ^ l5 ^ -bistetraliydropyi'anyloxy-20-p-entyl-, 5,13-trans-triene.

409821/1132

A mixture of 110 mg of 6-methyl-l,. ^ - diacetO3? Y-llrf »l - ^ [- bistetralTydj; o | iyra- -n5 ^r ioxyprost- ² 4-, 5,13-tra« s-trien , 50 mg of anhydrous potassium carbonate and 2 ecm of anhydrous methanol were stirred for 18 hours under an argon atmosphere at room temperature. The solvent was then eliminated under reduced pressure, water was added and the product was extracted with ether. The ether extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure; in this way one obtained δ-methyl-l ^ ot-dihydroxy-llotiSBC ^ istetrahydropyrany loxypros t a- * f-, 5 »1 3- trans-triene.

After oxidation of the last-mentioned compound with 8N-chromic acid and subsequent hydrolysis of the tetrahydropyranyloxy functions with aqueous 65 ^ acetic acid according to the procedure of Example 5, 6-methyl-9-keto-Il «t.l5 <-dihydroxyproe% a- ^, 5,13-trans-irienoic acid (XI; β = H; R = hydroxy; R ⁵ = methyl; η = 4), *

In a similar way, starting from 6-methyl-l, 9 * <- diacetoxy-15i (-tetrahydropyranyloxyproöta-4 _> 5,13-trans-triene 6-ethyl-l, 9 ^ -diacetoxy-l IeC ₁ i 54 - bistrahydropyranyloxypros ta-4,5,13-trans-triene

6-propyl-l, 9 "t-diacetoxy-IIK, ISet-bistetrahydropyranyloxyprosta-'ij., 5,13-trans-triene

6-methyl-l, 9fli-diacetoxy-li ^, ISet-bistetrahydropyranyloxy-ao-bis-norprosta- ^ f 5 "13-trans-trien"

4 »5» 13-trans-trien

6,20-dimethyl-l, 9o (-diacetoxy-llei,
■ 4 "» 5113-trans-triene

6-methyl-l, 9 <i-diacetoxy-llÄ, ls ^ -bis-bis-tetrahydropyranyloxy-ao-ethylprosta ^ -1 5 «13-trans-triene and

- 409821/1132

6-methyl-l, 9 * -diacet oxy-ll «f, iSefc-bistetrahydropyranyloxy ^ O-pentylprosta-

the following end products

6-methyl-9-keto-l ^ -hydroxyprosta- ^ ·, 5,13-trans-trienoic acid 6-ethyl-9-keto-l 1 * 1,15 ^ -dihydroxyprosta- ^, 5> 13-trans-trienoic acid 6-propyl-9-keto-llel, l ^ Jk-dihydroxyprosta- ^, 5113-trans-trienoic acid 6-methyl-9-keto-ll _e (, 15dk-dihydroxy-20-bisnorprosta- ⁱ l-, 5 »13 -trans-trienoic acid 6-methyl-9-keto-lleO lSet-dihydroxy ^ O-norprosta ^, 5,13-trans-trienoic acid 6 _i 20-dimethyl-9-keto-l lol, 15 <{- dihydroxyprosta-4, 5113-trans-trienoic acid 6-methyl-9-keto-LLJ (, 15ft-dihydroxy-20-äthylprosta- ⁱ f, 5 '13-trans-trienoic acid, and 6-methyl-9-ke to-11 "C, 15 < -dihydroxy-20-pentylprosta- ^ -, 5 , 13-trans-trienoic acid.

Example 17-A

Example Y] was repeated using 8R ~ 6-methyl-l, 9-diacetoxy-II (£, 15 ^ -bisetrahydropyranyloxyprosta- ⁱ t - ', 5tl3-trans-triene as the starting compound, whereby the £ R - $ - * Ethyl-9-keto-II «{ ₍ 15« iL-dihydroxyprosta-4,5,13-trans-trienoic acid (8R-antimers of XI ^ R = H; R = hydroxy; R = methyl; η = K) as Final product received. '

In a similar way, starting from the corresponding 8R-6-alkyl, 9etdiacetoxy-15rf-tetrahydropyranyloxy- or -IIIH.lScirbis-tetrahydropyranyloxyprosta- ⁱ <-, 5.13-trans-triene compounds, the following end products & ^ - 6-methyl-9- keto-15c (-hydroxypro sta- ^, 5,13-trans-trienoic acid ^ -6-ethyl-9-keto-11 ^ <, 15 * -dihydroxyprosta-4,5,13-trans-trienoic acid ^ -6-propyl -9-keto-llot, 15o (-dihydroxyprosta- ^ _l 5, i3-tans-trienoic acid & ^ - 6-methyl-9-keto-l lot, 1 S ^ -dihydroxy ^ O-bisnorprosta- ^, 5.13 -trans-trienoic acid% -6-methyl-9-keto-llcl, 15 ^ -dihydroxy-20-norpro3ta - ^, 5,13-trans-trienoic acid ER-6,20-dimethyl-9-keto-l IeI, 15 * -dihydroxy.prosta-'t »·, 5,13-trans-trienoic acid m-6-methyl-9-keto-ll ^ _f 15 * -dihydroxy-20-ethylprpsta-4-, 5,13-trans-trienoic acid and . . . ., "

--- 409821/1132

8R-6-methyl-9-keto-l 1 *, 15rt-dihydroxy-20-penty lprosta-Λ, 5113-trans-trienoic acid.

Example 18

A solution of 100 mg of 6 i -methyl-1,6 £, ^ - triacetoxy-lloCl ^ - 'bistetrahydropyranyloxyprost- ⁱ l ~ in-13-trans-ene in 3 ecm of anhydrous ether was on OC. cooled and treated under an argon atmosphere with one molar equivalent of Litihiumdimethylkupfer (prepared according to Example 7, Part A.). The reaction mixture was ^{stirred for 5 hours at 0} ° C., a saturated ammonium chloride solution was added and the mixture was stirred for 1 hour and extracted with ether. The organic extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on Florisil. The fractions eluted with 80:20 methylene chloride ether yielded the pure Ij-.ö-dimethyl-l.SJfA-diacetoxy-llet, ^ tfl-bistetrahydropyranyloxyprosta- ^, 5,13-trans-triene (VIII; R and. R ⁵ = Methyl; R = tetrahydropyranyloxy;

Similarly, the use of 6 gave z-methyl-1,6 | ^ / rtriacetoxy-lSiC-tetrahydropyranyloxyprost-A-yn-13-trans-ene

6 ζ -ethyl-1,6 *, 9dt-triacetoxy-1 lrf, 15 ^ -bis-tetrahydropyranyloxyprost-4-yn-l3-trans-en

6 T-Propyl-1,6 ι, 9 ^ -triacetoxy-II ^, ^ ci-bistetrahydropyranyloxyprost-4-yn-13-trans-en

6 | -Methyl-1,6> , 9 ^ -triacetoxy-l 1 ^, 1 S ^ bistetrahydropyranyloxy ^ O-bisnorprost-4-yn-13-trans-en and

6 V -Methyl-1,6 ί, 9 ^ -triacetoxy-lI ₀ J, l ^ -bisistrahydropyranyloxy ^ O-ethylprost - ^ - in-13-trans-en

as starting materials the following compounds 4,6-diraethyl-l, 9 ^ -diacet oxy-15 ((t-tetfcahydropiyranyloxyprosta- ^, 5,13-trans-crien

- 4 09821/1132 "

- Hot »IS ^ -t-istetrahydropyfaiiyloxypiOsta- ^ »5 * 13-trans-trieri

^ ethyl-6-propyl-I, 9 ^ IaCStOXy-Ilit ISD bistettfaW ^ '5113'-trans-tr ⁱ ia

^ 6-Dimethyl-l, ^ diacetoxy-ilef ^^ bistetrahydte prosta- ⁱ 4-, 5, l3-tr £ ms ^ ti'ien and '

pros ta- ^ t, 5 f i 3 ^

In a similar manner, by using 1 molar equivalent of lithiumdiatßylcupfef and lithiumdipropylcopper, atist parts of IIIithiiMdimethylkupfer 6t-methyl-1,6 f ^? , ^^ triacetö ^ -lleClSet ^ bxstetrahydropyranylo ^ pröst - ^ - in-13-trans-en in ^ -Ethyl-6-methyl-i, Stf-diäeetöxy-lltf »15e (-bis tetrahydropyranyloxyprösta-4-, 5 _t 13- trans-triene and ^ -propyl-ö-methyl-l, 9efe "diaGetoxy-ll | (, 15 _fl (converted -biötetrahydropyranyloxyprosta-4 ₄ 5" 13-trans-trien * B e is ρ ie 1 18 ~ A.

Following the procedure of Example 18, 8R-6 became c-methyl-1,6 | _# 9 ^ -triaGetoxyll ^ * 15 <C- 'bis-tetrahydfopyranyloxypröst- ⁱ 4 -'- in-i3-trans-ene in 8R - ^, 6-dimethyl-l, 9 1 i ^^ - diacetcoor-ll ^ .l ^ bis-tetrahydropyranyloxyprosta- ^, % 13-trans-triene (8R-antimers of ¥ 111; R and Br = methyl; R = tetranydropyranylöxy; η = 4) converted ». .

In ähnlieher was thus obtained by using 8R-6 I ^ Tethyl-l, 6 γ, 9 _- i-triaGetoxy-i5 _e {-tetranydropyfanyloxyprostif-in-l 3-trans-en

8R-6 J -ethyl-1,61,9 / -triacetöxy-llet, I5 <irbistrahydföpyranyloxyprost- ^ 4-in-13-trans-ene

% -6 j-Propyl-1,6 ξ ^^, ^ - triacetoxy-llot.lS ^ -bis tetrahydropyranyloxyprost- ^ -in-13-trans-ene

8R-6 ^ ^ lethyl-i, 6 ^ _r 9jKriacetoxy-i 1 *, 15 ^ -bis-tetrahydropyranyloxy-20-bis-

8R-6 ί -Methyl-1,6 ί, 9 ^ - trie cetoxy-llof, lÄi-bistetrahydropyranyloxy-20-ethylprost - ^ - in-13-trans-en

as starting materials the following compounds • 8R-4,6-dimethyl-l, ^ [- diacetoxy-l ^ -tetrahydr opyranyloxyprosta-4,5,13-trans-triene

^ - ^^ tethyl-o-ethyl-l,% (- diaeetoxy-l1e (, 1 ^ -bisistrahydropyranyloxyprosta-4,5,13-trans-triene

^ _i | ._Methyl-6-propyl-l, 9 ^ -diacetoxy-ll <j ( _f 15o (-bisetrahydropyranyloxyprosta- ^ »5113-trans-trien

^ Jf _t 6-Dimethyl-l, 9öt-diacetoxy-llol _f 15ot-bistetrahj ^I -dropyranyloxy-20-bisnorprosta- ^, 5fl3-trans-trien and

^ - ^, 6-dimethyl-l, 9oί-diacetoxy-llβί | 15ot ■ bistetrahydropyranyloxy-20-ethyl- - ^, 5fl3-trans-trien.

By using a molar equivalent of lithium diethyl copper or lithium dipropyl copper instead of lithium dimethyl copper "one got the ent speaking ^ methyl or ^ ethyl derivatives.

Example 19

Examples k and 5 were repeated using 4,6-dimethyl-l, S ^ -diacetoxyllrf, lStC-bistetrahydropyranyloxyprosta - ^^, 13-trans-triene as starting material, whereby one obtained in succession:

4,6-Dimethyl-l, 9 ^ -dihydroxy-llrf, ΐχ-bistetrahydropyranyloxyprosta-4,5i13-trans-triene

4,6-Dimethyl-9-keto-ll _i (, 15 ^ -bis tetrahydropyranyloxyprosta-4,5,13-transtrienoic acid and

4,6-dimethyl-9-keto-llo ^ 15ot-dihydroxyprosta-4,5,13-trans-trienoic acid (XI; R and R ⁵ = methyl; R ¹ "= hydroxy; n '= 4).

409821/1132

In a similar way, starting from h, 6-dimethyl-1, 9ol-diacetoxy-15 ^ -tetrahydropyranyloxypros ta-Λ, 5,13-trans-triene ^ -Methyl-6-ethyl-l, 9d-diaceto: xy -ll | i, 154-bistetrahydropyranylo3q7prosta- ^ ₁ 5 »13-trans-triene 4-methyl-o-propyl-1» 9e (-diacetoxy'-il «i, 15 # f-bistetrahydropyranylo3! y prosta- ¹ ^ t 5 * 13-trans-triene.

^ -Ethyl-o-methyl-l, 9RF-diaceto3qsr-lleJ, lSli ^{bistetrahydropiyranyloxyprosta--2} J-, 5 j 13-trans-trien ^ - propyl-6-niethyl-l, Stf-diacetoxy-ll ^, 15βJ - bistrahydropyranyloxyprosta- ^ s5813-trans-trien

prosta-4,5β 13-trans-triene tind

^ 15113-trans-triene the following compounds as end products k, 6-dimethyl-9-keto-15e (-hydroxy-prosta- ¹ <·, 5113-trans-trienoic acid ^ -Methyl-o-ethyl ^ -keto-lltf, 1 ^ -dihydroxyprosta- ^, 5,13-trans-trienoic acid 4-methyl-6-propyl-9-ketol 1 ^, 15Ä-dihydroxyprosta- ^ _s 5,13-trans-trienoic acid ^ -ethyl-o -methyl ^ -keto-lleC, 15e (-dihydroxyprosta- ^, 5,13-trans-trienoic acid 4-propyl-6-methyl-9-keto-lla {, 15 ^ -dihydroxypr.osta-4,5,13- trans-trienoic acid k, 6-dimethyl-9-keto-ll 4, lSd-dihydroxy ^ O-bisnorprosta- ^, 5 ₁ 13-trans-trienoic acid uu ^! 4-, 6-diniethyl-9-keto-ll _i t _f l5 _e {_dihydroxy-20-ethylprcBta - ^, 5 _f 13-transtrienoic acid.

409821/1132

Example 19-A

Example k and 5 were repeated using wn £ & - 4,6-dimethyl-l _f 9e (-diacetoxy- -11 *, 15 ^ -bis tetrahydropyranyloxyprosta - ^, 5,13-trans-triene as starting material, whereby one consecutively received:

8R-4,6-Dimethyl-l ^ / - dihydroxy-ll ^ .lSoi-tetrahydropyranyloxyprosta-. 4-, 5,13-trans-triene
eR_ / i. _t 6-Dimethyl-9-keto-11of, 15 ^ -bis tetrahydropyranyloxyprosta- ¹ f, 5tl-3-trans- trienoic acid and

8R-4 , 6-Dimethyl-9-keto-l 1 oi, 15 ^ -dihydroxyprds ta-4,5,13-tens-t r ien acid re (8R-antimers of XI} R and R ^ = methyl; R = hydroxy; η = ^).

- in a similar way one obtained from

-8β-Λ, 6-dimethyl-l, 9 / -diacetoxy-l 5 «(- tetrahydropyranyloxyprosta- 4,5AJ- _tr-anstrien

^ - ^ - M ethyl-6-ethy 1-1,9 «(- diacetoxy-l 1« I, lSdl-bistetrahydropyranyloxyprosta- ^ t5 »13-trans-trien - ·.

£ R_4Jiethyl-6-propyl-l, 9o (-diacetoxy-ll ^, 15 _fl f.bistrahydropyranyloxyprosta- ^ t5 »13-trans-triene
^ -4_Athji-6-methyl-l , 9 «<- diacetoxy-ll *, 15« ^ - bistetrahydropyranyloxyprosta-4 · 15tl3-trans-triene

& ^ - ^ - Propyl-6-rriethyl-l, 9 ^ -diacetoxy-ll "(, ISeJ-bistetrahydropyranyloxyprosta- ^ ^- 15113-trans- trien

BR-A-, 6-dimethyl-l, 9U-diacetoxy-llei, 15ef-bistetrahydropyranyloxy-20-bisnorprosta - ^. Si13-trans-triene and

8R-J »-, 6-dimethyl-l, 9A-diacetoxy-llaί, i5βt ■ bistetrahydropyranyloxy-20-äthylprosta-Λ, 5.13-trans-triene

the following end products as starting material:

- € ß-4,6-Dimethyl-9-keto-15 _e (-hydroxyprosta- ^, 5,1.3-trans-trienoic acid% -44! Ethyl-6-ethyl-9-keto-llci, 15Ä-dihydroxyprosta-4 , 5,13-trans-trienoic acid 8R-4Ji'ethyl-6-propyl-9-keto-llol _f 15c (-dihydroxyprosta- ^, 5,13-trans-trienoic acid Ä-methyl-9-keto-l 1A, 15ot-dihydroxyprosta-4,5,13-trans-trienic acid

409821/1132

Eäl-M-däinethyl-9-keto-ll '*, 15 <Ä-dihydroxy-20-bisnorprosta- ^, 5,13-transtrienoic acid and

8R-4,6-dimethyl-9-keto-ilot, 15d-dihydro3? Y-20-ethylprosta-4,5,13-transirienoic acid.

example 20th

A solution of 453 mg of 6-methyl-l, 9 * l-diacetoxy-ll «l, 15i (-bisetrahydropyranyloxyprosta-4,5,13-trans-triene in 5 ecm of methanol was cooled to -10 ° C. and under a Argon atmosphere treated with 1.1 molar equivalents of potassium carbonate. The reaction mixture was stirred for 6 hours at -10 ° C * and then evaporated to dryness under reduced pressure; water was added and the product was extracted with ether. The ether extract was washed with saturated sodium chloride solution, evaporated dried over magnesium sulfate and concentrated under vacuum to dryness. the residue was purified by thin layer chromatography and gave the pure 6-methyl-9o <-acetoxyliet ^»1 5 ^ .- bistetrahydropyranyloxyprosta-A-, 5" 13-trans-trien-l-ol (XII, R - H,

'S. = Methyl; R = tetrahydropyranyloxy; η = k).

Oxidation of the above compound with 8N-chromic acid according to the procedure of Example 5 gave 6-methyl-9oi-acetoxy-lloi, 15ot-bistetrahydropyranyloxyprosta-4 _t 5,13-trans-trienoic acid (XIIIj R = H; R ^ = methyl ; R = tetrahydropyranyloxy; η = k).

A mixture of 300 rag 6- ^ ethyl-9 ₉ i-acetoxy-ll ^ i, 15o (-bisetrahydropyranyloxyprosta-4,5,13-trans-trienoic acid, 5 ecm anhydrous methanol and 150 mg

anhydrous potassium carbonate was stirred for 18 hours / at room temperature under an argon atmosphere.

Then the solvent was eliminated under reduced pressure, it became Added water and then acidified with acetic acid. The product was extracted with ether and the organic extract with saturated sodium chloride solution washed, dried over magnesium sulfate and under reduced

409821 / T 132

Pressure evaporated to dryness; This gave 6-methyl-9et-hydroxyllbl, 15JL-bistetrahydropyranyloxypro; sta- ^ 4,5,13-trans-trienoic acid (XIV; R = H; R ^ = methyl; R = tetrahydropyranyloxy; η = 4).

A solution of 50 mg 6-41ethyl-9e (-hydroxy- 1.lol, 15 "l-bistetrahydropyranyloxyprosta-4,5,13-trans-trienoic acid in 0.15 ecm tetrahydrofuran was with 1.3 ccm 65- ^ iger The reaction mixture was stirred for 4 hours at 45 ° C., ^{cooled to 0} ° C. and evaporated to dryness under reduced pressure; the oily residue was purified by thin layer chromatography using chloroform: methanol (9: 1) as the eluent purified and delivered the pure 6-methyl-9ol llet, 15 * t-trihydroxy-

c in

prosta-4,5,13-trans-trienoic acid (XV; R = H; R-methyl; R = hydroxy;

In a similar manner, the use of 4,6-dimethyl-1,9 «i-diacetoxy-l 54, - tetrahydro pyranyloxyprops ta-'f, 5» 13-trans-triene k, 6-dimethyl-l, 9 «(-Diaoetoxy- Hol, 15,1-bistet rahydropyranyloxypr osta- ^ i 5113-trans-trien

^ -Methyl-ö-ethyl-l, 9 ^ -diacetoxy-ll ^, lSJrbisetrahydropyranyloxyprosta-

² * -t5 » ¹ 3-trans-triene ■

4-Kthyl-6-propyl-1 ^ «(- diacetoxy-llel, 1501-bistetrahydropyranyloxyprosta- ^ »5ι13-trans-trien

4-ethyl-6-methyl-l, 9 "(- diacetoxy-l 1Λ, 15" (- bistetrahydropyranyloxyprosta-4,5,13-trans-triene

VPropyl-6-methyl-l, 9t (-diacetoxy-II V, 15c (-bisetrahydropyranyloxyprostä-4,5,13-trans-triene

4,6-dimethyl-1,9 "(-diacetoxy-l 1, {, 15 ^ -bis-tetrahydropyranyloxy-20-bisnorprosta-4,5,13-trans-triene and

4,6-dimethyl-l, 9A-diacetoxy-ll » _t 15 * -bisetrahydropyranyloxy-20-ethylprosta-4,5» 13-trans-triene

■ - 409821/1132

- 1Oi -

the following end products as starting material:

k " 6-D ± m.ethjl-9di HeIUl 5" Ä-trihydroxyprosta-Λ _% 5A 3-trans-trienoic acid 4-4iethyl-6-ethyl-9ei, 11%. 15 ^ -trihydroxypro sta-Λ, 5,13-trans-trienoic acid ^ ethyl-6-proiyl-9a, ll *, 15a-trihydroxyprosta- ^, 5 »13-trans-trienoic acid 4-ethyl-6-methyl -9d "^ I- * * * 5.et-tr ihydroxyprostä- ^, 5113-trans-trienoic acid ^ -propyl-ö-raet 1 ^ 1-9 ^ ,, llet, 15s | -trihydropxyprosta-4, 5 _f 13-trans -trienic 4.6 ~ dime thyl-9RF, 1 l "t" 154 ° tr iigrdroxy-2NC-bisnorprosta- ^z * ', 5 "13-trans-trienoic acid, and

4 ₀ S-Dimethyl-9eif 1 Id ^ l Sa-trihydroxy ^ O-ethylprosta- ^ f, 5 , 13-trans-trienoic acid. Example '2Q-A

Example 20 was repeated using 8R-6-methyl-l, 9e {-diaceto3! Y-llei, 15e (-. I) istetrahydropyranylo2yprosta-Λ, 58l3-trans-triene as starting material and thus provided the ^ -6-MetlQrl -9 ^, lle (, 15 <-trihydroxyprosta- ⁱ <-, 5 _l 13-

ς 1 "

trans ~ trienoic acid (£ R-antireate of XV; R = H $ R ^ = methyl; R = hydroxy;

_n = yy.) as the end product. ·

In a similar way, using 8R-4 ₉ 6-dimethyl-l "9e (-diacetoxy-15ei-tetrahydropyranyloxyprosta-

^ 85 «13-trans-trien"

o ^ - ^ f, 6-dimethyl-l, 9ei-diacetoxy-l lot, 154-bistetrahydropyranyloxyprosta- ^ «5 * 13-trans-trien

^ - ^ ■ -Methyl-6-ethyl-l, 9 «t-diacetoxy-l 1 jsf _e 15ai-bistetrahydropyranyloxy prost a- ^. 5 »13-trans-trien

£ R-4-ethyl-6-propyl-l, 9ot-diacetoxy-ll «, 15 <{- bistetrahydropyranyloxyprosta-4-, 5.13-trans-trienes

^ - ^ - Ethyl-o-methyl-l ^ J-diacetoxy-lloi.lSef-bistetrahydropyranyloxyprosta- ^ 15 »13-trans-trien

% -4-Propyl-6-methyl-l, 9 _t f-diacetoxy-llqi _f l-5 ^ -bis-tetrahydropyranyloxyprosta-4 ·, 5j 13-trans-triene

409821/1132

8R- ^, 6-dimethyl-l ^ "* - diacetoxy-llei, 15, {- bistet rahydropyranyloxy-20 -bisnorprosta- ^, 5,13-trans-triene and

prosta - ^, 5,13-trans-triene

the following end products as starting material:

8Β.-Λ , o-dimethyl- ^, 1 sol-dihydroxyprosta- * »-, 5« 13-trans-trienoic acid aR-Λ, 6-dimethyl-9 ^ _f 11β (, 15 «4-1 rihydroxyprost a- ^ , 5 "13-trans-trienoic acid & ft ^ - * iethyl-6-ethyl-90 <, 11X, 15" C-trihydroxyprosta-4,5,13-trans-trienoic acid 8K-4-ethyl-6-propyl -9j _f Hell ^^ trihydroxyprosta- * »', 5,13-trans-trienoic acid ÖR _ ^ _ Ethyl-6-methyl-9el, 1 lelt 15drtr ihydroxyprosta-4,5,13-trans-trienoic acid 8R-Λ-propyl -6-me thy l-9 "(, HoU 15" t-trihydroxyprosta- ^, 5,13-trans-trienoic acid

acid and

^ -Λ, 6-diethyl-9 ^ sί »ll't, 15 ^ -trihydroxy-20-äthylprosta- ^ί ^ _f 5,13-trans-trienoic acid.

Example 21

Excess ethereal diazomethane was added to a solution of 500 mg of 9-keto-11, 15 "t-dihydroxyprosta- ^, 5" 13-transtrienoic acid in 10 ecm of methylene chloride and the reaction mixture was kept at room temperature for 30 minutes. Then it was evaporated to dryness in vacuo and yielded the 9-keto-IIW, 15fcdihydrcsxyprosta-4.5 _{tons of} 13-trans-trienoic acid methyl ester.

The above crude compound was dissolved in 10 cc of methanol and the obtained Solution to OC. cooled down. 250 mg of sodium borohydride were added to the cold solution added and the reaction mixture stirred at room temperature for 30 minutes. Then the solvent was eliminated under reduced pressure, it became Added water and extracted the product with ethyl acetate. The organic extract became neutral with dilute hydrochloric acid solution and then with water washed, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel using methylene chloride / ethyl acetate mixtures

~ - 409821/1132

purified and thus yielded the methyl trihydroxyprosta- ^, 5,13-trans-trienoate and methyl trihydroxyprosta-1 *, 5,13-trans-trienoate in approximately equal amounts (XVI; R and W = H; R = hydroxy; R = methyl; η = K) .

Similarly, was obtained by use of 9-keto-15rf hydroxyprosta- ⁱ 4 _'I 5' 13-trans-trienoic acid 9-keto-15 ^{"i-hydroxy-20-i} 4- äthylprosta- 5ti3 _{t-trans-trienoic} acid 9-keto-1, 15dl-dihydroxy-20-bisnorprosta-4,5,13-trans-tenenoic acid 9-keto-llel, ISdl-dihydroxy ^ O-ethylprosta- ^, 5t 13-trans-trienoic acid 9-keto -ll «*, ^ eirdihydroxy - ^ - pentylprosta- ^, 5,13-trans-trienoic acid 'ί | -Methyl-9-keto-li ^ <, 15dl · dihydΓoxyprosta-4,5, l3-trans-trienoic acid 6- Methyl-9-kefco-llol, 15 _e (-dihydroxyprosta-4 _f 5,13-trans trienoic acid and ί ^ -propyl-6-methyl-9-keto-liol _t 15ot-dihydroxyprosta- ⁱ , 5t 13-trans -trienoic acid as starting material the following compounds:

9oi "15 <- ^D i ^h ydroxyprosta-A, 5tl3 trans triensäureraethylester and 9SS" 15p (-E) - hydroxyprosta- ^, 5A 3-trans-trie acid methyls art.

9 "(i l5o (-dihydroxy-20-ethylprosta- ^, 5" i3-trans-trienoic acid methyl ester and 9ß, 15e (-dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid methyl ester; 9et 11 ot, 15 Jt-Trihydroxy-20-bisnorprosta- ⁱ <, 5113-trans-trienoic acid methyl ester and 9β, ÜA, 15o (-Trihydroxy-20-bisnorprosta-4,5,13-trans-trienoic acid methyl ester; 9e (, il «tt l ^ ol-trihydroxy ^ O-ethylprosta- ^, 5,13-trans-trienoic acid methyl ester and 9ß _> lloi _# 15 «i-trihydroxy-20-ethylprosta- ⁱ 4- _t 5,13-. trans-trienoic acid methyl ester; 9rft 11 ei, 15c (-Trihydroxy-20-pentylprosta-i | -, 5,13-trans-trienoic acid methyl ester and 9ß, 1 Id, 15 «(- trihydroxy-20-pentylprosta-Λ, 5,13-trans-trienoic acid methyl ester; ■ 4- Methyl-9 /, lloi, 15 ^ -trihydroxyprosta-i <- _f 5,13-trans-trienoic acid methyl ester and 4-methyl-9ß, 11 <A, 15e (, - trihydroxyprosta- ^, 5,13-trans- trienoic acid methyl ester; 6-methyl-9o <, 11 «, 15t * -trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester and 6-methyl-9ß-Hot» 15o (- trihydroxyprosta-4,5,13-t rans- triens acid methyl ester; and

~ - 409821/1132

- '; . -: ?? 5532A

- 108 ^ -propyl-6-inetl5rl-9o (illA, 15fll-trihydroKyprosta-if, 5,13-trans-trienoic acid- Methyl ester and i {-prop3rl-6-methyi-9ß-lle (t15A-trihydroxyprosta- ^, 5il3-transtrienoic acid methyl ester.

Example 21-A

Example 21 was repeated using EE-9-keto-11of _t i5fll-dihydro: xyprosta-Jf, 5,13-trans-trienoic acid as starting material and thus gave the following end products: 8R-9e (, llrffi5 «t-trihydro7yprosta- 4,5,13-trans-trienoic acid ethyl ester and £ R-9ß _f ll (jt, l5t trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester in approximately equal amounts (8R-antires vcai XVI; R and R = H; R ¹ " = Hydroxy; R = methyl; η = 4).

In a similar way, using {fo_9_Keto-15cf-hydroxyprosta-4,5,13-trans-trienoic acid ^ -9-keto-15ot-hydroxy-20-ethylprosta- ⁱ l-, 5-13-trans-trienoic acid 8R was obtained -9-Keto-11Q (, 15 <fc-dihydroxy-20-bisnorprosta- ² i ·, 5 »13-trans-trienoic acid

f, 5,13-trans-trienoic acid - ^^, 13-trans-trienoic acid

8R-4-methyl-9-keto-llo (, 15el-dihydroxyprosta-4,5 »13-trans-trienoic acid ^ -6-methyl-9-keto-llsll _t 15e (-dihydroxyprosta - ^, 5 _t 13-trans -trienoic acid and a-4-propyl-6-methyl-9-keto-ll ₀ i, 15 _i (Ldihydroxyprosta-4 _f 5,13-trans-trienoic acid as starting material the following compounds:

£ R-9ei, 15 "ArDihydroxyprosta - ^, 5,13-trans-trienoic acid ethyl ester and £ R-9ß-15, (- Dihydroxyprosta-4,5,13-trans-trienoic acid methyl ester; 8R-9of, ISJrDihydroxy ^ O-ethylprosta ^ -, 5,13-trans-trienoic acid methyl ester and a-9β, 15ά-dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid methyl ester; ^ - ^, ll «^ _f 15 _ö ^ -TrihydΓoxy-20-bisnorprosta- 4.5 _{t of} 13-trans-trienoic acid methyl ester and 8R-9β, Ii ^, 15ot-trihydroxy-20-bisnorprostaJ * _t 5,13-trans-trienoic acid methyl ester;

409821/1132

£ R-9öCf lld, 15d rTrihydroxy-20 äthy prosta -! *) -, 5 '13-trans-triensäureraethylester and £ R-9SS, lloi _f 15 ^ -Trihydrosy-20 äthylprosta- ⁱ i-, 5, 13-trans-trienoic acid methyl

ester;

8R ~ 9 <A 11 ^ 9 15b trihydroxy-20-pentylprasta- ⁱ i-, 5 * 13-trans-triensäuremethylester and ^ -9ß, ll 'i, 15rf, -trihydro7y-20 pentylprosta- ⁱ 4' _l 5tl3 -trans-trienoic acid methyl ester;

& -441ethyl-9ei, ll «t, 15 <it-Trihydroxyprosta-4,5 _t 13-trans-trienoic acid methyl ester and 8R-A41ethyl-9ßjllet _t 15Jt" trinydro3 ^ prosta-4, ij _s 13-trans -trienäureraethyl-

8R-6-methyl-9 * i »ll * _t 15 ^ -trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester and ^ -6-methyl-9ß , ran, 1 S ^ -trihydroxyprosta- ^, 5 , 13- trans-trienoic acid methyl esters and

8R-4-propyl-6-methyl-9oi _t ll9C, i5ef-tr ihydroxyprosta- ^, 5 $ 13-trans-trienoic acid methyl ester and 8R-4-propyl-6-methyl-9ß, llei, 15e (-trihydroxyprosta-4, 5 »13-trans-trienoic acid methyl ester.

Example 22

A mixture of 400 mg of 9 ^ - ^ 7droxy-lloi, 15e (-bis tetrahydropyranyloxyprosta-4-f5tl3-trans-trienoic acid and 60 ecm of essential diazomethane was kept at room temperature for 30 minutes. Then the solvent was under vacuum evaporated and delivered.so the 9a-5-hydroxy-11,15-bis-tetrahydropyranyloxyprosta-4,5t13-trans-trienoic acid methyl ester (XIV-A; R and R ^ = H; R = Tetrahydropyranylosy; η = 4).

The corresponding free acids were obtained in a similar manner following connections:

9at-Hydroxy-15ci-tetrahydropyranyloxypr osta-4,5,13-trans-trienoic acid methyl ester & -methyl-9c (-hydroxy-1 1 «, 15o6-bis tetrahydropynranyloxyprosta-4,5,13-trans-trienoic acid methyl ester
4,6-dimethyl-9o (-hydro3cy-15o (-te trahydrofyranyloxyprosta-ii ', 5,13-trans-

trienoic acid methyl ester

- 409821/1132

- no -

4,5,13-trans-trienoic acid methyl ester ^ -propyl-o-metal ^ l - ^ - hydroxy-llct.l ^ -bis tetrahydropyranyloxyprosta-A, 5,13-trans-trienoic acid methyl ester 9-keto-llei, 15 "(- bistetral ^ rdropyranyloxyprosta- ⁱ J ', 5,13-trans-trienoic acid methyl ester

9-Keto-15d-tetrahydropyranyloxyprosta-4, 5, 13-trans-trienoic acid methyl ester 4-methyl-9-keto-1 suffered from 15 ^ -bis tetrahydropyranyloxyprosta- ^, 5,13-trans- ^ trienoic acid methyl ester ~ 641ethyl-9-k6to_ll ^ _t 15 ^ -bis tetrahydropyranyloxyprosta-4,5 »13-transtrienoic acid methyl ester Λ, 6-dimethyl-9-keto-ll Φ, ISot-bistetrahydropyloxyprosta-Λ, 5» 13-trans-trienoic acid methyl ester 4-propyl-6-methyl- 9-keto-lliC _t 15 (fc-bistetrahydropyranyioxyprosta- ^ »5113-trans-trifinsäuremethcy: lester 9-keto-llct, lSdt-bistetrahydropyranyloxy-ZO-bisnorpros ta-Λ ₁ 5,13-ll-transtrienoic acid methyl ester 9-keto · ^ RbisternrahydroρyΓanyloxy-20-methylpΓosta- ■ ^t ^ _t 5 _f 13-tΓanstriensäureraethylester 9-keto-llei, IS'i-bistetrahydropyranyloxy - ^ - ethylprosta- ^, 5,13-transtrienoate methyl ester A-methyl - ^ - keto-llot. lSet-bistetrahydropynranyloxy-aO-ethylprosta- ^. S, 13-trans-trienoic acid methyl ester 9 * -Hydro3? y-15 << - tetrahydropyTanyloxy-20-norprosta-4,5,13-trans-trienoic acid ethyl ester

9ot-hydroxy-l 1, "15"<- Biste trahydropyranylo3qjr-20 -äthylprost a-4,5,13-trans-hydroxy-11 triensäuremethylester 9U <15cί-bistetrahydropyranyloxy-20 pentylprosta- ⁱ ^, 5,13-trans -trienoic acid methyl ester and

- A09821 / 1

- Ill -

9el-Hydrcay-15cl-tetrahydropyTanyloxy-20-ethylproesta- ^, 5f 13-transtrienoic acid methyl ester. . " Example 22-A " ■ Following the procedure of Example 22, & 3.-9tf-Hydroxy-lltf, 15 ^ bistetrahydropyranyloxyprosta- ⁴ * -, 5 »13-trans-trienoic acid in SR-S ^ -iydroxy-ll ^, 15 ^ -bis tetrahydropyranyloxyprosta-4 _f 5 _{r converted to} 13-trans-trienoic acid methyl ester (8R-Antüneres from XIVA; R and R ^ = H; R = tetrahydropyranyloxyr η = 4).

The corresponding free acids were obtained in a similar manner

-following connections:

-8R-9of-Hydroxy-15j (-tetrahydroyrany loxyprostä-4,5 »13'-trans-trienoic acid methyl ester
- ^ - 6-methyl-9 <) (- hydroxy-llo (il5e (-bis tetrahydropyranyloxyprosta-4 _t 5tl3 - methyl transtrienoate

ER-4,5-dimethyl-9oi-hydroxy-15of-tetrahydropyranyloxyprosta- ⁱ f _# 5-13-transtrienoic acid methyl ester

8R-4-methyl-6-ethyl-9 _i t-hydrox ^ llclUl5 * (- bistetrahydropyranyloxyprosta · -4 »5t13-trans-trienoic acid methyl ester

ö ^ - ^ - Propyl-o-methyl - ^ - hydroxy-lläl.lSti-bistetrahydropyränyloxyprosta- ^ i5 | 13-trans-trienoic acid methyl! ester

6 ^ -9-Keto'-ll (ii, 15i (-bis tetrahydropyranyloxyprosta-4i5,13 ^ trans-trienoic acid methyl ester

& ^ - 9-Keto-15rf-tetrahydropyranyloxyprosta-4 _t 5,13-trans-trienoic acid methyl ester.

8R-4 ^ etiiyl-9-keto-llot _t ISoi-bis.-tetrahydropyranyloxyprosta-ii ·, 5,13-transtrienoic acid methyl ester

6 ^ -64le ethyl-9-keto-l 1 «ι, 15t * -biste trahydropyranyloxyprosta-4,5,13-transtrienoic acid methyl ester

8R-4,6-dimethyl-9-keto-liotl5όt-bistetrahydropyΓanyloxyprosta-4 _i 5,13-tΓanstrienoic acid methyl ester

- 409821/1132

- 112 m 4 ~ propyl-6-methyl-9-keto-l I4, 15 ^ -bistetrahydropyranyloxypros ta-Λ, 5,13-trans-triensäuremethylester

8R-9-keto-llo (, 15 ^ -bistahydropyΓanyloxy-20-bisno3 ^ 3rosta-4 _t 5,13-transtrienoic acid methyl ester
^ _9_Keto-llol, 15d ( ₁ -t> istetrahydropyranyloxy-20-methjrlprosta-4,5,13-transtrienoic acid methyl ester

8R-9-keto-11,15-bis-tetrahydropyranyloxy-20-ethylprosta-4,5,13-transtrienoic acid methyl ester

a - ^ - methyl-9-keto-11of, 15 ^ -bis tetrahydropyranyloxy-20-ethylprosta-4,5,13-tranö-trienesäviremethylester

^ _9 ₀ ^ Hydroxy-15 _l (-tetrahydropyranyloxy-20-norprosta- ⁱ f _t 5.13-transtrienoic acid methyl ester

trans-trienoic acid methyl ester

^ -9 ^ -Hydroxy-l 1 o (, 15o (-t) iste trahydropyranyloxy-20-pentylprosta- ^ _f 5 _f 13 trans-trienoic acid methyl ester and
^ R-90 (-I ^ ⁱ droxy-15 «t-tetrahydropyranyloxy-20-ethylprosta- ⁱ <·, 5,13-transtrienoic acid methyl ester.

Example 2_3_

The examples I ₁ 2, 3, 6 (Part A) aand 22 were prepared using hydroxy-4 _'0 tetrahydropyranylioxy it-5-i3- (3 "ß-tetrahydropyranyloxyoct-l ^ll (t) -en-1?" - yl) -cyclopent-1 · «fy ^ -acetaldehyde-1,2« -hemiacetal repeated as starting material, whereby the following compounds were obtained in succession: 1,6 j, 9i <-Trihydroxy-llo (, 15ß-bistetrahydropyranyloxyprost-4- in-13-trans-en 116? t9et-Triacet03gr-lloi, 15ß-bistetrahydropyranyloxyprost - ^ - in "13-trans-en 119 ^ -diacetoxy-lloe, 15ß-bis tetrahydropyranyloxypros ta-4,5,13-trans-triene 9i (-Acetoxy-ll _i i _t 15ß-bistetrahydropyranyloxyprosta- ^ _t 5,13-trans-trien-l-ol 9it-hydroxy-lloi, 15ß-bistetrahydropyranyloxyprosta-'t <., 5,13-trans-trienoic acid and 9 «I-Hydroxy-ll ^ _f 15ß-bistetrahydropyranyloxyprosta-4 _t 5,13-trans-trienoic acid-

methyl ester (XIV-A; R and R ⁵ = H; R ¹ '= tetrahydropyranyloxy; η = 4). ~ "'409821/1132

B ice pie 1- 23-A

Example I ₀ 2 "3 ₉ 6 (part A) and 22 i-rare using I ¹ hydroxy - *! · Y-tetrahydropyranyloxy-5 'ß- (3" ß-tetrahydropyranyloxyoct-1 "(t) -en-

-acetaldehyde-! ₀ 2 ⁸ -faemiaeetal as the starting material repeated ₉ x so that the following compounds were obtained in succession: ER-1 "6 i ₀ 9 ^ -Trihydro3gr-> 114 ₉ 15ß-bistetrahydropyranylo3 ^ prost - =. 4-yn ~ 13-trans-ene
8R-1 ₈ 6 1 ₀ 9c (-T ^ iacetoxy-I1415ß-bistetrahydropyranyloxyprost - = ^ - in-l3-trans-en

s15ß-bistetrahydropyrany loxyprosta- ^ ₈ 5 _S 13-trans ~ trien-i-ol% -9 ^ -hydroxy-llo ( _{> s} 15ß-bistetrahydropyranyloxyprosta- ⁱ f _s 5 ₀ 13-trans-trienoic acid and

% -96f-Hydroxy-114 »15ß-bistetrahydropyranylo3qφrosta ■ Λ ₀ 5" 13-trans-trienoic acid methyl ester (^ -Antiraeres of XIVAs R and R ^ = H? E = tetrahydropyranyloxy; η = ^).
Example 2 ^

A solution of 500 rag 9el ~ hydroxy-11 ^ ₈ 15 ~ bis-tetrahydropyranyloxyprosta- ^> 5 ₉ 13 = trans-thienoic acid methyl ester in 10 ecm 65% aqueous acetic acid was stirred at room temperature for 18 hours, then evaporated to dryness under reduced pressure and the residue dissolved in ethyl acetate and the solvent eliminated by distillation under vacuum. The residue was purified by chromatography on 50 g of "Florisil". The fractions eluted with diethyl ether-ethyl acetate (80:20) gave the pure 9 g {, llc (, 15β-trihydroxyprosta »^, 5 _i) i3» trans-trienoic acid methyl ester (XVI ₈ R and R ^ = Hj R ¹ "= hydroxy; R ^ '= methyl; η. = *) ..

In a similar way, one obtained from the corresponding Ue *, 15c $ -Bbisrahydropyranyloxy- or 15ct-tetrahydropyranyloxy compounds as starting materials the following connections:

409821/1132

- Ι'Λ -

9ee, Heltl5 «t-Trihydroxyprosta-4- _t 5 _f 13-trans-trienoic acid ethyl ester 9JL, ISrfrDihydroxyprosta- ^, 5,13-trans-trienoic acid methyl ester 6-methyl-9er, ll« <, 15ofc-trihydroxyprosta-4 ·, 5 » 13-irans-trienoic acid methyl ester

i * - * lethyl-6-äthy l-9af _ä 11 d, 15 Λ-t rihydr oxyprosta-.il ·, 5,13-trans-trienoic acid metal ester,

^ -Propyl-o-rnetterl- ^, H «t, 15d (-trihydro3 £ yprosta-i- ₉ 5» 13-trans-trienoic acid methyl ester

9, ( _t 15 ^ -dihydroxy-20-norprosta-i {-, 5s 13-trans-trienoic acid methyl ester 94, 11 ^ 1.15 "^ trihydroxy-20-ethylpros ta-4,5,13-trans-trienoic acid methyl ester 9e (Hai, 15-trihydroxy-20-jL pentylpros ta-Λ, 5 ₁ 13-trans-triensäuienebhylester

9t (, 15et-Dihydroxy-20-äthylprosta- f ^i, _t 13 5-t3 ^ ans-triensäuremethy! Ester.

Example 24-A

According to Example 24, the £ R-9ci-hydroxy-llci _e 15β-bistetrahydropyranyloxyprosta- ⁱ 4-, 5 _t 13-trans-trienoate methyl ester in ciea 9 | ~ 9 ^ Ho {»15β-trihydroxyprosta- ^, 5,13-trans -trienoic acid met} green ester (8R-anti-

«I in ixt

meres of XVIj R and Ir = H; R = hydroxy? R = methyl; η = k) .

In a similar way, the corresponding 8R-11of, 15e (-bistrahydropyranyloxy- or & ^ - 15ot-Tetrahydropyranylo3 (3nrerbindungen the following products:

8R-9c /, ll ⁸ *! Iset-Trihydroxyprosta- ^, 5 _f 13-trans-trienoic acid methyl ester £ R-9rf _t 15o (-dihydroxyprosta- ⁱ 4-, 5,13-trans-trienoic acid ethyl ester ^> 8R-6-methyl-9e <i HeC ₁ 15ei -tr ihydroxyprosta-Λ, 5,13-trans-trienoic acid methyl ester 6 ^ -4,6-dimethyl-9 »t _t 15e (-dihydroxyprosta-4,5 _t 13-tranS-trienoic acid methyl ester 8R-4 ^ ethyl-6- ethyl-9oi, i lo (, 15oi-tr ifcQrdroxyprosta-Λ, 5,13-trans-trienene remethyl ester

8R-4-propyl-6-methyl-90 <, HoC, lSei-trihydroxyprosta-4,5,13-trans-triene-ethyl ester

409821/1132

- 115 15 dt-dihydroxy-20-norprosta-iJ- , 5 A 3-trans-trienoic acid methyl ester

8R-9el, 1W, 15 Λ-trihydroxy-20-pentylpros ta-Λ, 5,13-trans-triene acid methyl ester

and '

8R-9ei, 15dt-dihydroxy-20-ethylpro gta-Λ ₈ 5 »13-trienoic acid methyl ester.

example 25th

To a solution of 750 mg of 9 'i _t llö (, 15SS-Trihydroxyprosta- ^ _t 5tl3-trans-triensäuremethylester in 15 cc of anhydrous tetrahydrofuran, 3 g of activated manganese dioxide was added and the reaction mixture stirred for 6 hours at room temperature. The manganese dioxide was filtered off and with Acetone washed and the combined filtrates evaporated to dryness under reduced pressure The residue was redissolved in tetrahydrofuran and stirred as above with another 3 gm manganese dioxide batch, this process was repeated twice. After final evaporation of the solvent and purification of the residue was purified by chromatography on "Florisil" is the pure 9 ^ fllArDihydroxy-15 ketoprosta- ⁱ "-, 5,13-trans-triensäuremethylester (XVIIj R and ^R5 = Hj R ^1" = Hydroxyj η = ^).

By repeating the above procedure using the 9EF, lle _<f 15o ⁽ⁱ -Trihydroxyprosta- 4-, 5 _t 13-trans-triensäuremethylesters as a starting material was obtained 9oi.H "i-Dihydroxy-15-ketoprosta- ⁱ <_'f 5il3 -trans-trienoic acid methyl ester.

Similarly, from the
9 JLt 1 SoC-Dihydroxyprosta- ^, 5,13-trans-trienoic acid methyl ester 6-ethyl-9o <, lloi, 15o (-trihydroxyprosta- ^, 5,13-trans-trienoic acid methyl ester 4,6-dimethyl-9ii _f 15et-dihydroxyprosta - ⁱ i-, 5,13-trans triensäuremethylester ^ methyl-o-ethyl ^ oi, 11 ', 15e (-trihydroxyprosta-4,5,13-trans-triensäuremethylester

^ -Propyl-6-methyl-9ii, llo (, 15o <-trihydroxyprosta-i | - _f 5,13-trans-trienoic acid methyl ester

409821/1132

·, 5t 13-trans-trienoic acid methyl ester

-irihydroxy-20-ethylprosta-4,5,13-trans-trienic acid methyl ester 9ji, 11 *, 15dl-trihydroxy-20-pentylprosta- ⁱ } -, 5> 13-trans-trienoic acid methyl ester 9dt 15 ^ -dihydro3 {y-20 -äthylprosta-4,5,13-trans-trienoic acid methyl ester. 9ß, ll «t, 15 <t-trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester and 6-methyl-9β-II * U 15cl, -trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester as starting materials the following products 9el-Hydroxy-15-ke toprosta-4-, 5 _f 13-trans-trienoic acid methyl ester 6-methyl-9of1 ldl-dihydroxy-15-ketoprosta-4,5 , 13-trans-trienoic acid methyl ester 4,6-pime ■ thy.l-9βt-hydroxy-15-ketoprosta- ² ^ ·, 5t 13-trans-trienoic acid methyl ester ^ - methyl-6-ethyl-9oit H «H-dihydroxy-15-ketoprosta-4,5113-trans- trienoic acid methyl ester

4-propyl-6-methyl-9 </ t lloi-dihydroxy-15-ketoprosta-4,5, 13-trans-triensäuremethylester ·.
9JL-hydroxy-l 5-keto-20-norprosta- ⁱ · 4, 5t 13-trans-triensäuremethylester 9rftll _{"t-Dihydroxy-15-keto-20-t-4} äthylprosta 5t 13-trans-triensäuremethylester 9βί, lldL-dihydroxy -15-keto-20-pentylprosta- ⁱ 4-, 5i 13-trans-trienoic acid methyl ester 9i (-Hydro ^ r-15-keto-20-ethylprosta- ⁱ f _l 5 · 13-trans-trienoic acid methyl ester 9fiyllflC-dihydroxy-15- ketoprosta- ^/ ^ ·, 5,13-trans-trienoic acid methyl ester and 6-methyl-9ßj111-dihydroxy-15-ket oprosta- ^, 5113-trans-trienoic acid methyl ester.

Example 25-A

According to Example 25, the 8R-9 "(tlle (, 15β-trihydroxyprosta-4-, 5,13-transtrienoic acid methyl ester in 8R-9ei, 11 et-dihydroxy-15-ketoprosta-Jj-, 5,13-transtrissic acid methyl ester converted (8R-antimers of XVII; R and R ^ = H;

R = hydroxy; η = 4).

Similarly, the corresponding 8R-9 <rf, 15et-dihydroxy or 8R - 9tt, 1 Ιοί, 15o (-TrihydroxyproBtatrensäuremethylesterverbindungen as starting materials receive the following products:

409821/1132

13-trans-trienoic acid methyl ester

A-4-methyl-6-ethyl-9 ^ _s 1 l ^ -dihydrojqy-l ^ -ketoprosta = ^ "5 , 13 = trans-trienoic acid methyl ester

acid ethyl ester

£ R-9 ^ -Hydroxy-15-keto-20-norprosta-4 ₈ 5s 13-trans-trienoic acid methyl ester 8R * -9 «k 1 l <dl-Dihydroxy-15-keto-20 = ethylpros ta-Λ, 5» 13-trans-tifenic acid, methyl ester

FiR-9e ^ -Hydroxy-15-keto-2O-ethylprosta-4 ₉ 5 ₀ 13 = -trans-trienoic acid eth3glester 8R-9stll «(- Dihyciroxy-15-ketoprosta-4 _s 5el3-trans-trienoic acid methyl ester and ^ -6-methyl -9β, 11 ^ -dihydroxy-15-ketoprosta- ^ ₈ 5 _s 13-trans-trienoic acid methyl ester Example 26

A, To a mixture of 6 ecm hexamethyldisilazane and 1 _S 2 ecm trinethylchlorosilane, a solution of 200 mg 9gli> ll ^ -dihydroxy-15-ketoprosta ~ ⁱ * -, 5tl3-trans-trienoic acid methyl ester in 20 ecm xi anhydrous tetrahydrofuran was added with stirring under a Argon atmosphere "was added and the resulting mixture was stirred under anhydrous conditions for 16 hours at room temperature. Then it was evaporated to dryness under reduced pressure" the residue was dissolved in 10 ecm of toluene and the solvent was eliminated under vacuum; this procedure was repeated several times to provide the crude 9ΛIW-bis- $ rimethylsilyloxy) -15-ketoprosta- ^, 5113-trans-trienoic acid methyl ester (XVIIIj R and R ^ = H; R ⁷ = trimethylsilyloxy, η = Ur) .

B. The above crude product .wurde dissolved in 20 ecm Was'serfisLem diethyl ether and the

obtained solution in a dry ice-acetone bath to -78 ° C. cooled down. To the cold solution became an ether solution of 1.1 molar equivalents with stirring

"* ■ 4 0 9821/1 132

-Methyllithium (2.8 ecm 0.22M methyllithium in ether) added dropwise under an argon atmosphere. The mixture obtained was allowed to come to room temperature with stirring and stirred at this temperature for a further 2 hours. Then it was poured into a saturated ammonium chloride solution, the ethereal phase was separated off, washed with saturated sodium chloride solution ₉ -dried over magnesium sulphate and evaporated to dryness in vacuo; in this way the crude 9e {"II & -Bis- (triinethylsilyloxy) -15" -hydroxy-15 T methylprosta- ^, 5jl3-trans-trienoic acid methyl ester (mixture of 15 "(-hydroxy-15β-methyl- and 15β-hydroxy- 15 ₀ ( _l -methyl compounds); (XIX; R and R ^ = H; R = methyl; R ^f = trimethylsilylo>y; η = k) .

JD. A solution of 250 mg of the crude 9 _< j [tll (Ä, -Bi ^s - (t ^r i ^j: ' ^ie thylsilyloxy) -15 f-hydroxy-15T-methylprosta-4,5ii3-trans-trienoic acid methyl ester in 10 ecm 70 Aqueous methanol was kept at room temperature for 2 hours, then the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by thin layer chromatography using "EthyLaoetut: ether (75:25) as the eluent. The individual isomers were thus obtained, dh 9d _t HoU IS ^ -Trihydroxy-lSß-methylprosta- ^, 5,13-trans-trienoic acid methyl ester and 9 ^, llc (, 15ß-trihydroxy-15cA-methylprosta- ^ -, 5fl3-trans-triene-

"5 1" 6

methyl acid ester in pure form (XX; R and R = H; R = hydroxy; R = Methyl; η = 4).

By repeating the procedures of this example using the rest Compounds of Example 25 as starting materials in Part A were obtained the following end products:

9ei, 15ft-dihydroxy-15β-methylprosta- ^ -, 5,13-trans-trienoic acid methyl ester and 9il5β-dihydroxy-15ot-methylprosta- ⁱ + ·, 5,13-trans-trienoic acid methyl ester; 6 _} 15β-dimethyl-9of, llel, 15et-trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester and 6,15ol-dimethyl-9oi, llo <, 15β-trihydroxyprosta- ⁱ +, 5t13-trans-trienoic acid methyl ester;

~ · 409821/1132

4 ₀ 6 "15ß-trimethyl-9eie1 let, 15 <5 £ = trihydroxyprost a-4,5» 13-trans-trienoic acid methyl ester and 4,6,15e (-trimethyl-9e {i 1 Ie ^ ₃ 15ß ~ tribydroxyprosta- 4 ₉ 5,13-trans-trienoic acid methyl ester;.

methyl ester and 4 _s 15 ^ -dimethyl-6-ethyl-94,, llsJ, 15ß-trihydrosypposta-4 ₉ 5,13-trans-tris acid methyl ester;

^ -Propyi-6,15J3-dimethßrl-9oi "11 ^ 515eC-trihydroxyprosta" ⁱ f _i 5113-trans-trienoic acid ethyl ester and 4-Propr5rl-6jl5o (-dimeth5rl-9si, ll "a" 15ß-trihydroxyprosta- ⁱ f, 5 , 13-trans-trienoic acid methyl ester j

9y? ₁ 15Ä-Dihydro ^ -15ß-ynethyl-20.-iiorprosta = ⁱ i- _s 5,13-trans-trienoic acid methyl ester and 9 ^ t 15ß-Dih, ydroxy-15 ^ -methyl-20-norprosta-Λ, 5 »13 -trans-trienoic acid methyl ester; 9d $ HdI, 15 «<- trihydroxy-15ß-methyl-20-ethylprosta- ^, 5 _f 13-trans-trienoic acid ethyl ester and 9 ^" H <£ _f 15ß-trihydroxy-15d-methy 1-20-ethylprosta- ^ f , 5,13-trans-trienoic acid methyl ester; -

9o ( _t 1 Ιοί, ISöC-Trihydroxy-lSß-methyl ^ O-pentylpros ta-Λ, 5,13-trans-trienoic acid methyl ester and 9ci »1 lot, 15ß-trihydroxy-15e (-inethyl-20 -pentylprosta- ^, 5 »13-transtrienoic acid methyl ester;

9e _(f 15 ^ -dihydroxy-15SS-methyl-20-A äthylprosta _f 5,13-trans-triensäuremethylester and 9 <415ß-dihydroxy-l 5ot- ^me thyl-20-äthylprosta-4,5,13-t rans -trienoic acid methyl ester;

9β s 15t / -dihydroxy-15β-ynethylprosta-4,5,13-trans-trienoic acid methyl ester and 9β * 15β-dihydroxy-1,5et-methylprosta-Λ, 5,13-trans-trienoic acid ethyl ester; and 6,15β-Diiaethyl-9β ₁ 15 «i-dihydroxyprosta-4,5,13-trans-trienoic acid methyl ester and 6,15jt-dimethyl-9βjlSβ-dihydroxyprosta- 1,5,13-trans-trienoic acid methyl ester. Example 26-A

By repeating the procedures of Example 26 namely A, B and C with 8R-9AlloC-Dihydroxy-IS-ketoprosta- ^ t ·, 5,13-trans-trienoic acid methyl ester as starting material one after the other received the

~ - · 409821/1132

8R-9 "<t ll <-Bis- (trimethylsilyloxy) -15-ketoprosta - ^, 5 _t 13-trans-trienoic acid methyl ester

8R-9 * t, ll <* - bis (trimethylsilyloxy) -15o (-hyciroxy-15 X -methylprosta - ^, 5113-trans-trienoic acid ethyl ester and

8fU9e (, licl., 15 \ -Trihydroxy-15 y-methylprosta-4,5,13-trans-trienoic acid methyl ester (8R-antimers of XX; R and R ^ = H; R = hydroxy; R = methyl; η = ^ ), the l ^ -hydroxy- ^ ß-methyl and 15ß-Hydro3y-15et "i'iethyl isomers were separated by thin layer chromatography.

When the remaining compounds of Example 25-A were used as starting materials in Using Part A, the following end products were obtained:

£ R-9 «(» 15o (-dihydroxy-15ß-methylprosta- ^, 5 »13-trans-trienoic acid methyl ester and 8t-9fl (, 15ß-dihydroxy-15d, -methylprosta-4-, 5,13-trans- methyl trienoate; &2; -6 _l 15β-Diji] ethyl-9 _e {, ll _e i, 15 _e (-trihydroxyprosta- ^, 5,13-trans-trienoic acid methyl ester and 8R-6,15ii-dimethyl-9 «illofilS3 -trihydroxyprosta- ^ jS, 13-trans-trienoic acid methyl ester;

8 ^ .- 4,6,15ß-Tr ime thyl-9o (»1 lot, 15cl-trihydroxypros t a-4,5 * 13-t ran s-trienoic acid methyl ester and 6Ώ-Λ, 6,15, (- tri-ethyl-9 · !, llg (, 15ß-trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester)

ER - ^ -, 15ß-Dimethyl-6-ethyl-9oi, H «/ t 15a (-trihydroxyprosta-4,5,13-trans-trienoic acid methyll ester and 8R-4,15o {-Dimethyl-6-ethyl-9i / llt (, 15ß-trihydroxyprosta- ^ 15t13-trans-trienoic acid methyl ester;

£ R-4-propyl-6,15ß-dimethyl-9EF, lloi, 15i ⁽ⁱ -trihydroxyprosta- i-, 5,13-trans-triensäuremethylester and% -4-propyl-6,15e / -dimethyl-9 <* Het 15β-trihydroxyprosta- ^, 5,13-trans-trienoic acid methyl ester;

^ -9et, 15 «i-Dihydroxy-15ß-net hyl-20-norprosta-4,5,13-trans-trienoic acid methyl ester and% -9oi, 15β-dihydroxy-l 5 it-methyl-20-nor per sta-4,5,13-trans-trienoic acid methyl ester;

409821/1132

methylester, 8R-9 <£, lle £, 15SS-trihydroxy-15 "(- methyl-20-äthylprosta- ⁱ i _'t 5,13-transtriensäuremethylester;

8R-9ot, lleit 15 "(- trihydrosy-15β-ynethyl-20-pentylprosta- ⁱ , 5x13-tren s-trienic acid methyl ester and 8R-9ot, llet, 15β-trihydroxy-l ^ C-methyl-20 -pentylprosta- ^ _i 5 · 13-trans-trienoic acid methyl ester *;

£ R-9ei "154-dihydroxy-15SS-raethyl-20 äthylprosta- ⁱ i- _e 59l3-trans-triensäureraethylester and 8R 9ek 15SS = dihydroxy-154- ^me thyl-20-äthylprosta-4, 5 * 13- trans-trienoic acid methyl ester;

8R-9β _$ 154.-Dihydroxy-15β-methylprosta- ^, 5-13-trans-trienoic acid frothyl ester and% -9β, 15β-dihydroxy-15 ^ -methylprosta-. ⁱ f _s 5sl3-trans-trienoic acid methyl esterj and 8 |> -6,15β-D imethyl-9β-l 5a- ⁽ⁱⁱⁿ y ^d - ^r ' ^QX yP ^r osta-Λ, 5113-t rans = trienoic acid methyl ester and ^^ _s 15c ^ -Diraethyl-9ß., 15ß-dihydroxyprosta- ¹ i- _f 5--13-trans-trienoic acid methyl ester. ...

Example 2?

20 mg of 9% of 15% trihydroxy-15β-methylprosta- * J-, 5 ₈ 13-trans-trienoic acid methyl ester were dissolved in a mixture of 2 ml of methanol, 2 ml of water and 50 mg of potassium carbonate. The reaction mixture was maintained for 16 hours under a nitrogen atmosphere at 40 Go _s if were added 10 cc of water and the reaction mixture was evaporated under reduced pressure to half volume "Then it was acidified with 50- $ acetic acid and extracted several times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure; in this way one obtained 9oJ ₈ llt of 15e4-trihydroxy-15β = methylprosta- ⁱ {' _l) 5813-trans-trienoic acid (XXI; R and R ⁵ = H; R ¹ "= hydroxy; R ⁶ = methyl; η = Λ ).

In a similar way, the 9ei _f 15Ä-dihydroxy-15ß-methylprosta- ⁱ f, 5 »13-tertiary methyl ester and. 6,15o-dimethyl-9 ^, ll «( _f 15ß-trihydroxyprosta-4,5 * 13-transtrienoic acid methyl ester converted into the corresponding free acids.

- ~ - 409821/1132

Example 27 was repeated using 8R-9o, 11ofc, 15- "trihydroxy-15ß-methylprosta - ^^ tl ^ -trans-trienoic acid methyl ester and gave 8R-9" i, 1 IdL, 15 * -Trihydroxy-15ß- methylpros ta-4, 5,13-trans-trienoic acid (8R-antimers of XXI; R and R ⁵ = Hj R ¹ "= hydroxyl R = methyl; η = k).

Similarly, Si ^ oh

trienoic acid methyl ester and 8R-6,15Ä-dimethyl-9i <, 11 ^, 15β-trihydroxyprosta-4,5-13-trans-trienoic acid methyl ester are converted into the corresponding free acids.
Example 28

A. A suspension of 4 g of crude pancreatic lipase (Sigma L-3126) in a 0.1 M sodium chloride and MO ecm O.OSM-calcium chloride solution in water at 25 ⁰ C.

Stirred for 1 hour, then for one hour at 5000 rpm at 25-3 ° C. centrifuged and the supernatant liquid to one with IN sodium hydroxide solution pH value of 7.2-7, ^ 4 · neutralized and directly for hydrolysis of the prostaglandin derivatives used in the present invention.

B. 42 mg 90150 (trihydroxy-15β-niethylprosta- ⁱ ' _{! 1} 5 _{liters of} ethyl 13-trans-trienoate were dissolved in 30 ml of the lipase solution prepared in part A by sonication at 37 ° C. for 20 minutes stirred magnetically minutes at 25-26 ⁰ C. to give constantly ceased during the reaction period the pH is adjusted with lN-sodium hydroxide 7t2-7f ^. Then, the Reaktionsnischung using a 0.2N hydrochloric acid solution to a pH of was 2.5 acidified and the product extracted a few times with ethyl acetate and ether from the solution. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was dissolved in methylene chloride and chromatographed on 3 g of "Florisil". The column was successively with methylene chloride-diethyl ether mixtures, diethyl ether, diethyl ether-ethyl acetate mixtures, pure ethyl acetate and

409821/1132

an O ^ O-ethyl acetate-methanol mixture eluted. The fractions eluted with the last-mentioned solvent mixture yielded the pure 9e (, 11-1, 15o (-trihydroxy-15β-methylprosta- ^ _t 5-13-trans-trienoic acid, which was identical to the product obtained in Example 27).

Similarly, the remaining alkyl ester compounds obtained as final products in Example 26 were converted into the corresponding free acids. Example 28-A "

By repeating Example 28, Part B, the 8R- oi, ll "/, 15 ^ -trihydroxy-15β-methylprosta-4,5 | 13-trans-trienoic acid methyl ester hydrolyzed and provided using the lipase solution prepared in Part A of Example 28 sq. the SR-9oi "ll" <"15Jr-trihydroxy-15β-methylprosta-4,5" 13-trans-trienoic acid, the ■ was identical to the product obtained in Example 27-A.

Similarly, the remaining methyl ester compounds of Example 26-A converted into the corresponding free acids.

Example 2 £

A solution of 500 mg ^ keto-llot.lSoC-bistetrahydropyranyloxyprosta- ² <- »5il3-trans-trienoic acid methyl ester in 10 ecm 65- # aqueous acetic acid was stirred at room temperature for 18" hours, then evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate and the solvent was eliminated by distillation under vacuum. The residue was purified by chromatography on 50 g of "Florisil". The fractions eluted with diethyl ether-ethyl acetate (80:20) gave the pure 9-keto-llcf, 15o ( -dihydroxy-

prösta - ^, 5,13-trans-trienoic acid methyl ester (methyl ester of XI; R and R- ^ = Hj

1" "

R = hydroxy; η = * t ·).

In a similar way, the corresponding 9-keto-llo (, 15g <-bisetrahydropvranyloxy- or 15 ^ -monotetrahydropyranyloxy compounds of Example 22 the following products: -

409821/1132

9-Ketc ^ l5 ^ -hydroxyprosta ^, 5il3-trans-trienoic acid methyl ester ^ -Methyl-9-keto-lloC, 15e (-dihydroxyprosta-4, 5,13-trar, s-vtrienoic acid methyl ester 6-methyl-9-keto-l I * .. 15 «t-dihydroxyprosta- ^, 5» 13-trans-triensäuremethylester ^ _t 6-Dimetl ^ l-9-keto-llJ _t 15rf-dihydro ^ y-prosta- ⁱ l ', 5 »13- methyl trans-trienoate ⁱ l-propyl-6-methyl-9-keto-II "( _f 15" t-dihydroxyprosta-4 _f 5t13-trans-trieno methyl ester

9-keto-llrf, 15 * (- dihydroxy-20-bisnorprosta-4,5,13-trans-trienoic acid methyl ester 9-keto-11 ^, 15 ^ -dihydroxy-20-methylprosta ~ ⁱ <-, 5il3-trans-trienoate methyl ester 9- Keto-ll.l, IS ^ -dihydroxy-ZO-ätkörlprosta- ^, 5,13-trans-trienoic acid methyl ester and 4-methyl-9-ket o-ll e (, lSei-dihydroxy - ^ - ethylprosta- ^, 5 » 13-trans *, trienoic acid methyl ester.

Example 29-A

Example 29 was repeated using the 8R-9-keto-lle (, 15o (-bisetrahydropyranyloxyprosta-4,5fl3-trans-trienoic acid methyl ester as starting material and thus gave the ^ -9-keto-llrf, 15A-dihydroxyprosta-Λ _t 5tl3-trans-trienoic acid

C Λ Il

methyl ester (methyl ester of the fiR antimer of XIj R and Ir = H; R "= hydroxy, η = Ψ).

In a similar way, the corresponding 8R-9-keto-llo (, 15c (-bis-tetrahydropyranyloxy- or% -15 «C monotetrahydropyranyloxy compounds of Example 22-A includes the following products:

£ R-9-Keto-15 «t-hydroxyprosta-4,5t 13-trans-trienoic acid meth (ylester ο ^ -Λ-Met hyl-9-keto-l I ₀ J, 15e (-dihydroxypros ta-Λ, 5, 13-trans-trienoic acid methyl ter ^ -6-J-methyl-9-keto-llo < _f 15 _< (-dihydroxyprosta- ^, 5,13-trans-trienoic acid methyl ester S1-Jf ₁ 6-diraethyl-9-ke to-llrf, 15i (-dihydroxypros ta- ^, 5,13-trans-triensäureme t hyl-

ffi_i »._ Propyl-6-methyl-9-keto-llet, 15et-dihydroxyprosta- ⁱ f, 5,13-trans-trienoic acid methyl ester

21/113

ER-9-keto-l1β (, 15 ^ -dihydroxy-20-bisnorpro sta-4,5.13-trans-trienoic acid met hyTe ster ^ -9-keto-llol, 15a (-dihydroxy-20-methylprosta-4,5,13 -trans-trienoic acid methyl ester ER_9_Keto-llel, 15 ^ -dihydroxy-20-äthylprosta- ^| f, 5,13-trans-trienoic acid methyl ester and

8R-4-Methyl-9-keto-11 ₀ (, ^ flt-dihydroxy ^ O-ethylprosta- ^, 5,13-trans-trienoic acid methyl ester.

Example 3jD_

A solution of 400 mg of hydroxylamine hydrochloride and 500 mg of sodium acetate in .10 ecm of methanol-water was added to a solution of * JO0 mg of 9-keto-llot, 15 ^ -dihydroxjprosta- ^, 5,13-trans-trienoic acid methyl ester in 3 ecm of methanol (1: 1) added. The resulting mixture was kept at room temperature for 18 hours under an argon atmosphere, then the solvent was eliminated under reduced pressure. The residue was taken up in water and the mixture was extracted with ethyl acetate. The organic phase was separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo; the 9-hydroxy imino-11 ₀ ^ 15 * (-

C ill

dihydroxyprosta-4,5f13-trans-trienoic acid methyl ester (XXIIj R and R ^J = H; R = hydroxy; ή = 4). '.

The remaining 9-keto compounds of Example were obtained in a similar manner 29 the corresponding oximes, i.e. the

9-Hydroxyimino-15o (-hydroxyprosta- ⁱ 4 ·, 5,13-trans-trienoic acid methyl ester 4-Methyl-9-hydroxyimirio-II "(, 15" (- dihydroxyprosta-4 ·, 5,13-trans-trienoic acid methyl ester '. o-Methyl ^ -hydroxyimiiio-llol, 150 ^ -dihydroxyprosta- ⁱ »-, 5,13-trans-trienoic acid- · methyl ester
4,6-dimethyl-9-hydroxyimino- III, lSet-dihydroxyprosta- ^, 5,13-trans-trienoic acid methyl ester

^ -Propyl-o-methyl - ^ - hydroxyimino-II cG ISX-dihydroxyprosta- ^, 5,13-transtrienoic acid methyl ester

* "*" ■ '409821/1132

9-Hydroxyimino-l lo (, 154-dihydroxy-20 -bisnorpros ta -k, 5, i 3-trans-trienoic acid ethyl ester 9-I ^ droxyimino-ll (i, 15 ^ -dihydro2gr-20-methylprosta- ⁱ i- _t 5 | 13-trans-trienoic acid ethyl ester 9-hydroxyimino-lrf, l ^ -dihydroxy-IIO-ethy lprosta- ^, 5-13-trans-trienoic acid ethyl ester and VMethyl ^ -hydroxyimino-llrf, 15 "(- dihydroxy-20- Ä.ethylprosta- ^, 5,13-transtrienoic acid methyl ester.

Example 30-A

Following the procedure of Example 30, ¹ K) O mg% -9-keto-llei _f 15ei-dihydroxyprosta - ^, 5 '13-trans-triensäuremetfcQrlester in the 6R-9-hydroxyimino-Pa ra lle l, 15oidihydroxyprosta-4,5il3-trans -trienoic acid methyl ester converted (8R-antimers of XXII; R and R ⁵ = H; R ¹ "= hydroxy; η = * f)

In a similar manner ärhielt from the other 9-keto compound of Example 29-A, the corresponding oximes, ie the 6 ^ -9-hydroxyimino-15 _e ⁽ⁱ -hydroxyprosta- i-, 5,13-trans-81-4- triensäuremethylester Methyl-9-hydroxyimino-11of, 15 (- dihydroxyprosta- ^, 5-13-trans-trienoic acid methyl ester o ^ -6-methyl-9-hydroxyimino-l 1, (, 15ai-dihydroxyprosta-A-, 5> 13-trans-trienoic acid methyl ester ER-Λ, 6-dojnethyl-9-hydroxy imino-llet, 15o (-dihydroxyprosta- ¹ i ·, 5,13-trans-trienoic acid methyl ester 8Ä - ^ - propyl-6-methyl-9- hydroxyiinino-llel, 15c (-dihydroxyprosta-4,5 | 13-trans-trienoic acid methyl ester

8R-9-hydroxyimino-ll * {15 ^ -dihydroxy-20-bis. norprosta-4,5, 13-trans-triensäure- - methylester

Oil 9-hydroxy imino-11 ^, 15e ^ -dihydroxy-20-methylprosta- ¹ 4-, 5113-trans-trienoic acid methyl ester

409821/1132

- 127 - 7355-324

^ _9-Hydroxyiraino-lle ^ l5e ^ -dihydrDxy-20-äthylprosta- ^/ <-, 5.13-trans-trienoic acid- * methyl ester and

o ^ - ^ - methyl- ^ hydroxyimüio-ll ^, 15 ^ -dihydroxy-20-äthjrlprosta- ⁱ i-, 5,13-trans-

trienoic acid methyl ester. ·

example 31

1 g of activated was added to a solution of 250 mg of 9-hydroxyimino-1X _e 1, 15 ^ dihydroxyprostä- ^z J-, 5tl3-trans-trJsnäureraethylester in 5 ecm anhydrous tetrahydrofuran. Manganese dioxide was added and the reaction mixture was stirred for 6 hours at room temperature. The manganese dioxide was filtered off, washed with acetone and the combined filtrates evaporated to dryness under reduced pressure. The residue was redissolved in tetrahydrofuran, stirred with a further 1 g of manganese dioxide as above; this procedure was repeated twice. After the final evaporation of the solvent and purification of the residue by chromatography on "Florisil", the pure 9-Hydroxyimiiioll (^ - hydroxy-15-ketoprosta- ² f _f 5 »13-trans-trienoic acid methyl ester (XXIII; R and R ⁵ = H; R ¹ "= hydroxy; η = k) .

By repeating the above procedure using the remaining 9-hydroxyimino compounds from Example 30 as starting materials, the corresponding 15-keto derivatives were obtained, such as, for example:

9-Hydroxyimino-l 5-ketoprosta-4,5,13-trans -trienoic acid eme thyl ester 4-Methyl-9-hydroxyimino-il _e (-hydroxy-15-ke toprosta-Λ, 5,13-trans-trienoic acid methyl ester ■

6-methyl-9-hydroxy imino-11 et-hydroxy-15-ketoprostaJ4-, 5,13-trans-trienoic acid methyl ester

4,6-Dimethyl-9-hydroxyimino-ile (-hydroxy-15-ketoprosta-4,5,13-trans-trienoic acid methyl ester

4-Propyl-6-methyl-9-hydrbxyimino-llot-hydroxy-15-ketoprosta-4,5,13-tetns-trienoic acid methyl ester

"" 409821/1132

9-Hydroxyimino-ll dt-hydroxy-lST.keto ^ O-bisnorpros ta - ^ -, 5-13-trans-trienoic acid methyl ester 9-Hydroxyimino-11 (- hydroxy-15-ke t o-20-met hyipro st a-4,5,13-trans-triensauremethylester 9-hydroxyimino-ll ^ • hydroxy-15-keto-20-ätlOrlprosta- ^z lt; 5.13-trans-triensä \ xremethylester and ^ -methyl-9-hydroxyimino ll ^ -hydro ^ -15-keto-20-äthylprosta- ⁱ t-, 5 »13-transtrienoic acid methyl ester.

Example 31 -A By repeating Example % , the ^ -9-hydroxyimino-ll _e /, 15 _e (-dihydroxyprosta- ^/ f, 5 »13-trans-trienoic acid ester in ^ -9-Ifydroxyiinino-llöl-hydroxy-

l5-ketoprosta - ^, 5-13-trans-trienoic acid methyl! ester converted (8R-antimers of ΧΧΠΙ; R and R ⁵ = H; R ¹ "= hydroxy; η = ^).

By repeating the same procedure using the remaining 8R-9-hydroxyimino compounds Example 30-A gave the corresponding 15-keto derivatives, namely:

^ _9_Hydroxyimino-15-ketopro sta-Λ, 5,13-trans-trienoic acid methyl ester ER-4-methyl-9-hydro3? Yimino-l 1 g (-hydroxy-15-ketoprosta-4 _f 5 , 13-trans-trienoic acid methyl ester & ^ -641eth3i-9-hydroxyimino-ll ^ -hydroxy-15-ketoprosta- ² f, 5,13 - trans-triene-acid methyl ester £ ß - ^, 6-dimethyl-9-hydroxyijtiino-llg (-hydroxy-15- ketoprosta- ^ _t 5,13-transtrienoic acid _{methyl ester & _if_p r} opyl-6-methyl-9-hydroxy imino-11 ^, - hydroxy-15-ketoprosta- ^, 5,13-transtrienoic acid methyl ester% -9-hydroxyimino-ile (- hydroxy-15-keto-20-bisnorprosta- ^ _t 5,13-trans-trienoic acid methyl ester

& _9_Hydro3yimino-il ^ -hydroxy-15-ketb-20emethylprosta-4,5 _f 13-trans-triene-acid methyl ester Λ09821 / 1132

8Rr-9-hydroxy imino-1 lefc-hydr oxy-15-ke to-20 -äthy lprost a-Λ, 5113-trans- trienoic acid methyl ester and -

trienoic acid methyl ester.
Example 3_2

A. To a mixture of 3 anhydrous tetrahydrofuran was added under an argon atmosphere and the resulting mixture was stirred at room temperature under anhydrous conditions for 16 hours. Then it was evaporated to dryness under reduced pressure, the residue was dissolved in 10 ecm of toluene and the solvent was eliminated under vacuum. This process was repeated a few times and thus gave the crude methyl 9-triillethylsilyloxyinino-llo ^ _r trimethylsilyloxy-15-ketoprosta- ^ 5-13-trans-trienoate (XXIV; R and Έτ = H; η = 4-).

B. The above crude product was dissolved in 20 ecm of anhydrous diethyl ether and the resulting solution was heated to -78 ° C. in a dry ice-acetone bath. cooled down. An ether solution of 1.1 molar equivalents of methyllithium (2.7 ecm O, 22M methyllithiura in ether) was added dropwise to the cold solution under an argon atmosphere. The resulting mixture was allowed to come to room temperature with stirring and stirred for a further 2 hours at this temperature. Then it was poured into a saturated ammonium chloride solution, the ethereal phase was separated off, washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness in vacuo; the crude 9-trimethylsilyloxyimino-1 lit-trimethylsilyloxy-15 ί hydroxy-15 t -raethylprosta-4 _t 5,13-trans-trienoic acid ethyl ester (mixture of 151- and 15β-compounds; XXV ₅ R and R ⁵ = H ; R ⁶ = Me; R? = Trimethylsilyloxy, R ⁷ '= trimethylsilyl; η = ^).

■ "■■ ~~ 409821/1132

C. A solution of 250 mg of the crude 9-trimethylsilyloxyimino-II, f-trimethylsilyloxy-15 ^ -hydroxy- <-methylprosta- ^ jStlS-trans-trienoic acid methyl ester in 10 cc of 70 # aqueous methanol was added for 18 hours under a carbon dioxide atmosphere held. Then the reaction mixture was evaporated to dryness under reduced pressure and the residue was subjected to thin layer chromatography Purified using ethyl acetate-ether (75:25) as the eluant.

This gave the individual isomers, ie the 9-hydroxyimino-llel, 15et-dihydroxy-15ß-methylprosta- ⁱ f, 5-13-trans-trienoic acid methyl ester and 9-K ^ dTOXyimino-ilet, 15ß-dihydroxy-15e (-methylprosta - ⁱ i ', 5 »13 ° trans-trienoic acid methyl ester in pure form.

D. To a solution of 150 mg of 9 ~ hydroxyimino-ll ^, 15dl-dihydroxy-15ß-methylprosta- ^ »5» 13-trans-trienoic acid methyl ester in 3 ecm of methanol was a Solution of 150 mg thallium (III) nitrate. added in 3 ecm of methanol. The reaction disagreement was stirred for 10 minutes at room temperature and the precipitate formed was filtered off and washed with methanol. 5 ecm dilute acetic acid was added and the mixture was stirred for 5 minutes. Then it was extracted with ether and the organic extract with saturated sodium chloride solution washed, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was collected by chromatography "Florisil" cleaned. The fractions eluted with diethyl ether-ethyl acetate (9: 1) provided the pure 9-keto-lld, 15o {-dihydroxy-15ß-methylprosta-4,5 »13-trans-trienoic acid methyl ester (XXVI; R and R * = H; R = hydroxy; R = methyl;

By repeating the above procedures using the following compounds in part A:

^ 4! Ethyl-9-hydroxyiInino-IIβ <-hydroxy-15-ketoprosta- ¹ ^, 5 »13-trans-trienoic acid methyl ester

'"··· 409821/1132

6-Methyl-9-hydroxyimino-i l ^ -hydroxy-i 5-ket opro sta-4,5113-trans-trienoic acid methyl ester

4,6-Dirae thyl-9-hydroxyimino-l l ^ -hydr oxy-15-ketoprosta-4 "5,13-tens-trienoic acid anethy ! ester

4-propyl-6-methyl-9-hydroxyimino-ll ^ -lO''droxy-15-ketoprosta- ^, 5 »13-trans-

trienoic acid methyl ester ■

9-Hydroxyiaiino-II ^ -hydr oxy-15-ke'to-20-bisnorprosta- ^ i-, 5 * 13-trans-trienoic acid methyl ester

9-Hydroxyimino-11J-hydroxy-1 5-keto-20-methylprosta- ⁱ ·, 5-13-trans-trienoic acid methyl ester

9-Hydroxyiraino-llo ^ -hydroxy-15-keto-20-äthyiprosta- ^ί 4 ·, 5fl3-trans-trienoic acid methyl ester and

^ -Methyl-9-hydroxyimino-II ^ -nydroxy-15-keto-20-ethylprosta- ⁱ f, 5il3-transtrienoic acid methyl ester

the following end products were obtained 4,15β-dimethyl-9-keto-IIc (t 15c (-dihydroxyprosta-4,5,13-trans-triene-acid methyl ester and 4 _f 15 "(-diraethyl-9-keto-IIol _f 15β-dihydroxyprosta - ^, 5-13-trans-trienoic acid methyl ester; 6,15β-diraethyl-9-keto-lloi _f 15o (-dihydroxyprosta-4,5,13-trans-trienoic acid ethyl ester and 6,15ol-dimethyl-9-keto-llei , 15β-dihydroxyprosta-4.5 _t 13-trans-triens aureraethylesterj

4,6,15ß-Trimet hyl-9-ke to-11 tf, 15 << - dihydroxypro s ta-4,5,13-trans-tnensäuremethylester and 4,6,15 * t-trimethörl-9-keto-l-lel, 15β-dihydroxyprosta-4,5,13-trans-trienoic acid methyl ester;

4-propyl-6,15β-D3-methyl-9-keto-lle (, 15o (-dihydroxyprosta-4,5,13-transtrienoic acid methyl ester and 4-propyl-6,15e (-dimethyl-9-keto-llg (, 15β-dihydroxyprosta-4,5,13-trans-trienoic acid emethylester;

9-keto-lld, ISet-dihydroxy-lSiB-methyl-aO-bisnorprosta- ^, 5,13-trans-trienoic acid-

methylester and 9-keto-11 ^ 15SS-dihydroxy-15 ₀ i-metlwl-20 bisnorprosta-4,5,13-trans-triensäuremethylester;

~ "409821/1132

- 132 9-keto-ll * 15 ^ -dihydroxy-15ß »20-diraethylprosta- ^, 5fl3-trans- € riensaure ~ methyl ester and 9-keto-ll ₀ kl5ß-dihydroxy-15j, 20-dimethylprosta- ⁱ l ', 5, 13-transtrienoic acid methyl ester;

9-Keto-l let, 15 ^ -diliydroxy-15ß-methyl-20-ethylprosta-4,5,13-trans-trienoic acid methyl ester and 9-keto-lle (, l5ß-dilcrdroxy-l ^ -methyl-20-ethylprosta- ^, 5.13-trans-trienoic acid ethyl ester; and

4,15ß-diraethyl-9-keto-ll _e t, ^ irdihydroxy ^ O-ethylprosta - *! -, 5.13-trans-trienoic acid methyl ester and k, 15Jt-D5niethyl - ^ - keto-lle (, 15ß-dihydroxy-20- Ethyl prosta-4,5,13-trans-trienoic acid ethyl ester.

By repeating the procedure of Parts B and D using methyl 9-hydroxyimino-15-ketoprosta-4,5,13-trans-trienoate as starting material, a mixture of 9-keto-15 ^ -hydroxy-15β-methylprosta- ^ was obtained t5tl3-trans-trienoic acid methyl ester and the 15ß-Hydro3qy-153 ^ -metlorisomer (XXVI; R, R ^ and R = H; R = methyl; η = U-) , which was separated by chromatography on "Florisil".

Example 32-A

Following the procedures of Example 32, Parts A, B, C and D, the 8R-9-Hydro3Qrimino-ll ^ -hydroxy-IS-ketoprosta- ^, 5,13-trans-trienoic acid methyl (yl esters in succession converted to the

ER-9-Trimethylsilyloxyiraino-ll ^ -tr inethylsilyloxy-lS-ketoprosta- ^, 5,13-trans-trienoic acid methyl ester

εΚ-9-trimethylsilyloxyimino-l 1 ^ -trime thylsilyloxy-15 .ί -hydroxy-15 ί -methylprosta-Λ, 5t 13-trans-trienoic acid ethyl ester

9R-9-Hydroxyimino-IIol, 15 | -dihydroxy-15 | -methylprosta-4,5,13-transtrienoic acid methyl ester and

% -9-Keto-IIId _t 155 -Dihydroxy-15 i-methylprosta-4,5,13-trans-trienoic acid methyl ester

409821/1132

(8R-antimers of XXVI, R and R = H; R '= hydroxy; R = methyl; η = 4), where the 15e <-hydroxy-15β-niethyl-. and 15β-hydroxy-15 «(- methyl isomers by Thin-film chromatography were separated.

If in part A the δΈ-15-ketoverbs in fertilize from Example % -k were used as starting materials, then the following end products were obtained: St - *} ·, 15ß-Dimethyl-9-keto-1 IU, 15o ( -dihydroxy pro sta-Λ, 5,13-trans-trienoic acid methyl ester and 8R-4,15o (-dimethyl-9-keto-llc <, 15β-dihydroxy pro sta-4,5,13-trans-trienoic acid methyl ester;

6R * 6,15ß-dimethyl-9-keto-II <*, 15 * -dihydroxjpros t a-4,5,13-trans-triensäuieme methyl ester and 8R-6,15o (-dimethyl-9-keto-1 lot _t 15β-dihydroxyprosta-4,5,13-trans-trienoic acid methyl ester;

8R-4-, 6,15ß-trimethyl-9-keto-llei, 15gf-dihydroxyprosta - ^, 5il3-trans-trienoic acid methyl ester and SR - ^. o.lSoC-trimethyl-g-keto-ll ^, 15ß-dihydroxyprosta-4,5,13-tran s-trienoic acid ethy ester;

^ - ^ .- Propyl-6,15ß-dimethyl-9-keto-lleC, 15 ^ -dihydroxyprosta-4,5 _f 13-trans-trienoic acid methyl este ^ and 8 [1-Λ-Ρ ropy 1-6.15 # (-dimethyl-9-keto-l 1 (^, 15ß-dihydroxyprosta- ^ t 5t 13-tans-trienoic acid ethyl ester;

8R-9-keto-llo (, 15Ot-dihydroxy-15β-methyl-20-bisnorprosta-4,5,13-trans-trienoic acid methyl ester and 8R-9-keto-llot, 15β-dihydroxy-15o {-itiethyl-20-bisnorprosta-4,5,13-trans-trienoic acid methyl ester;

8R-9-keto-'llot, 15a (-dihydroxy-15ß, 20-diraethylprosta-4,5 _f 13 ~ trans-trienoic acid methyl ester and 8R-9-keto-lla (^ 15ß-dihydroxy-15o { _f 20-diinethylprosta- 4.5 _{tons of} 13-trans-tetraic acid methyl ester;.

8R-9-keto-llei, I5e (dihydroxy-15i-raethyl-20 - äthylprosta-4,5,13-trans-triensäuremethylester and 8R-9-keto-lleUl5ß-dihydroxy-15oi-ra ^e thyl-20 Ethyl prostate-4,5,13-trans-trienoic acid ethy ester and

8R-4,15ß-Dimethyl-9-keto-ll _Q (, 15 ₀ l-dihydroxy-20-ethylprosta-4,5,13-transtrienoic acid methyl ester and 8R-4,15ß-dimethyl-9-keto-llfl (, 15ß -dihydroxy-20-ethylprosta-4.5 _t 13-.trans-trienoic acid methyl ester.

409821/1132

By repeating the Verfahrers of Example 32, Part B and D using the ^ -9-Hydrcoqyiraino-15 ketoprosta ⁱ = i-, 5,13-trans-triensäuremethylester as a starting material to give a mixture of ^ -9-keto-15et -hydroxy-15ßmethylprosta- ^, 5,13-trans-trienoic acid methyl ester and of the 8R-J.5ß-hydroxy-.15e (-methyl-isoneren (8R-antimers of XXVI; R, R ^ and R "= H; R = Methyl; η = ^), which were separated by chromatography on "Florisil".

Example 3_ß_

Following the procedure of Example 28, the 9-keto-llei, 15o (-dihydroxy-15β-methylprosta-4,5,13-tens-trienoic acid methyl ester was converted into the 9-keto-llei, 15c (-dihydroxy-15β-methylprosta - ^, 5 »13-trans-trienoic acid converted (XXVII; R and R ^ = H; R ¹ " = hydroxy; R = methyl; η = h) .

Similarly, the remaining compounds of Example 32 were converted to the corresponding free acids.
Example 33-A

According to the procedure of Example 28, the 8R-9-keto-ll _e i, 15 _i (-dihydroxy-15ßmethylprosta-Λ, 5t 13-trans-trienoic acid methyl ester was converted into the 8R-9-keto-llct, 15e (- dihydroxy-15ß-methylprosta- ^ _f 5,13-trans-trienoic acid (8R-antimers of XXVII; R and R ^ = H; R = hydroxy; R = methyl; η = 4).

Similarly, the remaining compounds from Example J2-A. converted into the corresponding free acids.
Example 3jf

A mixture of 100 mg 9ßtlH15et-trihydroxy-prostate ⁱ i _'f 5,13-trans-triensäureraethylester, 10 cc of methanol, 10 cc of water and * »00 mg of potassium carbonate was hours at 40 ° C. kept under a nitrogen atmosphere. The reaction mixture was then diluted with water and evaporated to half its volume under reduced pressure; then it was acidified to pH 2 with 2N hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were dried over magnesium sulfate and under reduced pressure to dryness

409821/1132

? 35532A - 135 -

evaporated. This gave the 9β, lle4, i5 «tr-trihydroxyprosta- ⁱ 4-, 5,13-trans-trienoic acid (XVI; R and R ⁵ = H; R ¹ " = hydroxy; R ^ = H; η = 4) .

Similarly, the corresponding methyl esters became the following Connections made:

9β, 15ol-dihydroxy pro sta-4,5,13-trans-trienoic acid 9β, 15el-pihydroxy-20-ethylprosta-4 ₁ 5,13-trans-trienoic acid 9β, llöl, 15c (-Trihydroxy-20-bisnorprosta- ⁱ t ·, 5,13-trans-trienoic acid 9β, Hol, 154-trihydroxy-20-ethylprosta- ^, 5,13-trans-trienoic acid 9β, 11 (k, 15ΰ ^ -Trihydroxy-20 -pen ty lprosta-4 , 5,13-trans-trienoic acid 4-methyl-9ß, Hol »15c (-trihydroxyprosta-4,5,13-trans-trienoic acid 6-methyl-9ß, Ho (, 15cA-trihydroxyprosta-4,5,13- trans-traenoic acid and 4-propyl-6 ^ methyl-9ß, lldl »15 (* <- trihydroxyprosta- ⁱ t-, 5,13-trans-trienoic acid.

Example 3 ^ -A

Following the procedure of Example 3 ^ the 8R-90, 116 <, 15o (-Trihydroxyprosta-4,5,13-trans-tr methyl ester into the 8R-9ß, 110f, 15 "(- trihydroxyprosta-

5 1 "

4,5 »13-trans-trienoic acid (8R-antimers of XVI; R and R ^ = H; R = hydroxy; R = H; η = 4) converted.

Similarly, the following are obtained from the corresponding methyl esters links

8R-9β, 15 (^ - 1) ihydroxyprosta-4,5,13-trans-trienoic acid 8R-9β, 15i (-dihydroxy-20-ethylprosta-4 _t 5,13-trans-trienoic acid 8R-9β, ll <( tl5ol-Tr: ihyalroxy-20-bisnorprosta-4,5,13-trans-trienoic acid 8R-9ß, ll «l, ^ ol-trihydroxy ^ O-ethylprosta- ^, 5,13-trans-trienoic acid 8R-9ß, llol, 15ίt-trihydroxy-20-pentylprosta-4 _t 5,13-trans-trienoic acid · 8R-4-methyl-9β, 11 <A, 150 (-trihydroxyprosta-4,5,13-trans-trienoic acid 8R-6 -methyl-9SS _f lle (ii5ö (-trihydroxyprosta-4,5,13-trans-trienoic acid, 8R-4-propyl-6-methyl-9SS, ot 11, 15 * -trihydroxypros ta-4,5,13-trans -trienoic acid.

409821/1132

Example 3_5_

An ethereal solution of diazomethane was added to a solution of 100 mg The mixture was kept at room temperature for 1 hour and then evaporated to dryness under reduced pressure, giving the 9 ^ 11ΐ) 1,1 ^ -Τνί hydroxyprosta- ^, 5 »13-trans-trieno-methyl ester.

Similarly, the

4-Ethyl-9-keto-llol _l 15 (<- dihydroxyprosta-4,5,13-trans-trienoic acid ^ -Methyl-9oi, 1 loH, 15dt-trihydroxyprosta-4,5,13-trans-trienoic acid 9 * 1 , 15 <-dihydroxypros ta- ^ f, 5,13-trans-trienoic acid

9o ("15e {-dihydroxy-20-ethy lprosta- ^, 5,13-trans-trienoic acid 4-, 6-dimethyl-9ol _f 11«, ^ tf-trihydroxyprosta- ^, 5,13-trans-trienoic acid 9- Keto-llol, 15iV-dihydroxy-20-norprosta- ^ ·, 5,13-trans-trienoic acid 9-keto-IIIC, ISflt-dihydroxy-EO-methylprosta- ^ jS, 13-trans-trienoic acid 9-keto-15i -hydroxy-20-ethylprosta- ^, 5,13-trans-trienoic acid 6-methyl-9-keto-llcil, 15o (-dihydroxy-20-pentylprosta- ^, 5,13-trans-trienoic acid 9fll, lle ( , 15ot-trihydroxy-20-norprosta-4,5 »13-trans-trienoic acid and ^ ■ _t 6-dimethyl-9oi, llo (, 15ol-trihydroxy-20-ethylprosta- ^, 5,13-trans-trienoic acid in converted to the corresponding methyl ester.

Using diazoethane instead of diazomethane gave a similar result Way the ethyl esters of the above acids.

Example 35-A

By repeating the procedure of Example 35, the & Ή.-9 "ί, 11", 15ο (-trihydroxyprosta-4,5,13-trans-trienoic acid converted into the corresponding methyl ester.

409821/1132

- 1 'IV -

235532A

Similarly, from the

gR_4_Xthyl-9-keto-llc ( _t 15ol-dihydroxyprosta- ^, 5, 13-trans-trienoic acid ot-4-methyl-9 * "11", 15 "st-trihydroxyprosta-4,5 ₁ 13-trans-trienoic acid 8R -9et »lS ^ t-Dihydroxyprosta- ^, 5t 13-trans-trienoic acid 8R-9ol, 15A-dihydroxy-20-ethylprosta-A, 5,13-trans-trienoic acid 8R- * l, 6-dimethyl-9ef , licit 15ol-trihydroxy prosta- ^, 5> 13-trans-trienoic acid 8R-9-keto-llc (, I5e (-dihydroxy-20-norprosta- ^, 5113-tran s-trienoic acid 8R_9-ket ol IJ, 15 # t-dihydroxy-20-methylprosta-4,5,13-trans-trienoic acid £ R-9-keto-15c6-hydroxy-20-ethylprosta-4,5,13-trans-trienoic acid o ^ -6-methyl -9-keto-lij, 15o (-dihydroxy-20-pentylprosta- ⁱ l ', 5t 13-trans-trienoic acid 8R-9fl (, Hol, 15ίt · TΣ · ihydroxy-20-norprosta-4,5,13-trans -trienoic acid and 8R- * J-, 6-dimethyl-9flit llei, 15öt-trihydroxy-20-ethylprosta-4 _f 5,13-trans-trienoic acid, the corresponding methyl esters.

By using diazoethane instead of diazomethane, the ethyl esters of the above 8R-prostatic acids.

example %

To a solution of 100 mg of 9-keto ~ ll _fl (15 ^"| ^ J dihydroxyprosta- ⁱ · _t ,, 5 13-trans-trienoic acid in 10 cc of methanol were added 2.6 cc of a 0.1N solution of Natriumhydroxidzugefügt and The mixture was stirred at room temperature for 1 hour, then it was evaporated to dryness under reduced pressure and yielded the sodium salt of 9-keto-llot, 15ot-dihydroxyprosta-4.5 _{t of} 13-trans-trienoic acid »

By using 1.1 molar equivalents of potassium hydroxide (in the form of a 0.1N solution) instead of the sodium hydroxide in the above procedure, this was obtained Potassium salt of 9-Ketp-lloi, 15et "dihydroxyprosta- ^, 5,13-trans-trienoic acid.

40982 1/1132

Similarly, the potassium and sodium salts were prepared the other, Prostatriensäurederivate obtained in Example 5, 6, 8, _r 9, 10, 11, 12, 17, 19, 20, 28 and 33rd

Example 36-A

According to the procedure of Example % , the 8R-9trf, 11 ", lSoC-trihydroxyprosta- ^, 5t13-trans-trienoic acid was treated with 1.1 molar equivalents of a 0.1N solution of sodium hydroxide and yielded the corresponding sodium salt.

By using 1.1 molar equivalents of potassium hydroxide (in the form of a 0.1N solution) instead of sodium hydroxide, the potassium salt of 8R- 9tt 11 * 15 «t-trihydroxypros ta- ¹ *, 5» 13-trans-trienoic acid was obtained .

Similarly, the sodium and potassium salts of the other _{.8R-prostrienoic acid derivatives obtained in Examples 5A, 6A, 8A, 9A 1} 10A, IU, 12A ₁ 17A ₁ 19A ₁ 20A, 28A and 33A were prepared.
Example 37

To a solution of 100 mg 9 *, H *, ISd-Trihydroxyprosta- ^, 5,13-trans-trienoic acid in 10 ecm of methanol a mixture of 3 ecm of conc. Ammonium hydroxide solution and 5 ecm of methanol were added. The obtained mixture was left for 2 hours at room temperature stirred and then evaporated to dryness; so. one got the ammonium salt der 9d, llo (, 15 * -Trihydroxyprosta- * i-, 5,13-trans-trienoic acid.

By using dimethylamine, diethylamine, or dipropylamine instead of Ammonium hydroxide in the above process, the corresponding salts of the 9 * tt Holt 15 * -trihydroxyprosta-4,5,13-trans-trienoic acid were obtained.

Similarly, were the ammonium, dimethylamine, diethylamine and dipropylamine salts the other prostanoic acid derivatives of the above examples, such as the amine salts of

4Q9821 / 1132

9-keto-llet, 15o (-dihydroxyprosta-ii-, 5t 13-trans-trienoic acid 4-ethyl-9-keto-lle (, 15c (- (iihydroxyprosta- ⁱ f _l 5,13-trans-trienoic acid '9 "<15<-Dihydroxyprosta- ⁱ i-, 5 '13-trans-trienoic acid 4-Me thyl-9e (, LLEH * 15 * -trihydroxyprosta-4,5,13-trans-trienoic acid ^ -propyl-9RF, llct, 15 ^ trihydroxyp: rosta-4,5,13-trans-trienoic acid 6-methyl-9-keto-15o (-hyolroxyprost'a- ⁱ l ·, 5,13-trans-trienoic acid k, 6-dimethyl-9-keto -llo £, l ^ fil-dihydroxyprosta - ^. S, 13-trans-trienoic acid 4-methyl-6-ethyl-9e (, HoC, 15 "(- trihydroxypro sta- ^ _t 5,13-trans-trienoic acid 9j {tl5öl-dihydroxy-15ß-methylprosta-4,5,13 "trahs-trienoic acid 9-keto-lloi, 15o {-dihydroxy-15ß-niethylpro st a - ^, 5t 13-trans-trienoic acid 9-keto-lloi, 15ol-dihydroxy-20-norprosta- ^, 5 »13-iians-trienoic acid 9-keto-llei _t 15X-dihydroxy-20-ethylprosta- ⁱ t-, 5f 13-trans-trienoic acid and 9e (» 11 ° t »15et -Trihydroxyprosta- ^, 5,13-trans-trienoic acid etc.

example 37-A

According to Example 37, the 8R-9rf, llel, 15ol-trih (hydroxyprosta- ^ _f 5 _> 13-trans-trienoic acid was converted into the corresponding ammonium al ζ.

By using dimethylamine, diethylamine or dipropylamine instead of ammonium hydroxide, the corresponding salts of 8R-9o (, 116 (, 15oC-trihydroxyprosta- ⁱ 4-, 5t 13-trans-trienoic acid.

Similarly, the ammonium, dimethylamine, diethylamine and dipricylamine salts of the other 8R-prostanoic acid derivatives prepared in the above examples such as the amine salts of

^ -9-keto-llöl, 15ot-dihydroxypro sta-4,5,13-trans-trienoic acid 6R- ⁱ i-ethyl-9-keto-ll0i, 1 S ^ -dihydroxyprosta- ^, 5,13-t rans- trienoic acid 6 ^ -9c ", l ^ -dihydroxyprosta- ^, 5,13? trans-trienoic acid £ R- ⁱ -methyl-9c", 11 ", lSof-trihydroxyprosta- ^, 5,13-trans-trienoic acid eil, 5,13-trans-trienoic acid

40 9821/1132

- IkO -

8R-6-methyl-9-keto-15o (-hydrcxyprosta-4,5.13-trans-trienoic acid 8R-4-, 6-dimethyl-9-keto-llot, 15e (-dinydroxyprosta-4 _t 5,13-trans- trienoic acid 8R-9U, 15 ^ dihydroxy- ^ S-methylprost a- ^, 5,13- trans-trienoic acid 8R-9-keto-llol, ^ d-dihydroxy- ^ ß-methylprosta- ^, 5, 13-trans- trienoic acid ^ -9-Ke to-1 lo { ₁ 15β ^ dihydroxy-20-norpros t a-4,5113-trans-trienic acid 8R-9-keto-lldU 15dl-dihydroxy-20 -ethylpposta- ^, 5 »13 -trans-trienoic acid 8R-9i3, lloi, 154r-trihydroxyprosta-4,5113-trans-trienoic acid etc.

Example 38

A mixture of 100 mg 90 (i ¹ - ¹ ^ il5ö (-Trihydroxyprosta - ^, 5fl3-trans-trienoic acid methyl ester, ΟΛ ecm pyridine and 0.8 ecm acetic anhydride was left to stand for 1 hour at room temperature, then evaporated to dryness under reduced pressure and the residue dissolved in ethyl acetate dissolved. There were 50 mg Natrimbisulfat added and the solution filtered through ".Celite diatomaceous earth. the FII appeared was evaporated under reduced pressure to dryness and yielded the 9 _e (, llot" 15c (-Triaeetoxyprosta-4, 5t 13-trans-trienoic acid methyl ester.

Were propionic, caproic and cyclopentylpropionic anhydride in the above procedure used as an esterifying agent, the corresponding triesters of the methyl ester of 9 ^ 11tf, 15 << - trihydroxyprosta-4,5,13-trans-trienoic acid were obtained.

Similarly, the other prostatric acid derivatives obtained in Examples 6, 8, 9, 10, 11, 12, 1?, 19, 20, 3 ^ and 35 were converted to the corresponding di- or triesters. This gave, for example, the following compounds -9-keto-l 1ς (, 15oC-diacetoxyprosta-4,5,13-trans-trienoic acid 9-keto-llo (, 15c (-diacetoxyprosta-4,5,13-trans-trienoic acid methyl ester 9-keto-l let, 15 ei-dipropionoxyprosta-Jj-, 5,13-trans-trienoic acid ethyl ester 9W, 15 * -diacetoxyprosta- ⁱ +, 5,13-trans-trienoic acid

409821/1132

9 ^ 1, lloi, 15 * -Triacetoxy-4-methylprosta- ⁱ f, 5.13- trans- trienoic acid 9 ^ 1.1 lot, 15 Jt-tripropionoxy- ^ - ethylprosta- ² ) -, 5t 13-trans-trienoic acid 9df He * »15 * -Tricaproxy-4-propylpro sta-4,5113-trans-trienoic acid 9-keto-llol, 1 ^ -diacetoxy - ^ - methylprosta- ^, 5,13-trans-trienoic acid methyl ester 9-keto-llΛ | 15ä ^ diacetoxy- ² t-ethylprosta-4 _f 5,13-trans-trienoic acid methyl ester 6-methyl-9-ket o-llrf, 15o (-diacet cocypro sta- ^ f, 5113-trans-trienoic acid 4-methyl-6- ethyl-9-keto-llel, 15ct-dipropionoxyprosta- ⁱ 4 ·, 5t 13-trans-trienoic acid 4,6-dimethyl-9ot, llct, 15ct-triaeetoxyprosta-4,5 ₁ 13-trans-trienoic acid 4-propyl-6 -metl # -l-9 ^ 11rtt 15o (-tricaproxyprosta-4,5t 13-trans-trienoic acid 9-keto-llej, 15e (-diacetoxy-20-ethylprosta- ^ ·, 5,13-trans-tifenic acid 9 -Keto-15c (-propionoxy-20-äthylpro sta- ^ ·, 5113-trans-trienoic acid 9 · (»HdU 15öl-TΓiacetoxy-20-bisnorprosta- ⁱ ^ ·, 5t 13-trans-trienoic acid 9ß _f llot, 15ei -Tricaproxyprosta-4,5,13-trans-triBic acid and 9Λ Hot, 15ot-Ti * iacetoxy-20-pentylprosta- ⁱ t-, 5t 13-trans-triene acid, etc.

Example 38-A

Treatment of the methyl 8R-9Oi ₁ H ^ t 15o ^ -trihydroxyprosta-4,5,13-trans-trienoate with acetic anhydride in pyridine according to the procedure of Example 38 gave the 8R-9J, 11 ei, 15o (-triacetoxyprosta-4 _f 5,13-trans-trienoic acid methyl ester.

Were obigen.Verfahren propionic, caproic and Cyclopentylpropionsäureanhydrid used as the esterifying agent, then afforded the corresponding triesters of Methyles'teis 8R-9 _e <, lloi, 15o (-Trihydroxyprosta - ^, 5 _t 13 trans-trienoic acid.

Similarly, the others, in Example 6A, 8A, 9A, 10A, HA, 12A, 1? A, 19A, 20a, 3 ^ A and 35A obtained prostatric acid derivatives into the corresponding Di- or Trieste converted.

409821/1132

For example, the following compounds were obtained £ R_9_Keto-llei, 15i-diacetoxyprosta-4,5,13-trans-trienoic acid 8R-9-keto-ll ^ t, IS ^ -diacetoxyprosta- ² ^ »13-trans-trienoic acid methyl ester £ R-9-keto-ll ^, 15et-dipropionoxyprosta-4,5,13-trans-trienoic acid ethyl ester 8R.-9dl »lSrf-diacetoxyprosta- ^, 5,13-trans-trienoic acid CR ^ ettllett ^ dt-triacetoxy- ^ -riiethylprosta- ^^, 13-trans-trienoic acid 8R-9g (, HfC, ^, (- tripropionoxy - ^ - ethylprosta- ^, 5,13-trans-trienoic acid 8R-9o (, llt (, 15it-tricaproxy- ⁱ i-propylprosta- ^z <', 5,13-trans-trienoic acid £ R-9-keto-llfli, lS ^ t-diacetbxy - ^ - methy ^ XDsta- ^, 5 t ¹ 3-tran s-trienoic acid methyl ester £ Bft -9-Keto-l led, 15 ot- diacetoxy - ^ - äthylprosta- ^, 5113-trans-triensäxrremethiylester ^ -o-methyl ^ -keto-lVfi ^ -diacetoxyprosta - ^. S, 13-trans-trienoic acid ^ - ^ 4'IetlTyl-6-ethyl-9-keto-Pa ra lle l, 15e {-dipropionoxyprosta - '+ 5' 13-trans-trienoic acid aa_if _{(6-Diinethyl-9 e} {, LLOC ^»1 5ET-triacetoxyprosta- ⁱ i · , 5,13-trans-trienoic acid 8R-4-propyl-6-inethyl-9it, hot »15it-tricaproxypro sta- ^, 5,13-trans-triß nsäuie a_9_Keto-llel _t 15fl (-diacetoxy-20-äthylprosta-4,5 _f 13-trans-trienoic acid ER_9_Keto-15 «{- propionoxy-20-äthylprosta- ⁱ 4-, 5,13-trans-trienoic acid 8R-9otf 1 lei, 15 "t-Tr iacetoxy-20 bisnorpr os ta ^, 5,13- tran s- trie acid SR 9SS, Ho (, 15öt-Tricaproxyprosta - ^ - _t 5,13-trans-trie acid and £ R- 9aCllot, 15 “it-triacetoxy-20-pentylprosta-14-, 5.13-trans-trienoic acid, etc.

Example 22

A solution of 100 mg 9oi, ll «i-bis (trimethylsilyloxy) -15-ketoprosta- ⁱ l-, 5,13-trans-trienoic acid methyl ester in 20 ecm of anhydrous ether was cooled to -20 ° C. and, with stirring and under a argon atmosphere with 6 molar equivalents Jt \ methylmagnesium bromide in ether dropwise. The temperature of the reaction mixture was set to OC. allowed to come, a further 6 molar equivalents of methylmagnesium bromine solution were added and the mixture obtained was stirred for a further 2 hours, after which 5 ecm of methanol were added after this time. The resulting mixture was diluted with ether

U 09821/1132

and washed several times with saturated sodium chloride solution. The ethereal extract was evaporated dried over magnesium sulfate and concentrated under vacuum to dryness and yielded the crude 9 ⁱ ^ ll ^ bis (trimethylsilyloxy) -15? - hydroxy-15 ^ -methylprostar- ⁱ l, 13.5-trans-triensäuremethylester, the after hydrolysis of the protective trimethylsilyloxy and purification by thin layer chromatography in accordance with example 26, part C to the pure hydroxy-15SS-methylprosta-4,5fl3-trans-triensäuremethylester and trihydroxy-L5D (- ^me thylprosta- ⁱ f _f 5il3-trans-triensäuremethylester (XX; R and R

1 "6

= H; R = hydroxy; R = methyl; η = k) provided; The esters were identical to the compounds obtained in Example 26.

Example 39-A ■.

Example 39 was repeated using the 8R> _r 9 ^, ll _< ^ -Bis- (trimethylsilyloxy) -15-ketoprosta ^, 5 »13-trans-trienoic acid methyl ester as starting material and gave the 6Ή-9 <χ, 11 ^ as end products , 15 ^ -Trihydroxy- ^ ß-methy 1-prosta- ⁱ 4-, 5 »13-trans-trienoic acid methyl ester and 6 ^ -9o / tllUi ^:

methylprosta-4,5,13-trans-trienoic acid methyl ester (8R-antimers of XX; R and R ^

1 "6

= H; R = hydroxy; R = methyl; η = k), which were identical to the compounds obtained in Example 26A. -

Example Λθ

6 ecm of a mixture of N-trimethylsilyldiethylamine and anhydrous acetone were added to 280 mg of methyl 9% -dihydroxy-15-ketoprosta- ^{i 4-, 5,13-trans-trienoate, and the reaction mixture was at} Maintained room temperature under an argon atmosphere for 6 hours, then evaporated to dryness under reduced pressure and the oily residue dissolved in 10 ecm anhydrous tetrahydrofuran. The resulting solution was cooled to -78 ⁰ C., and treated dropwise under an argon atmosphere with 1.4 cc of 2N-methylmagnesium bromide in ether treated, the temperature of the reaction mixture below -60 ° C. was held. The reaction mixture was kept at -78 ° C for a further 5 hours.

4 0 9 8 2 1/113 2

stirred, diluted with saturated ammonium chloride solution and extracted with ether. The organic extract was washed with saturated ammonium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was dissolved in 10 ecm of 7% aqueous methanol and treated with 0.1 ecm of a 0.213 mixture of acetic acid and water, the reaction mixture being ^{kept at 0} ° C. for 18 hours. It was then evaporated to dryness in vacuo and the residue purified by thin layer chromatography using a mixture of methylene chloride-ether-methanol (50: 4-555) as the eluent. Thus, one obtained the 9ei, llei _f 15il-trihydroxy-lS3-methylprosta- ² *, 5i 13-trans-trienoic acid methyl ester and 9 "(i Hrfi 15ß-trihydroxy-15i-methylprosta- ⁱ 4-, 5-13-trans- methyl trienate in pure form The compounds were identical to the products obtained in Example 26.

Example * K) -A

Following the procedure of Example 40, the 8R-9 * /, ll «l-dihydro: xy-15-ketoprosta- ^, 5,13-trans-trienoic acid ethyl ester in the 8R-9 * f, llo (, l5 <-trihydroxy -15ßmethylprosta- ⁱ <-, 5,13-trans-trienoic acid methyl ester and 8R-9e (, llrt, 15ß-trihydroxy-15oC-methylprosta-4,5,13-'trans-trienoic acid methyl ester converted with the in Example 26A and 39A were identical.

409821/1132

Claims (1)

Claims (1 \ - Process for the preparation of a compound in the form of racemic Mixtures or an 8R antimer with the formulas: COOR in which R and R- ⁷ each represent hydrogen, methyl, ethyl or propyl; R is hydrogen, hydroxy or a customary hydrolyzable ester or Ether of the same signifies; 2 3 R and R are each hydroxy or a conventional hydrolyzable ester or Mean ether of the same; Zj. R for hydrogen, lower alkyl or the non-toxic, pharmaceutical are acceptable salts of compounds in which R is hydrogen; η is an integer from 2 to 9; and the wavy line (X) the tf or ß configuration or a mixture the same means characterized in that one a) "a racemic compound or its l'R-antimers of the formula: 409821/1132 H OH OTHP in which R denotes hydrogen or tetrahydropyranyloxy, with the DüiMumsalz of Pent - ** · -in-i-ol in an inert organic solvent to form a trihydroxyacetylenic compound of the formula OH l OH OTHP ,1' treats, in which R and η have the above meaning; b) converting the acetylenic compound of step a) into a triester or c) selectively oxidizes the hydroxyl group at C-6; d) the dihydroxyketoacetylenic compound of step e) with an alkyl lithium or an alkyl magnesium halide in which the alkyl group is methyl, Is ethyl or propyl to form a racemic compound or a 8R antimers thereof with the formula: OH Γ " Oh OH OTHP 11 5 ' treated, in which R ¹ and η have the above meaning and R is methyl, ethyl or propyl; 40982 1/1132 e) the 6-alkylacetylenic compound from stage d) into a trieste *! delt; f) a triester from stage b) or e) with a lithium dialkyl copper reagent to form a racemic compound or its 8R antimers the formula: "- OAc ■. ·· .- ·. • ι treated, in which R ₁ R, R ^ and η have the above meaning and Ac stands for an acyl group with 1-k carbon atoms; g) the compound from step f) is hydrolyzed under basic conditions; h) oxidizing the mono- or dihydroxylated compound from step g); i) the protected hydroxyl groups remaining in the molecule are hydrolyzed; j) the hydroxyl groups optionally esterified or etherified and / or the carboxylic acid group converts to an alkyl ester or a pharmaceutically acceptable salt thereof; and ·. k) the keto group in the alkyl esters of the 9-keto compounds from step j) for Formation of a mixture of the corresponding 9cd- and 9-ß-hydroxy compounds selectively reduced and the alkyl ester group hydrolyzed by chemical or enzymatic methods. 2. - Method according to claim 1, characterized in that the connections are racemic mixtures. 3.- The method according to claim 2, characterized in that in step a) 5-15 molar equivalents of the dilithium salt of pent - ^ - in-l-ol in diethyl ether solution are used, and the reaction under practically anhydrous conditions and under an inert atmosphere at around room temperature ~. 409821/1132 to be led. k, - Process according to Claim 2, characterized in that acetyl chloride is used as the reagent in step b). 5 · - The method according to claim 2, characterized in that the oxidation in Stage c) is carried out with aktivxertera manganese dioxide. 6, - The method according to claim 2, characterized in that the esterification in Step e) is carried out using methyl lithium and acetyl chloride as reagents. 7.- The method according to claim 2, characterized in that as a reagent in Stage f) lithium dimethyl copper is used. 8. Method according to claim 7 »characterized in that k molar equivalents of lithium dimethyl copper in ether solution are used, the reaction at a temperature between approximately -78 ° C. and about -5O ⁰ C. for a period between about 3-7 hours and under an inert atmosphere, using a racemic compound of the formula: AcO OTHP. receives, in which R, R, η and Ac have the above meaning. 9, - Method according to claim 7, characterized in that 1 molar equivalent L'ithiumdimethylkupfer used in ethereal solution and the reaction at about 0C. is carried out for about 3-7 hours under an inert atmosphere, with a racemic compound of the formula as an intermediate product: AcO ^(CI Vn " ^CH 3 I ¹ '5
is obtained in which R, R, η and Ac have the above meanings. 10.- The method according to claim 7 »characterized in that the basic Hydrolysis in stage g) using excess anhydrous potassium carbonate for hydrolyzing both acyloxy groups present at C-I and C-9 is carried out. 11.- The method according to claim 2, characterized in that the basic Hydrolysis in stage g) using about a molar equivalent anhydrous potassium carbonate to selectively hydrolyze the primary acyloxy group at the C-I. 12, - Method according to claim 2, characterized in that h as a reagent .for the oxidation of step) a 8N Chrcmsäurelösung using stoichiometric amounts of this reagent used and the reaction is durchgeführt- at about -10 ⁰ C. for about 2 hours . 13 · - Method according to claim 2, characterized in that the tetrahydropyranyloxy groups in stage i) using aqueous solutions of acetic acid, Oxalic acid or tartaric acid can be hydrolyzed. 1 ^ .- The method according to claim 13, characterized in that as the hydrolyzing agent 65- ^ aqueous acetic acid is used. 15 · - Method according to claim r, characterized in that the connections are the SR antimers. . 16. - Method according to claim 15, characterized in that in step a) 5-15 molar equivalents of the dilithium salt of pent-4-yn-1-ol in diethyl ether solution can be used, the reaction being carried out under practically anhydrous conditions under an inert atmosphere at about room temperature will. 409821/1132 17.- The method according to claim 15, characterized in that acetyl chloride is used as the reagent in step b). 18.- The method according to claim 15, characterized in that the oxidation in stage c) is carried out with activated manganese dioxide. 19 · - Process according to Claim 15, characterized in that the esterification in step e) is carried out using methyl lithium and acetyl chloride as reagents. 20.- The method according to claim I5, characterized in that as a reagent in Stage f) lithium dimethyl copper is used. 21.- The method according to claim 20, characterized in that 4 molar equivalents Lithium dimethyl copper in ethereal solution can be used, with the reaction at a temperature between about -78 C. and about -50 C. for the duration of about 3-7 hours under an inert atmosphere to form an 8R-antimer Compound of the formula: R OTHP 1 '5 is carried out as an intermediate, where R, R, η and Ac the above Be have meaning. 22. - Method according to claim 20, characterized in that 1 molar Equivalent lithium dimethyl copper in ether solution used and the reaction at around OC. for a period of about 3-7 hours under an inert atmosphere to form an 8R-antomeric compound of the formula (CH ₂ ) _n -0H ₃ is carried out as an intermediate, where R, R ^, η and Ac have the above 409821/1 ^ 2 have performance. 23, - Method according to claim 20, characterized in that the basic Hydrolysis of step g) using excess anhydrous potassium carbonate to hydrolyze both acyloxy groups present at C-I and C-9. ■ 2k, - Process according to claim 15, characterized in that the basic hydrolysis of stage g) ^ is carried out using about one molar equivalent of anhydrous potassium carbonate for the selective hydrogenation of the primary acyloxy group on the CI. 25.- The method according to claim I5 »characterized in that as a reagent for the oxidation of stage h) an 8N chromic acid solution in stoichiometric amounts is used, the reaction being carried out at about -10 C. for about 2 hours will. 26.- The method according to claim I5, characterized in that the tetrahydropyranyloxy groups hydrolyzed in step i) using aqueous solutions of acetic acid, oxalic acid or tartaric acid. 27.- The method according to claim 26, characterized in that 65 - $> strength aqueous acetic acid is used as the hydrolyzing agent. 28.- Process for the preparation of a compound in the form of racemic mixtures or 8R antimers of the formula: 409821/1132 in goblets R and Ir each represent hydrogen, methyl, ethyl or propyI; R is hydrogen, hydroxy or a customary hydrolyzable ester or ether the same means; R is hydrogen, lower alkyl or the nontoxic, pharmaceutically acceptable salts of the compounds in which R is hydrogen; R represents methyl, ethyl or propyl;
η is an integer from 2 to 9; and the wavy line (?) denotes the o (- and / or ß-configuration, with the proviso that - when R is in the ^ -position - the hydroxyl group bonded to the same carbon atom as R is in the ß-position; and - if R is in ß-position - the hydroxyl group bonded to the same carbon atom as R is in C ^ -position,
characterized in that one ' a) a racemic compound or an 8R-antimer of the formula: OTHP (XA) in which R, R ⁵ and η each have the above meaning and R is hydrogen or tetrahydropyranyloxy, converts into an allyl ester; b) hydrolyzing the tetrahydropyranyloxy groups; C ₁ ) protects the 9-keto groups as an oxime; d) selectively oxidizes the hydroxyl groups at C-15; e) the hydroxyl groups on C-II - if present - as trimethylsilyl ethers protects; 409821/1132 f) treating the 15-keto compound with at least 1.1 molar equivalents of an alkyl lithium or an alkyl magnesium halide in which the alkyl group is methyl, ethyl or propyl to form the corresponding 15 \ -hydroxy-15 Z -alkyl derivatives; g) the trimethylsilyloxy group - if present - hydrolyzed; h) separating the 15o (-hydroxy-15β-alkyl and 15β-hydroxy-15e (-alkyl isomers; i) the oxime is hydrolyzed to the corresponding keto compound; j) hydrolyzing the alkyl ester group by chemical or enzymatic methods; and k) optionally the secondary hydroxyl groups - if present - esterified or etherified and / or the carboxylic acid function in the pharmaceutically acceptable Converts salts. 29, - Method according to claim 28, characterized in that as connections racemic mixtures can be used. 30. - Method according to claim 28, characterized in that as connections the 8R antimers are used. 31.- Process for the preparation of a compound in the form of racemic mixtures or 8R antimers of the formula: E ³ . Ir5 in which R and R ⁵ each represent hydrogen, methyl, ethyl or propyl; R denotes hydrogen, hydroxy or a customary hydrolyzable ester or ether thereof; 40982 1/1132 2255324 R ^ for hydros or a common hydrolyzable ester or ether thereof stands; R is hydrogen, lower alkyl or the nontoxic, pharmaceutically acceptable salts of the compounds in which R is hydrogen; R is methyl, ethyl or propyl;
η is an integer from 2 to 9; and the wavy line (?) means the o (and / or ß configuration with the The prerequisite that - if R is in the oi position - those on the same carbon atom as R bonded hydroxyl group is in ß-position, and - when R is in ß-position stands - the hydroxyl group attached to the same carbon atom as R. is in the oL position, characterized in that one a) the hydroxyl group at C-15 in a chemical compound or an 8R antimer of the formula: OH } COOCH, E ¹ '. . OH in which R, R and η have the above meaning and R is hydrogen or Tetrahydropyranyloxy, selectively oxidized; b) protects the hydroxyl groups present as trimethylsilyl ether; c) the tri-ethylsilyloxy-15-keto compound with at least 1.1 molar equivalents an alkyl lithium or alkyl magnesium halide in which the Alkyl group is methyl, ethyl or propyl, to form the corresponding 15> -hydroxy-15 <-alkyiderivates treated; d) hydrolyzing the trimethylsilyloxy groups present; 409821/1 132 e) the 15 [beta] -hydroxy-15 [beta] -alkyl and 15 [beta] -hydroxy-15o (-alkyl isomers); f) hydrolyzing the alkyl ester group by chemical or enzymatic methods; and g) the secondary hydroxyl groups present are optionally esterified or etherified and / or converting the carboxylic acid function to the pharmaceutically acceptable salts. 32, - Method according to claim 31 »characterized in that as connections racemic mixtures can be used. 33 · - Method according to Claim 31, characterized in that as connections the 8R antimers are used. ■ y ±. ~ Process for the preparation of compounds according to Claim 1, characterized in that (A) for the preparation of the racemic compounds or 8R-ani.imers of the formulas (A) , 3 409821/1132 in which R and R denote hydrogen, methyl, ethyl or propyl; R represents hydrogen, hydroxy or a customary hydrolyzable ester or The ether of the same; 2 3
R and R each represent hydroxy or a customary hydrolyzable ester or ether thereof; R stands for hydrogen, a lower alkyl group or the pharmaceutically acceptable L is free , non-toxic salts of compounds in which R is hydrogen; η is an integer from 2 to 9;
(a) a "racemic compound or the l'R-antimer of the formula: (CH ₂ ) _n -CH ₃ OTHP ^ in -which R is hydrogen or tetrahydropyranyloxy, with a dilithium salt of pent - ^ - in-l-ol in an inert organic solvent Formation of a trihydroxyacetylenic compound of the formula: OTHP 40982 1/1132 ■ - 157 - O ο C C Q O / in which R and η have the above meaning, treated; (b) converting the acetylenic compound from step a) into a triester or (c) selectively oxidizes the hydroxyl group at C-6; (d) the acetylenic dihydroxyketo compound from step c) with an alkyl lithium or an alkylmagnesium halide in which the alkyl group Is methyl, ethyl or propyl to form a compound of the formula: Oh ... 1 '5' treated, where R and η have the above meaning and R for methyl, ethyl or propyl; (e) converting the acetylenic 6-alkyl compound from step d) to a triester; (f) a triester from step b) or e) with a lithium dialkyl copper reagent to form a compound of the formula: _r 'eP> C = C = C <O ^^ OAc OAc OTHP I ¹ 5 treated, in which R, R, R ^ and h have the above meaning and Ac for an acyl group with 1-Λ carbon atoms; (g) hydrolyzing the compounds from step f) under basic conditions; (h) the mono- or dihydroxylated compound obtained in step g) is oxidized; (i) hydrolyzing the protected hydroxyl groups remaining in the molecule; and 409821/1132 (j) / the hydroxyl groups optionally esterified or etherified and / or the Carboxylic acid group into an alkyl ester or a pharmaceutically acceptable one Converts its salt; or (k) selectively reducing the keto group in the alkyl esters of the 9-keto compounds from step j) to form a mixture of the corresponding % - and 9β-hydroxy compounds and hydrolyzing the alkyl ester group by chemical or enzymatic processes; (B) for the preparation of the racemisehen compounds or 8R-antimers of Formula: COOR ⁴ (C) in which R and R ⁵ each represent hydrogen, methyl, ethyl or propyl; R denotes hydrogen, hydroxy or a customary hydrolyzable ester or ether thereof; R for hydrogen, lower alkyl or the non-toxic, pharmaceutical acceptable salts of the compounds in which R is hydrogen; R is methyl, ethyl or propyl;
η is an integer from 2 to 9; and the wavy line (?) indicates the ot and / or ß configuration with the proviso that when R is in the c / position, the hydroxyl group bonded to the same carbon atom as R is in the ß position, and when R is is in the β-position, the hydroxyl group bonded to the same carbon atom as R is in the oi-position; --- 409821/1132 (a) a racemic compound or an 8R-antimer of the formula: OTHP '(XA) in -which R, R and η have the above meaning and R is hydrogen or Tetrahydropyranyloxy means converted to an alkyl ester; <b) hydrolyzes the tetrahydropyranyloxy groups; {c) protects the 9-keto group as an oxime; (d) selectively oxidizes the hydroxyl group at C-15; (e) Any hydroxyl group present on the C-llo (as trimethylsilyl ether protects; (f) the 15-keto compound with about 1.1 molar equivalents of an alkyl lithium or alkyl magnesium halide in which the alkyl group is methyl, ethyl or propyl, to form the corresponding 15 <-hydroxy-15 ς -alkyl derivatives treated; (g) hydrolyzing the trimethylsilyloxy group which may be present; (h) separates the 15o-hydroxy-15 [beta] -alkyl and 15 [beta] -hydroxy-15o (-alkylisanes; (i) hydrolyzing the oxime to the corresponding keto compound; (j) hydrolyzing the alkyl ester group by chemical or enzymatic methods; and - (k) optionally esterifying the secondary hydroxyl group which may be present or etherified and / or the carboxylic acid function into a pharmaceutically acceptable one Salt converts; 409821/1132 (C) for the preparation of the racemic compounds or BR-antomers of the formula 4 COOR * in which R and R ^ each represent hydrogen, methyl, ethyl or propyl; R is hydrogen, hydroxy or a customary hydrolyzable ester or ether the same means; · ' Br stands for hydroxy or a customary hydrolysable ester or ether thereof; R is hydrogen, lower alkyl, or the non-toxic, pharmaceutically acceptable Means salts of the compounds in which R is hydrogen; R represents methyl, ethyl or propyl; η is an integer from 2 to 9; and the wavy line (?) indicates the <£ - and / or ß-configuration, with the prerequisite, that, when R is in the oZ-position, which is attached to the same carbon atom we R bonded hydroxyl group is in the ß-position, and when R is in the ß-position the hydroxyl group bonded to the same carbon atom as R is in (/ position, (a) a racemic compound or an 8R-antimer of the formula: OH COOH J ?! ¹ bTHP
5 (XIVA) «, in which R, R and N each have the above meaning and R is hydrogen or tetrahydropyranyloxy is converted to an allyl ester; 409821/1132 (b) hydrolyzes the tetrahyclropvranyloxy groups; · (c) selectively oxidizes the hydroxyl group at C-15; (d) protects the hydroxyl groups present as trimethylsilyl ether; (e) the trimethylsilyloxy-15-keto compound in about 1.1 molar equivalents an alkyl lithium or alkyl magnesium halide in which the alkyl group is methyl, ethyl or propyl to form the corresponding 15s-hydroxy-15 <-alkyl derivatives treated; . (f) hydrolyzes the trimethylsilyloxy groups present; (g) the 15o-hydroxy-15β-3-alkyl and 15β-hydroxy-15c (-alkyl isomers separates; (h) "the alkyl ester group is hydrolyzed by chemical or enzymatic processes; and."
, »If necessary (i) / the secondary hydroxyl groups present optionally esterified or esterified ether and / or the carboxylic acid function into a pharmaceutically acceptable salt converts. 35 · - Method according to claim 3 ^, characterized in that the connections are racemic mixtures. 36, - Method according to claim 3 ^ i, characterized in that the connections are the 8R antimers. 409821/1132 37 · - Compounds of the following formulas in the form of racemic mixtures or their 8R antimers (A) COOR COOR COOR (C) C = C = C κ >> H( (D) .COOR in which R and K each represent hydrogen, methyl, ethyl or propyl; R is hydrogen, hydroxy or a customary hydrolysable ester or ether the same means; 2 3
R and R ^ are each hydroxy or a conventional hydrolyzable ester or Mean ether of the same; R represents methyl, ethyl or propyl; 409821/1132 R stands for hydrogen, a lower alkyl group or the pharmaceutically acceptable / 4. non-toxic salts of compounds in which R is hydrogen means; η is an integer from 2 to 9; and the wavy line ( \ ) indicates the ^ - and / or ß-configuration, with the prerequisite that - when R is in the "(position - the hydroxyl group bonded to the same carbon atom as R is in the ß-position, and - if R is in ß-position - the hydroxyl group attached to the same carbon atom as R is in the _1β (position. 38.- Compounds according to claim 37t, characterized in that they are racemic Mixtures are. 12 3 39 · - Compounds according to claim 38, characterized in that R, R and R ^ 4 5 each represent hydroxy and R, R and R each represent hydrogen. 40.- Compounds according to claim 38, characterized in that R, R, R and c. 2 3 R ^ each represent hydrogen and R and R ^ each represent hydroxy. 41, - Compounds according to claim 38, characterized in that R is methyl, Means ethyl or propyl, R, R and R- ^ each stand for hydroxy and R and R- * each represent hydrogen. 42.- Compounds according to claim 38, characterized in that R is methyl, Means ethyl or propyl, R and Rr each stand for hydroxy and R, R and R5 each represent hydrogen. 43.- Compounds according to 'claim 38, characterized in that R is methyl, 12 3 - Means ethyl or propyl, R, R and R each stand for hydroxy and R and R each represent hydrogen. 44 -.- Compounds according to Claim 38, characterized in that R stands for methyl, ethyl or propyl, R and R ^ are hydroxy and R, R and R are each hydrogen. ^ _{Q g} g _{2 γ} , ^ ₃₂ ^ 5.- Compounds according to claim 38 »characterized in that R and R each- 12 3 because for methyl, ethyl or propyl, R, R and R ^{J are} each hydroxy Jl ₄ .
mean and R stands for hydrogen. k6.- Compounds according to claim 38, characterized in that R and R ⁵ each 2 3 because they stand for methyl, ethyl or propyl, R and R ^ each mean hydroxy 1 k ten and R and R each represent hydrogen k-7 compounds according to claim 38, characterized in that η has a value of k . * »- 8.- Compounds according to claim 38, formula (A), characterized in that Ii c. 12th R, R and R ^ are hydrogen, R and R are hydroxy, η has a V / erb of h and the compounds the 9-keto-ll (X, 15 ^ d ± hydroxyprosta-4,5,13-transtrienoic acid or the non-toxic, pharmaceutically acceptable salts of-, are the same. ^ 9 · - Compounds according to claim 38, formula (A), characterized in that e 4 1 2 R and R ^ each represent hydrogen, R represents methyl, R and R each represent hydroxy and η has a value of 4 and the compound of the 9-keto X
llöt, 15ot-d ^ hydroxyprosta - ^, 5j 13-trans-trienoic acid methyl ester. '"'" ..rf .--- "'' ¹
50, - Compounds according to claim 38, formula (A), characterized in that 1 h c 2 ■ R, R, K and R ^ each stand for hydrogen, R is hydroxy and η is a Has a value of 4 and the compounds are 9-keto-15e (-hydroxyprosta - ^ -, 5,13-transtrienoic acid or their non-toxic, pharmaceutically acceptable salts. 51.- Compounds according to claim 38, formula (A), characterized in that R h 5 12 represents methyl, R and R. represent hydrogen, R and R each represent hydroxy and η has a value of k- and the compounds the 4-methyl-9-ketollt <, 15 ^ -dihydroxyprosta-4,5 _t 13- trans-trienoic acid or its non-toxic, pharmaceutically acceptable salts. 40 9 821/1132 - 155 - Compound according to claim 38, formula (A), characterized in that R stands for methyl, R, R and R each mean hydrogen, R stands for hydroxy and η has a value of k and the compounds are methyl-9 -keto-15ot-hydroxyprosta-A, 5t 13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 53.- Compounds according to claim 38, formula (A), characterized in that R l ± . c 12 and R are each hydrogen, R is methyl, R and R. each represent hydroxy and η has a value of k and the compounds are 6-methyl-9-keto-llo (, 15et-dihydr.oxyprosta-4,5il3-trans-trisic acid and the nontoxic, pharmaceutically acceptable salts thereof . 5k.- Compounds according to claim 38, formula (A), characterized in that R, R and R 'are each hydrogen, R * is methyl, R is hydroxy and η has a fourth of k and the compounds are 6-methyl -9-keto-15e <hydroxyprosta- ^, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 55 ^ - Compounds according to claim 38, formula (A), characterized in that R and R each represent methyl, R and R each represent hydroxy, R represents hydrogen and η has a value of k and the compounds k-, 6 - ' Dimethyl-9-keto-llet, 15 "fc-dihydroxyprosta-4,5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts are. 56.- Compounds according to claim 38, formula (A), characterized in that R 5 2 Ik and R ^v each represent methyl, R represents hydroxy, R and R each represent hydrogen and η has a value of k and the compounds k, 6- dimethyl-9-keto-15 ^ -hydroxyprosta-4,5,13 -Trans-trienäuiB and their non-toxic, pharmaceutically acceptable salts. 409821/1132 57 · - Compounds according to claim 38, formula (A), characterized in that R _t • R and TL each represent hydrogen, R and R each represent hydroxy and η has a value of 6 and the compounds are 9-keto-II ^ _t 15o (-ftihydroxy-20-äthylprosta-Jf, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 58.- Compounds according to claim 38, formula (A), characterized in that R, R, R and R ^ each represent hydrogen and R is hydroxy, and η has a value of 6 and the compounds 9-keto-15el-hydroxy-20-äthylprosta-Jf, 5 »13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. 59 · - Compounds according to claim 38, formula (B), characterized in that Jf 5 12 3 R, R and R each represent hydrogen, R, R and R each represent hydroxy mean, the wavy line stands for the oC configuration and η a value of Jf has and the compounds the 9 ^ 11rt «15rt-Trihydroxyprosta- ^, 5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. 60.- Compound according to claim 38, formula (B), characterized in that R 5 Jf 12 3 and R are each hydrogen, R is methyl, R, R and R are each stand for hydroxy, the wavy line means the oi-configuration and η has a value of Jf and the compound of the 9 «i, Hei, 15et-trihydroxyprosta-Jft5fl3-trans-trienoic acid methyl ester is. 6l.- Compounds according to claim 38, formula (B), characterized in that R, Jf 5 12 3 R and R each represent hydrogen, R _1, R and R ^ each represent hydroxy, the wavy line represents the o (configuration and η has a value of 6 and the compounds the 9tf, ll * »15 * -trihydroxy-20-ethylprosta -Jf, 5-13-transtrienoic acid and its non-toxic, pharmaceutically acceptable salts. 62._ Compounds according to claim 38, formula (B), characterized in that R, Jf 5 12 3 R and R ^ each represent hydrogen, R, R and R ^J each represent hydroxy 409821/1132 The wavy line stands for the ß-configuration and η has a value of k and the compounds the 9ß, llct, 15o (-Trihydroxyprosta- ⁱ J ' _! 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts are. 63 »- Compounds according to claim 38, formula (B), characterized in that UI 12 3 R, R and R ^ each represent hydrogen, R, R-c and R ^ each represent hydroxy stand, the wavy line stands for the ß-configuration and η has a value of 6 has and the compounds the 9ß, llol, 15e (-trihydroxy-20-äthylprosta-i | -, 5,13-trans- € rienoic acid and their non-toxic, pharmaceutically acceptable salts. . · 6 * K compounds according to claim 38, formula (B), characterized in that R, 1 A- 5 2 3 R, R and R each represent hydrogen, R and R ^ each represent hydroxy, the. Wavy line stands for the ^ -configuration and η has a value of h and the connections the 9c { _/ L ^ ä-Dihydroxyprosta-A- _! , 5 »13-t.trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 65 »- Compounds according to claim 38, formula (B), characterized in that R, R" R and R each represent hydrogen, R and R each represent hydroxy, the wavy line represents the β-configuration and η a value of k and the compounds jiie 9ß, 15ci-dihydroxyprosta- ⁱ 4 ', 5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. 66.- Compounds according to claim 38, formula (B), characterized in that R ₅ R, R and B? each represents "hydrogen, R and R ^ each represent hydroxy, the wavy line represents the ^ configuration and η has a value of 6 and the compounds the 9rf, 15 </ r ^D i ^h ydroxy-20-äthylprosta- ^, 5,13-transtrienoic acid and its non-toxic, pharmaceutically acceptable salts. 40982 1/1132 - 158 - 67, - Compounds according to claim 38, formula (B), characterized in * that R ₁ R ¹ , R and Ί? each represent hydrogen, R and R ³ each represent hydroxy, the wavy line represents the β-configuration and η has a value of 6 and the compounds die gßjl ^ -Dihydro ^ r-ZO-äthylprosta - ^. S.lS- transtrienoic acid and its non-toxic, pharmaceutically acceptable salts. 68, - Compounds according to claim JQ, formula (B) _1, characterized in that H. < 12 3 R represents methyl, R and R each represent hydrogen, R, R and R each represent hydroxy, the wavy line represents the tf configuration and η has a value of 4 and the compounds are 4 ^ ethyl-9tf, llo <, 15o (.- trihydroxyprosta- ⁱ l- _f 5 »l-3-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 69 »-compounds according to claim 38, formula (B), characterized in that 1 k ς 2 3 R represents methyl, R, R and Ir "each represent hydrogen, R and R ^J each represent hydroxy, the wavy line represents the oi configuration and η has a value of 4 and the compounds k-tt ethyl-9 <& 1 ^ -dihydroxyprosta-4,5, r3 "are trans ~ trienoic acid and its non-toxic, pharmaceutically acceptable salts. 70, - Compounds according to claim 38, formula (B), characterized in that 'S? represents methyl, R and R each represent hydrogen, R ¹ , R ² and 'S? each stand for hydroxyl, the wavy line means the ißi configuration and η has a value of k and the compounds the 6-methyl-9 _ö f _t llai, 15fl (-trihydroxyprosta ^ _t 5 »13-trans-trienoic acid and its non- are toxic, pharmaceutically acceptable salts. 409821/1132 71.- Compounds according to claim 38t formula (B), characterized in that IT represents methyl, R, R and R each represent hydrogen, R and R ^J each represent hydroxy, the wavy line represents the © (configuration and η has a value of k and the compounds are the 6-41ethyl-9o (»15j <-dihydroxyprosta-4-, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. ■. 72, - Compounds according to claim 38, formula (B), characterized in that c 12 3- R and R each represent methyl, R, R and R each represent hydroxy, H.
R denotes hydrogen, the wavy line stands for the of-configuration and η has a value of ^ and the compounds 4-, 6-dimethyl-9c6llet | lib (-trihydroxyprosta-4,5,13-trans-trienoic acid and its non- are toxic, pharmaceutically acceptable salts. ■ 73 · - Compounds according to claim 38, formula (B), characterized in that e. 2 ■ 3 - ■ ■ 1 R and R ^ each represent methyl, R and R ^ each represent hydroxy, R and R each stand for hydrogen, the wavy line for the oC configuration and η has a value of ^ and the compounds ^, 6-dimethyl-9oi, 15dt-dihydroxyprosta-4,5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. 7 ^ .- compounds according to claim 38, formula (C) and (D), characterized in that that the hydroxy group at C-15 in oi configuration and the alkyl group in the same position is in ß-configuration. 75 · τ compounds according to claim 3 &, formula (C) and (D), characterized in that that the hydroxy group on C-15 in ß-configuration and the alkyl group in same position in el configuration. 9821 /.1 132 76.- Compounds according to claim 38, formula (C), characterized in that R, R and R ^ each represent hydrogen, R represents hydroxy, R represents β-methyl, and η has a value of k and the compounds the 9-keto-Ile ^, i5 ^ -dihydroxy-15ß-methylprosta- ^, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 77 · - Compounds according to claim 38, formula (C), characterized in that R, R, R and R each represent hydrogen, R is β-methyl and η has a value of k and the compounds are 9-keto-15fli -hydraxy-15β-methylprosta-4 ', 5 »13-' trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 78.- Compounds according to claim 38, formula (D), characterized in that 4 * 5 1 3 R, R and R each represent hydrogen, R represents hydroxy, R represents Ot-hydroxy stands, R ß-J4ethyl and η has a value of Ψ and the Compounds the 9 "fcll *, 15 <^ Trihya ^ oxy-15ß-methylprosta- ^, 5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable sali, e are. 79 · - Compounds according to claim 38, formula (D), characterized in that R, R, R and R each represent hydrogen, R represents ot-hydroxy, R represents β-methyl and η has a value of ^ and the Compounds which are 9 "dihydroxy-15β-methylprosta- ^/ f, 5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. 80.- Compounds according to claim 37 in the form of the 8R antimers. 12th 81, - Compounds according to claim 80, characterized in that R, R and R k 5 each represent hydroxy and R, R and Br each represent hydrogen. 1 * t-82. compounds according to claim 80, characterized in that R, R, R and <2 3 Έ / each represent hydrogen and R and R ^J each represent hydroxy. 409821/1132 83.- Compounds according to claim 80, characterized in that * <äaß R for methyl, • 12 3 4 · · ' Ethyl or propyl, R, R and R ^ each represent hydroxy. And R and Br each represent hydrogen ,. 8 * 4 ·, - compounds according to claim 80 _r characterized in that R is ethyl, 2 3 1 4- Ethyl or propyl, R and R ^ are each hydroxy and R, R and R ^ each represent hydrogen, 85 · - Compounds according to claim .80, characterized in that R is methyl, Ethyl or propyl, R, R and R ^ are each hydroxy and R - and R each stand for hydrogen. 86.- Compounds according to claim 80, characterized in that R represents methyl, ethyl or propyl, R and 'Br each represent hydroxy and R, R and R each represent hydrogen. 87 »- connections according to claim 30» characterized in that "R and R ^ each- 1 -2 3 because they stand for methyl, ethyl or tropyl, S, R and R each stand for hydroxy M- and R is hydrogen. 88, - connections according to claim SD, characterized in that R and U each 2. ' 3 -because for methyl, ethyl or propyl steten, R and Jr. Each mean Hydros and R and R each mean Jür "Viasserstoff' stand, 89, - connections according to claim 80 _; , characterized in that; n has a value of Λ. 90-- Compounds according to claim 80 ₁ iOrmel (A), characterized in that R, R and R- ^ each represent hydrogen, 1 ma. R, each denotes Hydroxjr and η has a value of h imä the compound en the 8E- 9 ^ dihydroxyprosta - ^, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 0S821 / 1132 - 172 - 235532Λ 91.- Compound according to claim 80, formula (A), characterized in that I Λ O- R and R- * each denote hydrogen, R denotes methyl, R and R each denote hydroxy and η has a value of k and the compound of 8R-9-Ketollet, 15 «t-dihydroxyprosta- ¹ i-, 5f 13- trans-trienoic acid methyl ester. 92, - Compounds according to claim 80, formula (A), characterized in that R, R, R and R * each mean hydrogen, R stands for hydroxy and η has a value of k and the compounds have the 8R-9-keto 15ol-hydroxyprosta-4,5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 93.- Compounds according to claim 80, formula (A), characterized in that R represents methyl, R and R each represent hydrogen, R and R each represent hydroxy and η has a value of k and the compounds are 8R-4 ~ methyl-9-keto-llol, 15p (.- dihydroxyprosta- ^{i i;,} 5,13-trans-tri.ensäure and their non-toxic pharmaceutically acceptable salts " 9 ^ - · - Compounds according to claim 80, formula (A), characterized in that 1 4 5 2 R represents methyl, R, R and R each represent hydrogen, R represents hydroxy and η has a value of ^ and the compounds are 811-4-methyl-9-keto-15el-hydroxyprosta-4,5fl3-trans-trienoic acid ^mi ^ ^{L are} their non-toxic, pharmaceutically acceptable salts. 95 · - Compounds according to claim 80, formula (A), characterized in that 4 5 12 R and R are each hydrogen, R is methyl, R and R are each are hydroxy and η has a value of 4 and the compounds are 8R-6 ^ 1ethyl-9-keto-ilot, 15et-dihydroxyprosta- ^, 5,13-trans-triQioic acid and their non-toxic, pharmaceutically acceptable salts. 96.- Compounds according to claim 80, formula (A), characterized in that 1 4- * ί 2 R, R and R each represent hydrogen, R ^ represents methyl, R represents hydroxy stands and. η has a value of 4 and the compounds the 8R-6-methyl-9-keto- 409821/1132 15o (-hydroxyprosta-4,5 »13-trans-trienoic acid and its non-toxic, pharmaceutical are acceptable salts. 97.- Compounds according to claim 80, formula (A), characterized in that • ti 12 4 R and R ^ each represent methyl, R and R each represent hydroxy, R represents hydrogen and η has a value of h and the compounds 8R-4,6-dimethyl-9-keto-llflt, 15 «t-dihydroxyprosta - ^z i-, 5t are 13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 9-8.- Compounds according to claim 80, formula (A), characterized in that ■ 5 2 14 R and R ^ each represent methyl, R denotes hydroxy, R and R each represent hydrogen and η has a value of 4 and the compounds 8R_- ^ •, 6-dimethyl-9-keto-15et-hydroxyprosta- ^, 5 _{t are} 13-tfans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 99 · - Compounds according to claim 80, formula (A), characterized in that 4 5 12 R, R and R each represent hydrogen, R and R each represent hydroxy and η has a value of 6 and the compounds are 8R-9-keto-lloc, 15e (-dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. - 100.- Compounds according to claim 80, formula (A), characterized in that 14 5 2 R, R, R and R each represent hydrogen, R represents hydroxy and η has a value of 6 and the connections have the eR ^ - prosta-4,5f13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable Salts are. . . 101.- Compounds according to claim 80, formula (B), characterized in that 4 5 12 3 R, R and R each represent hydrogen, R, R and R each represent hydroxy, the wavy line represents the oC configuration and η has a value of 4 and the compounds 8R-9rf _f lIeI, 15dl-trihydroxyprosta-4,5 , 13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 409821/1132 102, - compound according to claim 80, formula (B), characterized in that c 'k 12 3 R and R ^ each represent hydrogen, R denotes methyl, R, R and R ^v each represent hydroxy, the wavy line denotes the ei configuration and η has a value of k and the connection of 8R-9 «i, lloi, 15eC-Trihydroxyprosta- ^ »5,13-trans-trienoic acid methyl ester. 103 · - Compounds according to claim 80, formula (B), characterized in that dai3 2 (.C 12 3 R, R and R ^ each represent hydrogen, R, R and R ^J each represent hydroxy, the wavy line represents the of configuration and η has a value of 4 and the compounds 8R-9rf, llo <, 15 ^ - Trihydroxy-20-ethylprosta-4-, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 10 ^ J -.- Compounds according to claim 80, formula (B), characterized. That 4 · 5 1-23 R, R and R each represent hydrogen, R, R and R each represent hydroxy, the wavy line represents the ß configuration and η a value * of k- and the compounds 8R-9ß, HoCi l5ot-Trihydroxyprosta-4,5,13-transpharmaceutical acceptable trienoic acid and its non-toxic / salts. 105 · - Compounds according to claim 80, formula (B), characterized in that k 5 12 3 • R, R and R ^ each represent hydrogen, R, R and R each represent hydroxy, the wavy line means the ß-configuration and η has a value of 6 and the compounds 8R-9ß, H «< _f 15 ^ - Trihydroxy-20-ethylprosta- ^, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 106.- Compounds according to claim 80, formula (B), characterized in that 1 k- 5 2 3 R, R ', R' and R each represent hydrogen, R and R each represent hydroxy stand, the wavy line stands for the gf configuration and η a fourth of 4 -hat and the compounds 8R-9 «t, 15 (^ - Dihydroxyprosta-4,5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. 409821/1132 10? .- Compounds according to claim 80, formula. (B), characterized in that R, R ¹ , R and R ^ each stand for hydrogen , R and Έτ each mean hydroxy, the wavy line stands for the ß-configuration and η has a value of k and the compounds are the o ^ -9ß, lf & -Bihydroxyprosta- ^, 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 108, - Compounds according to claim 80, formula ^ B), characterized in that R, R, R and R ^ each represent hydrogen, R and R ^ each represent hydroxy mean, the wavy line stands for the of-configuration and η a value of 6 and the compounds 8R-9ci, 15 ^ -dihydroxy-20-äthylprosta-4,5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts are. 109 · - Compounds according to claim 80, formula (B), characterized in that ι h. κ ' 2 3 R, R, R and R ^ each represent hydrogen, R and K each represent hydroxy. mean, the wavy line 'stands for, the ß-configuration and η has a value of 6 and the compounds the & ^ - 9ß, 15o ^ dihydroxy-20-äthylprosta- ⁱ 4 ⁱ , 5il3'-trstrienoic acid and its non-toxic, are pharmaceutically acceptable salts. 110.- Compounds according to claim 80., formula (B), characterized in that R represents methyl, R and ~ Ά each represent hydrogen, R, R and R ^ each represent hydroxy, the wavy line represents the oC configuration , and η has a value of k and the compounds are the 8R --- 4-methyl-9e <_> llol, 15x-ti * ihydroxyprosta- ^ ', 5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts are. 111.- Compounds according to claim So, formula (B) _1, characterized in that R stands for methyl, R, R and R ^ each stand for hydrogen, R and R ^ jevieils mean hydroxy, the light line stands for the (^ configuration and η has a value of k "and the compounds the ■ 8R- ^ let; hyl-9 ^, l ^ -dihydroxy ^ prosta-4 _f 5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable 4098 2 1 / -1 132 are bare salts. 112, - Compounds according to claim 80, formula (B), characterized in that Br represents methyl, R and R each represent hydrogen, R, R and R each represent hydroxy, the wavy line represents the ^ -configuration and η is one Has a value of 4 and the compounds are the 8R-6-methyl-9if | llof »15i (-trihydroxyprosta-4,5,13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts. 113 · - Compounds according to claim 80, formula (B), characterized in that ς 1 4 3 3 R ^ stands for methyl, R, R and R each mean hydrogen, R * and R · ^ each stand for hydroxyl, the wavy line for the «(configuration and η has a value of 4 and the compounds 8R-6-44ethyl-9« i, 15 ^ -dihydroxyprosta-4,5,13-trans-trienoic acid and their non-toxic, pharmaceutically acceptable salts. 114, - Compounds according to claim 80, formula (B), characterized in that c. 12 3 R and Br each represent methyl, R, R and R each represent hydroxy, 4th
R stands for hydrogen, the wavy line stands for the cf configuration and η has a value of 4 and the compounds 8R-4, 6-dimethyl-9ef, HOi, 15 <X-trihydroxyprosta - ^, 5,13-trans- trienoic acid and its non-toxic, pharmaceutically acceptable salts. 115.- Compounds according to claim 80, formula (B), characterized in that c 2 3 1 R and R ^ each represent methyl, R and Br each represent hydroxy, R 4th
and R each stand for hydrogen, the wavy line denotes the d configuration • and η has a value of 4- and the compounds 8R-4,6-dimethyl-9 | l » ¹ 5jL-dihydroxyprosta-4,5, 13-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts are. 409821/1132 116.- Compounds according to claim 8O ₅ formula (C) and (D) _0, characterized in that the hydroxyl group on C-15 is in the oC configuration and the alkyl group in the same position in ß-configuration « 117 · »* Compounds according to claim 80 _f formula (C) and (D)" characterized in that the hydroxyl group at C-15 is in the ß-configuration and the alkyl group in the same position is in the # -configuration ", 118.- Compounds according to claim 8O ₀ formula (C) _8, characterized in that R, R and R- each stand for mass, _s R is hydroxy, R is ß-methyl and η has a value of 4 ₉ and the associations the 8R-9-Ketollei, 15 ^ -dihydrQxy _i il5ß-ra.ethyl-prosta = ⁱ 5'05ol3-trans-trienoic acid and its non-toxic, pharmaceutically acceptable salts säncL ''' 119o- Compounds according to claim ₉ 8O formula (D) _{0 5} characterized in that R, E, E and Br jewails constant for Masserstoff ,, R ß44ethyl means and η has a value of Λ and. the connections _di © Kiethylprosta- ⁱ i 9 5 _s i3-trans-trienoic acid "nd its non-toxic ₀ phaxmazeutisch acceptable salts 120.- Compounds according to claim 8O ₈ Fosmel (D) ₀ characterized, that 4 5 ■ 1 '3 R, R and R jex ^ eils - stand _{for 'hydrogen, E Hydrasj means 8} R stands for fli-hydroxy "R means β-methyl and η has a value of 4 and the compounds the 8R- säuie and their-non- = toxic ₉ -pharmazeisbisdi acceptable salts are » 121 o-compounds according to claim 8O ₈ formula (D) _5, characterized in that R ₁ R ₁ R and R ^ each represent hydrogen ₈ R ^J ^ - ^ rdroxy, R represents β-methyl and η has a value of 4 · Has and the compounds are the 8E-9elil5al ~ dihydroxy-1Sß-methylprosta- ^ aSplS ^ trans-trieneme and their non-toxic, pharmaceutically acceptable salts «" · 1/1 1 3 .: 122.- Medicament containing a compound according to claims 1 to 121. The patent attorney: 409321/1132