CH638773A5 - Prostane derivatives and process for their preparation - Google Patents

Description

The invention relates to new prostate derivatives, processes for their preparation and medicaments containing these compounds.

7

638773

From the very extensive state of the art of prostaglandins and their analogues, it is known that this class of substances is suitable for the treatment of mammals, including humans, because of their biological and phamacological properties. However, their use as a medicine often encounters difficulties. Most natural prostaglandins have an effect duration that is too short for therapeutic purposes, since they are metabolized too quickly by various enzymatic processes. The production of prostanoic acid derivatives has therefore gained great importance. All structural changes have the goal of increasing the duration of action and the selectivity of effectiveness.

The invention therefore relates to prostate derivatives of the general formula I.

wherein

Rj is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms, the rest of an inorganic acid or

U

11 r4

—C — N d —group r5

means where U is an oxygen or sulfur atom and R4 and R5 are a hydrogen atom, an optionally substituted alkyl, cycloalkyl, heteroaryl or aryl radical or an acid radical or R4 and Rs together can form a heterocyclic ring with 4-7 ring members,

A is a -CH2-CH2-, cis-CH = CH-, trans-CH = CH- or -C = C group,

B is a -CH2-CH2, trans-CH = CH or -C = C group, W is a free or etherified or esterified hydroxymethylene group,

a free or ketalized carbonyl group or a free, esterified or etherified ch3

I.

—C — group,

I.

OH

where the OH group can be a- or ß-permanent,

D and E together are a direct bond or D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C group,

E is an oxygen or sulfur atom or a direct bond,

R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms,

R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and

Z is a free or ketalized carbonyl group or a free or etherified or esterified hydroxymethylene group.

Physiologically acceptable acid residues are particularly suitable as the acid residue Ri. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cyclo-aliphatic, aro-5 matic, aromatic-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. Examples of the substituents are alkyl, hydroxyl, alkoxy, oxo or amino groups or halogen atoms.

Examples include the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecyl acid 15 re, lauric acid, tridecyl acid, myristic acid, triadecyl acid, pentadecyl acetic acid, pentadecyl acetic acid, pentadecyl acetic acid , tert-Butyles-sigsäure, chloroacetic acid cyclopentylacetic acid, cyclohexylacetic acid, cyclopentane-hexane carboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, Äthoxyessigsäure, mono-, di- and tri-20, aminoacetic acid, Diäthylaminoessigsäure, Piperidinoessigsäure, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid , Benzoic acids, nicotinic acid, isonicotinic acid, furan-2-carbon-25 acid, cyclopentylpropionic acid, substituted with halogen, trifluoromethyl, hydroxy or carboxy group. Those with up to 10 carbon atoms are considered as particularly preferred acyl radicals.

Examples of suitable sulfonic acids are methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, β-chloroethane-30 sulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cy-clohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N, N-dimethyaminosulfonic acid, N, N-N-pyridone -, Piperidino-, Pi-perazino-, N-methylpiperazino- and morpholinosulfonic acid 35 in question.

The usual inorganic acids, such as sulfuric and phosphoric acid, are also suitable.

Under one

U

40 ii r4

—C — N ^ —Group r5

a substituted carbamoyl or thiocarbamoyl radical 45 is to be understood. The carbamic acid or the thiocarbamic acid can be substituted on the nitrogen atom by an alkyl, cycloalkyl, aryl or acid residue. Preferred

U

II R4

50 —C — Nc ^ groups r5

are the carbamoyl groups.

Suitable alkyl groups R4 and R5 are preferably straight-branched or branched alkyl groups having 1-10 C atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, heptyl, hexyl, decyl, such as with 1-5 carbon atoms should be particularly preferred.

The alkyl groups R4 and R5 may optionally be 1-60 to poly-substituted by halogen atoms, alkoxy groups, optionally substituted aryl groups, dialkylamines and trialkylammonium.

Examples of substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamine, diethyl-65 amine, methoxy, ethoxy.

Cycloalkyl groups R4 or R5 are usually residues with 3-8 C atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl.

638773

8th

If R4 and R5 represent aryl groups, both substituted and unsubstituted aryl groups and heteroaryl groups can be considered, such as, for example, phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, a phenyl group, 1- 3 alkyl groups each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl or alkoxy group and thienyl, furyl, pyridyl. The substitution in the 3- and 4-position on the phenyl ring is preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl.

Acid residues of organic carboxylic acids and sulfonic acids with 1-15 C atoms are in particular those which belong to the aliphatic, aromatic, aromatic-aliphatic, cyclo-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. Examples of substituents are alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms.

Examples include the following carboxylic acids: acetic acid, propionic acid, butyric acid, isobutyric acid, Valerian acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, trimethyl acetic acid, diethyl acetic acid, tert.-butyl acetic acid, cyclopentyl acetic acid, cyclohexyl acetic acid, pheic acid, phe Methoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylamino-acetic acid, piperidinoacetic acid, morpholinoacetic acid, benzoic acid, benzoic acids substituted with halogen, trifluoromethyl, alkoxy, hydroxy or carboxy groups, furan-2-carboxylic acid, cyclopentylprc. Those with up to 6 carbon atoms are considered as particularly preferred acyl radicals.

Examples of sulfonic acids include methanesulfonic acid, ethanesulfonic acid, isopropylsulfonic acid, β-chloroethanesulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cy-clohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, p-methoxybenzenesulfonic acid, n-sulfonic acid, N, N-diethylaminosulfonic acid, N, N-bis- (β-chloroethyl) -aminosulfonic acid, N, N-diisobutylaminosulfonic acid, N, N-dibutylaminosulfonic acid, pyrrolidino-, piperidino-, piperazino, N-methylpiperadizino-, thio -pheno- and morpholinosulfonic acid in question.

If R4 and R5 form a ring together with the N atom, e.g. to understand the following rings, azetidine, pyrrolidine, piperidine, hexamethyleneimine, oxazolidine, morpholine, piperazine, N-alkylpiperazine, where alkyl can contain 1-5 carbon atoms, etc. straight-chain and branched-chain alkyl radicals with 1-4 carbon atoms, such as, for example, the methyl,

Ethyl, propyl, isopropyl, butyl, isobutyl and tert. Butyl residue. The methyl and the ethyl group are preferred.

The hydroxyl groups in W and in Z can be functionally modified, namely by etherification or esterification, it being possible for the free or modified hydroxyl groups in W and in Z to be a- or β-permanent.

The radicals known to the person skilled in the art are suitable as ether and acyl radicals. Easily removable ether residues such as, for example, tetrahydropyranyl, tetrahydrcfuranyl, a-ethoxyethyl, trimethylsilyl, dimethyl tert are preferred. butyl-silyl and tri-p-benzyl-silyl radical. Possible acyl radicals are those which have already been mentioned for Rx, and names which may be mentioned are, for example, acetyl, propionyl, butylryl and benzoyl.

If W is a carbonyl group, this can be functionally modified by ketalization using the methods known to those skilled in the art. The preparation of cyclic ketals with 1-3 C atoms in the ring, such as, for example, with ethylene glycol, propanediol (1,3), is particularly suitable.

2,2-dimethylpropanediol (1,3), cyclopentanediol (1,2) or glycerol.

Suitable alkyl groups R3 are straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, especially with 1-10, preferably 1-6, carbon atoms, which may optionally be substituted by optionally substituted aryl. Examples include methyl, ethyl, propyl, butyl, isobutyl and tert. Butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propionyl, pentenyl, benzyl and p-chlorobenzyl.

The cycloalkyl group Rs can contain in particular 4-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclo-15-pentyl-, cyclohexyl, methyl-cyclohexyl and adamantyl.

Examples of suitable substituted or unsubstituted aryl groups R3 are: phenyl, 1-naphthyl and

2-naphthyl, which can each be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups with

20 each have 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, alkoxy or hydroxy group. The substitution in the 3- and 4-position on the phenyl ring is preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy. Suitable heterocyclic groups R3 are preferably 5- and 1- membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl,

3-pyridyl, 4-pyridyl and others

The invention also relates to processes for the preparation of the prostate derivatives of the general formula I according to the invention.

The first method according to the invention is characterized in that prostan-oleols of the general formula

35 may II

40

OH

OI ^ Xa / W

"• y

- ^ 3

(ii)

45

wherein A, B, D, E, W, Z, R2 and Rs are defined above, and in which free hydroxy groups, with the exception of the 1-hydroxy group, are optionally protected as intermediates, are esterified accordingly to introduce the acid residue.

50 For the preparation of new compounds of formula I, wherein Rt the rest

55

U

—C — N:

Ra

H

means, said compounds of formula II with a compound of general formula III

60 U = C = N - R4

implemented.

Compounds of formula I, wherein Rj the rest

65 O

II R4

c — nc:

r5

at)

9

638773

means are obtained according to the invention by the compound of the general formula II described with carbamoyl chlorides of the general formula IV

O

II R4

Cl-C-Ne; (IV)

r5

implements.

Compounds obtained according to the invention can be separated into the epimers.

Compounds of the formula I in which W and Z represent carbonyl groups are obtained according to the invention from compounds of the formula I mentioned above in which W and Z represent hydroxymethylene groups by oxidizing the hydroxymethylene groups to carbonyl groups.

Compounds of the formula I in which A and B are -CH2-CH2 groups are prepared according to the invention from compounds of the formula I in which A and / or B represent a cis-CH = CH or trans-CH = CH group by hydrogenating the double bonds in the 5,6- and / or 13,14-position.

If W and Z in compounds of the formula I are hydroxymethylene groups, these compounds are obtained according to the invention from corresponding compounds of the formula I in which W and Z represent carbonyl groups by reducing the carbonyl groups to hydroxymethylene groups.

According to the invention, compounds of the formula I in which W and Z are esterified hydroxymethylene groups are obtained from compounds of the formula I in which W and Z represent hydroxymethylene groups by esterifying the hydroxyl groups.

According to the invention, compounds of the formula I in which W and Z are hydroxymethylene groups are obtained from corresponding compounds in which W and Z are esterified hydroxymethylene groups by hydrolysis.

The esterification according to the invention of the alcohols of the general formula II can be carried out in a manner known per se. For example, the esterification is carried out by reacting an acid derivative, preferably an acid halide or acid anhydride, in the presence of a base such as Na hydride, pyridine, triethylamine, tributylamine or 4-dimethylaminopyridine with an alcohol of the general formula II. The reaction can be carried out without solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, DMSO at temperatures above or below room temperature, for example between -80 ° C to 100 ° C, preferably at room temperature.

The reaction of the alcohols of the general formula II with compounds of the general formula III and IV can also be carried out in a manner known per se. For example, an alcohol of general formula II can be reacted with an isocyanate or thioisocyanate of general formula III or a carbamoyl chloride of general formula IV • optionally with the addition of a tertiary amine, such as triethylamine or pyridine. The reaction can be carried out without solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, methylene chloride, tetrahydrofuran, ether, benzene, toluene, DMSO at temperatures above or below room temperature, for example between -80 ° C to 100 ° C, preferably at 0-30 ° C.

If the starting product contains, in addition to the 1-group OH group, additional OH groups in the prostane residue,

so these OH groups are also esterified by the process according to the invention. If end products are ultimately desired whose additional hydroxyl groups are present as free hydroxyl groups in the prostane residue, one expediently starts from starting products in which these are temporarily protected by ether residues, which are preferably easily removable. If compounds are used as the starting product which have functionally modified OH groups in the prostane residue, for example due to ether formation, then after release of the functionally modified OH groups, these can be esterified in the end product, it being possible to introduce various acyl groups in the end product .

The etherified or esterified hydroxy groups can be released by known methods. For example, the cleavage of hydroxy protecting groups, such as the tetrahydropyranyl residue, in an aqueous solution of an organic acid, such as acetic acid, propionic acid, etc. or in an aqueous solution of an inorganic acid such as hydrochloric acid or tetrabutylammonium fluoride. To improve the solubility, a water-miscible inert organic solvent is expediently added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferred. The cleavage is preferably carried out at temperatures between 20 ° C and 80 ° C.

The ketalization can be carried out in a manner known per se. For example, heating is carried out with ethylene glycol in the presence of an acidic catalyst with separation of water. P-Toluenesulfonic acid and perchloric acid are particularly suitable as acidic catalysts.

35 The oxidation of hydroxy groups present can be carried out according to methods known per se with the usual oxidizing agents. For example, the 9-hydroxy group can be oxidized to the ketone using Jones reagent (J. Chem. Soc. 1953, 2555). It is preferred to work with an excess of the oxidizing agent in a suitable diluent, such as acetone, at temperatures between 0 ° C and -50 ° C, especially at -20 ° C. The reaction is generally complete in 5 to 30 minutes. The oxidation is preferably carried out after intermediate protection of the 15-hydroxy group by silylation (Chem. Comm. 1972, 1120). The silylation is carried out, for example, with N, N-diethyltrimethylsilylamine in acetone at -70 ° C. to + 20 ° C., preferably at -40 ° to 0 ° C. Silver carbonate on 50 “Celite” or Gollins reagent are suitable as further preferred oxidizing agents (Tetrahedron Letters 1968, 3363).

The reduction of the 9-keto group can be carried out with customary reducing agents, with sodium borohydride, lithium tri-tert-butoxy aluminum hydride, zinc borohydride or aluminum iso-55 propylate, in the presence of an alcohol, or potassium tri-sec .-- butyl borohydride , preferably with sodium borohydride at temperatures between -50 ° C and + 50 ° C, preferably at 0 ° C to 20 ° C. Depending on the reducing agent used, methanol, ethanol, isopropanol, diethyl ether, dioxane, tetrahydrofuran are preferred as solvents for this reaction. When reducing with sodium borohydride, methanol, ethanol or isopropanol is preferably used. The resulting a- and ß-OH-epimer mixture can be separated in the usual way by column or layer chromatography.

Any hydrogenation of C =C double bonds present in the primary product can be carried out by methods known per se.

638773

10th

The hydrogenation of the 5,6-double bond is preferably carried out in a manner known per se at low temperatures, in particular at −20 ° C., in a hydrogen atmosphere in the presence of an edemetal catalyst. For example, 10% Pd / carbon is suitable as a catalyst.

If both the 5,6 - and the 13, 14 - double bond are hydrogenated, the procedure is generally at a higher temperature, preferably at 20 ° C.

The alcohol of the general formula II used as starting material for the above process can be prepared, for example, by using an aldehyde of the general formula V

0

wherein B, D, E, W and R3 have the meanings given above, which is usually after Wittig reaction with a Ylene of the general formula IX

(c6h5) 3p = ch— (ch2) 3-cooe

(IX)

Esterification, e.g. with CH2N2 and optionally protecting the free hydroxyl group by silylation to give compounds of the general formula X.

10th

15

OCH-

(X)

(V)

\ / \ CH0

[E. J. Corey et al., J. org. chem. 39, 256 (1974)] with a phosphorane or phosphonate in a Wittig reaction to give an a, β-unsaturated carbonyl compound VI in which B, D, E and Rj have the meanings given above, the double bond of which is in the 13.14-position (Numbering according to PG numbering) can be hydrogenated if desired. q

'D-E-R ^

The reduction of the esters X to alcohols of the general formula II is preferably carried out using LiAlH4.

Alcohols of the general formula II can also be obtained from the prostaglandin derivatives of the general formula XI,

0 o

AAA / V

25th

A

-OR,

(XI)

30th

"THE-

(VI)

V

•THE,

After reducing the 15-keto group with zinc borohydride or adding alkylmagnesium bromide or alkyllithium to the epimeric 15a and 15β-alcohols (PG numbering), which can be separated if desired, and optionally introducing a hydroxy protecting group on the 15-C atom , e.g. with dihydropyran, compounds of the general formula VII are obtained

0

wherein A, B, D, E, W and R3 have the meaning given above and Re represents a hydrogen atom or a methyl-35 grappe, by optionally protecting free hydroxyl groups by esterification or etherification first and then either the 10.11 double bond (R2 = H) with NaBH4 in an alcohol, such as methanol or ethanol, hydrogenated and, if necessary, the 9-hydroxy group subsequently oxidized with Jones reagent or to saturate the 10,11 double bond with a dialkyl copper lithium reagent in an inert solvent such as ether or tetrahydrofuran to give compounds of general formula XII with the introduction of 11-alkyl-45 (R2 = alkyl)

M \ A / \

(VII)

50

C00R /

(XII)

B-W-D-E-R-

'THE,

wherein B, D, E, W and R3 have the meanings given above.

The lactone thus obtained can be reduced with diisobutylaluminum hydride to the lactol of the general formula VIII 'OH

55

B-W-D-E-R,

After ketalization of the 9-keto group or reduction of the keto group with, for example, sodium borohydride or K-selectride and optionally protection of the free hydroxy group by silylation and subsequent reduction with 60 lithium aluminum hydride, the alcohols of the general formula II are obtained.

The new prostate derivatives of the general formula I are valuable pharmaceuticals, since they have a comparable activity spectrum (VIII) 4111111 e * ne improved (higher specificity) and above all have a much longer effect than the corresponding natural prostaglandins. Compared to PGE and PGA derivatives, the new 11-deoxypro-staglandins are also characterized by greater stability.

I.

11

638773

In addition, some of the new compounds have improved antifertile activity. To trigger abortions, therefore, significantly smaller amounts of the new prostate derivatives are required compared to the natural prostaglandins.

When registering the isotonic uterine contraction on the anesthetized rat and on the isolated rat or guinea pig uterus, it is shown that the substances according to the invention are considerably more effective and their effects last longer than with natural prostaglandins. Some of the new prostate derivatives are suitable for inducing mentruation or for interrupting pregnancy after a single intrauterine or vaginal application. In addition, some of the compounds have a lu-teolytic effect and are suitable for synchronizing the sexual cycle in female mammals such as monkeys, horses, cattle, pigs, etc.

The good tissue specificity of the anti-fertilizing or antihypertensive substances according to the invention can be seen in the examination on other smooth muscular organs, such as on the guinea pig ileum or on the isolated rabbit trachea, where a significantly lower stimulation can be observed than with the natural prostaglandins .

Some of the active compounds according to the invention even show a bronchodilator effect on the isolated rabbit trachea in vitro and strongly inhibit gastric acid secretion. The antihypertensive and diuretic compounds also have a regulating effect on cardiac arrhythmias. However, their influence on other organ systems is very small.

For medical use, the active ingredients can be converted into a form suitable for inhalation, for oral, parenteral or local (for example vaginal) application.

Aerosol solutions are expediently prepared for inhalation.

For oral administration, for example, tablets, dragées or capsules are suitable.

Sterile, injectable, aqueous or oily solutions are preferably used for parenteral administration.

Suppositories, for example, are suitable and common for vaginal application.

The invention thus also relates to medicaments based on the compounds of the general formula I, which may contain customary auxiliaries and excipients.

The active compounds according to the invention can be used in conjunction with the auxiliaries known and customary in galenics, for example for the production of preparations for inducing abortion, for cycle control, for induction of birth or for the treatment of hypertension.

t

example 1

(5Z, 13E) - (15R) -l- (3-carboxypropionyloxy) -15-hydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-one

A mixture of 1.3 g (5Z, 13E) - (9S, 15R) -9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18, -19,20-tetranor- 5,13-prostadien-l-ol, 0.19 g of succinic anhydride and 2.3 ml of pyridine were stirred for 18 hours at room temperature under argon. The mixture was then evaporated in vacuo and the crude product was purified by column chromatography on silica gel with pentane ether (6 + 4), and 1.59 g (5Z, 13E) - (9S, 15R) -l- (3-carboxypropionyloxy) -9 were obtained -tri-benzylsiIyIoxy-15- (tetrahydropyran-2-yloxy) -16-phenoxy-17, -18,19,20-tetranor-5,13-prostadiene as a colorless oil.

IR: 1730, 1600, 1493, 975 cm "1.

A solution of 790 mg was added to 1.12 g of the hemisuccinate thus obtained in 32 ml of tetrahydrofuran

Tetrabutylammonium fluoride in 8 ml tetrahydrofuran (THF) and stirred for 5 hours at room temperature. The mixture was then diluted with water, acidified to pH 4 with 10% citric acid solution, extracted 3 × with ether, the organic phase was washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel with ether, 513 mg (5Z, 13E) - (9S, 15R) -l- (3-carboxypropionyloxy) -9-hy droxy-15- (tetrahy dropy ran-2-yIoxy) - 16-phenoxy-17,18,19, -20-tetranor-5,13-prostadiene as a colorless oil.

IR: 3500, 2945, 1730, 1600, 1495, 978 / cm.

The product was dissolved in 10 ml acetone. To this solution was added 0.60 ml of Jones reagent at -20 ° C. After 40 minutes, the excess reagent was destroyed by adding isopropanol. It was diluted with ether, shaken neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was stirred in 15 ml of a mixture of acetic acid / water / THF / (65/35/10) for 16 hours at room temperature, evaporated in vacuo and chromatographed on silica gel with chloroform / 5% methanol. 280 mg of the title compound were obtained as a colorless oil.

IR: 3590, 3400, 2930, 2860, 1735 (br.), 1600, 1589, 1496, 973 / cm.

The starting material for the title compound was prepared as follows:

la) (5Z, 13E) - (9S, 15R) -9-hydroxy-5- (tetrahydropyran-2-

-yloxy) -16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-

acid methyl ester

To a solution of 11.51 g of 4-carboxybutyltriphenyl-phosphonium bromide in 60 ml of abs. Dimethyl sulfoxide (DMSO) was added dropwise at 15 ° C to 48.2 ml of a solution of methanesulfonylmethyl sodium in DMSO (preparation: 3 g of 50% sodium hydride suspension were dissolved in 60 ml of absolute DMSO at 70 ° C for one hour) and the mixture was stirred for 15 hours Minutes at room temperature. A solution of 2.35 g (2RS, 3aR, 4R, 6aS, 3'R) -4 - [(E) -3- (tetra-hydropyran-2-yloxy) -4-phenoxy-l was added dropwise to the red ylene solution -butenyl] -2-hydroxyperhy-drocyclopenta [b] furan (German Offenlegungsschrift 2629834.0) in 45 ml abs. DMSO and stir for 2.5 hours at 50 ° C under argon. The reaction mixture was diluted with 300 ml of ice water and extracted three times with ether. The aqueous phase was then acidified to pH 5 with 10% citric acid solution, extracted four times with a mixture of ethyl acetate / ether (1 +1), the organic extract was shaken three times with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by filtration over silica gel (pentane / esigester 3 + 7). 2.30 g of the prostadienoic acid were obtained as a light yellow oil. For conversion into the methyl ester, the solution was dissolved in 50 ml of methylene chloride and a slight excess of an ethereal diazomethane solution was added at 0 ° C. After evaporation of the solvent, 2.35 g of the methyl ester was obtained as a light yellow oil.

IR: 3600, 3500, 2943, 1728, 1598, 1585, 1493, 975 / cm.

lb) (5Z, 13E) - (9S, 15R) -9-tribenzylsilyloxy-15- (tetrahydro-

pyran-2-yloxy) -16-phenoxy-17,18,19,20-tetranor-5,13-

-prostadien acid methyl ester

2 g of the methyl ester prepared according to Example la, 2.4 g of tribenzylsilyl chloride and 36 ml of pyridine were stirred for 6 hours at 45 ° under argon, concentrated in vacuo and the residue was filtered with ether / pentane (1 +1) over silica gel. 3.35 g of the tribenzylsilyl ether were obtained as a colorless oil. IR: 1732, 1600, 1495, 975 / cm.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

638773

12

le) (5Z, 13E) - (9S, 15R) -9-tribenzylsilyloxy-15- (tetrahydro-pyran-2-yloxy) -16-phenoxy-17,18,19,20-tetranor-5,13 - prostadiene -l-ol

In a solution of 3.3 g of the silyl ether prepared according to Example 1b in 140 ml of ether, 1 g of lithium aluminum hydride was added in portions at room temperature with stirring, the mixture was stirred for 3 hours, the excess of the reagent was destroyed by careful addition of ethyl acetate, and 2.2 ml of water were added. stirred for 60 minutes at room temperature, filtered and evaporated in vacuo. After filtration over silica gel with pentane / ether (3 + 7), 2.7 g of the 1-alcohol were obtained as a colorless oil.

IR: 3600, 2460, 2943, 1600, 1588, 1495, 978 / cm.

Example 2

(5Z, 13EM9S, 15R) -l- (3-carboxypropionyloxy) -9,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene

500 mg (5Z, 13E) - (9S, 15R) -l- (3-carboxypropionyloxy) - 9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18,19,20 -tetranor-5,13-prostadiene was stirred for 16 hours in a 10 ml mixture of acetic acid / water / THF (65/35/10) at room temperature, evaporated in vacuo and chromatographed on silica gel. With chloroform / methanol (9 + 1), 130 mg of the title compound was obtained as a colorless oil.

IR: 3590, 3400, 2935, 1730, 1600, 1493, 977 / cm.

Example 3

(5Z, 13E) - (15R) -1 - (3-carboxypropionyloxy) - 15-hydroxy-16, -16-dimethyl-5,13-prostadien-9-one

A mixture of 1.58 g (5Z, 13E) - (9S, 15R) -I6,16-dimethyl-9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) - 5,13-prostadien-l- ol, 270 mg of succinic anhydride and 5 ml of pyridine were stirred for 19 hours at room temperature under argon. The mixture was then evaporated in vacuo and the product was purified by column chromatography on silica gel. 1.44 g of (5Z, 13E) - (9S, 15R) - 1 - (3-carboxypropionyloxy) -16,16-dimethyl-9-tribenzylsilyl-oxy-15- (tetrahydropyran-2-yloxy) were obtained with ether. -5,13-prostadiene as a colorless oil.

IR: 2930, 1730, 1600, 1492, 980 / cm.

A solution of 884 mg of tetrabutylammonium fluoride in 15 ml of THF was added to 1.42 g of the hemisuccinate thus obtained in 70 ml of THF and the mixture was stirred at room temperature for 5 hours. The mixture was then diluted with water, extracted three times with ether, the organic phase was washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel with ether, 788 mg (5Z, 13E) - (9S, 15R) -1 - (3-carboxypropionyloxy) -16,16-dimethyl-9-hydroxy-15- (tetrahydropyran 2-yloxy) -5,13-prostadiene as a colorless oil.

500 mg of this product were dissolved in 15 ml of acetone and 0.7 ml of Jones reagent were added at −30 ° C. After 30 minutes the excess reagent was destroyed by adding isopropanol, diluted with ether and washed neutral with brine. After drying with magnesium sulfate, the evaporation residue was stirred with 12 ml of a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature. The mixture was evaporated in vacuo and the residue was chromatographed on silica gel with methylene chloride / 5% methanol and 153 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3500, 2930, 2858, 1732, 1600, 976 / cm.

The starting material for the title compound was prepared as follows:

3a) (5Z, 13E) - (9S, 15R) -16,16-dimethyl-9-hydroxy-15- (te-trahydropyran-2-yIoxy) -5,13-prostadienoic acid methyl ester To a solution of 3.55 g 4 Carboxybutyltriphenyl-phosphonium bromide in 18 ml of DMSO, 15.3 ml of a solution of methanesulfinylmethyl sodium in DMSO (preparation see Example la) was added dropwise at 15 ° C. and the mixture was stirred for 15 minutes at room temperature. A solution of 0.73 g (2RS, 3aR, 4R, 6aS, 3'R) -4 - [(E) -4,4 - dimethyl-3- (tetrahydropyran-2-yloxy) - was added dropwise to the red ylene solution. l -octenyl-] -2-hydroxy-perhydrocyclopenta [b] furan (DOS 2629934.0) in 15 ml DMSO and stirred for 2 hours at 50 ° under argon. The reaction mixture was mixed with 150 ml of ice water and extracted three times with a mixture of ether / ethyl acetate (1: 1). The aqueous phase was acidified to pH 5 with 10% citric acid solution and extracted three times with a mixture of ether / pentane (1: 1). The organic phase was washed neutral with water, dried over magnesium sulfate and evaporated to dryness in vacuo. Chromatography of the residue on silica gel with ether / pentane (8 + 2) gave 480 mg of the prostadienoic acid, which was converted into the oily methyl ester with diazomethane.

IR: 3600, 3500, 2940, 1730, 976 / cm.

3b) (5Z, 13E) - (9S, 15R) -16,16-dimethyl-9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester

950 mg of the compound prepared according to Example 3a, 130 g of tribenzylsilyl chloride and 20 ml of pyridine were stirred at 50 ° C. for 24 hours, concentrated in vacuo and the residue was filtered through silica gel with ether / pentane (1: 1). 1.50 g of the tribenzylsilyl ether were obtained as a colorless oil. IR: 2958, 1731, 1600, 1495, 973 / cm.

3c) (5Z, 13E) - (9S, 15R) -16,16-dimethyl-9-tribenzylsilyloxy - 15- (tetrahydropyran-2-yloxy) -5,13 -prostadien-1 -ol to a solution of 1 , 68 g of the silyl ether prepared according to Example 3b in 50 ml of ether, 310 mg of lithium aluminum hydride were added at room temperature, the mixture was stirred at room temperature for 1 hour, 2 ml of water were added dropwise, the mixture was stirred for a further hour, and the mixture was filtered and evaporated in vacuo. The crude product was purified by chromatography on silica gel with ether / pentane (1: 1). 1.59 g of the 1-alcohol were obtained as 01.

IR: 3600, 3450, 2940, 1600, 1494, 978 / cm.

Example 4

(5Z, 13E) - (9S, 15R) -l- (3-carboxypropionyloxy) -16,16-dimethyl-9,15-dihydroxy-5,13-prostadia

600 mg (5Z, 13E) - (9S, 15R) -l- (3-carboxypropionyloxy) - 9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -16,16-dimethyl-5,13-prostadiene (prepared according to Example 3) was stirred for 16 hours in 13 ml of a mixture of acetic acid / water / THF (65/35/10) at room temperature, evaporated in vacuo and chromatographed on silica gel. With chloroform / methanol (9 + 1), 160 mg of the title compound was obtained as a colorless oil.

IR: 3590, 3350, 2940, 1730-978 / óm. ''

Example 5 ■

(5Z, 13E) - (15S, Î6RS) -l- (3-carboxyprôpîonyloxy) -15-hydroxy-16-methyl-5,13-prostadien-9-one, '• ■

Under the reaction conditions of Example 3-, 1.35 g of (5Z, 13E) - (9S, 15S ', 16RS) -16-methyl-9-tri-benzylsilyloxy-15- (tetrahydropyrah-2-ylöxy) - 5,13-prostadien-l-ol and 220 mg succinic anhydride in 4 ml pyridine 1.40 g (5Z, 13E) - (9S, 15S, 16RS) -l- (3-carboxypropionyloxy) - 16-metfiyl-9 -triberizylsilyloxy-15- (te'trahydropyrän-2-yloxy) - 5,13-prostadiene as a colorless oil. '

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A solution of 860 mg of tetrabutylammonium fluoride in 14 ml of THF was added to 1.31 g of the hemisuccinate thus obtained in 60 ml of THF, the mixture was stirred at room temperature for 5 hours, diluted with water and extracted three times with ether. The organic phase was washed neutral, dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel with ether, 710 mg (5Z, 13E) - (9S, 15S, 16RS) -1 - (3-carboxypropionyloxy) -9-hydroxy-16-methyl-15- (tetrahy- dropyran-2-yloxy) -5,13-prostadiene as a colorless oil.

400 mg of this product in 15 ml acetone were mixed with 0.5 ml Jones reagent at −30 ° C. After 30 minutes, the excess of the reagent was destroyed by adding isopropanol, diluted with ether and washed neutral with brine, dried over magnesium sulfate, evaporated and the residue was stirred with 10 ml of a mixture of acetic acid / THF / water (65/10/35) 16 Hours at room temperature, evaporated in vacuo and the residue was chromatographed on silica gel with methylene chloride / 5% methanol. 130 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3510, 2950, 1730, 1600, 970 / cm.

The starting material for the title compound was prepared as follows:

5a) (5Z, 13E) - (9S, 15S, 16RS) -9-hydroxy-16-methyl-15- (te-trahydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester To a solution of 4.25 g 4 Carboxybutyltriphenyl-phosphonium bromide in 22 ml of DMSO was added dropwise at 15 ° C. with 18.4 ml of a solution of methanesulfinylmethyl sodium in DMSO (preparation see example la) and stirred for 15 minutes at room temperature. A solution of 0.88 g (2RS, 3aR, 4R, 6aS, 3'S, 4'RS) -4 - [(E) -4-methyl-3- (tetrahydropyran-2-yloxy) - was added dropwise to the red ylene solution. l-octenyl] -2-hydroxy-perhydrocyclopenta [b] furan (DOS 2629834.0) in 20 ml DMSO and stirred for 2 hours at 50 ° under argon. The reaction mixture was mixed with 200 ml of ice water and extracted three times with a mixture of ether / ethyl acetate (1: 1). The aqueous phase was acidified to pH 5 with 10% citric acid solution and extracted three times with a mixture of ether / pentane (1: 1). The organic phase was washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel with ether / pentane (8 + 2) gave 585 mg of the prostadienoic acid, which was converted into the oily methyl ester with diazomethane. IR: 3600, 3500, 2942, 1732, 978 / cm.

5b) (5Z, 15S, 16RS) -16-methyl-9-tribenzylsilyloxy-15- (tetra-hydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester 930 mg of the compound prepared according to Example 5a, 1.25 g of tribenzylsilyl chloride and 20 ml of pyridine were stirred at 50 ° C. for 16 hours, concentrated in vacuo and the residue was chromatographed on silica gel with ether / pentane (1: 1). 1.4 g of the tribenzyl ether were obtained as a colorless oil. IR: 2950, 1732, 1600, 1495, 975 / cm.

5c) (5Z, 13E) - (9S, 16RS) -16-methyl-9-tribenzylsilyloxy-15 - (tetrahydropyran-2-yloxy) -5,13-prostadien-l-ol A solution of 1.35 g of the Silyl ether prepared according to Example 5b in 45 ml of ether was mixed with 280 mg of lithium aluminum hydride, stirred for 1 hour at room temperature, added dropwise with 1.7 ml of water, stirred for a further hour, filtered and evaporated in vacuo. After purification by chromatography on silica gel with pentane / ether (1: 1), 1.21 g of the 1-alcohol was obtained as an oil. IR: 3600, 3450, 2950, 1600, 1495, 978 / cm.

Example 6

(5Z, 13E) - (9S, 15S, 16RS) -1 - (3-carboxypropionyloxy) -9.15 - dihydroxy-16-methyl-5.13-prostadiene

500 mg (5Z, 13E) - (9S, 15S, 16RS) -l- (3-carboxypropionyloxy) -16-methyl-9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -5.13- prostadiene (prepared according to Example 5) was stirred for 16 hours in 12 ml of a mixture of acetic acid / water / THF (65/35/10) at room temperature, evaporated in vacuo and the residue was chromatographed with chloroform / methanol (9 + 1) Silica gel. 135 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3300, 2945, 1730, 978 / cm.

Example 7

(5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -15-hydroxy-17-phenyl-18,19,20-trinor-5,13-prostadien-9-one

A mixture of 1.4 g (5Z, 13E) - (9S, 15S) -9-tribenzylsilyloxy-15- (tetrahydropyran-2-yIoxy) -17-phenyl-18,19,20 - trinor-5, 13-prostadien-l-ol, 0.21 g of succinic anhydride and 2.5 ml of pyridine were stirred for 18 hours at room temperature under argon. The mixture was then concentrated in vacuo and the crude product was purified by chromatography on silica gel. Pentane / ether (1: 1) gave 1.65 g of (5Z, 13E) - (9S, 15S) -l- (3-carboxypropionyloxy) -9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) - 17-phenyl-18,19,20 - trinor-5,13-prostadiene as a colorless oil.

IR: 1730, 1598.975 / cm.

A solution of 800 mg of tetrabutylammonium fluoride in 9 ml of THF was added to 1.20 g of the hemisuccinate thus obtained in 35 ml of tetrahydrofuran and the mixture was stirred at room temperature for 6 hours. The mixture was then diluted with water, acidified to pH 4 with 10% citric acid solution, extracted with ether, the organic phase was washed with brine, dried over magnesium sulfate and evaporated in vacuo. Purification by chromatography on silica gel with pentane / ether (1: 1) yielded 530 mg (5Z, 13E) - (9S, 15S) - l- (3-carboxypropionyloxy) -9-hydroxy-15- (tetrahydropyran - 2- lyoxy) -17-phenyl-18,19,20-trinor-5,13-prostadiene as a colorless oil.

IR: 3600, 3300, 2940, 1730, 1600, 977 / cm.

This 9-hydroxy compound was dissolved in 10 ml of acetone and mixed with 0.6 ml of Jones reagent at −20 ° C. After 40 minutes, the excess reagent was destroyed by adding isopropanol, diluted with ether and washed neutral with brine. After drying over magnesium sulfate, the evaporation residue was stirred in 15 ml of a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature, evaporated in vacuo and obtained after chromatography on silica gel with chloroform / methanol (9 + 1) 250 mg of the title compound as a colorless oil.

IR. 3600, 3400, 2940, 2860, 1734 (wide), 1600, 975 / cm.

The starting material for the title compound was prepared as follows:

7a) (5Z, 13E) - (9S, 15S) -9-hydroxy-15- (tetrahydropyran-2-yloxy) -17-phenyl-18,19,20-trinor-5,13-prostadienoic acid methyl ester

To a solution of 11.54 g of 4-carboxybutyltriphenyl-phosphonium bromide in 60 ml of abs. DMSO was added dropwise at 15 ° C. to 48 ml of a solution of methanesulfinylmethyl sodium in DMSO (preparation see example la) and the mixture was stirred for 15 minutes at room temperature. A solution of 2.3 g (2RS, 3aR, 4R, 6aS, 3'S) -4 - [(E) -3 - (tetrahydropyran-2-yloxy) -5-phenyl-l-pentenyl] was added dropwise to the red ylene solution. -2-hydroxy-perhydrocyclopenta [b] furan (DOS 2 629 834.0) in 40 ml

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DMSO and stirred for 3 hours at 50 ° C under argon. The reaction mixture was diluted with 300 ml of ice water and extracted three times with a mixture of ether / ethyl acetate (1: 1). The aqueous phase was then acidified to pH 4.5 with 10% citric acid solution, extracted four times with a mixture of ethyl acetate / ether (1: 1), this extract was shaken three times with brine, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel with pentane / ethyl acetate (3 + 7) gave 2.25 g of the prostadienoic acid, which was converted into the oily methyl ester in a conventional manner with diazomethane.

IR: 3600, 2945, 1730, 1600, 978 / cm.

7b) (5Z, 13E) - (9S, 15S) -9-tribenzylsilyloxy-15- (tetrahydro-pyran-2-yloxy) - 17-phenyl-18,19,20-trinor-5,13-prostadienic acid methyl ester

From 2 g of the methyl ester prepared according to Example 7a, analogously to Example 1b, 3.4 g of 9-tribenzylsilyl ether are obtained as a colorless oil.

IR: 1733, 1600, 978 / cm.

7c) (5Z, 13E) (- 9S, 15S) -9-tribenzylsilyloxy-15- (tetrahydro-pyran-2-yloxy) -17-phenyl-18,19,20-trinor-5,13-prosta-diene- l-ol

Analogously to Example 1c, 2.73 g of the 1-alcohol is obtained as a colorless oil from 3.4 g of the compound prepared according to Example 7b.

IR: 3600, 3460, 2940, 1600, 978 / cm.

Example 8

(5Z, 13E) - (9S, 15S) -l- (3-carboxypropionyloxy) -9,15-dihydroxy-17-phenyl-18,19,20-trinor-5,13-prostadiene

From 600 mg (5Z, 13E) - (9S, 15S) -l- (3-carboxypropionyloxy) -9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -17-phe-nyl-18,19,20 -trinor-5,13-prostadiene (prepared in Example 7) was obtained in analogy to Example 2 155 mg of the title compound as a colorless oil.

IR: 3600, 3400, 2940, 1730, 1600, 975 / cm.

Example 9

(5Z, 13E) - (15S) - 1- (3-carboxypropionyloxy) -15-hydroxy-15-methyl-5,13-prostadien-9-one

210 mg (5Z, 13E) - (15S) -9,9-ethylenedioxy-15-methyl-15 - (tetrahydropyran-2-yloxy) -5,13-prostadien-l-ol, 55 mg of succinic anhydride and 0 , 75 ml of pyridine was stirred for 24 hours at room temperature under argon. The mixture was then evaporated in vacuo and purified by column chromatography on silica gel with ether / pentane (1: 1). 155 mg (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) - 9,9-ethylenedioxy-15-methyl-15- (tetrahydropyran-2-yloxy) - 5,13-prostadiene were obtained as colorless oil.

IR: 3630, 2950, 2920, 2855, 1725, 1600, 975 / cm.

145 mg of the hemisuccinate thus obtained was stirred for 16 hours in 10 ml of a mixture of acetic acid / water / THF (65/35/10), then evaporated to dryness in vacuo and the residue was purified by filtration over silica gel with ether. 65 mg of the title compound were obtained as a colorless oil.

IR: 3590, 3300, 2928, 2858, 1728, 1600, 972 / cm.

The starting material for the above title compound was prepared as follows:

9a) 1 l-deoxy-15-methyl-prostaglandin E2

In a solution of 800 mg 15-methylprostaglandin-Aj, - methyl ester (E. W Yankee et al. JACS 96 (18), 5865 (1974)

in 15 ml of methanol, a solution of 900 mg of sodium borohydride in 14 ml of methanol and 1.5 ml of water was added dropwise at −20 ° C., the mixture was stirred at −20 ° C. for 15 minutes, neutralized with dilute acetic acid, concentrated in vacuo, and water was added and extracted three times with methylene chloride. The organic extract was shaken with water, dried over magnesium sulfate and evaporated in vacuo. 795 mg of the 9-hydroxy-10, ll-dihydro compound were obtained, which was dissolved in 18 ml of acetone and treated at 0.8 ° C. with 0.8 ml of Jones reagent. After 30 minutes at −20 ° C., the excess reagent was destroyed with isopropanol, 120 ml of ether were added, the mixture was shaken three times with 10 ml of brine each time, dried over magnesium sulfate and evaporated in vacuo. After chromatography on silica gel, 700 mg of the 10,11-dihydro compound were obtained as a colorless oil with ether.

IR: 3600, 2940, 1730, 976 / cm.

9b) (5Z, 13E) - (15S) -9,9-ethylenedioxy-15-hydroxy-15-methyl-5,13-prostadienoic acid methyl ester A mixture of 1.2 g of the compound prepared according to 9a, 7 ml of triethyl orthoformate, 7 ml of ethylene glycol and 7 mg of p-toluenesulfonic acid were stirred for 48 hours at room temperature under argon, diluted with ether, shaken with 5% sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography on silica gel with ether, 920 mg of the 9-ketaIs were obtained as a colorless oil

9c) (5Z, 13E) - (15S) -9,9-ethylenedioxy-15-methyl-15- (tetra-hydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester To a solution of 300 mg of that obtained according to Example 9b Compounds in 7 ml methylene chloride were added 85 mg dihydropyran and 1 mg p-toluenesulfonic acid at 0 ° C. After 15 minutes, the mixture was diluted with ether, shaken with bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. 350 mg of the 15-tetrahydropyranyl ether were obtained as a colorless oil IR: 2940, 1725, 1600, 970, 948 / cm.

9d) (5Z, 13E) - (15S) -9,9-ethylenedioxy-15-methyl-15- (tetra-hydropyran-2-yloxy) -5,13 -prostadien-1 -ol to a solution of 320 mg of Compound prepared according to Example 9c in 8 ml of ether was added 280 mg of lithium aluminum hydride, stirred for 30 minutes at 25 ° C, carefully added 1 ml of ethyl acetate, added 0.6 ml of water, stirred for 60 minutes, filtered and evaporated in vacuo. After chromatography on silica gel with ether, 250 mg of the 1-alcohol were obtained as a colorless oil IR: 3630, 3450, 2938, 1600, 875, 948 / cm.

Example 10

(5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -I5-hydroxy-5,13-prostadien-9-one

4.15 mg (5Z, 13E) - (15S) -9,9-ethylenedioxy-15- (tetrahydro-pyran-2-yloxy) -5,13-prostadien-l-ol, 120 mg of succinic anhydride and 2 ml of pyridine were stirred 24 hours at room temperature under argon. The mixture was then evaporated in vacuo and purified by column chromatography on silica gel with ether / pentane (1 + 1). This gave 375 mg (5Z, 13E) -15S) -l- (3-carboxypropionyloxy) -9.9-ethylenedioxy-15- (tetrahydropyran-2-yloxy) -5,13-prostadiene as a colorless 01.

IR: 3600, 2945, 1725, 1600, 975, 948 / cm.

350 mg of the hemisuccinate thus obtained was stirred for 16 hours in 16 ml of a mixture of acetic acid / water / THF (65 + 35 +10), evaporated in vacuo and the residue was purified by column chromatography on silica gel.

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With ether, 195 mg of the title compound were obtained as a colorless oil.

IR. 3600, 3320, 2935, 1730, 1600, 975 / cm.

The starting material for the above title compound was prepared as follows:

10a) (5Z, 13E) - (15S) -9,9-ethylenedioxy-15-hydroxy-5,13 - prostadienic acid methyl ester A mixture of 2.3 g II-deoxy-prostaglandin E2-methyl ester (prepared from II -Desoxy-prostaglandin-E2 (WP Schneider et al., J. Org. Chem. 38, 951 (1973) with diazo-methane in the usual way), 13 ml of triethyl orthoformate, 13 ml of ethylene glycol and 15 mg of p-toluenesulfonic acid 48 hours at room temperature under argon, diluted with ether, shaken with 5% sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography on silica gel, 2.1 g of the 9-ketal was obtained as colorless with ether Oil.

10b) (5Z, 13E) - (15S) -9,9-ethylenedioxy-15- (tetrahydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester To a solution of 910 mg of the compound obtained according to Example 10a in 20 ml of methylene chloride, 270 mg of dihydropyran and 4 mg of p-toluenesulfonic acid were added at an ice bath temperature. After 30 minutes, the mixture was diluted with ether, shaken with 5% sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo. 1.2 g of 15-hetrahydropyrany ether were obtained as a colorless oil.

IR: 2935, 1726, 1600, 973, 948 / cm.

10c) (5Z, 13E) - (15S) -9,9-ethylenedioxy-15- (tetrahydropyran-2-yloxy) -5,13-prostadien-l-ol To a solution of 1.1 g of that according to Example 10b prepared compound in 30 ml of ether, 800 mg of lithium aluminum hydride were added in portions, the mixture was stirred for 45 minutes at room temperature, the excess of the reagent was destroyed by dropwise addition of ethyl acetate, 1.8 ml of water were added, the mixture was stirred for 60 minutes, filtered and evaporated in vacuo. After chromatography on silica gel, 810 mg of the 1-alcohol was obtained as a colorless oil with ether,

IR: 3600, 3400, 2940, 1600, 976, 948 / cm.

Example 11

(5Z, 13E) - (15S) - 1- (3-carboxypropionyloxy) -15-hydroxy-11 a-methyl-5,13-prostadien-9-one

215 mg (5Z, 13E) - (15S) -9,9-ethylenedioxy-lla-methyl - 15- (tetrahydropyran-2-yloxy) -5,13-prostadien-l-ol, 60 mg of succinic anhydride and 1 ml of pyridine the mixture was stirred for 24 hours at room temperature under argon. The mixture was then evaporated in vacuo and purified by column chromatography on silica gel and ether / pentane (1: 1). 165 mg (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) - 9,9-ethylenedioxy-11 a-methyl-15- (tetrahydropyran-2-yloxy) - 5,13-prostadiene were obtained as a colorless oil.

IR: 3620, 3350, 2940, 1725, 1600, 976 / cm.

150 mg of the hemisuccinate thus obtained was stirred for 16 hours in 10 ml of a mixture of acetic acid / water / THF (65/35/10), then evaporated to dryness in vacuo and the residue was purified by filtration over silica gel with ether. This gave 72 mg of the title compound as a colorless oil.

IR: 3600, 3300, 2930, 1730, 1600, 978 / cm.

The starting material for the above title compound was prepared as follows:

Ila) (5Z, 13E) - (15S) -9,9-ethylenedioxy-15-hydroxy-lla-methyl-5,13-prostadienoic acid methyl ester. Analogously to Example 10a, 1.25 g of 11-de-oxy is obtained -lla-methyl-prostaglandin-E2-methyl ester (Chemistry and Industry 1973, 635) 1.05 g of the 9-ketal as a colorless oil. IR: 3600, 2940, 1732, 978, 948 / cm.

IIb) (5Z, 13E) - (15S) -9,9-ethylenedioxy-11 a-methyl-15- (tetra-hydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester In analogy to Example 10b, 05 g of the 9-ketal prepared according to Example IIa 1.3 g of the 15-tetra-hydropyranyl ether as a colorless oil.

IR: 2935, 1728, 1600, 975, 950 / cm.

Ile) (5Z, 13E) - (15S) -9,9-ethylenedioxy-lla-methyl-15- (tetra-hydropyran-2-yloxy) -5,13-prostadien-l-ol is obtained analogously to Example 10c from 1.3 g of the compound prepared according to Example IIb and 900 mg of lithium aluminum hydride, 920 mg of the 1-alcohol as a colorless oil. IR: 3600, 3400, 2940, 1600, 976, 948 / cm.

Example 12

(5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -l la, 15-dimethyl-15-hydroxy-5,13-prostadien-9-one

425 mg (5Z, 13E) - (15S) -9,9-ethylenedioxy-lla, 15-dimethyl-15- (tetrahydropyran-2-yloxy) -5,13-prostadien-1-ol, 125 mg of succinic anhydride and 2 ml of pyridine was stirred for 25 hours at room temperature under argon. The mixture was then evaporated in vacuo and the residue was purified by column chromatography on silica gel. This gave ether / pentane (1 +1) 380 mg (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -9,9-ethylenedioxy-Ila, 15-dimethyl-15- (tetra -hydropyran-2-yloxy) -5,13-prostadiene as a colorless oil. IR: 3600, 3300, 2935 ,. 1725, 1600, 976, 950 / cm.

380 mg of the hemisuccinate thus obtained was stirred for 16 hours in 25 ml of a mixture of acetic acid / water / THF (65/35/10), then evaporated in vacuo and the residue was purified by chromatography on silica gel. With ether, 195 mg of the title compound were obtained as a colorless oil.

IR. 3600, 3320, 2940, 1732, 1600, 978 / cm.

The starting material for the above title compound was prepared as follows:

12a) (5Z, 13E) - (15S) -9,9-ethylenedioxy-lla, 15-dimethyl-15-hydroxy-5,13-prostadienoic acid methyl ester In analogy to example 10a, 2.4 g of 11-des- oxy-11 a, 15-dimethyl-prostaglandin-E2-methyl ester (Chemistry and Industry 1973, 635) 1.3 g of the 9-ketal as a colorless oil.

IR: 3600, 2940, 1733, 978, 950 / cm.

12b) (5Z, 13E) - (15S) -9,9-ethylenedioxy-lla, 15-dimethyI-15 - (tetrahydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester

Analogously to Example 10b, 1.4 g of 15-tetra-hydropyranyl ether is obtained as a colorless oil from 1.3 g of the 9-ketal prepared according to Example 12a.

IR: 2940, 1730, 1600, 976, 950 / cm.

12c) (5Z, 13E) - (15S) -9,9-ethylenedioxy-lla, 15-dimethyl-15 - (tetrahydropyran-2-yloxy) -5,13-prostadien-l-ol in analogy to Example 10c from 1.4 g of the compound prepared according to Example 12b, 980 mg of the 1-alcohol as a colorless oil.

IR: 3600, 3400, 2940, 1600, 978, 948 / cm.

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Example 13

(5Z, 13E) - (15R) -l- (3-carboxypropionyloxy) -15-hydroxy-l la-

-methyl-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-

-9-one

A mixture of 500 mg (5Z, 13E) - (15R) -9,9-ethylene-dioxy-11 a-methyl-15- (tetrahydropyran-2-yloxy) - 16-phenoxy - 5,13-prostadien-l -ol, 110 mg of succinic anhydride and 3 ml of pyridine were left at room temperature for 16 hours, evaporated to dryness in vacuo and the residue was purified by filtration over silica gel with ether / pentane (6 + 4). 435 mg (5Z, 13E) - (15R) -l- (3-carboxypropionyloxy) -9.9-ethylenedioxy-llla-methyl-15- (tetrahydro-pyran-2-yloxy) -16-phenoxy- 17,18,19,20-tetranor prostadien as a colorless oil.

IR: 3600, 3450, 2950, 1730, 1600, 1493, 976, 948 / cm.

The hemisuccinate thus obtained was stirred for 16 hours in 20 ml of a mixture of acetic acid / water / THF (65 / 35/10), evaporated in vacuo and chromatographed on silica gel with methylene chloride. 190 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3450, 2940, 1735, 1600, 1495, 976 / cm.

The starting material for the above title compound was prepared as follows:

13a) (5Z, 13E) - (15R) -15-hydroxy-llla-methyl-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester A suspension of 2.45 g of copper (I ) iodide in 25 ml ether was added dropwise with stirring with an ethereal 1.6 m solution of methyl lithium until the copper iodide was dissolved. A solution of 1 g of tetranor-16-phenoxy-PGA2 methyl ester (DOS 2 322 673) in 50 ml of ether was added dropwise to this solution of dimethyl copper lithium at −30 ° C. The reaction mixture was then allowed to warm to 0 ° C. in the course of 60 minutes, saturated ammonium chloride solution was added carefully, the mixture was extracted several times with ether, the extract was shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After filtration through silica gel with ether, 850 mg of the 11a-methyl compound were obtained as an oil.

IR: 3600, 2940, 1735, 1600, 1495, 978 / cm.

13b) (5Z, 13E) - (15R) -9,9-ethylenedioxy-15-hydroxy-llla-methyl-16-phenoxy-17,18,19,20-tetranor-5,13-propadic acid methyl ester 840 mg of the compound obtained according to Example 13a was allowed to stand for 48 hours at room temperature with 5 ml of ethylene glycol, 5 ml of triethyl orthoformate and 10 mg of p-toluenesulfonic acid, then diluted with ether and the solution was shaken with bicarbonate solution and brine, dried over MgS04 and evaporated in Vacuum on. The crude product was filtered through pentane / ether (4 + 6) over silica gel. 800 mg of the 9-ketal were obtained as an oil.

IR: 3600, 2950, 1730, 1600, 1495, 975, 948 / cm.

13c) (5Z, 13E) - (15R) -9,9-ethylenedioxy-lla-methyl-15- (tetra-hydropyran-2-yloxy) -l 6-phenoxy-17,18,19,20-tetranor-- 5,13-prostadienoic acid methyl ester A solution of 780 mg of the ketal obtained according to Example 13b in 30 ml of methylene chloride was mixed with 0.6 ml of dihydropyran and 5 mg of p-toluenesulfonic acid at 0 ° C., after 30 minutes the mixture was diluted with further methylene chloride and shaken with Bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was filtered with pentane / ether (8 + 2) over silica gel. 750 mg of the tetrahydropyranyl ether were obtained as an oil.

IR: 2960, 1730, 1600, 1495, 978, 948 / cm.

13d) (5Z, 13E) - (15R) -9,9-ethylenedioxy-lla-methyl-15- (tetra-hydropyran-2-yloxy) -16-phenoxy-17,18,19,20-tetranor - 5 , 13-prostadien-l-ol 500 mg of lithium aluminum hydride were added in portions to a solution of 700 mg of the compound prepared according to Example 13c-5 in 25 ml of ether, the mixture was stirred for 30 minutes at room temperature and the excess of reagent was destroyed by dropwise addition of ethyl acetate 0.8 ml of water, stirred for 1 hour, filtered and evaporated in vacuo. After io chromatography on silica gel, 590 mg of the 1-alcohol was obtained as a colorless oil with ether.

IR: 3600, 2945, 1600, 1495, 975, 948 / cm.

Example 14

15 (5Z, 13E) - (15R) -l- (3-carboxypropionyloxy) -15-hydroxy-lla-16,16-trimethyl-5,13 -prostadien-9-one

495 mg (5Z, 13E) - (15R) -9,9-ethylenedioxy-lla-16,16-tri-methyl-15- (tetrahydropyran-2-yloxy) -5,13-prostadien-l-oI, 120 mg Succinic anhydride and 3 ml of pyridine were stirred for 20 hours at room temperature under argon. The mixture was then evaporated in vacuo and purified by column chromatography on silica gel. With ether / pentane (1 +1), 435 mg (5Z, 13E) - (15R) -l- (3-carboxypropionyloxy) - 9,9-ethylenedioxy-lla-16,16-trimethyl-15- (tetrahydropyran) were obtained -25 -2-yloxy) -5,13-prostadiene as a colorless oil.

IR: 3600, 3300, 2940, 1725, 1600, 975, 948 / cm.

400 mg of the hemisuccinate obtained in this way were stirred for 16 hours in 20 ml of a mixture of acetic acid / water / 30 THF (65/35/10), then evaporated in vacuo and the residue was purified by filtration on silica gel. With ether, 170 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3300, 2935, 1730, 1600, 978 / cm.

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The starting material for the above title compound was prepared as follows:

14a) (5Z, 13E) - (15R) -15-hydroxy-11 a, 16,16-trimethyl-5,13 - prostadienic acid methyl ester 40 A suspension of 1.3 g copper (I) iodide in 13 ml ether was added drop by drop with an ethereal 1.6 m solution of methyl lithium until the copper iodide was dissolved. A solution of 0.6 g of 16.16-45 dimethylprostaglandin A2 methyl ester (DOS 2 217 044) in 25 ml of ether was added dropwise to this solution of dimethyl copper lithium at −30 ° C. The reaction mixture was then allowed to warm to 0 ° C. within 60 minutes, saturated ammonium chloride solution was added carefully, the mixture was extracted three times with ether, the extract was shaken with brine, dried 50 over magnesium sulfate and evaporated in vacuo. After chromatography on silica gel with ether, 0.48 g of the ILA-methyl compound was obtained as an oil.

IR: 3600, 2940, 1735, 1600, 978 / cm.

55 14b) (5Z, 13E) - (15R) -9,9-ethylenedioxy-15-hydroxy-lla, -16,16-trimethyl-5,13-prostadienoic acid methyl ester. Analogously to Example 13b, 0.4 is obtained from g of the compound prepared according to Example 14a 0.36 g of the 9-ketal as a colorless oil.

60 IR: 3600, 2940, 1730, 1600, 975, 950 / cm.

14c) (5Z, 13E) - (15R) -9,9-ethylenedioxy-15- (tetrahydropyran-2-yloxy) -11 a, 16,16-trimethyl-5,13-prostadienoic acid methyl ester

65 Analogously to Example 13c, 0.45 g of tetrahydropyranyl ether is obtained from 0.4 g of the ketal prepared according to Example 14b as an oil.

IR: 2940, 1730, 1600, 978, 950 / cm.

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14d) (5Z, 13E) - (15R) -9,9-ethylenedioxy-lla, 16,16-trimethyl-15- (tetrahydropyran-2-yloxy) -5,13-prostadien-l-ol in analogy to example 13d, 0.49 g of the 1-alcohol is obtained as an oil from 0.6 g of the compound prepared according to Example 14c.

IR: 3600, 3300, 2940, 1600, 976, 950 / cm.

Example 15

(5Z, 13E) - (15S, 16R, S) -l- (3-carboxypropionyloxy) -lla, 16 - dimethyl-15-hydroxy-5,13-prostadien-9-one

480 mg (5Z, 13E) - (15S, 16RS) -9,9-ethylenedioxy-lla, 16-dimethyl-15- (tetrahydropyran-2-yloxy) -5,13-prostadien-1-ol, 115 mg of succinic anhydride and 2.5 ml of pyridine were stirred at room temperature for 24 hours. The mixture was then evaporated in vacuo and purified by column chromatography on silica gel. With ether / pentane (1 +1), 410 mg (5Z, 13E) - (15S, 16R, S) -l- (3-carboxypropionyloxy) - 9,9-ethylenedioxy-lla, 16-dimethyl-15- (tetrahydropyran-2 - yloxy) -5,13-prostadiene as a colorless oil.

IR: 3600, 3300, 2940, 1725, 1600, 975, 948 / cm.

390 mg of the hemisuccinate thus obtained were stirred for 16 hours in 18 ml of a mixture of acetic acid / water / THF (65/35/10), then evaporated in vacuo and the residue was purified by filtration on silica gel. With ether, 173 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3300, 2940, 1732, 1600, 978 / cm.

The starting material for the above title compound was prepared as follows:

15a) (5Z, 13EM15S, 16R, S) -15-hydroxy-lla, 16-dimethyl-5,13-prostadienoic acid methyl ester In analogy to example 14a, 0.8 g of 16-methyl-prostaglandin-Aj- methyl ester (DOS 2 217 044) 0.68 g of the III-methyl compound as an oil.

IR: 3600, 2940, 1735, 1600, 978 / cm.

15b) (5Z, 13EM15S, 16R, s) -9,9-ethylenedioxy-lla, 16-dimethyl-15-hydroxy-5,13-prostadienoic acid methyl ester In analogy to Example 13b, 0.6 g of the Compound prepared according to Example 15a 0.52 g of the 9-ketal as an oil.

IR: 3600, 2940, 1732, 1600, 975, 950 / cm.

15c) (5Z, 13E) - (15S, 16R, S) -9,9-ethylenedioxy-lla, 16-dimethyl-15- (tetrahydropyran-2-yloxy) -5,13-prostadienoic acid - methyl ester

Analogously to Example 13c, 0.53 g of tetrahydropyranyl ether is obtained as an oil from 0.5 g of the ketal prepared according to Example 15b.

IR: 2940, 1730, 1600, 975, 948 / cm.

15d) (5Z, 13EM15S, 16RS) -9,9-ethylenedioxy-lla, 16-di-methyl-15- (tetrahydropyran-2-yloxy) -5,13-prostadien-l-ol

Analogously to Example 13d, 0.39 g of the 1-alcohol is obtained as an oil from 0.5 g of the compound prepared according to Example 15c.

IR: 3600, 3330, 2938, 1600, 978, 948 / cm.

Example 16

(5Z) - (15R, 16R, S) -l- (3-carboxypropionyloxy) -15-hydroxy-16-methyl-5-prosten-9-one

Under the reaction conditions of Example 3, 1.3 g of (5Z) - (9S, 15R, 16RS) -16-methyl-9-tribenzyl-

silyloxy-15- (tetrahydropyran-2-yloxy) -5-prosten-l-ol and 215 mg succinic anhydride in 4 ml pyridine 1.32 g (5Z) - (9S, 15R, 16RS) -l- (3-carboxypropionyloxy ) -16-methyl-9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -5-prosten as an oil.

1.4 g of the thus obtained. Hemisuccinates in 60 ml THF were treated with a solution of 870 mg tetrabutylammonium fluoride in 14 ml THF, stirred for 5 hours at room temperature, diluted with water and extracted three times with ether. The organic phase was washed neutral, dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel with ether, 702 mg (5Z) - (9S, 15R, 16RS) -l- (3-carboxypropionyloxy) -9-hydroxy-16-methyl-15- (tetrahydropyran - 2- yloxy) -5-toast as an oil.

650 mg of this product in 20 ml of acetone were mixed at −20 ° with 0.7 ml of Jones reagent. After 30 minutes, the excess of the reagent was destroyed by adding isopropanol, diluted with ether, washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue 1 was stirred with 15 ml of a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature, evaporated in vacuo and the residue was chromatographed on silica gel. With methylene chloride / 5% methanol, 290 mg of the title compound was obtained as a colorless oil.

IR: 3600, 3450, 2940, 1730 / cm.

The starting material for the above title compound was prepared as follows:

16a) (IS, 5R, 6R, 3'R, 4'RS) -6- [3- (tetrahydropyran-2-yloxy) -4-methyl-1-octyl] -2-oxabicyclo [3.3.0] - octan-3-one

2.8 g (IS, 5R, 6R, 3'S, 4'RS) -6 - [(E) -3- (tetrahydropyran - 2-yloxy) -4-methyl-l-octenyl] -2-oxabicyclo [3.3 .0] octan-3-one (German Offenlegungsschrift 2,629,834.0) and 200 mg palladium (10% on carbon) in 50 ml ethyl acetate were stirred for 3 hours under a hydrogen atmosphere at room temperature, filtered and evaporated in vacuo. 2.8 g of the hydrogenated compound were obtained as an oil.

IR: 1770 / cm.

16b) (2RS, 3aR, 4R, 6aS, 3'R, 4'RS) -4- [4-methyl-3- (tetra-hydropyran-2-yloxy) -1-octyl] -2-hydroxy-perhydrocyclo- penta [b] furan

To a cooled to - 65 ° C solution of 2.8 g of the compound prepared according to Example 16a in 100 ml abs. Toluene was added dropwise under argon with 25 ml of a 20% solution of diisobutylaluminum hydride in toluene, the mixture was stirred at -65 ° C. for 30 minutes, the excess reagent was destroyed by the dropwise addition of isopropanol, 13 ml of water were added and the mixture was stirred at room temperature for 1 hour, filtered and washed the precipitate with methylene chloride and evaporated to dryness in vacuo. 2.65 g of the lactol were obtained as a colorless oil.

IR: 3600.3400.2945 / cm.

16c) (5Z) - (9S, 15R, 16RS) -9-hydroxy-16-methyl-15- (tetra-hydropyran-2-yloxy) -5-prostonic acid methyl ester

Following the procedure of Example 5a, 2.6 g of the lactol prepared according to Example 16b gives 2.5 g of the methyl ester as a colorless oil.

IR: 3600, 3500, 2940, 1735 / cm.

16d) (5Z) - (9S, 15R, 16RS) -16-methyl-9-tribenzylsilyloxy - 15- (tetrahydropyran-2-yloxy) -5-prostenic acid methyl ester

Analogously to Example 5b, 1.6 g of was obtained from

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Example 16c prepared methyl ester 1.95 g of the tribenzyl silyl ether as a colorless oil.

IR: 2945, 1732, 1495 / cm.

16e) (5Z) - (9S, 15R, 16RS) -16-methyl-9-tribenzylsilyloxy-15 - (tetrahydropyran-2-yloxy) -5-prosten-l-ol In analogy to Example 5c, 1 8 g of the compound prepared according to Example 16d 1.6 g of the 1-alcohol as an oil.

IR: 3600, 3400, 2945, 1495 / cm.

Example 17

(5Z) - (15R) -l- (3-carboxypropionyloxy) -16,16-dimethyl-15-hydroxy-5-prosten-9-one

Under the reaction conditions of Example 3, 2.1 g of (5Z) - (9S, 15R) -16,16-dimethyl-9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) -5-prosten-l are obtained from 2.1 g -ol and 340 mg succinic anhydride in 6 ml pyridine 2.15 g (5Z) - (9S, 15R) -1 - (3-carboxypropionyloxy) -l 6,16-dimethyl-9-tri-benzylsilyloxy-15- (tetrahydropyran -2-yloxy) -5-boast as a colorless oil.

A solution of 1.3 g of tetrabutylammonium fluoride in 18 ml of THF was added to 2.1 g of the hemisuccinate thus obtained in 80 ml of THF, the mixture was stirred at room temperature for 6 hours, diluted with water and extracted with ether. The organic phase was shaken three times with water, dried over magnesium sulfate and evaporated in vacuo. Chromatography on silica gel gave ether 1.1 g of (IZ) - (9S, 15R) -l- (3-carboxypropionyloxy) -16,16-dimethyl-9 - hydroxy-15- (tetrahydropyran-2-yloxy) -5-toast as oil.

1 g of this product in 24 ml of acetone was mixed with 1 ml of Jones reagent at −20 ° C., stirred for 30 minutes and the excess of the reagent was destroyed by isopropanol. It was diluted with ether, washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was stirred with 20 ml of a mixture of acetic acid / water / THF (65/35/10) for 18 hours at room temperature, evaporated in vacuo and the residue was chromatographed on silica gel. With methylene chloride / 5% methanol, 560 mg of the title compound was obtained as a colorless oil. IR: 3600, 3400, 2940, 1730 / cm.

The starting material for the above title compound was prepared as follows:

17a) (IS, 5R, 6R, 3'R) -6 - [- 4,4-dimethyl-3- (tetrahydropyran - 2-yloxy) -1-octyl] -2-oxabicyclo [3.3.0] octane 3-one In analogy to Example 16a, 3.6 g of (IS, 5R, 6R, 3'R) -6 - [(E) -3- (tetrahydropyran-2-yloxy) -4,4-dimethyl- 1-octenyl] -2-oxybicyclo [3.3.0] octan-3-one (DOS 2 629 834 0) 3.6 g of the hydrogenated compound as an oil.

IR: 1770 / cm.

17b) (2RS, 3aR, 4R, 6aS, 3'R) -4- [4,4-dimethyl-3- (tetrahy-dropyran-2-yloxy) -l-octyl] -2-hydroxy-perhydrocyclopenta [ b] furan Analogously to Example 16b, 3.5 g of lactol were obtained as an oil from 3.6 g of the compound prepared according to Example 17a.

IR: 3600, 3400, 2945 / cm.

17c) (5Z) - (9S, 15R) -9-hydroxy-16,16-dimethyl-15- (tetra-hydropyran-2-yloxy) -5-prostenic acid methyl ester In analogy to example 5a, 3.3 g of Lactols prepared according to Example 17b 3.2 g of the methyl ester as an oil.

IR. 3600, 3450, 2945, 1735 / cm.

17d) (5Z) - (9S, 15R) -16,16-dimethyl-9-tribenzylsilyloxy-15 - (tetrahydropyran-2-yloxy) -5-prostenic acid methyl ester In analogy to Example 5b, 3.2 g of the was obtained from Example 17c prepared methyl ester 3.6 g of the tribenzyl silyl ether as an oil.

IR: 2940.1732, 1495 / cm.

17e) (5Z) - (9S, 15R) -16,16-dimethyl-9-tribenzylsilyloxy-15-tetrahydropyran, -2-yloxy) -5-prosten-l-ol In analogy to Example 5c, from 3, 4 g of the compound prepared according to Example 17d 3.3 g of the 1-alcohol as an oil.

IR: 3600, 3400, 2940, 1495 / cm.

Example 18

(5Z, 13E) - (9S, 15S) -l- (3-carboxypropionyloxy) -lla, 15-dimethyl-9,15-dihydroxy-5,13-prostadiene and (5Z, 13E) - (9R, 15S ) -l- (3-carboxypropionyloxy) -lla, 15-dimethyl-9,15-dihydroxy-5,13-prostadiene

A solution 1 g of sodium borohydride in 120 ml of methanol became a solution of 300 mg (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -15-hydroxy-15-methyl at 0 ° C. within 15 minutes -5,13-prostadien-9-one (prepared according to Example 9) added dropwise in 30 ml of methanol. The mixture was stirred for a further 15 minutes at 0 ° C., then for 1 hour at room temperature, evaporated to dryness in vacuo at 25 ° C., diluted with water and acidified to pH 3.5 with dilute sulfuric acid, extracted three times with ether, the extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. After separation by preparative layer chromatography (silica gel, methylene chloride / iso-propanol 9 + 1), 124 mg of the 9a (9S) -hydroxy compound were obtained as a colorless oil and 105 mg of the 9β (9R) -hydroxy compound as an oil as a more polar component. IR (9a-OH): 3600, 3400, 2935, 1730, 1600, 978 / cm.

The IR spectrum of the 9β-OH compound was identical to that of the 9a-OH compound except for slight differences.

Example 19

(5Z, 13E) - (15R) -l-acetoxy-15-hydroxy-16-phenoxy-17,18, -19,20-tetranor-5,13-prostadien-9-one

A mixture of 1.5 g of the 1-alcohol prepared according to Example 1c, 6 ml of pyridine and 1 ml of acetic anhydride was left to stand at room temperature for 16 hours, evaporated in vacuo and filtered over silica gel with pentane / ether (7 + 3). 1.55 g of the 1-acetate were obtained as a colorless oil. IR: 2950, 1738, 1600, 1493, 1245, 978 / cm.

A solution of 800 mg of tetrabutylammonium fluoride in 8 ml of THF was added to 1.2 g of the 1-acetate thus obtained in 30 ml of THF and the mixture was stirred at room temperature for 5 hours. It was diluted with water, extracted with ether, the extracts washed with brine, dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel, 510 mg (5Z, 13E) - (9S, 15R) -l-acetoxy-9-hydroxy-15 - (tetrahydropyran-2-yIoxy) - were obtained with ether / pentane (6 + 4) - (9S, 15R) 16-phenoxy-17,18,19,20-tetranor - 5,13-prostadiene as an oil.

IR: 3600, 2940, 1737, 1600, 1495, 1245, 978 / cm.

0.6 ml of Jones reagent was added to a solution of 500 mg of this product in 10 ml of acetone at −20 ° C., the mixture was stirred at −20 ° for 30 minutes and the excess of the reagent was destroyed by adding isopropanol. It was diluted with ether, shaken neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in

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13 ml of a mixture of acetic acid / water-THF (65/35/10) was stirred for 16 hours at room temperature. The mixture was then evaporated in vacuo, chromatographed on silica gel with ether and 258 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3430, 2935, 2860, 1740, 1600, 1496, 1250, 976 / cm.

Example 20

(5Z, 13E) - (9S, 15R) -l-acetoxy-9,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene

300 mg (5Z, 13E) - (9S, 15R) -l-acetoxy-9-tribenzylsilyl-oxy-15- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18,19,20 - tetranor-5 , 13-prostadiene (prepared in Example 19) was stirred for 16 hours in 8 ml of a mixture of acetic acid / water / THF (65/35/10) at room temperature, evaporated in vacuo and chromatographed on silica gel. With chloroform, 120 mg of the title compound was obtained as a colorless oil.

IR: 3600, 3400, 2940, 1735, 1600, 1496, 1250, 978 / cm. Example 21

(5Z, 13E) - (15R) -1 - acetoxy-16,16-dimethyl-15-hydroxy-5,13 - prostadien-9-one

Analogously to Example 19, the title compound is obtained as a colorless oil from the compound prepared according to Example 3c.

IR: 3600, 3500, 2940, 2860, 1740, 1600, 1250, 978 / cm.

Example 22

(5Z, 13E) - (15S, 16RS) -l-acetoxy-15-hydroxy-16-methyl-5,13 - prostadien-9-one

Analogously to Example 19, the title compound is obtained as an oil from the compound prepared according to Example 5c. IR: 3600, 3450, 2950, 1740, 1600, 1255, 975 / cm.

Example 23

(5Z, 13E) - (15S) -l-acetoxy-15-hydroxy-17-phenyl-18,19,20 - trinor-5,13-prostadien-9-one

Analogously to Example 19, the title compound is obtained as an oil from the 1-alcohol prepared according to Example 7c. IR: 3600, 3420, 2940, 2860, 1740, 1600, 1250, 975 / cm.

Example 24

(5Z, 13E) - (15S) -l-acetoxy-15-hydroxy-15-methyl-5,13 - prostadien-9-one

A mixture of 500 mg (5Z, 13E) - (15S) -9,9-ethylene-dioxy-15-methyl-15- (tetrahydropyran-2-yloxy) -5,13-prosta-dien-l-ol (prepared according to Example 9d), 1 ml of pyridine and 0.5 ml of acetic anhydride were left at room temperature for 16 hours, evaporated in vacuo and the residue was stirred with 10 ml of a mixture of acetic acid / water / THF (65/35/10) 16 hours, evaporated in vacuo and the residue chromatographed on silica gel with ether and received 250 mg of the title compound as a colorless oil.

IR. 3600, 3300, 2930, 1740, 1600, 1245, 975 / cm.

Example 25

(5Z, 13E) - (15S) -1-acetoxy-15-hydroxy-5,13-prostadien-9-one In analogy to example 24, the title compound is obtained from the 1-alcohol prepared according to example 10c as a colorless oil.

IR: 3600, 3520, 2940, 1740, 1250, 975 / cm.

Example 26

(5Z, 13E) - (15S) -l-acetoxy-15-hydroxy-lla-methyl-5,13 - prostadien-9-one

In analogy to Example 24, the title compound is obtained from the 1-alcohol obtained according to Example 11c as a colorless oil.

IR: 3600, 3430, 2950, 1738, (1725), 1260, 978 / cm.

Example 27

(5Z, 13E) - (15S) -l-acetoxy-lla, 15-dimethyl-15-hydroxy-5,13 - prostadien-9-one

Analogously to Example 24, the title compound is obtained as a colorless oil from the compound prepared in Example 12c.

IR: 3600 ,, 3420, 2940, 1740, 1600, 1250, 978 / cm.

Example 28

(5Z, 13E) - (15R) -1-acetoxy-15-hydroxy-l 1 a-methyl-16-phenoxy-17, 18,19,20-tetranor-5,13-prostadien-9-one

Analogously to Example 24, the title compound is obtained as a colorless oil from the compound prepared in Example 13d.

IR: 3600, 3450, 1940, 1740, 1600, 1495, 1250, 976 / cm. Example 29

(5Z, 13E) - (15R) - 1-acetoxy-15-hydroxy-11 a, 16,16-trimethyl-5,13 -prostadien-9-one

Analogously to Example 24, the title compound is obtained as a colorless oil from the compound prepared in Example 14d.

IR: 3600, 3330, 2940, 1740, 1600, 1245, 978 / cm.

Example 30

(5Z, 13EM15S, 16RS) - 1-acetoxy-11 a, 16-dimethyl-15-hydroxy-5,13 -prostadien-9-one

Analogously to Example 24, the title compound is obtained as a colorless oil from the compound prepared in Example 15d.

IR: 3600, 3350, 2940, 1740, 1600, 1255, 975 / cm.

Example 31

(5Z) - (15R, 16RS) -1-acetoxy-15-hydroxy-16-methyl-5-prosten - 9-one

Analogously to Example 24, the title compound is obtained as a colorless oil from the compound prepared in Example 16e.

IR: 3600, 3450, 2945, 1740, 1255 / cm.

Example 32

(5Z) - (15R) - 1-acetoxy-16,16-dimethyl-15-hydroxy-5-prosten - 9-one

Analogously to Example 24, the title compound is obtained as a colorless oil from the compound prepared in Example 17e.

IR: 3600, 3450, 2940, 1740.1 255 / cm.

Example 33

(5Z, 13E) - (15R) -15-hydroxy-1-methoxyacetoxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-one

A mixture of 800 mg of the compound prepared according to Example 1c, 4 ml of pyridine and 1 ml of methoxyacetic acid chloride was stirred for 16 hours at room temperature under argon. The mixture was evaporated in vacuo and the residue was filtered through pentane / ether (7 + 3) over silica gel and 820 mg of the 1-methoxyacetate were obtained as a colorless oil.

IR: 2945, 1736, 1600, 1493, 978 / cm.

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A solution of 400 mg of tetrabutylammonium fluoride in 4 ml of THF was added to 600 mg of the 1-methoxyacetate thus obtained in 15 ml of THF and the mixture was stirred at room temperature for 6 hours. It was diluted with water, extracted with ether, the organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel, 320 mg (5Z, 13E) - (9S, 15R) - 9-hydroxy-l-methoxyacetoxy-15- (tetrahydropyran-2-yloxy) were obtained with ether / pentane (6 + 4) - (9Z, 13R) - -16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene as an oil. IR: 3600, 2940, 1737, 1600, 1495, 978 / cm.

0.3 ml of Jones reagent was added to a solution of 300 mg of this product in 8 ml of acetone at −20 ° C., the mixture was stirred at −20 ° C. for 30 minutes and the excess of the reagent was destroyed by adding isopropanol. It was diluted with ether, shaken neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was stirred in 7 ml of a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature. The mixture was then evaporated in vacuo, chromatographed on silica gel with ether and 120 mg of the title compound were obtained as an oil. IR: 3600, 3400, 2935, 1740, 1600, 1496, 976 / cm.

Example 34

(5Z, 13E) - (15R) -1-methoxyacetoxy-16,16-dimethyl-15-hydroxy-5,13-prostadien-9-one

Analogously to Example 33, the title compound is obtained as an oil from the compound prepared according to Example 3c. IR: 3600, 3450, 2940, 1740, 1600, 978 / cm.

Example 35

(5Z, 13E) - (15S, 16RS) -l-methoxyacetoxy-15-hydroxy-16-methyl-5,13-prostadien-9-one

Analogously to Example 33, the title compound is obtained as an oil from the compound prepared according to Example 5c. IR: 3600, 3450, 2945, 1738, 1600, 978 / cm.

Example 36

(5Z, 13E) - (15S) -1-methoxyacetoxy-15-hydroxy-17-phenyl-18,19,20-trinor-5,13-prostadien-9-one

Analogously to Example 33, the title compound is obtained as an oil from the compound prepared according to Example 7c. IR: 3600, 3450, 2940, 2860, 1740, 1600, 978 / cm.

Example 37

(5Z, 13E) - (15S) -15-hydroxy-l-methoxyacetoxy-15-methyl-5,13-prostadien-9-one

A mixture of 500 mg (5Z, 13E) - (15S) -9,9-ethylene-dioxy-15-methyl-15- (tetrahydropyran-2-yloxy) -5,13-prosta-dien-l-ol (prepared according to Example 9d), 3 ml of pyridine and 0.6 ml of methoxyacetic acid chloride were stirred for 16 hours at room temperature under argon. The mixture was evaporated in vacuo and the residue was stirred with 10 ml of a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature, evaporated in vacuo and the residue was chromatographed on silica gel. With ether, 264 mg of the title compound was obtained as a colorless oil.

IR: 3600, 3400, 2940, 1740, 1600, 976 / cm.

Example 38

(5Z, 13E) - (15S) -1 la, 15-dimethyl-15-hydroxy-l-methoxy-acetoxy-5,13-prostadien-9-one

Analogously to Example 37, the title compound is obtained as an oil from the compound prepared in Example 12c.

IR: 3600, 3450, 2945, 1740, 1600, 978 / cm.

Example 39

(5Z, 13E) - (15R) -15-Hydroxy-l 1 a-methyl-1-methoxy acetoxy - 16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-one

Analogously to Example 37, the title compound is obtained as an oil from the compound prepared in Example 13d. IR: 3600, 3450, 2940, 1738, 1600, 1494, 978 / cm.

Example 40

(5Z, 13E) - (15R) -15-hydroxy-l-methoxyacetoxy-lla, 16,16-trimethyl-5,13-prostadien-9-one

Analogously to Example 37, the title compound is obtained as an oil from the compound prepared in Example 14d. IR: 3600, 3400, 2940, 1740, 1600, 978 / cm.

Example 41

(5Z, 13E) - (15S, 16RS) -1 la, 16-dimethyl-15-hydroxy-l - methoxy acetoxy-5,13 -prostadien-9-one

Analogously to Example 37, the title compound is obtained as an oil from the compound prepared in Example 15d. IR: 3600, 3350, 2945, 1740, 1600, 976 / cm.

Example 42

(5Z) - (15R, 16RS) -5-hydroxy-l 6-methyl-1-methoxyacetoxy - 5-prosten-9-one:

Analogously to Example 37, the title compound is obtained as an oil from the compound prepared in Example 16e. IR: 3600, 3400, 2940, 1740 / cm.

Example 43

(5Z) - (15R) -16,16-dimethyl-15-hydroxy-l-methoxyacetoxy - 5-prosten-9-one

Analogously to Example 37, the title compound is obtained as an oil from the compound prepared in Example 17e. IR: 3600, 3400, 2940, 1738 / cm.

Example 44

(5Z, 13E) - (15R) -15-hydroxy-1 - [(N-methanesulfonyl) carbamoyloxy] -16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene - 9 -on

A solution of 180 mg of methanesulfonyl isocyanate in 12 ml of toluene was added to a solution of 1 g of the 1-alcohol prepared according to Example 1c in 12 ml of absolute toluene at 0 ° C. and the mixture was stirred at 25 ° C. for 1 hour. Then it was mixed with water, extracted with ether, the organic extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. After filtration of the residue over silica gel with methylene chloride, 945 mg (5Z, 13E) - (9S, 15R) -l - [(N-methanesulfonyl) -carb-amoyloxy] -9-tribenzylsilyloxy-15- (tetrahydropyran-2-yloxy) were obtained ) - 16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene as a colorless oil.

IR: 1720, 1600, 1493, 975 / cm.

A solution of 600 mg of tetrabutylammonium fluoride in 6 ml of THF was added to 900 mg of the compound thus obtained in 25 ml of THF and the mixture was stirred at room temperature for 6 hours. The mixture was then diluted with water, extracted three times with ether, the organic phase was washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. After purification on silica gel with ether, 530 mg of the 9-hydroxy compound was obtained as a colorless oil.

The product was dissolved in 10 ml acetone, and 0.6 ml Jones reagent was added at -20 ° C. After 40 minutes, the excess of the reagent was destroyed by adding isopropanol, diluted with ether, washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 10 ml of a mixture of acetic acid / water / THF (65/35/10). After 16 hours

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was evaporated in vacuo and the residue was chromatographed on silica gel with methylene chloride / 1% methanol. 280 mg of the title compound were obtained as a colorless oil.

IR: 3600, 3380, 1740, 1600, 1493, 1345, 976 / cm.

Example 45

(5Z, 13E) - (15R) -16,16-dimethyl-15-hydroxy-1 - [(N-methanesulfonyl) carbamoyloxy] -5,13-prostadien-9-one

Analogously to Example 44, the title compound is obtained as a colorless oil from the compound prepared in Example 3c.

IR: 3600, 3380, 1738, 1345, 979 / cm.

Example 46

(5Z, 13E) - (15R) -15-hydroxy-1 - [(N-methanesulfonyl) carbamoyloxy] -11 a-methyl-16-phenoxy-17,18,19,20-tetranor-5,13 --prostadien-9-one

A solution of 100 mg of methanesulfonyl isocyanate in 5 ml of toluene was added to a solution of 490 mg of the 1-alcohol prepared according to Example 13d in 5 ml of toluene at 0 ° C. and the mixture was stirred for 1 hour at room temperature. Water was added, the mixture was extracted with ether, the organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. After filtration of the residue over silica gel, 430 mg of the 1-sulfonyl compound were obtained with ether / pentane (8 + 2), which was stirred in 10 ml of a mixture of acetic acid / water / THF (65/35/10) at room temperature for 16 hours. The mixture was evaporated in vacuo and the residue was chromatographed on silica gel. With ether, 280 mg of the title compound were obtained as a colorless oil. IR: 3600, 3400, 1738, 1345, 976 / cm.

Example 47

(5Z, 13E) - (15R) -15-hydroxy-1-N, N-dimethylcarbamoyloxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-one

A solution of 1 g of the compound prepared according to Example 1c in 5 ml of pyridine and 0.5 ml of N, N-dimethyl-carbamoyl chloride was allowed to stand at room temperature for 16 hours, diluted with ether and shaken successively with dilute sulfuric acid, bicarbonate solution and brine, dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel with ether / pentane (1: 1). 850 mg of the urethane were obtained as an oil.

IR: 2950, 1700, 1600, 1495, 976 / cm.

A solution of 600 mg of the urethane in 15 ml of THF was mixed with a solution of 400 mg of tetrabutylammonium fluoride in 4 ml of THF and stirred for 5 hours at room temperature. The mixture was diluted with water, extracted with ether, the extract was shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After filtration over silica gel with ether, 380 mg of the 9-hydroxy compound were obtained, which was dissolved in 5 ml of acetone and oxidized at -20 ° C. using Jones reagent. The crude product was stirred without further purification with 8 ml of a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature. The mixture was then evaporated in vacuo and the residue was purified by chromatography on silica gel with methylene chloride. 190 mg of the title compound were obtained as an oil.

IR: 3600, 3450, 2935, 1740, 1702, 1600, 1495, 978 / cm.

Example 48

(13E) - (15R) -1 - (3-carboxypropionyloxy) -15-hydroxy-16-phen-oxy-17,18,19,20-tetranor-13-prosten-9-one

A solution of 540 mg (5Z, 13E) - (15R) -l- (3-carboxy-propionyloxy) -15- (tetrahydropyran-2-yloxy) -16-phenoxy-17, -

18,19,20-tetranor-5,13-prostadien-9-one (prepared according to Example 1) in 10 ml of ethyl acetate was mixed with 27 mg palladium on carbon (10%) and shaken under a hydrogen atmosphere at room temperature until it was taken up of 24 ml of hydrogen. The catalyst was then filtered off and evaporated in vacuo. The residue was stirred in 15 ml of a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature, evaporated in vacuo and the residue was chromatographed on silica gel with chloroform / methanol 5%. 320 mg of the title compound were obtained as an oil.

IR: 3600, 3400, 2930, 2860, 1735 (br.), 1600, 1589, 1496, 976 / cm.

Example 49

(13E) - (15R) -l- (3-carboxypropionyloxy) -15-hydroxy-16,16 - dimethyl-13-prosten-9-one

In analogy to Example 48, the title compound is obtained as an oil from the prostadia prepared in Example 3. IR: 3600, 3500, 2930, 2860, 1735, 1600, 976 / cm.

Example 50

(13E) - (15S, 16RS) -l- (3-carboxypropionyloxy) -15-hydroxy-16-methyl-13-prosten-9-one

Analogously to Example 48, the title compound is obtained as an oil from the prostadia prepared in Example 5. IR: 3600, 3450, 2950, 1730, 1600, 975 / cm.

Example 51

(13E) - (15S) -l- (3-carboxypropionyloxy) -15-hydroxy-15-methyl-13-prosten-9-one

280 mg (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -9.9 - ethylenedioxy-15-methyl-15- (tetrahy dropy ran-2-yloxy) -5.13 - prostadiene and 15 mg of palladium on carbon (10%) in 8 ml of ethyl acetate were shaken under a hydrogen atmosphere at room temperature until 12 ml of hydrogen were taken up. The mixture was then filtered and the evaporation residue was stirred with a mixture of acetic acid / water / THF (65/35/10) for 16 hours at room temperature, evaporated in vacuo, the residue was dissolved in 50 ml of ether, shaken with brine, dried over magnesium sulfate and evaporated in a vacuum. After purification by chromatography on silica gel with ether, 163 mg of the title compound were obtained as an oil.

IR: 3600, 3300, 2930, 1730, 1600, 976 / cm.

Example 52

(13E) - (15S) -1 - (3-carboxypropionyloxy) -11 a, 15-dimethyl-15 - hydroxy-13-prosten-9-one

Analogously to Example 51, the title compound was obtained as a colorless oil from the prostadia prepared in Example 12.

IR: 3600, 3400, 2940, 1733, 1600, 978 / cm.

Example 53

(13E) - (15R) -1 - (3-carboxypropionyloxy) -15-hydroxy-11 a-methyl-16-phenoxy-17,18,19,20-tetranor-13-prosten-9-one

In analogy to example 51, the title compound is obtained as an oil from the corresponding prostadia prepared in example 13.

IR: 3600, 3400, 2940, 1735, 1600, 1495, 978 / cm.

Example 54

(13E) - (15R) -1 - (3-carboxypropionyloxy) -15-hydroxy-11a, -16,16-trimethyI-13-prosten-9-one

Analogously to Example 51, one obtains from correl5

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Prostatiums prepared in Example 14, the title compound as an oil.

IR: 3600, 3300, 2935, 1732, 1600, 978 / cm.

Example 55

(13E) - (15S, 16RS) -l- (3-carboxypropionyloxy) -l la, 16-dimethyl-15-hydroxy-13-prosten-9-one

Analogously to Example 51, the title compound obtained as an oil is obtained from the corresponding prostadia prepared in Example 15.

IR: 3600, 3330, 2940, 1732, 16Ö0, 976 / cm.

Example 56

(13E) - (15R) - 1-acetoxy-15-hydroxy-l 6-phenoxy-17,18,19,20 - tetranor-13-prosten-9-one

In analogy to Example 48, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 19.

IR: 3600, 3400, 2940, 1735, 1600, 1498, 1250, 978 / cm. Example 57

(13E) - (15R) -1 - acetoxy-16,16-dimethyl-15-hy droxy-5,13 - prostadien-9-one

Analogously to Example 48, the title compound is obtained as an oil from the corresponding compound prepared in Example 21.

IR: 3600, 3400, 2860, 1738, 1600, 1250, 976 / cm.

Example 58

(13E) - (15S, 16RS) -l-acetoxy-15-hydroxy-16-methyl-13 - prosten-9-one

Analogously to Example 48, the title compound is obtained as an oil from the corresponding compound prepared in Example 22.

IR: 3600, 3450, 2945, 1740, 1600, 1250, 976 / cm.

Example 59

(13E) - (15S) -1-acetoxy-15-hydroxy-15-methyl-13-prosten-9-one

Analogously to Example 51, the title compound is obtained as an oil from the corresponding compound prepared in Example 24.

IR: 3600, 3320, 2935, 1740, 1600, 1240, 976 / cm.

Example 60

(13E) - (15R) -1-acetoxy-15-hydroxy-11 a-methyl-16-phenoxy-17,18,19,20-tetranor-13-prosten-9-one

In analogy to Example 51, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 28.

IR: 3600, 3450, 2945, 1740, 1600, 1495, 1245, 976 / cm. Example 61

(13E) - (15R) - 1-acetoxy-l 5-hydroxy-11 a, 16,16-trimethyI-13 - prosten-9-one

In analogy to Example 51, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 29.

IR: 3600, 3330, 2938, 1740, 1600, 1245, 976 / cm.

Example 62

(13E) - (15S, 16RS) -l-acetoxy-lla, 16-dimethyl-15-hydroxy-13-prosten-9-one

In analogy to Example 51, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 30.

IR: 3600, 3350, 2940, 1740, 1600, 1255, 978 / cm.

Example 63

(13E) - (15R) -15-Hydroxy-l-methoxyacetoxy-16-phenoxy-17,18,19,20-tetranor-13-prosten-9-one

In analogy to Example 48, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 33.

IR: 3600, 3420, 2935, 1740, 1600, 1498, 978 / cm.

Example 64

(13E) - (15R) -16,16-dimethyl-15-hydroxy-1-methoxy acetoxy - 13-prosten-9-one

In analogy to Example 48, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 34.

IR: 3600, 3450, 2940, 1740, 1600, 976 / cm.

Example 65

(13E) - (15S, 16RS) -5-hydroxy-l-methoxyacetoxy-16-methyl-13-prosten-9-one

In analogy to Example 48, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 35.

IR: 3600, 3400, 2940, 1738, 1600, 978 / cm.

Example 66

(13E) - (15S) -15-hydroxy-l-methoxyacetoxy-15-methyl-13 - prosten-9-one

In analogy to Example 51, the title compound is obtained as an oil from the corresponding prostadia prepared in Example 37.

IR: 3600, 3400, 2935, 1740, 1600, 978 / cm.

Example 67

(15R, 16RS) -l- (3-carboxypropionyloxy) -15-hydroxy-16-methyl-prostan-9-one

A solution of 300 mg (5Z) - (15R, 16RS) -l- (3-carboxypropionyloxy) -l 5-hydroxy-16-methyl-5-prosten-9-one (prepared according to Example 16) in 20 ml Ethyl acetate was shaken with 50 mg palladium on carbon (10%) for 30 minutes under a hydrogen atmosphere. The catalyst was filtered off, the solution was evaporated in vacuo and the title compound was obtained as an oil.

IR: 3600, 3450, 2935, 1732 / cm.

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Claims (19)

638773 2nd PATENT CLAIMS 1. Prostate derivatives of the general formula I wherein Rj is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms, the rest of an inorganic acid or a U II r4 —C —— Group r5 means, where U is an oxygen or sulfur atom and R4 and R5 are a hydrogen atom, an optionally substituted alkyl, cycloalkyl, heteroaryl or aryl radical or an acid radical or R4 and R5 together can represent a heterocyclic ring with 4-7 ring members, A is a -CH2-CH2-, cis-CH = CH-, trans-CH = CH- or -C = C group, B is a -CH2-CH2, trans-CH = CH or -C = C group, W is a free or etherified or esterified hydroxymethylene group, a free or ketalized carbonyl group or a free, esterified or etherified ch3 I. —C — group, OH where the OH group can be a- or ß-permanent, D and E together are a direct bond or D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C group, E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, R, a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and Z is a free or ketalized carbonyl group or a free or etherified or esterified hydroxymethylene group. 2. Compounds according to claim 1: (5Z, 13E) - (15R) -1 - (3-carboxypropionyloxy) -15-hydroxy-l 6- -phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-one, (5Z, 13E) - (15R) - l- (3-carboxypropionyloxy) -15-hydroxy-l 6, - 16-dimethyl-5,13-prostadien-9-one, (5Z, 13E) - (15S, 16RS) -l- (3-carboxypropionyloxy) -15-hy- droxy-16-methyl-5,13-prostadien-9-one, (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -15-hydroxy-15- -methy 1-5,13-prostadien-9-one, (5Z, 13E) - (15S) - 1- (3-carboxypropionyloxy) -15-hydroxy-17-phenyl-18,19,20-trinor-5,13-prostadien-9-one, (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -15-hydroxy-5,13- -prostadien-9-one, (5Z, 13E) - (15S) -l- (3-carboxypropionyloxy) -15-hydroxy-l la- -methyl-5,13-prostadien-9-one, (5Z, 13E) - (15S) -l- (3-carboxy-propionyloxy) -lla, 15-dime- thyl-15-hydroxy-5,13-prostadien-9-one, (5Z, 13E) - (15R) -l- (3-carboxypropionyloxy) -15-hydroxy-lla - methyl-16-phenoxy-17,18 , 19.20-tetranor-5.13-prostadien - 9-one, (5Z, 13E) - (15R) -l- (3-carboxypropionyloxy) -15-hydroxy-lla- . -16,16-trimethyl-5,13-prostadien-9-one, (5Z, 13E) - (15S, 16RS) -l- (3-carboxypropionyloxy) -lla, 16- -dimethyl-15-hydroxy-5,13 -prostadien-9-one, (5Z, 13E) - (15R) -l-acetoxy-15-hydroxy-16-phenoxy-17,18, - 19,20-tetranor-5,13-prostadien-9-one, (5Z, 13E) - (15R) -l-acetoxy-16,16-dimethyl-15-hydroxy-5,13- -prostadien-9-one, (5Z, 13E) - (15S, 16RS) -l-acetoxy-15-hydroxy-16-methyl-5,13- -prostadien-9-one, (5Z, 13E) - (15S) -l-acetoxy-15-hydroxy-17-phenyl-18,19,20- -trinor-5,13-prostadien-9-one, (5Z, 13E) - (15S) -l-acetoxy-15-hydroxy-15-methyl-5,13-prosta-dien-9-one, (5Z, 13E) - (15S) -l-acetoxy-15-hydroxy-5,13-prostadien-9-one, (5Z, 13E) - (15S) -l-acetoxy-15-hydroxy-lla-methyl- 5.13-per-stage-9-one, (5Z, 13E) - (15S) -l-acetoxy-lla, 15-dimethyl-15-hydroxy-5,13- -prostadien-9-one, (5Z, 13E) - (15R) -l-acetoxy-15-hydroxy-lla-methyl-16-phen- oxy-17,18,19,20-tetranor-5,13-prostadien-9-one, (5Z, 13E) - (15R) -l-acetoxy-15-hydroxy-l la, 16,16-trimethyl- -5,13-prostadien-9-one, (5Z, 13E) - (15S, 16RS) -l-acetoxy-lla, 16-dimethyl-15-hy- droxy-5,13 -prostadien-9-one, (5Z) - (15R, 16RS) -1-acetoxy-15-hydroxy-16-methyl-5-prosten - 9-one, (5Z) - (15R) -1 - acetoxy-16-16-dimethyl-15 -hydroxy-5-prostene - 9-one, (5Z, 13E) - (15R) -15-hydroxy-l-methoxyacetoxy-16-phenoxy- -17,18,19,20-tetranor-5,13-prostadien-9-one, (5Z, 13E) - (15R) -l-methoxyacetoxy-16,16-dimethyl-15-hy- droxy-5,13-prostadien-9-one, (5Z, 13E) - (15S, 16RS) -l-methoxyacetoxy-15-hydroxy-16- -methyl-5,13-prostadien-9-one, (5Z, 13E) - (15S) -l-methoxyacetoxy-15-hydroxy-17-phenyl-18, - 19.20-trinor-5.13-prostadien-9-one, (5Z, 13E) - (15S) - 15-hydroxy-l-methoxyacetoxy-15-methyl- -5,13-prostadien-9-one, (5Z, 13E) - (15S) -lla, 15-dimethyl-15-hydroxy-l-methoxy- acetoxy-5,13-prostadien-9-one,, (5Z, 13E) - (15R) -15-hydroxy-lla-methyl-l-methoxyacetoxy- -16-phenoxy-17,18,19,20-tetranor-5,13 -prostadien-9-one, (5Z, 13E) - (15R) -15-hydroxy-l-methoxyacetoxy-lla, 16,16- trimethyl-5,13-prostadien-9-one, (5Z, 13E) - (15S, 16RS) -lla, 16-dimethyl-15-hydroxy-l-meth- oxyacetoxy-5,13-prostadien-9-one, (5Z, 13E) - (15R) -15-hydroxy-1 - [(N-methanesulfonyl) carbamoyloxy] -16-phenoxy-17, -8.19 , 20-tetranor-5,13-prosta-dien-9-one, (5Z, 13E) - (15R) -16,16-dimethyl-15-hydroxy-1- [(N-methane sulf onyl) -carbamoyloxy] -5,13-prostadien-9-one, (5Z, 13E) - (15R) -15-hydroxy-l - [(N-methanesulfonyl) -carbamoyloxy] -11 a-methyl- 16-phenoxy-17,18,19,20-tetranor - 5,13-prostadien-9-one, (5Z, 13E) - (15R) -15-hydroxy-IN, N-dimethylcarbamoyIoxy - 16-phenoxy- 17,18,19,20-tetranor-5,13 -prostadien-9-one, (13E) - (15R) - 1-acetoxy-16,16-dimethyl-15-hydroxy-5,13-pro-stadien- 9-one. 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3rd 638773 3. Connections according to address 1: (5Z, 13E) - (9S, 15R) -l- (3-carboxypropionyloxy) -9.15-dihydroxy-16-phenoxy-17.18, 19.20-tetranor-5.13-prostadiene, (5Z , 13E) - (9S, 15R) -l (3-carboxypropionyloxy) -l6,16-dime- thyl-9,15-dihydroxy-5,13-prostadiene, (5Z, 13E) - (9S, 15S, 16RS) -l- (3-carboxypropionyloxy) -9.15- dihydroxy-16-methyl-5,13-prostadiene, (5Z, 13E) - (9S, 15S) -l- (3-carboxypropionyloxy) -9.15-dihy- droxy- 17-phenyl-18,19,20-trinor-5,13-prostadiene, (5Z, 13E) - (9S, 15S) -1 - (3-carboxypropionyloxy) -11 a, 15-di- methyl-9,15-dihydroxy-5,13-prostadiene, (5Z, 13E) - (9R, 15S) -l- (3-carboxypropionyloxy) -lla-15-di- methyl-9,15-dihydroxy-5,13-prostadiene and (5Z, 13E) - (9S, 15R) -l-acetoxy-9,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor -5.13 -prostadiums. 4. Compounds according to claim 1: (13E) - (15R) -1 - (3-carboxypropionyloxy) -15-hydroxy-16-phenoxy-17.1 8,19,20-tetranor-13-prosten-9-one, (13E) - (15R) -1 - (3-carboxypropionyloxy) -15-hydroxy-l 6.16- -dimethyl-13-prosten-9-one, (13E) - (15S, 16RS) -1 - (3-carboxypropionyloxy) -15-hydroxy- -16-methyl-13-prosten-9-one, (13E) - (15S) -l- (3-carboxypropionyloxy) -15-hydroxy-15-me- thyl-13-prosten-9-one, (13E) - (15S) -l- (3-carboxypropionyloxy) -lla, 15-dimethyl-15- -hydroxy-13-prosten-9-one, (5Z) - (15R, 16RS) -15-hydroxy-16-methyl-l-methoxyacetoxy- -5-prosten-9-one, (5Z) - (15R) -16,16-dimethyl-l 5-hydroxy-l-methoxyacetoxy-5 - prosten-9-one, (13E) - (15R) -l- (3-carboxypropionyloxy) -15-hydroxy-lla-me- thyl-16-phenoxy-17,18,19,20-tetranor-13-prosten-9-one, (13E) - (15R) - l- (3-carboxypropionyloxy) -15-hydroxy-11 a, 16.- 16-trimethyl-13-prosten-9-one, (13E) - (15S, 16RS) -l- (3-carboxypropionyloxy) -l la, 16-dime- thyl-15-hydroxy-13-prosten-9-one, (13E) - (15R) -l-acetoxy-15-hydroxy-16-phenoxy-17,18,19,20- -tetranor-13-prosten-9-one, (5Z) - (15R, 16RS) -1 - (3-carboxypropionyloxy) - 15-hydroxy-l 6- -methyl-5-prosten-9-one, (5Z) - (15R) -1 - (3-carboxypropionyloxy) -16,16-dimethyl-15- -hydroxy-5-prosten-9-one, (13E) - (15S, 16RS) - 1-acetoxy-15-hydroxy-16-methyl-13-pro-sten-9-one, (13EH15S) -1-acetoxy-15-hydroxy-15-methyl-13-prosten-9 - one, (13E) - (15R) -l-acetoxy-15-hydroxy-l la-methyl-16-phenoxy- -17,18,19,20-tetranor-13-prosten-9-one, (13E) - (15R) -l-acetoxy-15-hydroxy-lla, 16,16-trimethyl-13 - prosten-9- on, (13E) - (15S, 16RS) -l-acetoxy-l la, 16-dimethyl-15-hydroxy- -13-prosten-9-one, (13E) - (15R) - 15-hydroxy-1-methoxyacetoxy-16-phenoxy-17, - 18,19,20-tetranor-13-prosten-9-one, (13E) - (15R) -16,16-dimethyl-15-hydroxy-1-methoxy acetoxy- -13-prosten-9-one, (13E) - (15S, 16RS) -15-hydroxy-1-methoxyacetoxy-16-methyl- -13-prosten-9-one and (13E) - (15S) -15-hydroxy-1-methoxyacetoxy-15-methyl-13 - prosten-9-one. 5. Connection according to claim 1: (15R, 16RS) -l- (3-carboxypropionyloxy) -15-hydroxy-16-methyl-prosten-9-one. (i) "THE, E. io what Rt is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms or the rest of an inorganic acid, A is a -CH2-CH2-, cis-CH = CH-, trans-CH = CH- or 15 -C = group, B is a -CH2-CH2, trans-CH = CH or -CEE C group, W is a free or etherified or esterified hydroxymethylene group, a free or ketalized carbonyl group or a free, 20 esterified or etherified CH3 -C — Group, OH 25th where the OH group can be a- or ß-permanent, D and E together are a direct bond or 30 D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C group, E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and 40 Z is a free or ketalized carbonyl group or a free or etherified or esterified hydroxymethylene group , characterized in that prostan-l-ols of the general formula II 45 50 Oh S ^ aAA / (II) 55 wherein A, B, D, E, W, Z, R2 and R3 have the meanings given above and in which free hydroxy groups, with the exception of the 1-hydroxy group, are optionally protected as intermediates, are esterified accordingly. 60 7. The method according to claim 6, characterized in that compounds obtained are separated into the epimers. 65 6. Process for the preparation of prostate derivatives of the general formula I 638773 4th 8. Process for the preparation of prostate derivatives of the formula IC (IC) wherein Rj is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms or the rest of an inorganic acid, A is a -CH2-CH2-, cis-CH = CH-, trans-CH = CH- or -CEH C group, B a -CH2-CH2-, trans-CH = CH- or -C = C group, D and E together a direct bond or D a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C- Group, E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group and W 'and Z' are carbonyl groups, characterized in that compounds of the formula I in which W and Z are hydroxymethylene groups are prepared by the process according to claim 6 and these are oxidized to carbonyl groups. 9. Process for the preparation of prostate derivatives of the formula ID E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, 5 R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and Z is a free or ketalized carbonyl group or an io free or etherified or esterified hydroxymethylene group, characterized in that compounds of the formula I in which A and / or B denote a cis-CH = CH or trans-CH = CH group are prepared by the process according to claim 6, and the double bonds in 5.6 - and / or 13,14-position hydrogenated. 10. Process for the preparation of prostate derivatives of the formula IE 20th 25th (IE) -THE- a e. ■ D-E-R, wherein Rj is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms or the residue of an anoganic acid, A 'is a -CH2-CH2 group, B 'is a -CH2-CH2 group, W is a free or etherified or esterified hydroxymethylene group, a free or ketalized carbonyl group or a free, esterified or etherified wherein 30 Rx is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms or the rest of an inorganic acid, A is a -CH2-CH2, cis-CH = CH, trans-CH = CH or -C = -C group, 35 B a -CH2-CH2-, trans-CH = CH- or -C = C group, D and E together a direct bond or D a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C -Group, E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and W 'and Z' represent a free hydroxymethylene group, characterized in that compounds of the formula in which W and 50 Z represent carbonyl groups are prepared by the process according to claim 1 and the carbonyl groups in these compounds are reduced to hydroxymethylene groups. 11. Process for the preparation of prostate derivatives of the formula 55 V \ M / Rl CH, 60 -Group, OH where the OH group can be a- or ß-permanent, D and E together are a direct bond or D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C group, (IF) THE, 65 in which Rt is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms or the rest of an inorganic acid, 5 638773 -CH2-CH2-, cis-CH = CH- , trans-CH = CH- or A is a -C = C group, B a -CH2-CH2-, trans-CH = CH- or -C = C group, D and E together a direct bond or D a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C- Group, E is an oxygen or sulfur atom or a direct bond, Rj is a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and W 'and Z' are esterified hydroxymethylene groups, characterized in that compounds of the formula I in which W and Z are hydroxymethylene groups are prepared by the process according to claim 6 and the hydroxyl groups are esterified in these compounds. 12. Process for the preparation of prostate derivatives of the formula IG wherein Rj'a U —C — N; Ri R, Group means, where U can be an oxygen or sulfur atom and R4 can be a hydrogen atom, an optionally substituted alkyl, cycloalkyl, heteroaryl or aryl radical or an acid radical, A is a -CH2-CH2-, cis-CH = CH-, trans-CH = CH- or -C = C group, B is a -CH2-CH2, trans-CH = CH or -C = C group, 15 W is a free or etherified or esterified hydroxymethylene group, a free or ketalized carbonyl group or a free, esterified or etherified 20th <X? * OR, CH, —C — group, OH 25th •THE. (IG) B_ wherein Rx is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms or the rest of an inorganic acid, A is a -CH2-CH2-, cis-CH = CH-, trans-CH = CH- or -C = group, B is a -CH2-CH2, trans-CH = CH or -C = C group, D and E together are a direct bond or D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C group, E is an oxygen or sulfur atom or a direct bond, Ra is a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and W 'and Z' represent hydroxymethylene groups, characterized in that compounds of the formula I in which W and Z are esterified hydroxymethylene groups are prepared by the process according to claim 6 and the esterified hydroxymethylene groups are saponified in these compounds. 13. Process for the preparation of prostate derivatives of the formula IA where the OH group can be a- or ß-permanent, D and E together are a direct bond or D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = -C group, 30 E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, Rs is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and Z is a free or ketalized carbonyl group or a free or etherified or esterified hydroxymethylene group-40 pe, characterized in that prostan-l-ols of the general formula II Oh 45 50 ^ n \ aA / V Bm (II) B. wherein A, B, D, E, W, Z, R2 and R3 have the meanings given above and in which free hydroxy groups, with the exception of the 1-hydroxy group, are optionally protected as intermediates, with compounds of the general formula III U = C = N - R4 (III) 6o in which U and R4 have the meanings given above. B HL (IA) • D- e. E-Bj 65 638773 6 14. Process for the preparation of prostate derivatives of the general formula IB O Cl — C — N: R. rs (IV) a, ' = "SV, H. (IB) • D-E-fi. wherein Rj "a O —C — N: R, R5 -Group OH / z ^ j >>> Nss A A / V - wherein R4 and R5 have the meanings given above. 15. Medicament, characterized in that it contains at least one active ingredient component prostate derivatives of the general formula I OR, 15 (i) 'THE- means, where R4 and R5 represent a hydrogen atom, an optionally substituted alkyl, cycloalkyl, heteroaryl or aryl radical or an acid radical or R4 and R5 together can represent a heterocyclic ring with 4-7 ring members, A is a -CH2-CH2-, cis-CH = CH-, trans-CH = CH- or -C ■ "C group, B is a -CH2-CH2, trans-CH = CH or -C = C group, W is a free or etherified or esterified hydroxymethylene group, a free or ketalized carbonyl group or a free, esterified or etherified CH3 I. —C — group, OH where the OH group can be a- or ß-permanent, D and E together are a direct bond or D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C group, E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, Ra is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and Z is a free or ketalized carbonyl group or a free or etherified or esterified hydroxymethylene group, characterized in that prostan-l-ols of the general formula II 20th 25th wherein Rj is an acyl residue of an organic acid or sulfonic acid with 1-15 C atoms, the rest of an inorganic acid or U II R * —C —— Group r5 30 means, where U can be an oxygen or sulfur atom and R4 and R5 can be a hydrogen atom, an optionally substituted alkyl, cycloalkyl, heteroaryl or aryl radical or an acid radical or R4 and R5 together can represent a heterocyclic ring with 4-7 ring members, 35 A is a -CHj-CHj, cis-CH = CH, trans-CH-CH or -C = C group, B is a -CH2-CH2, trans-CH = CH or -C = C group, W is a free or etherified or esterified hydroxymethylene group, 40 a free or ketalized carbonyl group or a free, esterified or etherified CH, 45 -C — group, I. OH (ii) > d-e-r3 where the OH group can be a- or ß-permanent, D and E together form a direct bond or so D is a straight-chain or branched alkylene group with 1-5 C atoms or a -C = C group, E is an oxygen or sulfur atom or a direct bond, R2 represents a hydrogen atom or a straight-chain or branched alkyl group with 1-5 C atoms, R3 is a saturated or unsaturated alkyl group which may be substituted by optionally substituted aryl, a cycloalkyl, an optionally substituted aryl group or a heterocyclic group, and 60 Z is a free or ketalized carbonyl group or a free or etherified or esterified hydroxymethylene group, contain. wherein A, B, D, E, W, Z, R2 and R3 have the meanings given above and in which free hydroxy groups, with the exception of the 1-hydroxy group, are optionally protected as intermediates, with carbamoyl chlorides of the general formula IV 65