DE2616304A1 - 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

New prostanoic acid derivatives and

Process for their creation In the main patent .............................. (patent application P 25 23 676.4) prostane derivatives of the general formula I are described 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 denote hydrogen atoms or alkyl groups with 1-4 carbon atoms .

These compounds surprisingly show an excellent specificity of action and a longer duration of action as natural prostaglandins. So For example, if the uterotrophic effect is very good, there will be no stimulation of the intestinal and gastrointestinal tract Vascular muscles caused.

In further development of the main patent ............................

(Patent application P 25 23 676.4) it has now been found that compounds of the general formula Ia in which R1 is a represents, have at least as good selective effects.

The present invention accordingly relates to prostane derivatives of the general formula Ia where R1 is a denotes, where U represents an oxygen or sulfur atom and R6 represents an optionally substituted alkyl, cycloalkyl or aryl radical or an acid radical, and according to the main patent .................... ....

(Patent application P 25 23 676.4) P one linked via the C atom-1 represents any substituted prostane radical and R2 and R3 hydrogen atoms or alkyl groups with 1 to 4 carbon atoms.

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 17-position, alkylene groups, preferably methylene, in the 10,11- and / or 13,14-position, hydroxyl or functional modified hydroxyl groups in 9-, 11- and / or 15-position, oxo groups in 9-, 11- and / or 15-position, double bonds in 5,6-, 10,11-, 13,14- and / or 17,18-position, Triple bonds in the 13.14, 16.17 and / or 4.5 positions, 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 IIa wherein R11, 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 one or one 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 where the OH group can be α or β and functionally modified, D and E together denotes a direct bond or D a straight-chain or branched alkylene group with 1-5 carbon atoms or a 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, stands, where the ethylene group can be α or ß position, for stands when Z is a hydroxymethylene group or or -CH = CH- if Z is a carbonyl group, where the radical R5 is an alkyl or a free or functionally modified hydroxyl group a substituted carbamoyl or thiocarbamoyl radical should be understood. The carbamic acid or thiocarbamic acid can be substituted on the nitrogen atom by an alkyl, cycloalkyl, aryl or acid radical.

As alkyl groups It6 are straight or branched alkyl groups 1 - 10 carbon atoms to be considered, such as methyl, ethyl, propyl, isobutyl, Butyl, pentyl, heptyl, hexyl, decyl.

The Alkylgruppen.R6 can optionally be substituted one to several times be by halogen atoms, alkoxy groups, optionally substituted aryl groups, Dialkylamines and trialkylammonium.

Examples of substituents that may be mentioned are fluorine, chlorine or Bromine atoms, phenyl, dimethylamine, diethylamine, methoxy, ethoxy.

Preferred alkyl groups R6 are methyl, ethyl, propyl, isobutyl, Mention butyl, trichloromethyl, trifluoromethyl.

Cycloalkyl groups R6 are radicals with 4-8 carbon atoms, such as, for example Cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl.

Both substituted and unsubstituted groups can be used as aryl groups Aryl groups and heteroaryl groups such as phenyl, 1-naphthyl and 2-naphthyl, each of which may be substituted by. 1 - 3 halogen atoms, a phenyl group, 1 - 3 alkyl groups each with 1 - 4 carbon atoms, a chloromethyl, Fluoromethyl, trifluoromethyl or alkoxy group and thienyl, furyl, pyridyl. Preferred is the substitution in the 3- and 4-position on the phenyl ring, for example by fluorine, chlorine, Alkoxy or trifluoromethyl.

Organic carboxylic acids and sulfonic acids come along as acid residues 1 - 15 carbon atoms in question, those of the aliphatic, aromatic, aromatic-aliphatic, belong to cyclo-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. as Examples of substituents are alkyl, hydroxy, alkoxy-1 oxo or amino groups or halogen atoms mentioned.

The following carboxylic acids may be mentioned as examples: acetic acid, propionic acid, Butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, Caprylic acid, trimethyl acetic acid, diethyl acetic acid, tert.-butyl acetic acid, cyclopentyl acetic acid, Cyclohexylacetic acid, phenoxyacetic acid, phenoxyacetic acid, methoxyacetic acid, ono-, Di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, Morpholinoacetic acid, benzoic acid, with halogen, trifluoromethyl, alkoxy-1 hydroxy benzoic acids, furan-2-carboxylic acid, cyclopentylpropionic acid, substituted by carboxy groups. Particularly preferred acyl radicals are those with up to 6 carbon atoms considered.

As sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, Isopropylsulphonic acid, ß-chloroethanesulphonic acid 1 butanesulphonic acid, cyclopentanesulphonic acid, Cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid 1 p-methoxy-benzenesulphonic acid, N, N-dimethylaminosulphonic acid, N, N-diethylaminosulphonic acid, N, N-bis (ß-chloroethyl) -aminosulfonic acid, N, N-diisobutylaminosulfonic acid, N, N-dibutylaminosulfonic acid, Pyrrolidino, piperidino, piperazino, N-methylpiperazino, thiopheno and morpholino sulfonic acids in question.

The alkyl groups R2 and R are straight-chain and branched-chain .3 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 25 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 a- or ß-position.

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, Tetrahydrofuranyl, er-ethoxyethyl, trimethylsilyl, dimethyl tert.

butyl-silyl and tri-p-benzyl-silyl radicals as acyl radicals come the same as mentioned for R1 in question; may be mentioned by name, for example 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, 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 (1,3), 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, hexyl, heptyl, octyl, butenyl, isobutenyl, Propenyl, pentenyl, benzyl and p-chlorobenzyl.

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

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

Lower alkyl radicals with 1 - 2 5 carbon atoms can be used as the alkyl radical R Consider, 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-F4ryl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl et al.

The invention relates to the modification of the process according to the main patent ................ (patent application P 25 23 676.4) for the preparation of the new prostane derivatives of the general formula Ia from compounds of the general formula III wherein P, R2 and R have the meaning given above, and 5 free hydroxyl groups are optionally protected intermediately, characterized in that compounds of the general formula III with compounds of the general formula VU = C = N - R6 V, in which U and R6 are the The meaning given above has converted 1 and, if appropriate, subsequently releases protected hydroxyl groups and / or oxidizes or esterifies free hydroxyl groups and / or ketalizes or reduces free keto groups and / or hydrogenates or methylenates double bonds and / or introduces a double bond by splitting off water in the 10,11-position and, if necessary separates the epimers.

Compounds of the formula IV are suitable as preferred starting materials in which 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 reacted in modification of the process according to the main patent .................... (patent application P 25 23 676.4) in a manner known per se. For example you can have an alcohol the general formulas III or IV with an isocyanate or thioisocyanate of the general Formula V U = C = N - R6 V, in which U and R6 have the meaning given above, optionally with the addition of a tertiary amine, such as triethylamine or pyridine for Bring reaction. The reaction can be carried out without a 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 1000C, preferably at 0-300C.

In addition to the 1-unit 011 group, the output module also contains additional OII groups in the prostane residue, then these OH groups according to the invention Process also brought to reaction. If end products are ultimately desired, their additional Ilydroxylgruppen are present in the prostane residue as free hydroxyl groups, one expediently starts from starting products in which these preferably go through easily split off ether residues are intermediately protected. Are used as a starting product Compounds used that contain functionally modified OH groups in the prostane residue, for example through ether formation, have1 so can in the end product, after release of the functionally modified OEI groups, these are esterified, whereby one different Can introduce acyl groups in the final product.

The functionally modified hydroxyl groups are released according to known 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 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 200C and 300C.

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 oxidation of hydroxyl groups present is carried out according to known Methods made with the usual oxidizing agents. For example, the Oxidation of the 9-II-hydroxy group to the ketone with Jones reagent (J. Chem. Soc. 1953, 2555). One works with an excess of the oxidizing agent in a suitable one Diluents such as acetone at temperatures between OOC and -50 ° C, preferably at -200C, the Realction is generally over after 5 to 30 minutes. Preferably the oxidation takes place after the intermediate Protection of the 11- and 15-Ilydroxygruppe, for example by silylation (Chem. Comm. (1972), 1120). The silylation will for example with N, N-diethyltrimethylsilylamine in acetone at -700C to + 20 ° C, preferably at 4000 C to OOC. As further oxidizing agents are Silver carbonate suitable for "Celite" or Collins reagent (Tetrahedron Letters 1968, 3363).

The regioselective oxidation of 9,11-dihydroxy compounds which contain no oxidizable hydroxyl group in the 15-position, according to the expert known methods.

Jones reagent is preferably used to oxidize the 11a-hydroxy group or Collins reagent, during the regioselective oxidation of the 9a-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 -400C to + 200C, preferably at -30 ° C to -100C or with Collins reagent at -20 ° C to 300C, preferably at 0OC to 200C, in one against the oxidizing agent 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, Toluene1 xylene, ethyl acetate, Acetone1 tetrahydrofuran, diethyl ether and dioxane and other inert solvents be used. The reaction temperatures are between 200C and 11000 at the Silver carbonate or fetizone oxidation, preferably at the boiling point of the Solvent. During the oxidation with platinum / oxygen temperatures of preferably 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 ° C and 0 0 +50001 preferably at 0 0 to 20 0 carried out. As a solvent Depending on the reducing agent used, methanol can be used for this reaction, Ethanol, i-propanol, diethyl ether, dioxane, tetrahydrofuran. When reducing with Sodium borohydride is preferably used with methanol, ethanol or isopropanol. The resulting a- and ß-OH epimer mixture can in the usual way by column or layer chromatography.

Should C = C double bonds contained in the primary product, if desired are reduced, the hydrogenation is carried out by 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 200C.

The dehydration of the 9-oxo compound in which the 11-II-hydroxy group and a hydrogen atom is split off from the 10-position to form a prostaglandin A derivative, can be carried out under conditions that are generally known to the person skilled in the art will. In general, 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 000C. 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 per se. For example may be mentioned the reaction with diazo hydrocarbons, if appropriate in the presence of metal salts, the reaction with Dimethylsulfoxoniummethylid and the implementation according to Simmons-Smith with zinc and methylene dihalides.

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 200C and -10000C, preferably at OOC, in an inert solvent such as Diethyl ether; Tetrallydrofuran, 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 the methods known to the person skilled in the art, such as by column or layer chromatography or by fractionated Crystallization.

The preparation of compounds of the general formulas III or IV with fl2 and R3 meaning hydrogen is carried out according to the usual methods, for example, by converting a corresponding prostanoic acid derivative into a primary one Alcohol reduced. The reduction of prostanoic acid esters with lithium aluminum hydride is preferred.

The preparation of new compounds of the general formulas III or IV, in which R2 is an alkyl group and a hydrogen atom, is usually carried out for example by reducing a prostanoic acid derivative to the Aldehyde. The reduction is preferred on prostanoic acid esters with diisobutylaluminum hydride at -700C to -40 ° C in an inert solvent such as toluene, performed. The subsequent reaction of the aldehyde with alkyllithium provides OOC in an inert solvent, preferably in ether and tetrahydrofuran mixtures, the secondary alcohols of the compounds of the general formulas III and IV.

The preparation of new compounds of the general formulas III and IV, in which R2 and R3 are an alkyl group, is carried out according to the usual methods, for example by reacting a prostanoic acid ester with alkyl lithium at temperatures between -100C to + 100C, preferably at OOC in an inert solvent such as for example, ether and tetrahydrofuran mixtures with the formation of the tertiary Alcohols of the general formulas III and IV.

If free OII groups are desired in the end product, it is advisable to before the reduction to the C1 alcohols any free hydroxyl or to protect free oxo groups intermediately, for example by etherification or ketalization.

With the aid of the method according to the invention, for example also make the following compounds: (5Z, 13E) - (8R, 9S, 11R, 15S) -1- (N-acetylcarbamoyloxy) -5.13 prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-acetylcarbamoyloxy) -11,15-dihydroxy-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S) -1- (N-acetylcarbamoyloxy) -15-hydroxy-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-5,13-prostadien-9-one (5Z, 13E) - (aR, 12S, 15S) -1- (N-phenylcarballloyloxy) -15-hydroxy-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methyl-thiocarbamoyl-oxy) -5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methyl-thiocarbamayloxy) -11,15-dihydroxy-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy 5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-methyl-5, 1 3-prostadien-9, 11, 15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-15-methyl-5,13- prostadien-9-on (5Z, 13E) - (8R, 12S, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-15-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-methylcarbamoyloxy) -16-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S, 16RS) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S, 16RS) -1- (N-methylcarbamoyloxy) -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-16, 1 6-diethyl-5, 1 3-prostadien-9-one (5Z, 13E) - (t3R, 12S, 15R) -l- (N-methylcarbamoyloxy) -15-hydroxy-16, 1 6-dimethyl-5, 10, 1 3-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16-phenoxy-17.18 , 19-tetranor-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene- 9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-Metylcarbamoyloxy) -11,15-dihydroxy-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-5, 1 3-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16- (4-chlorophenoxy) -17,18,19,20-tetranor -5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-Metylcarbamoyloxy) -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20-tetranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -17-phenyl-18,19,20-trinor-5,13-prostadiene-9,11,15- triplet (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-Metylcarbamoyloxy) -11,15-dihydroxy- 1 7-phenyl- 18, 1 9, 20-trinor-5, 1 3-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-1 1-methyl-51 1 3-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methylcarbamoyloxy) -carbamayloxy] -15-methyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-15-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -15-hydroxy-15-methyl-5,10,13-prostatrien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16-methyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15S, 16RS) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -16,16-dimethyl-11,15-dihydroxy-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15R) -1 - [(N-methanesulfonyl) -carbamyloxy] -15-hydroxy-16,16, -dimethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5, 13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (3-trifluoromethylphenoxy) 17,181 191 20-tetranor-5, 1 3-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11, 15-dihydroxy-16- (3-trifluoromethylphenyl) -17,18,19,20-tetranor-5, 1 3-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (4-chlorophenol) -17.18, 19,20-tetranor-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20- tetranor-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (3-chlorophenoxy) -17,18,19,20-tetranor-5, 13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16- (3-chlorophenoxy) -17,18,19,20- tetranor-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (4-fluorophenoxy) -17,18,19,20-tetranor-5, 13-prostadione-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16- (4-fluorophenoxy) -17,18,19,20- tetranor-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -17-phenyl-18,19,20-trinor-5,13-prostadiene-9, 11.15-triplet (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11,15-dihydroxy-17-phenyl-18,19,20-trinor-5,13- prostadien-9-on (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dimethyl-15-hydroxy-5,13-prostadien-9-one (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -15-hydroxy-11-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-acetyl-carbamoyloxy] -15-methyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-acetylcarbamoyloxy) -11,15-dihydroxy-15-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15S) -1 - [(N-acetylcarbamoyloxy) -15-hydroxy-15-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-acetyl-carbamoyloxy) -16-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S, 16RS) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12R, 15S, 16RS) -1- (N-acetyl-carbamoyloxy) -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15R) -1- (N-acetyl-carbamoyloxy) -15-hydroxy-16,16-dimethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -16-pheoxy-17,18,19,20-tetranor-5,13-prostadiene-9, 11.15-triplet (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13- prostadien-9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor, 5,13- prostadiene 9,11,15 triol (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -11.15 dihydroxy-16- (-I; ri £ luoreletlzylphelloxy - 17, 18, 19, 20-tetranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -16- (4-chlorophenoxy) -17,18,19,20-tetranor-5,13- prostadiene 9,11,15 triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20-tetranor- 5.13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -17-phenyl-18,19,20-trinor-5,13-prostadiene-9,11, 15-triplet (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-17-phenyl-18,19,20-trinor-5,13- prostadien-9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -15-hydroxy-11-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -15-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-1 5-methyl-5, 1 3-prostadien-9-one (5Z 1 3E) - (811, 125, 155) -1 - (N-phenylcarbamoyloxy) -1 5-hydroxy-15-methyl-5,10,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-phenyl-carbamoyloxy) -16-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S, 16RS) -1- (N-phenylcarbamoyloxy) -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15R) -1- (N-phenylcarbamoyloxy) -15-hydroxy-16,16-dimethyl-5,10,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16-phenoxy-17,18,19,20, tetranor-5,13-prostadiene-9,11, 15, triplet (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene- 9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16- (3-trifluoromethyslphenoxy) -17,18,19,20-teranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16- (4-chlorophenoxy) -17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20-tetranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-17, phenyl-18,19,20-trinor-5,13-prostadiene-9- on (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -17-phenyl-18,19,20-trinor-5,13-prostadiene-9,11,15- triplet (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -15-hydroxy-11-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methyl-thiocarbamoyloxy) -15-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methyl-thiocarbamoyloxy) -11,15-dihydroxy-15-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy-15-methyl-5,10,13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S, 16RS) -1- (N-methyl-thiocarbamoyloxy) -11.1 5-dihydroxy-1 6-methyl-5, 1 3-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S, 16RS) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy-16 -tethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methyl-thiocarbamoyloxy) -11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15R) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy-16,16-dimethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methyl-thiocarbamoyloxy) -16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene-9, 11.15-triplet (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methyl-thiocarbamoyloxy) -16-phenoxy-11,15-dihydroxy-17,18,19,20-tertanor-5,13- prostadien-9-on (13E) - (8R, 12S, 15S, 16RS) -1- (N-methylcarbamoyloxy) -15-hydroxy-16-methyl-10,13-prostadien-9-one (8R, 12S, 15S, 16RS) -1- (N-methylcarbamoyloxy) -15-hydroxy-16-methyl-10-prosten-9-one (1 3E) - (811, S, 15S, 16RS) -1- / tN-methanesulfonyl) -carbamoyloxy7-15-hydroxy-16-methyl-10, 13-prostadien-9-one (8R, 12S, 15S, 16RS) -1 - [(N-methylsulfonyl) -carbamoyloxy] -15-hydroxy-16-methyl-10-prosten-9-one (13E) - (8R, 12S, 15S, 16RS) -1- (N-acetylcarbamoyloxy) -15-hydroxy-16-methyl-10,13-porostadien-9-one (8R, 12S, 15S, 16RS) -1- (N-acetylcarbamoyloxy) -15-hydroxy-16-methyl-1 O-prosten-9-one (13E) - (8R, 12S, 15R) -1- (N-methylcarbamoyloxy) -16,16-dimethyl-15-hydroxy-10,13-prostadien-9-one (8R, 12S, 15R) -1- (N-methylcarbamoyloxy) -16,16-dimethyl-15 hydroxy-1 O-prosten-9-one (13E) - (8R, 12S, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16,16 dimethyl-15-hydroxy-10,13-prostadien-9-one (8R, 12S, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -16,16-dimethyl-15-hydroxy-10-prosten-9-one (10E) - (8R, 12S, 15R) -1- (N-acetylcarbamoyloxy) -16,16-dimethyl-15-hydroxy-10,13-prostadien-9-one (81t-, 12S, 15R) -1 - (N-acetylcarbamoyloxy) -16, 16 6-dimethyl -15-hydroxy-10-prosten-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy3-15-hydroxy-11,15-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-acetylcarbamoyloxy) -15-hydroxy-11,15-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-11,15-dimethyl-5,13-prostadien-9-one (13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-11,15-dimethyl-13-prosten-9-one the new prostane derivatives of the general formulas Ia and Ila are valuable pharmaceuticals, because they have a much stronger and, above all, essential, with a similar range of effects have a longer effect than the corresponding natural prostaglandins.

The new prostaglandin analogs of the E: -, D- and F-type are very effective strongly luteolytic, i.e. to trigger a luteolysis one needs significantly less Dosages than with the corresponding natural prostaglandins.

Much smaller amounts of the are also used to trigger abortions new prostaglandin analogs are required compared to the natural prostaglandins.

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 last longer than natural ones Prostaglandins.

The new prostane derivatives are suitable after a single intrauterine Application Pine to induce menstruation or to interrupt 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 cylilus in female mammals such as monkeys, rabbits1 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 known Less stimulation can be observed than with the natural prostagladins.

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 are dieretic.

The active ingredients of the F-series according to the invention have less of an effect Your therapist as a natural prostaglandin F2a, what a therapeutic application is of great benefit. For medical use, the active ingredients can be Application the inhalation, transferred form suitable for oral or parenteral administration will. Aerosol or spray solutions are expediently prepared for inhalation.

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

For parenteral administration, sterile, injectable, aqueous or oily solvents used.

The invention thus also relates to medicaments based on the compounds the general (1 formulas 1 and II and the usual auxiliaries and carriers.

The active ingredients according to the invention should be used in conjunction with the Galenik known and usual Hilstofen, for example for the production of preparations to trigger an abortion, to control the cycle or to initiate a birth to serve. For this purpose, sterile, aqueous solutions containing 0.01-10 pg / ml of the active compound should be administered as an intravenous infusion. For the production Aqueous isotonic solutions are the compounds of the general formulas I and II particularly suitable. To increase the solubility, alcohols such as ethanol, Ethylene glycol and propylene glycol, can be added.

Example 1 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyl-oxy) -5,13-nrostadiene- , 11,15-triol To a solution of 300 mg of the 1-alcohol obtained according to Example 1 b) 1.2 ml of methyl isocyanate were added successively in 5 ml of absolute tetrahydrofuran and 3 drops of triethylamine, left to stand overnight at room temperature, evaporated in the Vacuum to dryness and the residue was purified by filtering through silica gel Ether / pentane (1: 1). 305 mg of the corresponding urethane were obtained as colorless 01.

IR (CHCl3): 3470, 2943, 1700, 1650, 1020, 975 / cm Stir 250 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methyl carbamoyloxy) -11,15-bis (tetrahydropyran-2-yloxy) -9-tribenzylsilyloxy-5,15-prostadiene in 15 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10) for 5 hours at 50 ° C., evaporated in vacuo and the residue was purified by chromatography on silica gel with ether / dioxane (7 + 3). 105 mg of the title compound were obtained as colorless oil.

IR (CHCl3): 3605, 3470, 2935, 1700, 1650, 1512, 1080, 972, 947 / cm NMR (CDCl3): # 5.3-5.6m, 4H olefin. Protons 3.8-4.3 m, 5H carbinol. Protons and -CH2-CH2-O 2.85 d, 7Hz)) -NH-CH3 2.78 d, 7Hz) 0.88 t, 7Hz 3H, -CH2-CH3 That Starting material for the above reaction was prepared as follows: 1 a) 1.00 g prostaglandin F2α-methyl ester -11,15-bis- (tetr2 «hydropyranyl) ether (obtained from the corresponding acid, see J. Amer. Chem. Soc. 91, 5675 (1969), with diazomethane) dissolved in 25 ml of pyridine, 1.40 g of tribenzylsilyl chloride were added and the mixture was stirred 5 hours at 500C under argon. After distilling off the solvent in vacuo the oily residue was chromatographed on silica gel with ether / pentane mixtures. This gave 2.05 g of the corresponding 9-tribenzylsilyl ether as colorless Oil.

1 b) 2.05 g of the silyl ether in 80 ml of absolute ether are added at room temperature in portions with 0.5 g of lithium aluminum hydride, stirred for 2 hours at 20 ° C, destroyed the excess reagent with t ethyl acetate, added 1.2 ml of water to, stirred for 1 hour at 200C, filtered and evaporated in vacuo. One received 1.95 g of (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -11.15, bis (tetrahydropyran-2-yloxy) -9, which is completely uniform by thin layer chromatography tribenzylsilyloxy-5,13-prostadien-1-ol.

The 111 spectrum (in chloroform) showed no carbonyl vibration more.

For example 2 (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyl-oxy) -11,15-dihydroxy-5,13-prostadien-9-one 300 mg of (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-bis- (tetrahydropyran-2-yloxy) -5,13-prostadiene-9- were stirred on with 9 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10) for 6 hours at 4000, then evaporated to dryness in vacuo. After purifying the residue Chroniatography on silica gel (ether / ethyl acetate 7 + 3) gave 145 mg of the Title compound as a colorless oil.

IR (CHCl3): 3605, 3470, 2940, 1735, 1700, 1650, 1512, 1085, 972, 948 / cm The starting material for the above reaction was prepared as follows: 2 a) A solution of 370 mg of the urethane prepared according to Example 1 and 110 mg Tetrabutylammonium fluoride in 30 ml of tetrahydrofuran was stirred for 2 hours at OOC, diluted with water, extracted with ether, shaken the organic extract with brine, dried over magnesium sulfate and evaporated to dryness in vacuo. To Filtration through silica gel with ether gave 205 mg of (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-bis- (tetrahydropyran-2-yloxy) -5 , 13-prostadien-9-ol as a colorless oil.

2 b) to a solution of 290 mg of the 9-hydroxy compound obtained above 0.25 ml of Jones reagent was added dropwise to 8 ml of acetone at -20 ° C. and the mixture was stirred for 25 minutes at -200C, the excess reagent destroyed by adding isopropanol, diluted with ether and shaken neutral with brine. After drying over magnesium sulfate and Evaporation gave 265 mg (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-bis- (tetrahydropyran-2-yloxy) -5,13-prostadie-9 -on as a colorless oil.

IR (CHCl3): 3470, 2945, 1735, 1700, 1650, 1080, 972, 948 / cm B e i s p i e l 3 (5Z, 13E) - (8R, 12S, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-5,10,13-prostatrien-9-one 250 mg of the PGE derivative prepared according to Example 2 were stirred in 16 ml of 90% strength Acetic acid 16 hours at 60 ° C, evaporated in vacuo and purified the residue by preparative layer chromatography (silica gel, ether). 165 mg were obtained the title compound as a colorless oil.

IR (CHCl3): 3600, 3500 (broad), 2940, 1700, 1602, 978 / cm.

For example 4 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -5,13-prostadiene-9,11,15-triol To a solution of 405 mg of the 1-alcohol obtained according to Example 1b in 10 ml 145 mg of metal sulfonyl isocyanate were added to absolute toluene at OOC and the mixture was stirred Hour at 20 - 2500, mixed with water, shaken out with ether, washed the Extract with brine, dried over magnesium sulfate and evaporated in vacuo. To Filtration of the residue through silica gel with methylene chloride gave 390 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11,15-bis (tetrahydropyran-2-yloxy) -9-tribenzyloxy-5, 13-prostadia as a colorless oil.

In analogy to Example 1, 120 mg of the title compound are obtained from 300 mg as a colorless oil.

IR (CHCl3): 3600, 3380, 1720, 1400, 1346, 1020, 975 / cm.

13 e i s p i. R 15 (5Z, 13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-5,13-prostadien-9-one In analogy to Example 2, from 250 mg (5Z, 13E) (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-bis (tetrahydropyran-2-yloxy) -5, 13-prostadien-9-one 112 mg of the title compound as a colorless oil.

IR (CHCl3): 3600, 3400, 2940, 1735 (shoulder), 1720, 1400, 1345, 1020, 976 / cm The starting material for the above reaction was prepared as follows: 5 a) In analogy to Example 2 a), 400 mg of that prepared in Example 4 were obtained 9-tribenzylsilyloxy compound and 120 mg tetrabutylammonium fluoride 210 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11,15-bis- (tetrahydropyran- 2-yloxy) -5,13-prostadien-9-ol as a colorless oil.

5 b) In analogy to Example 2 b), 210 mg of the above were obtained prepared compound and 0.2 ml Jones reagent 170 mg (5Z, 13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy7-11,15-bis- (1; etrahydropyran- 2-yloxy) -5,13-prostadien-9-one as a colorless oil.

Example 6 (5Z, 13E) - (8R, 12S, 15S) -1 - [(N-methanesulfonyl) -carbamoyl-oxy] 15-hydroxy-5,10,13-prostatrien-9-one 200 mg of that prepared according to Example 5 were stirred PGE derivative in 12 ml of 90% acetic acid for 16 hours at 60 ° C., evaporated in vacuo and purified the residue by preparative layer chromatography (silica gel, Methylene chloride / isopropanol 9 + 1). 105 mg of the title compound were obtained as colorless Oil.

IR (CHCl3): 3600, 3500, 2944, 1710, 1603, 978 / cm

Claims (1)

patent claim ii cho 1. Prostane derivatives of the general formula Ia where it1 is a Denotes a group, where U represents an oxygen or sulfur atom and R6 represents an optionally substituted alkyl, cycloalkyl or aryl radical or an acid radical, and according to the main patron ................. (Patent application P 25 23 676.4) P one linked via the C atom-1 represents any substituted prostane radical and R2 and R3 hydrogen atoms or Denote alkyl groups with 1 - 4 carbon atoms. 2.) Prostane derivatives of the general formula IIa wherein R1, R2 and R3 have the meaning given above, A denotes a -CH2-CH2- or cis-CH = CH- or trans-CH = CH- group, a -CH2-CH2- or trans-CH = CH- group or one or one 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 -Group, where the OH group can be α or β and functionally modified, D and E together denotes a direct bond or D a straight-chain or branched alkylene group with 1-5 C atoms or a E denotes an oxygen or sulfur atom or a direct bond, R4 denotes an alkyl group, a cycloalkyl group, an optionally substituted aryl group, a benzodioxol-2-yl group, a heterocyclic group. Group, Z a carbonyl or a free or functionally modified hydroxymethylene group, where the ethylene group can be α or β, for when Z represents a hydroxymethylene group or represents or -CH = CH- when Z is a carbonyl group, the Zur radical denoting an alkyl or a free or functionally modified hydroxyl group. 3.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyl-oxy) -5,13-prostadiene-9,11,15-triol 4.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N -methylcarbamoyl-oxy) -11,15-dihydroxy-5,13-prostadien-9-one 5.) (5Z, 13E) - (8R, 12S, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-5,10,13-prostatrien-9-one 6.) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy7-5,13-prostadiene-9,11,15-triol 7.) (5Z, 13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-5,13-prostadien-9-one 8.) (5Z, 13E) - (8R, 12S, 15S) -1 - [(N-methanesulfonyl) -carbamoyl-oxy] -15-hydroxy-5,10,13-prostatrien-9-one 9.) Modification of the process according to the main patent ................... (Patent application P 25 23 676.4) for the preparation of the new prostane derivatives of the general formula Ia from compounds of the general formula III in which P, R2 and R3 have the meanings given above and free hydroxyl groups are optionally protected as intermediates, characterized in that compounds of the general formula III are mixed with compounds of the general formula VU = C = N - R6 in which U and R6 have the meanings given above , reacts and then optionally releases protected hydroxyl groups and / or oxidizes or esterifies free hydroxyl groups and / or ketalizes or reduces free keto groups and / or hydrogenates or methylenates double bonds and / or introduces a double bond by splitting off water in the 10,11-position and optionally separates the epimers. 10.) Modification of the process according to the main patent ................. (Patent application P 25 23 676.4) for the preparation of the new prostane derivatives of the general formula IIa from compounds of the general formula IV in which R2, R3, A, Z1, X, - Y, B, W, D, E and R4 have the meaning given above and free hydroxyl groups are optionally protected as intermediates, characterized in that compounds of the general formula IV are mixed with compounds of the general Formula VU = C = N - R6 in which U and R6 have the meaning given above, reacts and optionally then releases protected Ilydroxy groups and / or oxidizes or esterifies free hydroxyl groups and / or ketalizes or reduces free keto groups and / or hydrogenates or methylenates double bonds and / or by splitting off water in the 10,11-position introduces a double bond and optionally separates the epimers. 11.) Medicines based on the compounds of the general formula Ia, 12.) Medicines based on the compounds of the general formula IIa.