DE3115997A1 - Novel prostaglandins and prostacyclins, process for their preparation and their use as medicaments - Google Patents

Abstract

The invention relates to compounds of the formula I <IMAGE> in which R1 denotes prostaglandin or prostacyclin radicals, Y denotes oxygen, sulphur, imino or N-(C1-C4-alkyl)imino, Q denotes the radical (CR6R7)p, where p can be 0 to 3, R2 denotes hydrogen, alkyl optionally substituted by a hydroxy or amino group and having 1-6 C atoms, C1-C4-alkoxycarbonyl, cyano or di-C1-C4-alkylaminocarbonyl, R3, R4, R5, R6 and R7 denote hydrogen, alkyl optionally substituted by a hydroxy or amino group and having 1-6 C atoms or aryl, R3 and R4 together denote trimethylene, tetramethylene or 1,3-butadienylene if R2 and R5 together represent a direct bond, which have pharmaceutical activity, inter alia abortive and hypotensive action. They are prepared by a customary method.

Description

New Prostaglandins and Prostacyclines, Methods for Theirs

Manufacture and its use as a medicine description The invention relates to new prostaglandins and prostacyclins, processes for their Manufacture and their use as pharmaceuticals.

As biological conversion products of three-, four- (arachidonic acid) and fivefold unsaturated naturally occurring C-20 fatty acids are especially important Prostaglandins, prostacyclines and thromboxanes, especially in the form of their analogues, of great therapeutic importance.

For the interaction of these substances with the receptor, i.

for the selectivity and duration of the biological effect as well as for the metabolism (ß-oxidation) the functionality of the l-carboxyl group is of great importance Importance. Compared to the 1-carboxylic acids have l-esters, l-amides and in particular l-sulfone - or l-acylamides a changed biological spectrum of activity «like. i.a. T.K.Schaaf and H.J. Hess, J.Med.Chem. 22, 1540 (1979) off.

But all of these groups, like the l-esters or amides, are either neutral or acidic like the l-acylsulfonamides. That is why it was of great interest to the l-carboxyl group in prostaglandins, prostacyclins and thromboxanes, as well as their analogs without theirs To change the value, to convert it into basic derivatives.

With the help of a new method described in DE-OS 50 47 759 it is now easily possible to use the l-carboxyl group of prostaglandins and prostacyclins and their derivatives into the corresponding basic A2-oxazolines, A2-thiazolines or A2 imidazolines as well as their higher-level analogues such as e.g. 5,6-dihydro-4H-1,5-oxazines, 5,6-dihydro-4H-1,3-thiazines and tetrahydropyrimidines to convict.

These new derivatives show a changed and more selective biological Spectrum of activity and are chemical and metabolic, especially in the case of prostacyclines significantly more stable and therefore effective for longer.

The invention relates to prostaglandins of the general formula I, a prostaglandin residue in R1 where A stands for - (CH2) n-, - (CH2) mO-, -CF2- (CH2) m- with n = 1-3 and m = 1-2 and -CH ~ CH-CH2-, -CH2-CH = CH- and B-X1 for - (CH2) 3- or -CH = C = CH-, AB-X1 for - (CH2) 5-, AB for - (CH2) o-, - (CH2) nO-, -CF2- (CH2) n-, -CH = CH- (CH2) m-, - (CH2) m-CH = CH- with m = 1-2, n = 1-5 and o = 1-4 and X1 for a cis-alkenylene with R8 and R9 as hydrogen or C1-C6-alkyl and A for -CH2-, B for oxygen or -CH2- and X1 for m-phenylene, D for oxygen, hydrogen and α- or ß-hydroxy, hydrogen and a- or β-halogen or CH2, E for oxygen, hydrogen and α-hydroxy, hydrogen and α-CH3 or hydrogen and α-CH2OH, R9 X2 for -CH2-CH2-, -C # C- or a trans-alkenylene with R8 and R9 in the meaning given above, X3 for -X4 for - (, CH2) n- with n = 1-3 or with R10 and R11 as hydrogen, fluorine, methyl, methoxy, X5 for -CH2-, oxygen, sulfur or a direct bond and (3-trifluoromethylphen X6 for phenyl, 3- or 4-chlorophenyl, α- or B-naphthyl, 2 - or 3-furyl, 2- or 3-thienyl, 2-, 5- or 4-pyridyl or, if X; represents a direct bond, for the radicals - (CH2) mC # C-CH3 with m = 1-2, -CH (CH3) -CH2-CH2-CH3, - (CH2) 3-CH # CH2 or -CH2-C # C-CH2-CH3, or RleiUen Prostacyclinrest in which A, E and X2-X6 have the same meaning as given above and Z1 represents oxygen or CH2, if at the same time Z2 represents hydrogen or cyano, and Z1 represents nitrogen, if Z2 represents H2 Z3 H2 or oxygen and Y oxygen, Sulfur, imino or N- (C1-C4-alkyl) -imino, Q is the radical (CR6R7) p, where p can be 0 to 3, R2 is hydrogen, alkyl with 1-6 C- which is optionally substituted by a hydroxy or amino group Atoms, C1-C4-alkoxycarbonyl, cyano or di-C1-C4-alkylaminocarbonyl, R3, R4, R5, R6, R7 are hydrogen, alkyl with 1-6 carbon atoms or aryl, optionally substituted by a hydroxy or amino group, and R4 together trimethylene, tetramethylene or 1,5-butadienylene when R2 and R5 together represent a direct bond.

71 9 represent 1-6 carbon atoms, these are to be understood as radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, hexyl, isohexyl, which may be replaced by hydroxy, amino, nitro, Fluorine, chlorine, bromine, C1-C4-alkoxycarbonyl, di-Cl-C4-alkylaminocarbonyl, C1-C4-alkylaminocarbonyl, Tri-C1-C4-alkylsilyloxy-, tetrahydropyranyloxy or benzoyloxy, preferably through Hydroxy, amino or chlorine can be substituted.

Preferred alkyl radicals for R2 to R9 and R12 are those with 1-4 carbon atoms. These alkyl radicals can also be substituted, preferably by hydroxy or Amino.

For Y meaning N-alkyl, there are alkyl radicals with 1-4 carbon atoms into consideration, as they have already been mentioned e.g. for R2.

For the radicals R51, R4, R5, R6, R7 as aryl there are phenyl, a- and ß-naphthyl, preferably phenyl.

The following alkyl radicals are used for R2 meaning alkoxycarbonyl for alk: methyl, ethyl, propyl, iso.propyl, butyl, sec.-butyl, tert.-butyl and benzyl.

Dialkylaminocarbonyl in the meaning of R2 should be a radical in the alkyl is a straight-chain saturated alkyl radical with 1-4 carbon atoms (methyl1 ethyl, Propyl, butyl) represents.

In (CR6R7) p- as a possibility of Q, p can be between 0 and 5. Compounds with p = 0 or 1 are preferred.

Halogen in the meaning of D can be fluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred.

The invention also relates to a process for the preparation of compounds of the general formula I, characterized in that a compound of the general formula II, R1 - COOR12 II, in which R1 is trialkylsilyl has the meaning given above and R12 is hydrogen, is used in a manner known per se -C6-alkyl denotes, optionally after protecting any free hydroxyl groups present with an amine of the general formula III, wherein R2, R3, R4, R5, Q and Y have the meanings given above, is reacted with the aid of organic phosphines or phosphonium salts and perhalogenated hydrocarbons or ketones in the presence of tertiary bases and optionally then separates isomers in any order and / or releases protected hydroxyl groups and / or free hydroxyl groups esterified or etherified and / or hydroxyl groups oxidized and / or oxo groups reduced and / or double or triple bonds hydrogenated.

The ether and acyl protecting groups for free hydroxy radicals are those residues known to the person skilled in the art can be considered. Easily split off ether residues are preferred such as tetrahydropyranyl, tetrahydrofuranyl, a-ethoxyethyl, trimethylsilyl, Dimethyl-tert-butyl-silyl and tri-p-benzyl-silyl radical. The acyl residues are same as mentioned for R5 in question; Examples include acetyl, Propionyl, butyryl, benzoyl.

All prostaglandins and prostacyclins are used as starting products II, which have a GOOR12 group in the l-position (R12 e.g. H, C1-C6 alkyl), in Consideration.

Preferred amines III for the cyclization to # ²-N-heterocycles are in the 5-ring series ethanolamine, 2-aminopropanol, 2-methyl-2-aminopropanol, tris (hydroxymethyl) methylamine, o-aminophenol, cysteamine, 1,2-ethylenediamine, o-phenylenediamine, 1-amino-2-methylaminoethane, 1-amino-2-phenylamino- or 2-benzylaminoethane, and in the 6-ring series 3-aminopropanol, 2,3,3- Trimethyl-3-aminol-propanol, 3-aminopropanethiol, 1,3-diaminopropane or 1,3-diaminopropane of the formula insofar as they have not yet been named, p determines the ring size of the # 2 heterocycles of the general formula I. For example, this results in

for p = 0 # ²-oxazolines, # ²-thiazolines and # ²-imidazolines, for p = 1 5,6-dihydro-4H-1,3-oxazines, 5,6-dihydro-4H-1,3-thiazines and tetrahydropyrimidines and for p = 2 and 3 the corresponding 7- or 8-membered rings.

Organic phosphines or phosphonium salts can be used [(R13) 3P # -O-R14] ClO4 #, CF3SO3 #, Cl # Br # or J # and (R13) 2 P-R14 with R13 in the meaning Aryl (phenyl, α- or ß-naphthyl, preferably phenyl), aralkyl (with 7-10 Carbon atoms as already stated above), alkyl (with 1-6 carbon atoms, see remainder for R2), Cycloalkyl (with 5-7 carbon atoms), O-aryl (phenyl, α- or ß-naphthyl, preferably Phenyl, O-alkyl (with 1-6 carbon atoms, see radicals for R2) and di- (C1-C4-alkyl) -amino (preferably dimethylamino) or as [(C6H5) 3P # -O-P # (C6H5) 3] 2CF3SO3 # [[(CH3) 2N] 3P # -O-P # [N (CH3) 2] 3] 2CF3SO3 # or [[(CH3) 2N] 3P # -Cl] ClO4 # i.e. R14 = O-P # (C6H5) 3; OP [N (CH3) 2]; Cl.

Because the reaction rate is in the order described above decreases, (R13) 3P for R13 = aryl, preferably phenyl, are therefore most reactive (C6H5) 3P / CCl4, (C6E5) 3P / C2C16, e [(C6H5) 3P # -O-P # (C6H5) 3] 2CF3SO3 # or [(C6H5) 3P-Cl] Cl; [(C6H5) 3P-Br] Br f (C6H5) 3P0-JJJ; (C6H5) 2P-C1 or polymeric aromatic phosphines, in which triarylphosphines are chemically bound to a polymeric matrix, preferred Reagents.

Perhalogenated aliphatics and aralkyls are used as electrophilic components as well as carbonyl compounds such as CCl4, CBrCl3, CBr2 Cl2, CClBr5, CBr4, C2Cl6, C6H5-CCl3, CCl3-CO-CCl3, CCl3-CH3, CHBr3, CCl3 CN, CCl3-CHO etc. but preferably CCl4.

as azoester R11OOC-N = N-COOR11 with R11 = CH3, R2H5, CH2CCl3, preferably with R11 = CH3, C2H5.

As tertiary amines, e.g. trimethylamine, triethylamine, tri-n-propylamine, Tributylamine, diisopropylethylamine, dicyclohexylethylamine, benzyldimethylamine, pyridine, Lutidine, collidine, 2-dimethylaminopyridine, 4-dimethylasinopyridine, quinoline, 1,4-diazobicyclo [4,3.0] non-5-ene (DSN), 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) 1,4-diazabicyclo [2.2.2] octane (DABCO), preferably triethylamine and pyridine are used.

The reaction takes place in non-protic or absolute solvents Solvent mixtures such as CC14, chloroform, methylene chloride, benzene, toluene, diethyl ether, Tetrahydrofuran, ethyl acetate, acetonitrile, dimethylformamide (DHF) or sulfolane, preferably carried out in acetonitrile, pyridine or DHF.

The reaction proceeds at temperatures between -20 ° C. and 100 ° C., preferably at +1000 to + 30 ° C.

It is advantageous to use equivalent amounts per carboxyl or ester group of the amine component (X-hydroxy- and #-mercaptoamine and w ~ diamine). That tertiary phosphine (preferably triphenylphosphine) and the electrophile (preferably CCl4 or C2z16) are in 2-5 times the molar excess, preferably 3-4 times molar excess, based on the carboxyl group. Of phosphonium salts like [(C6H5) 3P # -O-P # (C6H5) 3] 2CF3SO3 # you need at least 2-3 equivalents.

From the tert. Amine (preferably triethylamine) is expediently used also 2-5 equivalents, preferably at least 4 equivalents. An excess of triethylamine causes a better solubility of the amine salts of the carboxylic acids.

Since the reaction of trisubstituted phosphines (R13) 3P (preferably Triphenylphosphine) with halogen compounds, preferably CC14, over a whole series of reaction products takes place [cf.

R.Appel, Angew. Chem. , 863 (1975) j and the first reaction products, e.g. [(C6H5) 3P # -CCl3] Cl # are optimal for the cyclization, it is convenient to use the Triphenylphosphine in solution (preferably in acetonitrile) slowly to the mixture the other reactants to add dropwise to high yields of the desired prostaglandins or Prostacycline I.

Man. can attach these compounds to very deactivated adsorbents like e.g. aluminum oxide (A IV-V) or silica gel to which 30-40% water has been added, if possible, chromatograph with the application of pressure, without using large amounts these substances are decomposed during chromatography.

According to the method described in DE-OS 30 47 759 can substituted carboxylic acids R'-COOH in the presence of amines of the general formula II very easily with tertiary phosphines, especially triphenylphosphine, in the presence of halogen compounds such as, in particular, carbon tetrachloride and a tert. base preferably triethylamine or DBN, DBU or with) .Q (C6H5) 3] 2CF3SO3 # to the already mentioned 2-substituted # ²-oxazolines, # -imidazolines or 5,6-dihydro-4H-1,3-oxazlnen, Convert 5,6-dihydro-4H-thiazines or tetrahydropyrimidines.

The not yet cyclized B-hydroxy, MeMercapto- or aminoalkylamides as isolable intermediates, like the carboxylic acids can be used for cyclization.

For example, prostaglandin F2α can be very easily sought after protection of the reactive hydroxyl groups by silylation (if these hydroxyl groups are not anyway by other protective groups such as acyl, tetrahydropyranyl or silyl groups blocked) directly with ethanolamine in the presence of triphenylphosphine, carbon tetrachloride and triethylamine in absolute acetonitrile or N, N-dimethylformamide for persilylation React A2-oxazoline, from which the trimethylsilyl protective groups are formed by aqueous or alcoholic lye Can be easily removed in the 9, 11 and 15 positions.

But one can also use prostaglandins and prostacyclines as well as their analogues directly without protection of their hydroxyl groups under carefully controlled conditions with triphenylphosphine, carbon tetrachloride and triethylamine, especially in abs. Acetonitrile, acetonitrile-pyridine, N, N-dimethylformamide or N-methylpyrolidone or sulfolane to the corresponding derivatives of the I-carboxyl group such as A2-oxazolines, a2-Thiazoline2-imidazolines and their A2-oxazines, etc. implement without these free Hydroxyl groups of the starting substances changed or their corresponding chlorine derivatives being transformed.

The functional modification of the free OR groups takes place according to the methods known to those skilled in the art. For the introduction of the ether protection groups, for example with dihydropyran in methylene chloride or chloroform using an acidic Condensing agent, such as p-toluenesulfonic acid, reacted.

The dihydropyran is used in excess, preferably in the 4 to 10 times the amount of the theoretical requirement. Implementation is usually finished after 15-30 minutes at OOC-300C.

The acyl protecting groups are introduced by adding a compound of the general formula I in a manner known per se with a carboxylic acid derivative, such as acid chloride, acid anhydride and others.

The release of a functionally modified OH group to the compounds of the general formula I is carried out by known methods. For example, the Splitting off of xether protecting groups in an aqueous solution of an organic acid, such as acetic acid, propionic acid, etc. or in an aqueous solution of a inorganic acid such as hydrochloric acid. For improvement the solubility is expediently a water-miscible 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. Cleavage is preferred at Temperatures between 200C and 800C carried out.

The cleavage of the silyl ether protective groups takes place, for example with tetrabutylammonium fluoride. Suitable solvents are, for example, tetrahydrofuran, Diethyl ether, dioxane, methylene chloride, etc. The Abspalten'wird is preferably at temperatures performed between OOC and 800C.

The saponification of the acyl groups is carried out, for example, with alkali or alkali metals Alkaline earth carbonates or hydroxides in an alcohol or an aqueous solution of one Alcohol. Aliphatic alcohols come into consideration as alcohols, such as, for example Methanol, ethanol, butanol, etc., preferably methanol. As alkali carbonates and Hydroxides are potassium and sodium salts, but the potassium salts are preferred. Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, Calciumhydroxy'd and barium carbonate. The reaction takes place at -10 ° C. to 700 ° C., preferably at 250C, the hydroxyl groups present are oxidized according to methods known per se made with the usual oxidizing agents. For example, oxidation the 9-hydroxy group to the 9-ketone with Jones reagent (J.Chem.Soc. 1953, 2555), with further free hydroxyl groups in the molecule, e.g. in the 11- and / or 15-position, be selectively protected beforehand in a known manner.

One works with an excess of the oxidizing agent in an inert one Solvents, such as acetone, at temperatures between 30 ° C. and -500 ° C., preferably at around -20 ° C. The reaction is generally complete in about 5 to 30 minutes.

The new prostaglandin analogues of formula I have a very strong luteolytic effect, i.e. to trigger a luteolysis one needs much lower dosages than with the corresponding natural prostaglandins.

Also for triggering abortions, especially after oral administration, are much smaller amounts-of the new prostaglandin analogues 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 last longer than natural Prostaglandins.

The new prostaglandin derivatives are suitable after one-time enteral or parenteral administration to induce menstruation or pregnancy to interrupt. They are also useful for synchronizing the sexual cycle common mammals such as rabbits, cattle, horses, pigs, etc.

The good tissue specificity of the antifertile agents according to the invention Substances shows up on examination on other smooth muscle organs, such as for example on the guinea pig ileum or on the isolated rabbit trachea, where there is much less stimulation than natural stimulation Prostaglandins.

The active compounds of the E series according to the invention show on the isolated Rabbit trachea in vitro even have a bronchodilatory effect and strongly inhibit gastric acid secretion.

The reduction of the 9-keto group to produce the corresponding 9β-Hydroxy compounds are made with one suitable for the reduction of ketones Reducing agents such as sodium borohydride. The resulting mixture of epimers is separated, for example, in the usual way by column or layer chromatography.

If C = C double bonds contained in the primary product are to be 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 about -20 ° C, in a hydrogen atmosphere carried out in the presence of a noble metal catalyst. As a catalyst is for Example 10% palladium on carbon suitable.

If both the 5,6 and the 13,14 double bond are hydrogenated, then one works at a higher temperature, preferably at about 200C.

If the starting material used is the ester of the general formula II are not known, they can be easily extracted from the known carboxylic acids Reaction with diazoalkanes in an inert solvent, preferably in diethyl ether or produce methylene chloride.

The trialkylsilyl esters (R12 = trialkylsilyl) are usually formed in the trialkylsilyl ether formation of the OH groups to be protected.

The prostacyclines of this invention are antihypertensive and bronchodilatory. They are also suitable for inhibiting platelet aggregation. Consequently ask the new prostacyclin derivatives of the formula I are valuable active pharmaceutical ingredients represent.

In addition, they show a similar spectrum of activity when compared with corresponding prostaglandins, a higher specificity and, above all, a substantial one longer effectiveness. Compared to PGI2, they are characterized by greater stability .the end. The high tissue specificity of the new prostaglandins shows itself in the examination on smooth muscle organs, e.g.

on the guinea pig ileum or on the isolated rabbit trachea; Where significantly less stimulation can be observed than during the application natural prostaglandins of the E, A or F type.

The new ProstaSyclin analogs have those typical for prostacyclins Properties such as lowering of the peripheral arterial and coronary vascular Resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering the systemic blood pressure without at the same time Decrease stroke volume and coronary blood flow; Treatment of stroke, Prophylaxis and Therapy of coronary heart disease, coronary thrombosis, of myocardial infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, Therapy of shock, inhibition of bronchoconstruction, inhibition of gastric acid secretion, Sytoprotection of the gastric and intestinal mucosa; antiallergic properties, lowering pulmonary vascular resistance and blood pressure, promotion renal blood flow, use in place of heparin or as an adjuvant in the Dialysis of hemofiltration, preservation of blood plasma, especially of Preserved platelets1 inhibition of labor pains, treatment of pregnancy toxicosis, Increase in cerebral blood flow etc. In addition, the new prostaglandin analogs have antiproliferative properties.

The dose of the compounds is 1-1500 g / kg / day when applied to human Administered to patients. The unit dose for the pharmaceutical acceptable Carrier is 0.01-100 mg.

When administered orally to conscious, hypertensive rats in doses of 100. ' -. The compounds according to the invention show a stronger 500 g / kg body weight antihypertensive and longer lasting effect than PGE2 and PGA2, without like PGE2 Diarrhea or PGA2 cardiac arrhythmias.

For parenteral administration, sterile, injectable, aqueous or oily solutions are used. For oral application, for example, tablets, Dragees or capsules are suitable.

The invention thus also relates to medicaments based on the compounds of the general formula I and customary auxiliaries and carriers.

The active ingredient according to the invention should be used in conjunction with the Galenics known and common auxiliaries, e.g. for the production of antihypertensive agents to serve.

Example 1 (5Z, 13E) - (8R, 9E, 11R, 12R, 15S) -9,11,15-triacetoxy-2- (2-oxazoline-2 yl) -l-nor-5,13i-prostadiene 207 mg (0.43 mmol) 9,11,15-triacetyl-prostaglandin-F in 2 ml abs. Acetonitrile and dissolved with 0.45 ml of a molar solution of ethanolamine in acetonitrile, 394 mg (1.5 mmol) triphenylphosphine, and 5.3 ml of a molar solution added triethylamine in acetonitrile. The pale yellow colored clear solution is cooled to 2 ° C internal temperature. Within 5 minutes, 0.86 ml of a molar solution of carbon tetrachloride in acetonitrile was added dropwise and then Stirred for 4 hours at 20C. After 48 hours of standing at room temperature, the reaction mixture becomes concentrated without heating and four times with 15 ml dist. Hexane extracted. After narrowing and crystallization of the triphenylphosphine oxide from hexane gives 196 mg (90.2V. the theory) of the title compound.

Example 2 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -2- (2-oxazolin-2-yl) -1-nor-5,13-prostadiene-9,11,15-triol 5.16 mg (lmol) of the compound prepared according to Example 1 are dissolved in 15 ml of methanol dissolved, the solution cooled to OOC and treated with 15 ml of 2N NaOH. After 50 minutes Stirring in an ice bath is stirred for 2 hours at room temperature. After gentle narrowing the reaction solution on a rotary evaporator at 250C to approx. 10 ml is mixed with 10 ml of water diluted and extracted four times with 20 ml of ethyl acetate each time. After drying over Na2S 0k and concentration, the substance absorbed in the methylene chloride is prepared preparatively Silica gel separated with chloroform / methanol (9: 1) as the mobile phase, first with ethanol and then eluted three times with a little carbon tetrachloride. Yield 178 mg (46.9 96 of theory).

Example 3 (5Z, 13E) - (8R, 9S, flR, 12R, 15S) -2- (2-oxazolin -? - yl) -1-nor-5.15 prostadien-9,11,15-triol 177 mg (Oi5 mmol) prostaglandin-F2α are in 5 ml least. Hexamethyldisilazane (HMDS) suspended, with evolution of NH3 and A clear colorless solution forms after 30 minutes of heating.

After 1.5 hours of heating at 1400 bath temperature, excess becomes HMDS peeled off in vacuo. and the residue for 30 minutes at 400 bath temperature and 0.2 mBar dried on the oil pump.

The residue is abs in 5 ml. Acetonitrile dissolved, 786 mg (3mMol) Triphenylphosphine and 1.05 ml (7.5 mmol) of triethylamine were added and while cooling with ice 0.5 ml of a molar solution of ethanolamine in acetonitrile was added dropwise. Then takes place Addition of 1.5 ml rather molar solution of carbon tetrachloride in acetonitrile and Stand overnight at room temperature. After concentrating in vacuo, five times each Washed 75 ml of hexane. The crystals formed are separated from the oily residue, and the oily residue taken up in 15 ml of methanol and with cooling with 5 ml 2N NaOH was added, the mixture was stirred at 200 for 30 minutes. After concentration in vacuo to approx. 5 ml is mixed with 10 ml of water and extracted four times with 10 ml of ethyl acetate each time. After drying the ethyl acetate phases with Na2S04 and concentrating, 208 mg of one remain light brown oily residue. After preparative thin layer chromatography on SiO2 with chloroform / methanol (9: 1) as the mobile phase is eluted with 500 ml of ethanol, concentrated and dried on the oil pump for 1 hour at 200 and 1.5 mbar. yield 105 mg (54.2 of theory).

Example 4 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -2- (2-oxazolin-2-yl) -1-nor-5,13-prostadiene-9,11,15-triol 177 mg (0.5 mmol) of prostaglandin F2α are in 15 ml of abs. Acetonitrile dissolved and under argon with 0.7 ml of triethylamine, 0.5 ml of one molar solution of ethanolamine in acetonitrile and 0.5 ml of carbon tetrachloride were added. Within of 8 hours at about 200C 655 mg (2.5 mmol) of triphenylphosphine in 15 ml of abs. Acetonitrile was added dropwise with stirring. Then another 20 hours at 2000 touched. After concentration in vacuo, the residue is dissolved in 20 ml of ethyl acetate and 15 ml of water was added and the aqueous phase was extracted three times with 10 ml of ethyl acetate each time. The combined ethyl acetate phases are dried over Na2SO4 and concentrated. the Chromatography of the ethyl acetate solution (10 ml) with water-saturated ethyl acetate Al2O3 (basic, act IV) gives 127 mg (66.9%) of the title compound as oil.

Example 5 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -2- (4,4-dimethyl-2-oxazolin-2-yl) -1 nor-5,13-prostadien-9,11,15-triol Analogously to Example 3, 177 mg (0.5 mmol) Prostaglandin-F2 with 0.5 ml of a molar solution of 2-amino-2-methyl-1-propanol implemented in acetonitrile. Yield 98 mg (48.3% of theory).

Example 6 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -2- (2-thiazolin-2-yl) -1-nor, 5,13-prostadien-9,11,15-triol Analogous to Example 3 from 177 mg (0.5 mmol) prostaglandin-F2 « and 57 mg (0.5 mmol) of 2-aminoethanethiol-hydrochl.ori.d under argon.

Yield 115 mg (57% of theory).

Example 7 1-Decarboxy-2- (oxazolin-2-yl) - (5R, 6R) -5-bromo-prostaglandin-I1 Analogously to Example 4 from 216 mg (0.5 mmol) (5R, 6R) -5-bromo-prostaglandin-I1 and ethanolamine. Yield 125 mg (4.4% of theory).

Example 8 1-Decarboxy-2- (oxazolin-2-yl) prostaglandin-I2 125 mg (0.27 mmol) of the compound prepared according to Example 7 with 5 ml of abs. Toluene added and 0.25 ml of DBU was added under argon. After 8 hours of stirring at 60-65 ° C, concentrate, Chromatography on SiO2 with ethyl acetate / methanol (9: 1) results in 43 mg (42.3% of the Theory) of a light yellow viscous oil.

Example 9 2- [4- (E) - (1S, 5S, 6R, 7R) -7-Hydroxy-6 - [(E) - (3S, 4RS) -3-hydroxy-4-methyl-oct-1- en-6-yn-yl] bicyclo [3.3.0] octan-3-ylidene) butyl] -2-oxazoline Analogously to example 4 from 50 mg (0.14 mmol) 5 - {(E) - (1S, 5S, 6R, 7R) -7-hydroxy-6-E) - (4Rs) -3a-hydroxy-4-methyl- oct-l-en-6-ynylj-bicyclo [3.3.0] octan-3-ylidene} pentanoic acid and ethanolamine under argon.

Yield 16 mg (29.6% of theory).

Example 10 2 - {(E) - (1S, 5R, 6R) -6-Hydroxy-6 - [(E) - (3S, 4RS) -3-hydroxy-4-methyl-1-octenyl] -2-oxabicyclo [3.3.0] octan-3-ylidene} -5- (2-oxazolin-2-yl) pentanenitrile Analogue Example 4 from 78 mg (0.2 mmol) hydroxy-6 - [(E) - (3S, 4RS) -3-hydroxy-4-methyl-1-octenyl] -2-oxa bicyclo [3.3.0] octan-3-ylidene} pentanoic acid and ethanolamine.

Yield 60 mg (72% of theory).

Claims (1)

Claims 1) Prostaglandins of the general formula I a prostaglandin residue in R1 where A stands for - (CH2) n-, - (CH2) mo-, -CF2- (CH2) m- with n = 1-3 and m = 1-2 and -CH = CH-CH2-, -CH2-CH = CH- and B-X1 for - (CH2) 3- or -CH = C = CH-, AB-X1 for - (CH2) 5-AB for - (CH2) o-, - (CH2) nO-, - CF2- (CH2) n-, -CH = CH- (CH2) m-, (CH2) m-CH = CH- with m = 1-2, - n = 1-3 and o = 1-4 and X1 for a cis-alkenylene with R8 and R9 as hydrogen or C1-C6-alkyl and A for -CH2-, B for oxygen or -OH2- and X1 for m-phenylene, D for oxygen, hydrogen and «- or ß-hydroxy, hydrogen and a- or β-halogen or CH2, E for oxygen, hydrogen and α-hydroxy, hydrogen and α-CH3 or hydrogen and α-CH2OH, 9 X2 for -CH2-CH2-, -C # C- or a trans-alkenylene with R8 and Rg in the meaning given above, X3 for X4 for - (CH2) n- with n = 1-5 or with R10 and R11 as hydrogen, fluorine, methyl, methoxy, for -OH2-, oxygen, sulfur or a direct bond and (3-trifluoromethylphenyl) X6 for phenyl, 3- or 4-chlorophenyl, α- or ß-naphthyl, 2 - Or 5-furyl, 2- or 5-thienyl, 2-, 3- or 4-pyridyl or, if XR is a direct bond, for the radicals - (CH2) mC # C-CH3 with m = 1-2, -CH (CH3) -CH2-CH2-CH3, - (CH2) 3-CH # CH2 or -CH2-C # C-CH2-CH3, or R1 is a prostacline residue in which A, E and X2-X6 have the same meaning as given above and Z1 represents oxygen or CH2, if at the same time Z2 represents hydrogen or cyano, and Z1 represents nitrogen, if Z2 represents H2 Z3 H2 or oxygen and Y oxygen, Sulfur, imino or N- (C1-C4-alkyl) -imino, Q denotes the radical (CR6R7) p, where p can be 0 to 3. R2 is hydrogen, optionally through a hydroxyl or amino group substituted alkyl with 1-6 carbon atoms, Cl-C4-alkoxycarbonyl, oyano or di-Cl-C4-alkylaminocarbonyl, R3, R4, R5, R6, R7 are hydrogen, optionally through a hydroxy or amino group substituted alkyl having 1-6 carbon atoms or aryl, and R4 together is trimethylene, tetramethylene or 1,3-butadienylene when R2 and R5 together represent a direct bond. 2) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -9,11,15-triacetoxy-2- (2-oxazolin 2-yl) -l-nor-5,13-prostadiene 5) (5Z, 13E) - (8R, 9S, ilR, 12R, 15S) -2- (2-oxazolin-2-yl) -l-nor-5,15 prostadiene-9,11,15-triol 4) (5Z , 13E) - (8R, 9S, 11R, 12R, 15S) -2- (4,4-dimethyl-2-oxazolin-2-yl) -l-nor-5,13-prostadiene-9,11,15- triol 5) (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -2- (2-thiazolin-2-yl) -1-nor-5,13 prostadiene-9,11,15-triol 6 ) 1-decarboxy-2- (oxazolin-2-yl) - (5R, 6R) -5-bromo-prostaglandin-I1 7) 1-decarboxy-2- (oxazolin-2-yl) -prostaglandin-I2 8) 2 - [4- (E) - (1S, 5S, 6R, 7R) -7-hydroxy-6 - [(E) - (3S, 4RS) -3-hydroxy-4-methyl-oct-1-en-6 -in-yl] bicyclo [3.3.0] octan-3-ylidene) butyl] -2-oxazoline 9) 2 - {(E) - (1S, 5R, 6R) -7-hydroxy-6- [ (E) - (3S, 4RS) -3-hydroxy-4-methyl-l-octenyl7-2-oxabicyclog3.). 0goctan-3-yliden-5- (2-oxazolin-2-yl) -pentanenitrile 10) Method for Preparation of compounds of the general formula I, characterized in that, in a manner known per se, a compound of the general formula II, R1 - COOR12 II, in which R1 has the abovementioned meaning a and R12 denotes hydrogen, trialkylsilyl or Cl-C6-ALkyl, optionally after protecting any free hydroxyl groups present with an amine of the general formula III, wherein R2, R3, R4, R5, Q and Y have the meanings given above, with the aid of organic phosphines or phosphonium salts and perhalogenated hydrocarbons or ketones in the presence of tertiary bases and optionally then separates isomers in any order and / or protected hydroxyl groups releases and / or esterifies or etherifies free hydroxyl groups and / or oxidizes hydroxyl groups and / or reduces oxo groups and / or hydrogenates double or triple bonds. 11) Medicinal products, consisting of one or more compounds according to Claim 1 and customary auxiliaries and carriers.