DE2523676A1 - Esters of 1-hydroxy prostaglandins - with stronger, more selective and longer lasting activities - Google Patents

Abstract

Prostane derivs. of formula (I), esp. those of formula (II) are new: (P is any substd. prostane residue; R1 = residue of a 1-15C organic carboxylic or sulphonic acid, of an inorg. acid or the gp. CUNHR6; U = O or S; R6 = opt. substd. acid, aryl, cycloalkyl or alkyl gp.; R2 and R3 = H or 1-4C alkyl; A is CH2CH2 or cis or trans CH=CH; B is CH2CH2, trans CH=CH, C C or - H CH- with the CH2 in a or beta-posn., W = CHOH, CO (both opt. functionally modified) or - (CH3)-, the OH being in alpha or beta posn. and opt. functionally modified; D = opt. branched 1-5C alkylene or C C; E = O, S or direct bond; D and E can together represent a direct bond; R4 = alkyl, cycloalkyl, opt. substd. aryl, benzodioxol-2-yl or heterocyclyl; Z = CO or opt. modified CHOH; X Y = - H CH-, CH2CH(...R5) or CH2CO when Z = CHOH or is CH2CH(...R5) or CH=CH when Z = CO; R5 = alkyl or opt. modified OH). Also new are intermediates (III) when R2 and R3 are not both H; (I) are similar to natural PG's but their action is stronger, more selective and longer lasting. They are variously useful as luteolytics; for termination of pregnancy (some 100 times as active as PGF2a); to synchronise ovulation in cows etc.; as bronchodilators, gastric acid secretion inhibitors; anti-arrhythmics; antihypertensives and diuretics. They effect uterine muscle with virtually no effect on intestinal or vascular muscles.

Description

Novel prostane derivatives and processes for their preparation The invention relates to new prostane derivatives and processes for their preparation.

It is known that the physiological effects of prostaglandins are of short duration both in the mammalian organism and in vitro, since they rapidly converted to a variety of pharmacologically inactive metabolic products will. In addition, it is known that the natural prostaglandins do not per se Have biological specificity that is necessary for a drug.

It was therefore desirable to use prostaglandin analogs with one of the natural ones Prostaglandins develop comparable spectrum of activity and structural changes undertake, through which the duration and selectivity of the fluidity is increased.

It has now been found that, surprisingly, prostan-1-ol ester an outstanding specificity of action and a longer duration of action than natural ones Possess prostaglandins. The compounds according to the invention show for example a very good effect on the uterus, while the intestinal and vascular muscles practically is not affected.

The invention relates to prostane derivatives of the general formula I where P represents an arbitrarily substituted prostane radical linked via the carbon atom 1, R1 an acid radical of an organic carboxylic or sulfonic acid with 1-15 carbon atoms or an inorganic acid, R2 and R3 'hydrogen atoms or alkyl groups with 1-4 carbon atoms mean.

The prostane residue P can be substituted in any way. Preferred are prostate residues P, as found in naturally occurring and artificially produced Prostaglandins occur.

As possible functional groups or substituents of the prostane residue Examples of P are: alkyl groups with 1-4 carbon atoms in 2-, 3-, 13-, 15-, 16-, 17-, 11- and / or 15-position, aryl groups, preferably phenyl, in the 11-position, alkylene groups, preferably methylene, in 10,11- and / or 13,14-position, hydroxyl or functionally modified hydroxyl groups in the 9, 11 and / or 15 position, oxo groups in the 9-, 11- and / or 15-position, double bonds in 5,6-, 10,11-, 13,14- and / or 17,18-position, triple bonds in 13,14-, 16,17- and / or 4,5-position, ketals in the 15-position, halogen atoms in the 10-, 14-, 16- and / or 17-position.

Preferred prostane derivatives of the present invention are compounds of the general formula II where R1, R2 and R3 have the meaning given above, A is a -CH2-CH2- or cis- CH = CH- or trans-CH = CH- group, B is a -CH2-CH2- or trans-CH = CH- Group or a --C --C group or one -CII CII- group, sCg where the methylene group can be in the α or β position, W represents a free or functionally modified hydroxymethylene group, a free or functionally modified carbonyl group or a C113 -C- group, OrI where the OII group can be α or β and functionally modified, D and E together denotes a direct bond or D denotes a straight-chain or branched alkylene group of 1 to 5 carbon atoms or a -C = C group, E denotes an oxygen or sulfur atom or a direct bond, 114 an alkyl group, a cycloalkyl group, an optionally substituted aryl group, a renzodioxol-2-yl group, a heterocyclic group, Z a carbonyl or a free or functionally modified hydroxymethylene group, X ... Y for stands, where the methylene group can be α or β, for when Z represents a hydroxymethylene group or represents or -CH = CH- when Z is a carbonyl group, where the radical 11 is an alkyl or 5 is a free or functionally modified hydroxyl group.

Physiologically compatible acid residues are possible as acid residues R1, Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, those of the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocyclic series.

I) these acids can be saturated, unsaturated and / or polybasic and / or be substituted in the usual way. Examples of the substituents are Mentioned alkyl, IIyd.roxy, alkoxy, oxo or amino groups or halogen atoms.

The following carboxylic acids may be mentioned as examples: formic acid, Acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, Caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, Lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethyl acetic acid, Diethyl acetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, Cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, Mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, Morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, with Benzoic acids substituted with halogen, trifluoromethyl, hydroxy or carboxy groups, Nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. as particularly preferred acyl radicals are those with up to 10 carbon atoms.

As sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, Isopropylsulphonic acid, ß-chloroethanesulphonic acid, butanesulphonic acid, cyclopentanesulphonic acid, Cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N, N-dimethylaminosulphonic acid, N, N-diethylaminosulphonic acid, N, N-bis (ß-chloroethyl) aminosulphonic acid, N, N-diisobutylaminosulphonic acid, N, N-dibutylaminosulphonic acid, pyrrolidino-, piperidino-, Piperazino-, N-methylpiperazino- and I-lorpholinosulfonic acid in question.

There are also the common inorganic acids, such as, for example Sulfuric and phosphoric acids.

The alkyl groups 112 and R3 are straight-chain and branched-chain alkyl radicals with 1 - 4 carbon atoms such as methyl, ethyl, Propyl, isopropyl, butyl, isobutyl and tert. Butyl residue. Preferred is the methyl and ethyl group.

The hydroxyl groups R5 and in W and in Z can be functionally modified be for example by etherification or esterification, the free or modified Ilydroxygruppen in W and in Z can be cx- or ß ...

The radicals known to the person skilled in the art are used as ether and acyl radicals Consideration. Easily split off atomic residues such as tetrahydropyranyl, Tetraiiydrofuranyl, α-ethoxyethyl, trimethylsilyl, dimethyl tert. butyl-silyl- and called tri-p-benzyl-silyl radical. As acyl residues come the same as mentioned for R1 in question; Examples include acetyl, propionyl, Butyryl, benzoyl.

If W is a carbonyl group, this can be according to the one skilled in the art known methods can be functionally modified, such as, for example, by ketalization. The preparation of cyclic ketals with 1-3 carbon atoms is particularly suitable in the ring, such as with ethylene glycol, propanediol (113), 2,2-dimethylpropanediol (1,3), Cyclopentanediol (1,2) or glycerine.

As the alkyl group R4, there are straight- and branched-chain, saturated ones and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1 - 6 carbon atoms, in question, optionally substituted by optionally substituted aryl can be substituted. Examples include methyl, ethyl, propyl, Butyl, isobutyl, tert. Butyl, pentyl, IIeXyl, heptyl, octyl, butenyl, isobutenyl, Propenyl, pentenyl, benzyl and p-chlorobenzyl.

The cycloalkyl group R4 in the ring can be 4-10, preferably 5 and 6 Contain carbon atoms. The rings can be formed by alkyl groups with 1 - 4 carbon atoms be substituted.

Cyclopentyl-, cyclohexyl and methyl-cyclohexyl may be mentioned as examples and adamantyl.

Examples of substituted or unsubstituted aryl groups R4 are into consideration: phenyl, 1-naphthyl and 2-naphthyl, each of which can be substituted by 1 - 3 halogen atoms, a phenyl group, 1 - 3 alkyl groups each with 1 - 4 carbon atoms, one chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, allcoxy or hydroxy group c.

Substitution in the 3- and 4-positions on the phenyl ring is preferred for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position Hydroxy.

Lower alkyl radicals with 1 to 2 carbon atoms are used as the alkyl radical 115 Re: 3cht, preferably the methyl radical.

The heterocyclic groups R4 are 5- and 6-membered heterocycles in question, the at least 1-heteroatom, preferably nitrogen, oxygen or Contain sulfur.

Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyriclyl, 4-pyridyl et al.

The invention also relates to a process for the preparation of the new prostane derivatives of the general formula I, characterized in that compounds of the general formula III where P, R2 and R3 have the meaning given above, optionally esterified after protection of free hydroxyl groups present in the radical P and optionally then liberates protected hydroxyl groups and / or oxidizes or esterifies free hydroxyl groups and / or ketalizes or reduces free keto groups and / or hydrogenates or hydrogenates double bonds Methylene-containing and / or introducing a double bond in the 10,11-position by splitting off water and optionally separating the epimers.

Compounds of the formula IV are suitable as preferred starting materials wherein R2, R3, A, Z, X, Y, B, W, D, E and R4 have the meanings given above.

The alcohols of the general formulas III and IV are esterified in a manner known per se. In the example, the esterification takes place in that Inan an acid derivative, preferably an acid halide or acid anhydride, in the presence a base such as Na hydride, pyridine, triethylamine, tributylamine or Reacts 4 dimethylaminopyridine with an alcohol of the general formula III. the Reaction can be carried out without a solvent or in an inert Solvent, preferably acetone, acetonitrile, dimethylacetamide, DMSO at temperatures above or below below room temperature, for example between -80 ° C to 1000C, preferably at room temperature, be made.

If the starting product contains not only the 1-position OH group, but also additional ones OH groups in the prostane residue, these OII groups are according to the invention according to the invention Process also pre-esterified. If end products are ultimately desired, their additional ones If hydroxyl groups are present as free hydroxyl groups in the prostane residue, it is expedient to do so voii starting products in which these are preferably easily split off Ethereal remnants are intermediately protected. If compounds are used as the starting product, the OII groups functionally modified in the prostane residue, for example through ether formation, have, so can in the end product, after the release of the functionally modified OH groups, these are esterified, introducing various acyl groups in the end product can.

The functionally modified hydroxyl groups are released l Laughing methods. For example, the elimination of hydroxyl protective groups, such as the tetrahydropyranyl radical, in an aqueous solution of an organic Acid, such as acetic acid, propionic acid, etc. or in an aqueous solution an inorganic acid, such as hydrochloric acid or tetrabutylammonium fluoride, carried out. To improve the solubility, a water-miscible one is expediently used inert organic solvent 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 split is preferably carried out at temperatures between 20 ° C. and (> 0 OOC C.

The ketalization takes place in a manner known per se. For example is with ethylene glycol in the presence of an acidic catalyst with water separation heated. Particularly acidic catalysts are p-toluenesulfonic acid and perchloric acid suitable. The ketalization of PG-E2 derivatives is carried out under the usual conditions Splitting off water in the 10, 11-position with formation of PG-A2 derivatives.

The oxidation of hydroxyl groups present is carried out according to known Methods taken with the usual oxidizing agents. For example, the Oxidation of the 5-II-hydroxy group to the ketone with Jones reagent (J. Chem. Soc. 1953, 2555). You work with an excess of the oxidizing agent in one suitable diluents, such as acetone, at temperatures between 0 ° C and -50 ° C, preferably at -20 ° C. The reaction is generally complete after 5 to 30 minutes. The oxidation is preferably carried out after an intermediate Protection of 11- and 15-hydroxy groups, for example by silylation (Chem. Comm. (1972), 1120). The silylation is carried out, for example, with N, N, -diethyltrimethylsilylamine in acetone at -700C to + 200C, preferably at -40 ° C to 0 ° C. performed. As a further oxidizing agent silver carbonate on "Celite" or Collins reagent are suitable (Tetrahedron Letters 1968, 3363).

The regioselective oxidation of 9,11-dihydroxy compounds found in 15-position do not contain an oxidizable hydroxyl group, is according to the expert known methods.

It is preferred to use for the oxidation of the 11α-hydroxy group Jones reagent or Collins reagent, while the regioselective oxidation of the 9α-hydroxy group with Fetizon reagent (Tetrahedron 29, 2867 (1973)), silver carbonate or platinum / oxygen (Adv. In Carbohydrate Chem. 17, 169 (1962)). Oxidation with Jones reagent is at -4O0C to + 20 ° C, preferably at -300C to -10 ° C or with Collins reagent at -200C to 300C, preferably at OOC to 200C, in an anti-oxidant inert solvent carried out. Methylene chloride, chloroform, Ethylene chloride, pyridine, etc., but preferably methylene chloride, can be used.

As a solvent for the oxidation with Fetizon reagent, silver carbonate or platinum with oxygen, benzene, Toluene, xylene, ethyl acetate, Acetone, tetrahydrofuran, diethyl ether and dioxane and other inert solvents be used. The reaction temperatures are between 200C and 1100C at the Silbercarbonat- or Fetizon-Oxyda tion, preferably at the boiling point of the Solvent. In the case of oxidation with platinum / oxygen, temperatures of 200C - 500C applied.

The reduction of the 9-keto group is carried out with conventional reducing agents carried out, for example with sodium borohydride, lithium tri-tert.-butoxy-aluminum hydride, Zinc borohydride, aluminum isopropylate in the presence of an alcohol, or potassium tri-sec-butyl borohydride reduced, preferably with sodium borohydride at temperatures between -50 0C and + 50 ° C, preferably at OOC to 200C. As a solvent for this Reactions come, depending on the reducing agent used, methanol, ethanol, i-propanol, diethyl ether, dioxane, tetrahydrofuran. When reducing with sodium borohydride methanol, ethanol or isopropanol is preferably used. The emerging A- and ß-OIf-epimer mixture can be obtained in the usual way by column or layer chromatography be separated.

Should C = C double bonds contained in the primary product, if desired are reduced, the Ilydri eration takes place according to methods known per se.

The hydrogenation of the 5,6 double bond is carried out in a manner known per se at low temperatures, preferably at -20 ° C, in a hydrogen atmosphere in the presence of a Noble metal catalyst carried out as a catalyst For example, 10% palladium on carbon is suitable.

If both the 5,6 and the 13,14 double bond are hydrogenated, then one works at a higher temperature, preferably at 20 ° C., The dehydration the 9-oxo compound, in which the 11-hydroxy group and a hydrogen atom the 10-position can be split off to form a prostaglandin A derivative, under Conditions as they are general to those skilled in the art. are known to be carried out. in the generally the dehydration takes place in a solution of an organic acid, such as acetic acid, or an inorganic acid such as hydrochloric acid, at temperatures between 200C and 80 ° C. The reaction has ended after about 2 to 17 hours.

The methylenation of the 10,11 and / or 13,14 double bond takes place in the case of the 9-oxo or 15-oxo compounds by methods known to sic. For example may be mentioned the reaction with diazo hydrocarbons, if appropriate in the presence of metal salts, the reaction with Dimethylsulfoxoniummethyl t d and the implementation according to Simmoiis-Smith with zinc and methylenedihalides.

A preferred embodiment is that one of the above Compounds with diazo hydrocarbons, such as diazomethane, diazoethane, Diazopropane, preferably with diazomethane. The reaction is for example in the presence of metal salts at temperatures between 20 ° C and -100 ° C, preferably at 0 ° C, in an inert solvent, such as Diethyl ether, tetrahydrofuran, glyme, diglyme, dioxane, preferably in diethyl ether, carried out. As metal salts, copper chloride, copper acetate, palladium-II-acetate, Palladium (II) chloride, preferably palladium (II) acetate, can be used.

The epimers are separated according to those known to the person skilled in the art Methods such as column or layer chromatography or by fractional crystallization.

The preparation of compounds of the general formulas III or IV with R2 and R3 meaning hydrogen is carried out according to the usual methods, for example, by converting a corresponding prostanoic acid derivative into a primary alcohol reduced. The reduction of prostanoic acid esters with is preferred Lithium aluminum hydride.

The preparation of new compounds of the general formulas rII or IV, where R2 is an alkyl group and R3 is a hydrogen atom usually for example by reducing a prostanoic acid derivative to Aldehyde. The reduction is preferred on prostanoic acid esters with diisobutylaluminum hydride at -70 ° C to -40 ° C in an inert solvent such as toluene. The subsequent reaction of the aldehyde with alkyllithium delivers at 00C in one inert solvents, preferably in ether and tetrahydrofuran mixtures, the secondary Alcohols of the compounds of the general formulas III and IV.

The creation of new compounds of the general formulas III and IV, in which R2 and 113 are an alkyl group, is carried out according to the customary Methods, for example by reacting a prostanoic acid ester with alkyl lithium at temperatures between -100C to + 100C, preferably at 0 ° C in an inert Solvents such as ether and tetrahydrofuran mixtures with formation the tertiary alcohols of the general formulas III and IV, will be in the end product If free OII groups are desired, it is expedient before the reduction to the C1 alcohols the free hydroxyl or free oxo groups which may be present as intermediates to protect, for example by etherification or ketalization.

The invention also relates to the new starting materials of the general formula III a, in particular of the general formula IV a in which P, A, Z, X, Y, B, W, D, E and R4 have the meaning given above and R2 and R3 represent hydrogen or alkyl having 1-4 carbon atoms, but R2 and R3 cannot simultaneously represent hydrogen atoms .

The new prostane derivatives of the general formulas I and II are valuable Pharmaceuticals, as they have a much stronger and more powerful spectrum of action with a similar spectrum of action all have a much longer effect than the corresponding natural prostaglandins.

The new prostaglandin analogs of the E, D and F type are very powerful Luteolytic, i.e. to trigger a T, uteolvse you need significantly less Dosages than with the corresponding natural prostaglandins.

Much smaller amounts of the are also used to trigger abortions new prostaglandin analogues im. Compared to the natural prostaglandins required.

When registering the isotonic uterine contraction on the anesthetized The rat and the isolated rat uterus shows that the substances according to the invention are much more effective and their effects age longer than natural ones Prostaglandins.

The new prostane derivatives are suitable after a single intrauterine Application to induce menstruation or interrupt a pregnancy. It is to be regarded as a therapeutic progress that - in addition to the surprising good dissociation of anti-fertile properties - also effects on other organ systems can be almost completely prevented. They are also suitable for synchronization of the sexual cycle in female mammals such as monkeys, rabbits, cattle, pigs etc.

The good dissociation of action of the substances according to the invention is shown when examining other smooth muscle organs, such as on the guinea pig ileum or on the isolated rabbit trachea, where one is essential Less stimulation can be observed than from the natural prostaglandins.

The active ingredients of the PG E series according to the invention show on the isolated Rabbit trachea in vitro bronchodilator effects and strongly inhibit gastric acid secretion and have a regulating effect on cardiac arrhythmias. The new connections of the PG A and PG E series also lower blood pressure and have a diuretic effect.

The active compounds of the F series according to the invention have a less bronchoconstrictive effect as a natural prostaglandin F2α, what for its therapeutic use of great advantage is. For medical use, the active ingredients can be packed into a form suitable for inhalation, for oral or parenteral administration will. It is advisable to prepare aerosol or spray solutions for horses for inhalation.

For oral administration, for example, tablets, coated tablets or Suitable for capsules.

For parenteral administration, sterile, injectable, aqueous or oily solutions are used.

The invention thus also relates to medicaments based on the compounds of the general formulas I and II and the usual auxiliaries and carriers.

The active ingredients according to the invention. should be used in conjunction with the in conventional auxiliary substances known from galenics, for example for the production of Preparations for triggering an abortion, for cycle control or for induction to serve a birth. For this purpose, sterile, aqueous solutions containing 0.01 - Containing 10 mg / ml of the active compound, administered as an intravenous infusion will. To produce aqueous isotonic solutions, the compounds are de general formulas I and II are particularly suitable. To increase solubility Alcohols such as ethanol, ethylene glycol and propylene glycol can be added.

For example 1 1 (5Z, 13E) - (@ R, 9S, 11R, 12R, 15S) -1-acetoxy-prostadiene-9,11,15-triol A mixture of 550 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien-1-ol, 2.5 ml of pyridine and 1 ml of acetic anhydride were left at room temperature for 14 hours stand. It was evaporated in vacuo and 600 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien were obtained as a light yellow 01.

IR (CHCl3): 1738, 1240 / cm The 1-acetate thus obtained was stirred for 4 Hours at 50 ° C. with 15 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and purified the residue by column chromatography on silica gel. With ether / ethyl acetate (8 + 2), 290 mg of the title compound were obtained as colorless 01.

In (CEICl3): 3600, 3430 (broad), 3000, 2930, 2860, 1738, 1240, 972 / cm WIfl (CDCl3): 6: 5.3-5.6 (4tI, m); 4.06 (2H, t, J = 6.5 Hz) g 3.85-4.28 (3H, m); 8.05 (3H, s); 0.90 (3H, t, J = 7Hz) The starting material for the above compound was manufactured as follows: a) Prostaglandin F2α-9,11,15-Tris (tetrahydropyran-2-yl) ether methyl ester To a solution of 153 mg PG F2α-methyl ester in 6 ml methylene chloride 0.45 ml of dihydropyran and 2 mg of p-toluenesulfonic acid were added at 5 ° C., and the mixture was stirred for 30 minutes at 0 ° C, added to 3 ml of saturated sodium bicarbonate solution, diluted with ether, shaken the organic phase twice with water, dried over magnesium sulfate and evaporated in a vacuum. Filtration of the evaporation residue through silica gel gave with ether / hexane (1 + 1) 216 mg of the title compound as a colorless oil.

TLC (ether / hexane 7 + 3): Rf value 0.75 b) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien-1-ol It was added dropwise to a suspension of 500 mg of lithium aluminum hydride in 25 ml of ether at 10 ° C a solution of 1 g of the compound prepared according to Example 1 a) in 25 ml of ether and stirred for 1.5 hours at room temperature.

Excess lithium aluminum hydride was then destroyed by adding ethyl acetate dropwise, adding 2 ml of water, stirring for 45 minutes at room temperature, filtered and evaporated in vacuo. After filtering the residue obtained via silica gel with Hexane / ether (3 + 2) 880 mg of the title compound as a colorless oil.

111 (CIICl3): 3600, 3430 (wide), 3000, 2938, 2860, 1600, 975 / cm NTm (DMSO-d6): 6: 5.2-5.55 (4H1m); 4.45 - 4.73 (3H, m); 4.3 (1, t, J = 5Hz); 0.88 (3H, t, J = 7Hz) Example 2 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-isobutyryloxy-prostadiene-9,11,15-triol A mixture of 300 mg of that according to Example 1 b). compound prepared, 2 ml Pyridine and 0.5 ml of isobutyric acid chloride were stirred for 14 hours at room temperature under argon. The mixture was evaporated in vacuo and the crude product obtained was (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-isobutyryloxy-9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien as yellowish Cl, which is obtained without further purification with 7 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) stirred for 5 hours at 50 ° C. After evaporation and chromatography of the residue on silica gel with ether / ethyl acetate (8 + 2) 160 mg of the title compound were obtained as colorless oil.

IR (CHCl3): 3600, 3430 (broad), 2938, 2860, 1725, 1160, 973 / cm NMR (CDCl3): #: 5.23-5.56 (4H, m); 4.05 (2H, t, J = 7Hz); 3.8-4.45 (3H, m); 1.16 (6H, d, J = 7Hz), 0.90 (3H, t, J = 6.5Hz) Eg p i e 1 3 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-benzoyloxy-prostadiene-9,11,15 triol A mixture of 500 mg of the compound prepared according to Example 1 b), 2 ml of pyridine and 0.5 ml of benzoyl chloride were stirred for 14 hours at room temperature under argon. Then 5 ml of water were added, the mixture was stirred for 2 hours at room temperature, extracted three times with ether, shook the organic extract twice with saturated Sodium bicarbonate solution, twice with water, dried over magnesium sulfate and evaporated in a vacuum. 545 mg of (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-benzoyloxy-9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien were obtained as a colorless oil which was completely uniform by thin-layer chromatography.

TLC (ether / hexane 7 + 3): Rf value 0.78 The 1-benzoate obtained in this way stirred one 5 hours at 50 C with 15 m; a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and cleaned the Backlog through preparative layer chromatography on silica gel plates with ether / dioxane (7 + 3) as Solvent.

1an received 254 mg of the title compound as colorless crystals. Melting point 42 ° C.

TLC (ether / dioxane 8 + 2): Rf value 0.27 IR (CHCl3): 3600, 3420 (broad), 3000, 2938, 2860, 1710, 1600, 1278, 970 / cm NMR (CDCl3): #: 7.4-7.6 (3H, m); 7.93 - 8.09 (2H, m); 5.25-5.58 (4H, m); 4.31 (2H, t, J = 7Hz); 0.90 (3H, t, J = 7Hz) B e i s p i e l 4 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-butyryloxy-prostadiene-9.11 1 15-triol One Mixture of 300 mg of the compound prepared according to Example 1 b), 2 ml of pyridine and 0.5 ml of butyric anhydride was allowed to stand at room temperature for 14 hours.

After evaporation, the crude product obtained was (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-butyryloxy-9,11,15-tris (tetrahydropyran-2-vloxy) -prostadien as a slightly yellow oil, which can be mixed with 7 ml of a mixture of glacial acetic acid / Water / tetrahydrofuran (65/35/10) stirred at 50 ° C for 4 hours.

Obtained after evaporation and chromatography of the residue on silica gel one with ether / ethyl acetate (8 + 2) 172 mg of the title compound as a colorless oil.

IR (CtICl3): 3600, 3430 (broad), 3000, 2930, 2360, 1737, 972 / cm example 5 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-decanoyloxy-prostadiene 9,11,15-triol A mixture from 200 mg of the compound prepared according to Example 1 b), 1.4 ml of pyridine and 0.4 ml of decanoic acid chloride were allowed to stand at room temperature for 14 hours, and mixed with 0.2 ml of water, left to stand for a further 2 hours, diluted with 50 ml of water and extracted three times with 30 ml of ether each time, the organic phase was shaken one after the other with saturated Sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in the Vacuum to dryness. The thus obtained (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-decanoyloxy9,11,15-tris (Tetrahydropyran-2-yloxy) -prostadien was with 5 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10) stirred at 50 ° C. for 5 hours. After evaporation, the mixture was chromatographed Silica gel with ether / ethyl acetate (9 + 1) and received 150 mg of the title compound as colorless oil.

111 (CHCl3): 3600, 3430 (broad), 2930, 2860, 1730, 970 / cm B. e i s p i e l 6 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(methoxy) acetoxy] prostate diene-9,11,15-triol A mixture of 310 mg of the compound prepared according to Example 1 b), 2 ml of pyridine and 0.5 ml of methoxyacetic acid chloride was stirred for 13 hours at room temperature Argon.

It was evaporated in vacuo and obtained as the crude product (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (methoxy) -acetoxy-9,11,15-tris (tetrahydropyran-2-yloxy) - prostadia as a yellowish oil, which can be mixed with 7 ml of a mixture of glacial acetic acid / Water / tetrahydrofuran (65/35/10) stirred at 48 ° C for 5 hours.

Obtained after evaporation and chromatography of the residue on silica gel one with ether / ethyl acetate (7 + 3) 158 mg of the title compound as a colorless oil.

111 (CHCl3): 3600, 3435 (broad), 3000, 2930, 2865, 1740, 975 / cm example 7 (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1-acetoxy-1-methyl-prostate-9,11,15-triol A mixture of 700 mg (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1-methyl-9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien-1- oil, 3.7 ml of pyridine and 1.5 ml of acetic anhydride left nian 14 hours stand at room temperature. It was evaporated in vacuo and 770 mg of the was obtained by thin-layer chromatography uniform (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1-acetoxy-1-methyl-9,11,15-tris (tetrcahydropyrall-2-yloxy) -prostadicn as a colorless oil.

TLC (ether / hexane 7 + 3): Rf value 0.73 IR (CHCl3): 3000, 2940, 2860, 1727, 1255, 978 / cm The 1-acetate thus obtained was stirred for 14 hours at room temperature with 20 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and purified the residue by column chromatography on silica gel. With ether / ethyl acetate (8 + 2), 385 mg of the title compound were obtained as colorless 01.

TLC (ether / dioxane 8 + 2): Rf value 0.29 111 (CHCl3): 3600, 3430 (broad), 3000, 2930, 2860, 1727, 1255, 978 / cm The starting material for the above compound was prepared as follows: a) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien-1-al To a solution, cooled to -65 ° C., of 1.68 g of the solution prepared according to Example 1 a) Compound in 80 ml of toluene was added dropwise to 12 ml of a 20% solution of diisobutylaluminum hydride in toluene, stirred for 15 minutes at -65 ° C, destroyed excess Reagent by dropwise addition of isopropanol, added 6 ml of water, left on Heat 5 ° C, stirred for 1 hour, filtered off from the precipitate and the filtrate evaporated in a vacuum to dryness.

This gave 1.68 g of the title compound as a colorless oil.

TLC (ether / hexane 7 + 3): Rf value 0.68 In (CHCl3): 3000, 2942, 260, 2730, 1721, 963 / cm NMR (DMSO-d6): #: 9.63 (1H, t, J = 2Hz); 5.15 - 5.55 (4H, m); 4.38-4.73 (3H, m); 0.85 (3H, t, J = 6.5Hz) b) (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1-methyl-9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien-1-ol To a solution of 1.68 s of the example 7 a) aldehyde produced in 57 ml of ether and 57 ml of tetrahydrofuran were added 0 ° C under argon 2.84 ml of an approx.

2m solution of methyllithium in ether, stirred for 20 minutes at 0 ° C, added 50 ml of saturated ammonium chloride solution, extracted three times with ether, twice broadly shook the organic extract water, dried over magnesium sulfate and evaporated in a vacuum. This gave 1.61 g of the title compound as a colorless one 01.

-DC (ether / Ilexan 7 + 3): Rf value 0.24 IR: 3600, 3450, 3000, 2940, 2860, 978 / cm For example 1 8 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-1,1-dimethyl-prostadiene-9, ll 115-triol A solution of 980 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1,1-dimethyl-9,11,15-tris- (tetrahydropyran-2-yloxy) -prostadien- 1-ol 296 mg of 4-dimethylaminopyridine and 2,3 were added in 30 ml of methylene chloride ml of acetic anhydride and left to stand at room temperature for 4 days. After evaporation The residue was filtered in vacuo with hexane / ether (1 + 1) through silica gel and received 985 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-1,1-dimethyl-9,11,15-tris- (tetrahydropyran-2-yloxy) -prostates as a colorless oil.

TLC (ether / hexane 7 + 3): Rf value 0.75 IR (CHCl3): 3000, 2940, 2860, 1723, 1260, 978 / cm The 1-acetate thus obtained was stirred for 14 hours at 25 ° C. with 18 ml a mixture of acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and purified the residue by column chromatography on silica gel. With ether / ethyl acetate (8 + 2), 380 mg of the title compound were obtained as a colorless oil.

IR (CIIC13): 3600, -3440 (broad), 3000, 2935, 2860, 1724, 1260, 978 / cm NMR (CDCl3): #: 5.2-5.6 (4H, m); 3.8-4.3 (3H, m); 1.98 (3H, s). 1.42 (6H, s). 0.88 (3H, t, J = 7Hz) The starting material for the above compound was prepared as follows: a) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1,1-dimethyl-9,11,15-tris- (tetrahydropyran-2-yloxy) -prostadien-1 -oil To a solution of 1.47 g of the compound prepared according to Example 1 a) in 48 ml of ether and 48 ml of tetrahydrofuran were given 7 ml of a 2 molar at 0 ° C. under argon Solution of methyllithium in ether. After 20 minutes it was diluted with ether and shaken with saturated saline solution, dried with magnesium sulfate and evaporated in vacuo a. This gave 1.53 g of the title compound as a colorless oil.

TLC (ether / hexane 7 + 3): Rf value 0.31 IR (CHCl3): 3600, 3430 (broad), 3000, 2940, 2860, 978 / cm Example 9 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-15-methyl-prostadiene 9,11,15-triol A mixture of 310 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -15-methyl-9,11,15-tris (tetrahydropyran-2-yloxy) -prostates -1-ol, 2 ml of pyridine and 0.5 ml of acetic anhydride were left at room temperature for 14 hours stand. It was evaporated in vacuo and obtained as crude product (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy- 15-methyl-9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien as a yellowish oil.

IR (CHCl3): 1738, 1240, 975 / cm The 1-acetate thus obtained was stirred 14 hours at room temperature with 8 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and purified the residue by chromatography on silica gel.

With ether / ethyl acetate (8 + 2), 152 mg of the title compound were obtained as a colorless oil.

IR: 3595, 3430 (broad), 3000, 2935, 2860, 1738, 1240, 975 / cm Das Starting material for the above compound was prepared as follows: a) (15S) -15-methyl-prostaglandin F2α-9,11,15-tris (tetrahydropyran-2-yl) ether methyl ester To a solution of 160 mg (15S) -15-methyl-PG F2α-methyl ester [Journal of the American Chemical Society 96 (18), 5865 (1974)] in 6 ml of methylene chloride was added 0.5 ml of dihydropyran at 50 ° C (freshly distilled) and 2 mg of p-toluenesulfonic acid, stirred for 30 minutes at 50 ° C., were on 4 ml of saturated sodium bicarbonate solution, diluted with ether, shook the organic phase twice with water, dried over magnesium sulfate and evaporated im, Valctlurn a. After filtering the evaporation residue over Silica gel with ether / hexane (1 + 1), 210 mg of the title compound were obtained as a colorless oil.

TLC (ether / hexane 7 + 3): Rf value 0.78 IR (CDCl3): 1736, 975 / cm b) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -15-methyl- 9,11,15-Tris (tetrahydropyran-2-yloxy) -prostadien-1-ol To a suspension of 100 mg lithium aluminum hydride a solution of 0.2 g of the prepared according to Example 9 a) was added dropwise at 5 ° C. to 5 ml of ether Compound in 5 ml of ether and stirred for 2 hours at 22 ° C. Then one destroyed Excess lithium aluminum hydride by adding dropwise ethyl acetate, added 0.5 ml of water, stirred 110 minutes at room temperature, filtered and evaporated in a vacuum. After filtration of the residue through silica gel, one obtained with IIexane / ether (3 + 2) 177 mg of the title compound as colorless 01.

IR (CHCl3): 3600, 3430 (broad), 2998, 2940, 2860, 976 / cm B. e i s p i e l 10 (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1-acetoxy-16-phenoxy-17,18,19, 20-tetranor-prostadiene-9,11,15-triol A mixture of 195 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -16-phenoxy-9,11,15-tris (tetrahydropyran-2-yloxy) -17,18,19,20- tetranor-prostadien-1-ol, 1 ml of pyridine and 0.5 ml of acetic anhydride were left for 14 hours at room temperature stand. It was evaporated in vacuo and 206 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1-acetoxy-16-phenoxy-9,11,15-tris (tetrahydropyran-2 yloxy) -prostadien as colorless 01.

IR (CHCl3): 3000, 2936, 2860, 1728, 1600, 1588, 1495, 1240, 973 / cm The 1-hoetat obtained in this way was stirred for 14 hours at room temperature with 8 ml of a Mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and purified the residue by layer chromatography on silica gel plates.

With ether / dioxane (8 + 2), 72 mg of the title compound were obtained as colorless Oil.

Ifl (CHCl3): 3595, 3440, 3000, 2940, 2860, 1728, 1600, 1588, 1495, 1240, 975 / cm The starting material for the above compound was prepared as follows: a) (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -16-phenoxy-9,11,15-tris (tetrahydropyran-2-yloxy) -17,18,19,20 -tetranorprostadienoic acid methyl ester To a solution of 140 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -16-phenoxy-9,11,15-trihydroxy-17,18,19,20-tetranorprostadienoic acid methyl ester (see German Offenlegungsschriften 2.223.365 and 2.322.673) in 4.5 nil methylene chloride 0.14 ml of dihydropyran and 1.5 mg of p-toluenesulfonic acid were added at 50 ° C., and the mixture was stirred Mimiting at 5 C, added to 4 ml of saturated sodium bicarbonate solution, diluted with Ether, the organic phase shook twice with water, dried over magnesium sulfate and evaporated in a vacuum. After filtering the residue through silica gel, it was obtained one with ether / hexane (1 + 1) 205 mg of the title compound as a colorless oil.

TLC (ether / hexane 7 + 3): Rf value 0.71 b) (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -16-phenoxy-9,11,15-tris (tetrahydropyran-2-yloxy) -17,18,19,20-tetranorprostadien-1-ol To a suspension a solution of 122 mg of lithium aluminum hydride in 7 ml of ether was added dropwise at 5 ° C of 238 mg of the compound prepared according to Example to a) in 7th ml of ether and stirred for 2 hours at room temperature.

The excess reagent was then destroyed by dropping it Addition of ethyl acetate, added 0.8 ml of water, stirred for 40 minutes at room temperature, filtered and evaporated in vacuo. After filtering the residue through silica gel with ether / hexane (3 + 2) 196 ing of the title compound was obtained as colorless 01.

IR (CHCl3): 3600, 3430, 3000, 2940, 2860, 1600, 1588, 1495, 975 / cm EXAMPLE 11 Example 10 is repeated, but using (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -16- (3-trifluoro) methylphenoxy) -9,11,15-trihydroxy-17,18,19,20-tetranor-prostadienoic acid methyl ester (see German Offenlegungsschriften 2.223.365 and 2.322.673), one obtains (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1-acetoxy-16- (3-trifluoromethylphenoxy) -17.18, 19,20-tetranorprostadien-9,11,15-triol as a colorless oil.

IR (CHCl3): 3600, 3430, 3000, 2940, 2860, 1730, 1600, 1592, 1490, 1240, 975 / cm EXAMPLE 12 If one proceeds according to Example 10, but using (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -16- (4-chlorophenoxy) -9,11,15-trihydroxy-17,18,19,20-tetranor-prostadienoic acid- methyl ester (see German Offenlegungsschriften 2.223.365 and 2.322.673), one obtains (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1-acetoxy-16- (4-chlorophenoxy) -17.18, 19,20-tetranor-prostadiene-9,11,15-triol as a colorless oil.

IR (CIlCl3): 3600, 3430 (broad), 3000, 2950, 2860, 1730, 1600, 1583, 1492, 1245, 975, 872, 828 / cm Example 13 If you proceed according to Example 10, however, using (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-prostadic acid melamine (German Offenlegungsschrift 2.234.709), one obtains (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-17-phenyl-18,19,20-trinor-prostadiene-9,11 , 15-triplet as a colorless oil.

IR (CHCl3): 3600, 3400 (broad), 3000, 2960, 2860, 1732, 1600, 1230, 975 / cm 2 e i s tl i e 7. 14 Proceed according to example 10, however using (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -9,15-dihydroxy-11-methylprostadienoic acid methyl ester (see Chemistry and Industry 1973, 635), this gives (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-11-methyl-prostadiene-9,15-diol as a colorless oil.

IR (CHC13): 3600, 3430 (broad), 3000, 2950, 2360, 1725, 1260, 978 / cm B e i s p i e 1 15 The procedure described in Example 10 is followed, but using (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -16,16-dimethyl-9,11,15-trihydroxy-prostadienoic acid methyl ester (see German Offenlegungsschrift 2.221.301), one obtains (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1-acetoxy-16,16-dimethyl-prostadiene-9,11,15-triol as a colorless oil.

IR (CHCl3): 3600, 3430 (broad), 3000, 2940, 2860, 1730, 1255, 978 /cm For example 16 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy prosta dlen-9-one To a solution of 93 mS of the 1-acetate prepared according to Example 1 1.2 ml of N, N-diethyltrimethylsilylamine were added in 4 ml of absolute acetone at -450C and stirred for 6.5 hours at -400C. Then diluted with 30 ml of ether, the one had previously cooled to -700C, shaken once with 5 ml of ice-cold sodium bicarbonate solution and twice with 5 ml of saturated sodium chloride solution each time, dried with sodium sulfate and evaporated in a vacuum. The 11,15-bis (trimethylsilyl ether) obtained in this way it was dissolved in 16 ml of absolute methylene chloride and a solution was added at +5 0C of 665 mg Collins reagent (see Org.

Syntheses Vol. 52, 5), stirred for 10 minutes, diluted with 50 ml of ether, filtered and evaporated in vacuo. For splitting off the silyl ether protective groups the residue was stirred with a mixture of 9 ml of methanol, 0.9 ml of water and 0.45 ml of glacial acetic acid for 45 minutes at room temperature. Then you dilute with 60 ml ether, shaken with 10 rA sodium bicarbonate solution, twice with 10 ml each saturated Sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. After purification by preparative layer chromatography (ether / dioxane 9 + 1 as eluent) 55 mg of the were obtained on silica gel plates Title compound as colorless Oil.

TLC (ether / dioxane 9 + 1): Rf value 0.35 III (CHCl3): 3600, 3400 (broad), 2993, 2960, 2930, 2860, 1738, 1730, 1602, 973 / cm NMR (CDCl3): #: 5.50-5.68 (2H, m); 5.22-5.44 (2H, m); 4.03 (2H, t, J = 7Hz); 3.93-4.18 (1H, m); 3.62 - 3.82 (1H, m); 2.05 (3H, s); 0.90 (3H, t, J = 7Hz) Example 1 17 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-isobutyryloxy-11,15-dihydroxyprostadien-9-one In analogy to Example 16, the 1-isobutyrate prepared according to Example 2 is obtained the title compound as colorless 01.

IR (CHCl3): 3600, 3430 (broad), 2998, 2938, 2860, 1740, 1725, 1160, 975 / cm B e i 5 n i e 1 18 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-benzoyloxy-11,15-dihydroxyprostadien-9-one In analogy to Example 16, the 1-benzoate prepared according to Example 3 is obtained the title compound as a colorless oil.

IR (CHCl3): 3600, 3425 (broad), 3000, 2940, 2860, 1740, 1712, 1600, 1278, 973 / cm Example 1 19 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-decanoyloxy-11,15-dihydroxyprostadien-9-one In analogy to Example 16, the 1-decanoate prepared according to Example 5 is obtained the title compound as a colorless oil.

IR (CHCl3): 3600, 3430 (broad), 3000, 2930, 2860, 1738, 1730, 970 / cm Example 1 20 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-butyryloxy-11,15-dihydroxyprostadien-9-one In analogy to Example 16, the 1-butyrate prepared according to Example 4 is obtained the title compound as a colorless oil.

IR (CHCl3); 3600, 3430 (wide), 3000, 2930, 2860, 1738 (wide), 974 /cm For example 1 21 (5Z, 13E) - (8R, 11R, 12R, 15S) -1 - [(methoxy) acetoxy] -11,15-dihydroxy-pro stadien- 9- on In analogy to Example 16, the prepared according to Example 6 is obtained 1-methoxyacetate the title compound as colorless 01.

IR (CHCl3): 3600, 3440 (broad), 3000, 2933, 2865, 1740 (broad), 975 / cm Example 1 22 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy-1-methyl-prostadien-9-one In analogy to Example 16, the 1-methyl-1-acetate prepared according to Example 7 is obtained the title compound as colorless 01.

IR (CHCl3): 3600, 3430 (broad), 3000, 2930, 2860, 1738, 1727, 1255, 973 / cm Example 1 23 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy-1,1-dimethyl-prostadiene- 9-on In analogy to example 16, one obtains from the according to B-example 8 manufactured 1,1-Dimethyl-1-acetate the title compound as colorless Ol-In (CTICl3): 3595, 3410 (broad), 2960, 2930, 2860, 1738, 1720, 1600, 1265, 970 / cm Example 1 24 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy -15-methyl-prostadien-9-one In analogy to Example 16, the 1-acetate prepared according to Example 9 is obtained the title compound as a colorless oil.

In (CIICl3): 3600, 3430 (broad), 2930, 2860, 1733 (broad), 1245, 975 / cm Example 25 (5Z, 13E) - (8R, 11R, 12R, 15R) -1-acetoxy-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prostadien-9-one In analogy to Example 16, the 1-acetate prepared according to Example 10 is obtained the title compound as colorless 01.

IR (CHCl3): 3600, 3440 (broad), 2940, 2860, 1-738, 1728, 1600, 1588, 1495, 1240, 975 - / cm B e 1 is) ie 1 2G (5Z, 13E) - (8R, 11R, 12R, 15R) -1-acetoxy-11,15-dihydroxy-16- (3-trifluoromethylphenoxy) -17,18,19,20- tetranor prostadia 9-one In analogy to Example 16, the one prepared according to Example 11 is obtained l-acetate the title compound as colorless 01.

IR (CHCl3): 3600, 3430 (broad), 3000, 2940, 2860, 1738, 1730, 1600, 1595, 1490, 1240, 975 / cm Example 1 27 (5Z, 13E) - (8R, 11R, 12R, 15R) -1-acetoxy-11.15-dihydroxy-16- (4-chlorophenoxy) -17.18 , 19,20-tetranor-prostadien-9-one In analogy to Example 16, the 1-acetate prepared according to Example 12 is obtained the title compound as a colorless oil.

IR (CHCl3): 3600, 3430 (broad), 3000, 2945, 2860, 1738, 1730, 1600, 1583, 1492, 1245, 976, 875, 830 / cm For 5 pie 1 28 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy-17-phenyl-18 , 19,20-trinor-prestadien-9-one In analogy to Example 16, the 1-acetate prepared according to Example 13 is obtained the title compound as an unbranded oil.

IR (CHCl3): 3600, 3400, (broad), 3000, 2960, 2860, 1738, 1731, 1600, 1250, 975 / cm Example 29 (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-15-hydroxy-11-methylprostadien-9-one In analogy to Example 16, the 1-acetate prepared according to Example 14 is obtained the title compound as a colorless oil.

IR (CHCl3): 3600, 3430 (broad), 3000, 2950, 2860, 1738, 1725, 1260, 978 / cm 13 e i s p i e 1 30 (5Z, 13E) - (8R, 11R, 12R, 15R) -1-acetoxy-11,15-dihydroxy-16,16-dimethyl-prostadien-9-one In analogy to Example 16, 1-acetate prepared according to Example 15 is obtained from the 1-acetate the title compound as a colorless oil.

IR (CHCl3): 3600, 3420 (broad), 2940, 2860, 1738, 1730, 1255, 975 /cm For example 31 (5Z, 13E) - (8R, 12S, 15S) -1-acetoxy-15-hydroxy-prosta-5,10,13-tricn-9-one A mixture of 100 mg of the acetate prepared according to Example 16 was stirred with 8 ril of a 90% strength aqueous acetic acid for 14 hours at 60.degree. Then steamed one in vacuo and the residue was purified by preparative layer chromatography (Ether) on silica gel plates. 63 mg of the title compound were obtained as colorless 01.

IR (CHCl3): 3600, 3460 (broad), 3000, 2960, 2935, 2860, 1735, 1702, 1240.970 / cm NMR (DCl3): #: 7.45 (1H, dd, J = 6 + 2.5Hz); 6.13 (1H, dd, J = 6 + 2Hz); 4.08 (2H, t, J = 6.5Hz); 8.05 (3H, s); 0.90 (3H, t, J = 6.5Hz) Eg sp ie 1 32 (5Z, 13E) - (8R, 12S, 15S) -1-acetoxy-15-hydroxy-15-methyl-prosta-5, 10.13-triene-9-one A mixture of 95 mg of the 1-acetate prepared according to Example 24 was stirred with 8 ml of a 90% strength aqueous acetic acid for 16 hours at 60.degree. Then steamed one in a vacuum and purified the residue by preparative layer chromatography (Ether) on silica gel plates. This gave 60 mg of the title compound as colorless Oil.

IR (CHCl3): 3600, 3450 (broad), 3000, 2960, 2935, 2860, 1735, 1702, 1240, 974 / an example of 33 (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1,9,11,15-tetraacetoxy-1-methyl-prostadiene A mixture of 530 mg (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1-methyl-9,11,15-tris (tetrahydropyran-2-yloxy) -prostadien-1-ol (For preparation see Example 7b) and 20 ml of acetic acid-water-tetrahydrofuran mixture (65/35/10) was stirred for 14 hours at room temperature under argon. Then steamed Inan in vacuo and the residue was purified by chromatography over silica gel. With ether / isopropanol (9 + 1) 210 mg (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1,9,11,15-tetrahydroxy-1-methyl-prostadiene were obtained as a colorless oil.

TLC (ether / dioxane 7 + 3): 0.21 The tetrol produced in this way was left for 14 hours with a mixture of 0.2 ml of acetic anhydride and 0.8 ml Pyridine stand at room temperature. After evaporation, the tetra-acetate was purified by filtration through silica gel. With ether / hexane (8 + 2), 280 mg of the title compound were obtained as colorless 01.

In (CIIC13): 3000, 2960, 2935, 2860, 1735, 1240, 975 / cm

Claims (1)

P atent claims 1.) Prostane derivatives of the general formula I where P is an arbitrarily substituted prostane radical linked via the carbon atom 1, R1 is an acid radical of an organic carboxylic or sulfonic acid with 1-15 carbon atoms or an inorganic acid, R2 and R3 represent hydrogen atoms or alkyl groups with 1-4 carbon atoms . 2.) Prostane derivatives of the general formula II where R1, R2 and R3 have the meaning given above, A is a -CH2-CH2- or cis- CH = CH- or trans-CH = CH- group, B is a -CH2-CH2- or trans-CH = CH- Group or a -C - C group or one -CII CH-Gru e 2 where the methylene group can be in the α or β position, W represents a free or functionally modified hydroxymethylene group, a free or functionally modified carbonyl group or a CII -C- group, OXI where the OII group can be α- or β-position and functionally modified, D and E together denotes a direct bond or D denotes a straight-chain or branched alkylene group with 1-5 carbon atoms or a -CC- group, E is an oxygen or sulfur atom or a direct bond, R4 is an alkyl group, a cycloalkyl group, an optionally substituted aryl group, a benzodioxol-2-yl group, a heterocyclic group, Z is a carbonyl or a free or functionally modified hydroxymethylene group, X ... Y for stands, where the methylene group can be α or β, for when Z represents a hydroxymethylene group or represents or -CH = CII- when Z is a carbonyl group, where the radical R5 is an alkyl or a free or functionally modified hydroxyl group. 3.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-prostadiene-9,11,15-triol 4.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-isobutyryloxy-prostadiene 9.11 1 1 5-triol 5.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-benzoyloxy-prostadiene-9.11.15 -triol 6.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-butyryloxy-prostadiene-9,11,15-triol 7.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-decanoyloxy-prostadiene-9,11,15 triol 8.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(methoxy) -acetoxy] - Prostadiene-9,11,15-triol 9.) (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1-acetoxy-1-methyl-prostadiene-9,11,15-triol 10 .) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-1,1-dimethyl-prostadiene-9,11,15-triol 11.) (5Z, 13E) - (8R , 9S, 11R, 12R, 15S) -1-acetoxy-15-methyl-prostadiene-9,11,15-triol 12.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- Acetoxy-16-phenoxy-17,18,19, 20-tetranor-prostadien-9,11,15-triol 13.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1-acetoxy- 16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-prostadiene-9,11,15-triol 14.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- Acetoxy-16- (4-chlorophenoxy) 17,18,19,20-tetranor-prostadiene-9, 11,15-triol 15.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-17-phenyl-18,19,20-trinor-prostadiene-9,11,25- triol 16.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1-acetoxy-11-methyl-prostadiene-9,15-diol 17.) (5Z, 13E) - (8R, 9S , 11R, 12R, 15R) -1-acetoxy-16,16-dimethylprostadien-9,11,15-triol 18.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11, 15-dihydroxy-prostadien-9-one 19.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-isobutyryloxy-11,15-dihydroxyprostadien-9-one 20.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-Benzoyloxy-11,15-dihydroxyprostadien-9-one 21.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-decanoyloxy-11,15- dihydroxyprostadien-9-one 22.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-butyryloxy-1,15-dihydroxyprostadien-9-one 23.) (5Z, 13E) - (8R, 11R , 12R, 15S) -1 - [(methoxy) acetoxy] -11,15-dihydroxy-prostadien-9-one 24.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy- 11,15-dihydroxy-1-methyl-prostadien-9-one 25.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy-1,1-dimethyl- prostadien-9-one 26.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy-15-methyl-prostadien-9-one 27.) (5Z, 13E ) - (8R, 11R, 1 2R, 15R) -1-acetoxy-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prostadien-9-one 28.) (5Z, 13E) - (8R, 11R, 12R, 15R) -1-acetoxy-11,15-dihydroxy-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-prostadien-9-one 29.) (5Z, 13E) - (8R, 11R, 12R, 15R) -1-acetoxy-11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20-tetranor-prostadien-9-one 30.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-11,15-dihydroxy-17-phenyl-18,19,20-trinor-prostadien-9-one 31.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1-acetoxy-15-hydroxy-11-methylprostadien-9-one 32.) (5Z, 13E) - (8R, 11R, 12R, 15R) -1-acetoxy-11,15-dihydroxy-16,16 -dimethyl-prostadien-9-one 33.) (5Z, 13E) - (8R, 12S, 15S) -1-acetoxy-15-hydroxy-prosta-5,10,13-trien-9-one 34.) ( 5Z, 13E) - (8R, 12S, 15S) -1-acetoxy-15-hydroxy-15-methyl-prosta-5,10,13-trien-9-one 35.) (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1,9,11,15-tetraacetoxy-1-methyl-prostadiene 36.) Compounds of the general formula III a where P is an arbitrarily substituted prostane radical linked via the carbon atom 1 and R2 and R3 denote hydrogen or alkyl with 1-4 carbon atoms, but R2 and R3 cannot denote hydrogen atoms at the same time. 37.) Compounds of the general formula IV a in which A, Z, X, Y, B, W, D, E and R4 have the meaning given above and R2 and R3 represent hydrogen or alkyl having 1-4 carbon atoms, but R2 and R3 cannot simultaneously represent hydrogen atoms. 38.) (5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1-methyl-9,11,15-tris- (tetrahydropyran-2-yloxy) -prostadien-1-ol 39. ) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1,1-dimethyl-9,11,15-tris- (tetrahydropyran-2-yloxy) -prostadien-1-ol 40.) ( 5Z, 13E) - (1RS, 8R, 9S, 11R, 12R, 15S) -1,9,11,15-tetrahydroxy-1-ethyl-prostadiene 41.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1,1-dimethyl-1,9,11,15-tetrahydroxy-prostadiene 42.) Process for the preparation of the new prostane derivatives of the general formula I, characterized in that compounds of the general formula I are used in a manner known per se III where P represents an arbitrarily substituted prostane radical linked via the carbon atom 1 and R2 and R3 represent hydrogen or alkyl with 1 - 4 carbon atoms, optionally esterified after protection of free hydroxyl groups present in the radical P and optionally subsequently releases protected hydroxyl groups and (l / or free hydroxyl groups oxidized or esterified and / or free keto groups ketalized or reduced and / or double bonds hydrogenated or methylenated and / or introduces a double bond by splitting off water in the 10,11-position and optionally separating the epimers. 43.) Process for the preparation of the new prostane derivatives of the general formula II, characterized in that in per se known quiet compounds of the formula IV in which A, -Z, X, Y, 2, W, D, E and R4 have the meanings given above and R2 and R3 are hydrogen or alkyl with 1-4 carbon atoms, optionally esterified in the P radical after protection of any free hydroxyl groups that may be formed and, if appropriate, subsequently releasing protected hydroxyl groups and / or oxidizing or esterifying free hydroxyl groups and / or ketalizing or reducing free keto groups and / or hydrogenating or methylenating double bonds and / or introducing a double bond by splitting off water in the 10, 11 position and optionally separating the epimers. 44.) Medicines based on the compounds of the general formula 1. 45.) Medicinal products based on the compounds of the general formula II.