EP0434707A1 - 6-oxo-9-fluor-prostaglandin derivatives, process for producing them and their use as drugs - Google Patents

Abstract

Derivatives of 6-oxo-9-fluor-prostaglandin have the formula (1), in which R1 represents the residues COOR2 or CONHSO2R2, where R2 is a C5-C6-cycloalkyl or C6-C12-aryl group or a pentagonal heterocyclic residue or hexagonal, or when R1 is COOR2, R2 can represent a hydrogen atom or a phenacyl free or substituted by 1-3 halogen atoms, A is a CH = CH or -C = C- group with E configuration, W is a free or functionally transformed hydroxymethylene group or a free or functionally transformed group (a), while the OH group can be located in alpha or beta, D is a straight or branched chain alkylene group having between 1 and 5 atoms or is a direct bond, E is a -C = C- group, a C2-C4-alkenyl group, or a group (b); R3 is a hydrogen atom, a C2-C4-alkenylene group, a C3-C10-cycloalkyl group, an optionally substituted C6-C12-aryl group or a pentagonal or hexagonal heterocyclic group, R4 is a hydrogen atom, a methyl group or a free or functionally transformed hydroxyl group, and when R2 represents a hydrogen atom, its salts with physiologically compatible bases, cyclodextrin alpha, beta or gamma clathrates. The invention also relates to the compounds of formula (I) encapsulated in liposomes, their production process and their pharmaceutical use.

Description

 6-oxo-9-fluor prostaglandin deriva te

 Process for their preparation and

 their pharmaceutical use

description

The invention relates to new 6-oxo-9-fluoroprostaglandin derivatives, processes for their preparation and their use as medicaments.

From the very extensive state of the art of prostaglandins, in particular of the E type and their analogues, it is known that, due to their biological and pharmacological properties, this class of substances is used for the therapy and prophylaxis of thromboses, infarcts and other cardiovascular diseases and for the therapy of Gastric ulcer is suitable. Structural changes therefore aim to prolong the duration of action, increase the selectivity of effectiveness and at the same time reduce the dose.

It has now surprisingly been found that the introduction of a fluorine atom into position 9 and the introduction of a triple bond into the 18, 19 or 19, 20 and / or 13, H position and the introduction of a methyl group into the 16 and / or 20-position of the lower chain of the 6-oκo-9-fluoroprostaglandin analogues improves the chemical and metabolic stability as well as the effectiveness, the selectivity is increased and the duration of action can be extended.

The compounds of this invention are useful in the therapy of diseases of the cardiovascular system, the stomach, the pancreas, the liver and the kidney. They have a hypotensive and bronchodilatory effect. They are suitable for inhibiting platelet activation. Consequently, the new 6-oxo-9-fluoroprostaglandin derivatives of the formula I are valuable active pharmaceutical ingredients.

The invention relates to 6-oxo-9-fluoroprostaglandin derivatives of the formula I.

wherein

R ^{1 represents} the radical COOR ² or CONHSO ₂ R ² with R ² meaning a C ₅ -C ₆ cycloalkyl or a C ₆ -C ₁₂ aryl group or a 5- or 6-membered heterocyclic radical or, if R ¹ is COOR ² , R ^{2 is} a

Can have hydrogen atom or a free or substituted by 1-3 halogen atoms phenacyl. an E-configured CH = CH or a -C = C group,

W is a free or functionally modified hydroxymethylene group or a free or functionally modified OH group, the OH group

 can be α- or ß-permanent,

D is a straight-chain or branched-chain alkylene group with 1-5 C atoms or a direct bond,

E is a -CΞC group, a C ₂ -C ₄ alkenylene group or a group,

R ^{3 represents} a hydrogen atom, a C ₁ -C ₁₀ alkenyl, C ₃ -C ₁₀ cycloalkyl or an optionally substituted C ₆ -C ₁₂ aryl group or a 5- or 6-membered heterocyclic group,

R ^{4 represents} a hydrogen atom, a methyl group or a free or functionally modified hydroxy group and, if R ^{2 has} the meaning of a hydrogen atom, the salts thereof with physiologically compatible bases, the α-, β- or γ-cyclodextrin clathrates of the compounds of the formula I and also compounds of formula I encapsulated with liposomes

As alkyl groups R ² straight or branched chain alkyl groups with 1-10 C atoms are meant, such as methyl, ethyl, propyl, isopropyl, butyl,

Isnbutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, heκyl, decyl. The alkyl groups R ² can optionally be substituted one to more times by

Halogen atoms, hydroxyl groups, C ₁ -C ₄ alkoxy groups, optionally substituted

C ₆ -C ₁₂ aryl groups, D1-C ₁ -C ₄ alkylammes and tri-C ₁ -C ₄ alkylammonium. Preferred alkyl groups are those which are monosubstituted. Examples of substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. Preferred alkyl groups R ² are those with 1-4 C atoms, such as methyl,

To name ethyl, propyl, dimethylaminopropyl, isobutyl and butyl. Suitable aryl groups R ² are both substituted and unsubstituted aryl groups, such as phenyl, α- or β-naphthyl and diphenyl. These groups can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxyl or alkoxy group with 1-4 C atoms his. The substituents in the 3- and 4-position on the phenyl ring are preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy. The cycloalkyl groups R ² can contain 3-10, preferably 5 and 6, carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl. Suitable heterocyclic groups R ² are 5- and 6-membered heterocycles, which preferably contain a heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. The hydroxyl groups R ⁴ , R ⁵ and in W can be functionally modified, for example by etherification or esterification, it being possible for the free or modified hydroxyl groups in W and R ^{5 to be} α- or β-permanent and free hydroxyl groups are preferred.

Suitable ethers and acyl radicals are the radicals known to the person skilled in the art. Easily cleavable ether radicals, such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, methoxyethyl, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl, theκyl-dimethylsilyl and α-tribenzylsilyl radical, are preferred. Acyl radicals which may be mentioned are, for example, acetyl, propionyl, butyryl and benzoyl. Suitable alkyl groups R ³ are straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1-7, carbon atoms, which may optionally be substituted by optionally substituted aryl. Examples include methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentyl, hexenyl, benzyl and p-chlorobenzyl. The cycloalkyl group R ³ can contain 3-10, preferably 3-6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.

Examples of substituted or unsubstituted aryl groups R ³ are phenyl, 1-naphthyl and 2-naphthyl, diphenyl, each of which is represented by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each having 1-4 carbon atoms

Chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C ₁ -C ₄ alkoxy or hydroxy group can be substituted. The substitution in the 3- and 4-position on the phenyl ring is preferred, for example by fluorine, chlorine, C ₁ -C ₄ -alkoxy or trifluoromethyl or in the 4-position by hydroxy.

Suitable heterocyclic groups R ³ are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

Suitable alkylene groups D are straight-chain or branched-chain, saturated and unsaturated alkylene radicals, preferably saturated ones with 1-10, in particular 1-5, carbon atoms, which can optionally be substituted by fluorine atoms. Examples include methylene, fluoromethylene, ethylene, 1, 2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene and 1-methyl-trimethylene. For salt formation with the free acids (R ² = H) are inorganic and organic

Bases suitable as they are physiologically tolerated by those skilled in the art

Salts are known. Examples include alkali metal hydroxides such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as etha called nolamine, diethylanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine etc. as C ₂ -C ₄ alkenylene group includes the following radicals: -CH = CH-, -CH = C (CH ₃ ) -,

-C (CH ₃ ) = CH- or -C (CH ₃ ) = C (CH ₃ ) -.

The invention further relates to a process for the preparation of the compounds of formula I, which is characterized in that a compound of formula II

wherein

 X is a or group,

R ^{5 is} a hydroxyl group and R ¹ , R ³ , R ⁴ , A, W, D and E have the meanings given above and free OH groups in R ⁴ , R ⁵ and W are protected with diethylaminosulfur trifluoride [M. Sharma, Tetrahedron Lett. 57j (197%); WJ

Middleton, J. Org. Chem. 40, 574 (1975)] or other fluorinating agents such as (HF) _n pyridine [GA Olah, Synthesis 786 (1973)], SeF ₄ Pyrιdιn [GA Olah,

J. Am. Chem. Soc. 96. 925 (1974)] or (C ₂ H ₅ ) ₂ N CF ₂ CHClF [EJ Bailey, Chem. Commun. 106 (1970); J. Kopecky, Chem. Ind. 271 (1969)] and, if appropriate, releases protected hydroxyl groups in X and oxidizes them to the ketone, and also releases protected hydroxyl groups in R ⁴ and W and / or free hydroxyl groups are esterified, etherified and / or an esterified carboxy group is saponified or a carboxy group with a physiologically acceptable base in a salt or with α-, ß- or γ-cyclodextrin in a clathrate, or encapsulated with liposomes.

The reaction of the compounds of general formula II to the compounds of general formula I is carried out with diethylaminosulfur trifluoride at -80 ° C to +40 ° C, preferably at -70 ° C to +20 ° C. As a solvent are dichloromethane, 1.1.2-trifluorotrichloroethane, pyridine, toluene, benzene, ethylene chloride and others, but preferably toluene and methylene chloride. The release of the functionally modified hydroxy groups R ⁴ , R ⁵ and in W and the oxidation of the released hydroxy group R ⁵ to the ketone is carried out according to the methods known to the person skilled in the art (DE 370853%).

The hydroxyl group in X is oxidized by the processes known to the person skilled in the art. Chromium sulfuric acid, for example, comes as the oxidizing agent

(Jones reagent), pyridinium chromate, pyridinium chlorochromate, Collins reagent or complexes of CrO ₃ with other amine bases such as benzotriazole and pyrazole in question. The reaction is carried out with Jones reagent at -40 ° C to 0 ° C, preferably at -30 ° C to -10 ° C, using the other oxidizing agents, preferably at -10 ° C to +25 ° C. Suitable solvents are methylene chloride, chloroform, ethylene chloride, acetone, pyridine, among others, but preferably methylene chloride and acetone.

For example, the cleavage of ether protecting groups in an aqueous solution of an organic acid, e.g. Acetic acid, propionic acid, citric acid u. a. or in an aqueous solution of an inorganic acid, e.g. Hydrochloric acid, or in the case of tetrahydropyranyl ethers using pyridinium p-toluenesulfonate, preferably in alcohols as a solvent or using anhydrous magnesium bromide, preferably in diethyl ether as a solvent.

To improve the solubility, a water-miscible inert solvent is advantageously added when using aqueous-acidic reaction conditions. For example, it has proven to be suitable Alcohols such as methanol and ethanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran, with tetrahydrofuran preferably being used.

The silyether protecting groups are cleaved off, for example, using tetrabutylammαnium fluoride. Tetrahydrofurao diethyl ether, dioxane, methylene chloride etc. are suitable as solvents.

The cleavage is preferably carried out at temperatures between 20 ° C and 80 ° C. The saponification of the acyl groups and prostaglandin esters is carried out according to the methods known to the person skilled in the art, such as, for example, with basic catalysts such as, for example, with alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or in the aqueous solution of an alcohol. Aliphatic alcohols such as, for example, methanol, ethanol, butanol, etc. are suitable as alcohols, but preferably methanol. Potassium and sodium salts may be mentioned as alkali carbonates and hydroxides. The potassium salts are preferred. Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and tree carbonate. The reaction is generally carried out at -10 ° C to +70 ° C, but preferably at +25 ° C.

The introduction of the ester group CO ₂ R ² for R ¹ , in which R ^{2 represents} an alkyl group with 1-10 C atoms, takes place according to the methods known to the person skilled in the art. The 1-carboxy compounds (R ² - H) are reacted, for example, with diazo hydrocarbons in a manner known per se. The esterification with diazo hydrocarbons takes place, for example, by dissolving the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the

1-carboxy compound, dissolved in the same or in another likewise inert solvent, such as e.g. Methylene chloride is mixed. After finished

Reaction in 1 to 60 minutes, the solvent is removed and the ester is purified in the usual way. Diazole alkanes are either known or can be prepared by known methods [Org. Reactions Vol. 8, pp. 389-394

(1954)].

The introduction of the ester group CO ₂ R ₂ for R ¹ , in which R ^{2 represents} a substituted or unsubstituted aryl group, takes place according to the methods known to the person skilled in the art. For example, the 1-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicycloheκylcarbodiimide in the presence of a suitable base such as pyridine, dimethylaminopyridine, triethylamine, in an inert solvent such as methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, but preferably chloroform. The reaction is carried out at temperatures between -30 ° C and +50 ° C, preferably at +10 ° C.

The prostaglandin derivatives of the formula I with R ¹ in the meaning of a hydrogen atom can be mixed with suitable amounts of the corresponding inorganic bases be converted into salts with neutralization. For example, when the corresponding prostaglandic acids are dissolved in water which contains stoichiometric amounts of the base, the solid inorganic salt is obtained after the water has been evaporated off or after a water-miscible solvent, for example alcohol or acetone, has been added.

The amine salts are prepared in a conventional manner. To do this, the prostaglandic acid is dissolved in a suitable solvent, e.g. Ethanol, acetone, diethyl ether or benzene and add 1 to 5 equivalents of the respective amine to this solution. The salt is usually obtained in solid form or is isolated in a conventional manner after evaporation of the solvent.

The functional modification of the free hydroxyl groups takes place according to the methods known to the person skilled in the art. To introduce the ether protecting groups, for example, with dihydropyran or methyl vinyl ether in methylene chloride or chloroform using catalytic amounts of an acidic condensing agent such as e.g. p-toluenesulfonic acid. The respective enol ether is added in excess, preferably in 1.5 to 10 times the theoretical amount. The reaction normally takes place at -10 ° C to +30 ° C and is complete after 2-30 minutes.

The acyl protective groups are introduced by reacting a compound of the formula I in a manner known per se with a carboxylic acid derivative, e.g. Acid chloride, acid anhydride, etc., implemented.

The new 6-oxo-9-fluor prostaglandin derivatives have the properties typical of this class of compounds, such as lowering peripheral arterial, coronary and pulmonary vascular resistance, lowering pulmonary blood pressure. Lowering systemic blood pressure without reducing stroke volume and coronary blood flow, promoting kidney blood flow and blood flow to other peripheral organs, increasing cerebral blood flow, inhibiting platelet activation and thrombus dissolution, inhibiting bronchoconstriction, inhibiting gastric acid secretion, gastric acid secretion, cytoprotection of the heart - and intestinal mucosa, the liver, cytoprotection in the pancreas and kidney as well as anti-allergic properties. Therefore, the new 5-oxo-9-fluor-prostaglandin derivatives are principally suitable for the treatment of stroke, the prophylaxis and therapy of coronary heart diseases, for Examples of coronary thrombosis, for the treatment of myocardial infarction, peripheral arterial diseases, for prophylaxis and therapy for other thromboembolic diseases and for arteriosclerosis, for chemical attacks of the CNS system and other circulatory disorders of the brain, for the treatment of hypertension and for the treatment of diseases associated with Increase in pulmonary vascular resistance such as pulmonary hypertension and for the treatment of shock and asthma. They can also be used to inhibit labor pains and to treat pregnancy toxicosis.

The new 6-oxo-9-fluoroprostaglandin derivatives can also be used to improve organ function after transplantation, for example in kidney transplantation, to prevent rejection reactions, instead of heparin or as an adjuvant in dialysis or hemofiltration and in the preservation of preserved blood plasma, for example preserved blood platelets. The new 6-oxo-9-fluor prostaglandin derivatives have an antimetastatic effect and antiproliferative properties.

The 6-oxo-9-fluoroprostaglandin derivatives of this invention can also be used in combination, e.g. with ß-blockers, diuretics, phosphodiesterase inhibitors, Ca antagonists, nothing teroidal anti-inflammatories, leukotriene synthetase inhibitors, leukotriene antagonists, thrombo-kinesan synthetase inhibitors or thrombo-kan antagonists.

The dose of the compounds is 1-1000 μg / kg / day when administered to the human patient. The unit dose for the pharmaceutically acceptable carrier is 10 μg to 100 μg.

Sterile, injectable aqueous or oily solutions are used for parenteral administration. Tablets, coated tablets or capsules, for example, are suitable for oral administration. The invention thus also relates to medicaments based on the compounds of the formula I and customary auxiliaries and excipients, including cyclodextrin lactate and encapsulation with liposomes.

The active compounds according to the invention are to be used in conjunction with the auxiliaries known and customary in galenics, for example for the production of hypotensive agents, platelet aggregation inhibitors or cytoprotectants. example 1

(9R, 11R, 13E, 15S, 16S) -6-oxo-9-fluoro-11,15-bis-hydroxy-16-methyl-18.18,19,19-te¬tradehydro-13-prostatic acid:

45 mg (81.7 μmol) of the compound shown in Example 1a were mixed with 2 ml of a glacial acetic acid: water: tetrahydrofuran (65:35: 10) mixture and the mixture was stirred at 23 ° C. for 15 hours. The mixture was concentrated in a water jet vacuum and residual acetic acid was removed azeotropically by repeated addition of toluene. The crude oil obtained was purified by chromatography on an analytical thin-layer plate. A mixture of dichloromethane and methanol was used as the eluent, and a mixture of chloroform and isopropanol as the eluent. 23 mg (60 μmol, 73%) of the title compound were isolated as a colorless oil.

IR (film): 3700-2400, 2960, 2920, 2850, 1710, 1410. 1375, 1095 and 975 cm ^-1 .

Example 1a

(9R.11R, 13E, 15S.16S) -6-oxo-9-fluoro-11,15-bis- (tetrahydropyran-2-yloxy) -16-methyl-1 8, 1 8, 1 9, 19-tetradehydro - 1 3-prosten acid:

48 mg (85 μmol) of the compound shown in Example 1b was dissolved in 1.4 ml of methanol, mixed with 0.5 ml of an aqueous potassium hydroxide solution and stirred at 23 ° C. for 2.5 hours. The methanol was removed in a water jet vacuum, diluted with a little water, acidified with saturated citric acid and extracted several times with a total of 15 ml of chloroform. The organic phase was washed with H ₂ O, dried over magnesium sulfate and isolated after filtration and removal of the solvent in a water jet vacuum 45 mg (82 μmol, 96%) of the title compound as a colorless oil.

IR (film) 3600-2500, 2950, 2860, 1710, 1440, 1130, 1030 1020, 970, 870 and 810 cm ^-1 . Example 1b

(11R.13E.15S, 16S) -6-oxo-11,15-bis- (tetrahydropyran-2-yloxy) -16-methyl-18,18,19 19-tetradehydro-8,13-prostadic acid methyl ester (A) and (9R, 11 R, 13E, 15S, 16S) -6- oxo-9-fluoro-11,15-bis- (tetrahydropyran-2-yloκy) -16-methyl-18,18,19,19-tetradehydro-13 -prostensauremethylester (B):

280 mg (498 μmol) of the compound shown in Example 1c was dissolved in 8.5 ml of anhydrous toluene, 395 μl of anhydrous pyridine were added, the mixture was cooled to -70 ° C. under an atmosphere of dry argon and 297 μl of diethylaminosulfur trifluoride were added. The mixture was allowed to warm slowly to 20 ° C., mixed with a few drops of a saturated sodium bicarbonate solution, diluted with water and extracted several times with dichloromethane. After drying over magnesium sulfate, filtration and concentration in a water jet vacuum, the residue was purified by chromatography on about 30 ml of fine silica gel under pressure. A mixture of n-hexane / ethyl acetate was used as the eluent. 31 mg (56.9 μmol, 11%) of the title compound A and 48 mg ('85 μmol, 17%) of the title compound B were isolated in each case as a colorless oil.

IR (film) from W: 2940, 2860, 1735, 1710, 1435, 1200, 1130, 1030, 1020, 970, 870 and 815 cm ^-1 .

Example 1c

(9S, 11R, 13E, 15S, 16S) -6-oxo-9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -16-methyl-18,18,19,19-tetradehydro-13- prostate acid methyl ester:

6.3 g (9.3 mmol) (5RS, 6RS, 16S) -5-iodine-16-methyl-18,18,19,19-tetradehydro-prostaglandin I ₁ -11,15-bιs- (tetrahydropyranylether) - methyl ester (preparation see DE 3708537 using dimethyl (2-oxo-3S-methyl-hept-5-ιnyl) phosphonate) was dissolved in 95 ml of anhydrous benzene, 20.5 ml of DBU were added and the mixture was stirred at 55 for 2 hours ° C under an atmosphere of dry argon. The mixture was diluted with 100 ml of ethyl acetate, washed several times with water, dried over magnesium sulfate and, after filtration and removal of the solvent, 5.1 g of a yellow oil were isolated. The residue was placed on a silica gel column and eluted after a two-hour residence time with a mixture of dichloromethane / ace volume. 4.28 g (7.6 mmol, 81%) of the title compound were isolated as a colorless oil.

IR (film): 3600-3200, 2950, 2860, 1740, 1715, 1440, 1355, 1200, 1130, 1020, 970, 865 and 810 cm ^-1 .

Example 2

(9S, 11R, 13E, 15S, 16S) -6-oxo-9-fluoro-11,15-dihydroxy-16-methyl-18.18.19,19-tetradehydro-13-prostatic acid:

48 mg (90 μmol) of the compound shown in Example 2a were reacted analogously to Example 1 and, after working up and chromatographic purification, 25 mg (65 μmol, 72%) of the title compound were isolated as a colorless oil.

IR (film): 3700-2400. 2960, 2920, 2850, 1710, 1410, 1375, 1090, 1040, 1010, 925 and 915 cm ^-1 .

Example 2a

(9S.11R, 13E, 15S, 16S) -6-oxo-9-fluoro-11,15-bis- (tetrahydropyran-2-yloxy) -16-methyl-18,18,19,19-tetradehydro-13- prostic acid:

The solution of 64 mg (116 μmol) of the compound shown in Example 2b in 500 μl acetone was cooled to -40 ° C., treated with 68 μl of a standardized chromosulfuric acid (Jones solution) and allowed to react for 2.5 hours. Excess oxidant was decomposed by adding 120 μl of isopropanol, allowed to warm to 0 ° C., diluted with water and, after an hour, extracted several times with chloroform. The organic extracts were washed neutral with water and saturated sodium chloride solution, dried over magnesium sulfate and the residue obtained after filtration and removal of the solvent was purified by chromatography on two analytical thin-layer plates. A mixture of dichloromethane and methanol was used as the eluent, and a mixture of chloroform / isopropanol as the eluent. 33 mg (60 μmol, 52%) of the were isolated Title compound as a colorless oil.

IR (film): 3600-2500, 2940, 2860, 1715, 1435, 1135, 1030, 1020, 970, 865 and 810 cm ^-1 .

Example 2b

(6RS, 9S, 11R, 13E.15S, 16S) -6-hydroxy-9-fluoro-11,15-bis- (tetrahydropyran-2-yloxy) - 16-methyl-18,18,19,19-tetradehydro- 13-prostic acid:

The solution of 196 mg (194 μmol) of the compound shown in Example 2c in 3.3 ml of anhydrous tetrahydrofuran was mixed with 1.16 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and left for 8 hours at 50 ° C. under an atmosphere react from dry argon, poured into ice water and extracted several times with dichloromethane. The organic extracts were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the residue obtained after filtration and removal of the solvent was purified by chromatography on 7 analytical thin-layer plates. A mixture of dichloromethane / methanol was used as the eluent and a mixture of chloroform / isopropanol as the eluent. 64 mg (116 μmol, 60%) of the title compound were isolated as a colorless oil.

IR (film): 3600-2500, 2940, 2860, 1725, 1710, 1445, 1130, 1020, 970 and 840 cm ^-1 .

Example 2c

(6RS.9S.11R.13E.15S, 16S) -6-tert-butyldimethylsilyloxy-9-fluoro-11.15-bis- (tetrahydropyran-2-yloxy) -16-methyl-18,18,19,19-tetradehydro -13-prostic acid:

195 mg (285 μmol) of the fluorine compound isolated according to Example 2d was saponified in analogy to Example 1a and, after workup and purification, 188 mg (282 μmol, 99%) of the title compound was isolated as a colorless oil. IR (film): 3600-2500, 2940, 2850, 1730, 1710, 1450, 1255, 1130 1075, 1030, 1020, 970, 835 and 775 cm ^-1 .

Example 2d

(6RS, 9S, 11R, 13E, 15S, 16S) -6-tert-butyldimethylsilyoxy-9-fluoro-11,15-bis- (tetrahydropyran-2-yloκy) -16-methyl-18,18,19,19 -tetradehydro-13-prostic acid methyl ester:

550 mg (811 μmol) of the compound shown in Example 2e were reacted analogously to Example 1b and, after workup and chromatographic purification, 330 mg (485 μmol, 60%) of the title compound were isolated as a colorless oil.

IR (film): 2940, 2850, 1740, 1435, 1250, 1130, 1110, 1075, 1030, 1020, 970, 835 and 770 cm ^-1 .

Example 2e

(6RS, 9R, 13E, 15S, 16S) -6-tert-butyldimethylsilyoxy-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) -16-methyl-18,18,19,19-tetradehydro -13-methyl prostate:

The solution of 775 mg (989 μmol) of the compound shown in Example 2f in 4 ml of anhydrous methanol was mixed with 120 mg of finely powdered potassium carbonate and the mixture was stirred at 45 ° C. for 8 hours under an atmosphere of dry argon. Water was added, the pH was brought to 4 by adding saturated citric acid, the mixture was extracted several times with dichloromethane, washed neutral with water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration and removal of the solvent, the residue was purified by chromatography on about 30 ml of fine silica gel using a gradient system composed of n-hexane / ethyl acetate. 551 mg (817 μmol, 82%) of the title compound were isolated as a colorless oil.

IR (film): 3600-3200, 2940, 2860, 1740, 1435, 1360, 1255, 1200, 1130, 1115, 1030, 1020, 970, 865, 835, 810 and 775 cm ^-1 . Example 2f

(6RS, 9R, 13E, 15S, 16S) -6-tert-butyldiphenylslylyoxy-9-benzoyloxy-11.15-bιs- (tetrahydropyran-2-yloxy) -16-methyl-18.18, 19.19-tetradehydro -13-methyl prostate:

The solution of 693 mg (1.02 mmol) of the compound shown in Example 2g in 25 ml of anhydrous toluene was mixed with 590 mg of triphenylphosphine, 277 mg of benzoic acid and 355 μl of diethyl azodicarboxylate. The yellow solution was allowed to stir for 5 hours at 23 ° C. under an atmosphere of dry argon, water was added, the mixture was extracted several times with diethyl ether and dried over magnesium sulfate. The residue obtained after filtration and removal of solvent was purified by chromatography on about 70 ml of fine silica gel using a gradient system composed of n-hexane / ethyl acetate. 776 mg (991 μmol, 97%) of the title compound were isolated as a colorless oil.

IR (film): 3040, 2940, 2850, 1740, 1715, 1600, 1430, 1360, 1250, 1200, 1110, 1020, 970, 860, 835, 810, 775 and 740 cm ^-1 .

Example 2g

(6RS, 9S, 13E, 15S, 16S) -6-tert-Butyldιmethylsιlyoxy-9-hydroxy-11,15-bιs- (tetrahydropyran-2-yloκy) -16-methyl-18,18,19,19-tetradehydro -13-prostate acid methyl ester:

1.168 g (1.49 mmol) of the compounds shown in Example 2h were dissolved in 6 ml of methanol, mixed with 2.5 ml of a 5% strength methanolic lithium hydroxide solution and stirred at 50 ° C. for 6 hours. It was concentrated in a water jet vacuum, mixed with water and dichloromethane, acidified by adding a saturated solution of citric acid and extracted several times with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and the hydroxy acid obtained after filtration and removal of the solvent was esterified at 5 ° C. with an ethereal diazomethane solution in analogy to Example 3. The residue obtained after the solvent had been drawn off again was purified by chromatography on about 70 ml of fine silica gel using a gradient system composed of n-hexane / ethyl acetate. 903 mg were isolated (1.33 mmol, 90%) of the title compound as a colorless oil.

IR (film): 3600-3200, 2940, 2850, 1740, 1435, 1360, 1250, 1200, 1030, 1020, 970, 835 and 775 cm ^-1 .

Example 2h

(6RS, 9S, 13E, 15S, 16S) -6-tert-butyldimethylsilyloxy-9-benzoyloxy-11,15-bis- (tetrahydropyran-2-yloκy) -16-methyl-18,18,19,19-tetradehydro -13-methyl prostate:

The colorless solution of 1.19 g (1.79 mmol) of the compound shown in Example 2i in 18 ml of anhydrous dimethylformamide was mixed with 305 mg of imidazole, 675 mg of tert-butyldimethylchlorosilane and stirred at 23 ° C. for 5 hours under one atmosphere dry argon. It was poured into ice-cold ammonium chloride solution, extracted several times with diethyl ether, washed with water and dried over magnesium sulfate. The residue obtained after filtration and removal of solvent was purified by chromatography on about 70 ml of fine silica gel using a gradient system composed of n-hexane / ethyl acetate. 1.16 g (1.49 mmol, 83%) of the title compound were isolated as a colorless oil.

IR (film): 3060, 2940, 2855, 1735, 1715, 1600, 1450, 1360, 1270, 1200, 1110, 1030, 1020, 970, 870, 835, 810, 775, 735 and 710 cm ^-1 .

Example 2i

(6RS, 9S, 13E, 15S, 16S) -6-hydroxy-9-benzoyloxy-11,15-bis- (tetrahydropyran-2-yloxy) -16-methyl-18,18,19,19-tetradehydro-13- methyl prostate:

1.32 g (1.99 mmol) of the compound shown in Example 2j was dissolved in a mixture of 16 ml of anhydrous methanol and 5 ml of anhydrous dichloromethane, cooled to -40 ° C. under an atmosphere of dry argon and a total of 455 was added in portions mg sodium borohydride. The mixture was left to react at -40 ° C. for 1 hour, mixed with 740 μl of glacial acetic acid and concentrated in a water jet vacuum. The residue was taken up in dichloromethane, washed several times with water, dried over magnesium sulfate and purified the residue obtained after filtration and removal of the solvent by chromatography on about 130 ml of fine silica gel using a gradient system composed of n-hexane / ethyl acetate. 1.19 g (1.78 mmol, 89%) of the title compound were isolated as a colorless oil.

IR (film): 3600-3300, 3060, 2940, 2870, 1735, 1715, 1600, 1450, 1370, 1275,

1200, 1115, 1020, 970, 870, 815 and 715 cm ^-1 .

Example 2j

(9S, 11R, 13E, 15S, 16S) -6-Ox0-9-benzoyloxy-11,15-bis- (tetrahydropyran-2-yloκy) - 16-methyl 18,18,19,19-tetradehydro-13-prostate acid, methyl ester :

1.13 g (2.0 mmol) of the compound shown in Example 1c was dissolved in 4.4 ml of anhydrous pyridine, cooled to 5 ° C. under an atmosphere of dry argon, 600 μl of benzoyl chloride were added dropwise and the mixture was stirred for 3.5 hours 23 ° C. It was poured into ice water, extracted several times with diethyl ether, dried over magnesium sulfate and the residue obtained after filtration and removal of the solvent was purified by chromatography on about 130 ml of fine silica gel using a gradient system composed of n-hexane / ethyl acetate. 1.33 g were isolated

 (1.99 mmol, 99%) of the title compound as a colorless oil.

IR (film): 3060, 2940, 2870, 1735, 1715, 1600, 1450, 1370, 1270, 1200, 1110, 1020, 970, 870, 815 and 715 cm ^-1 .

Example 3

(9R, 11R, 13E, 15S.16S) -6-oxo-9-fluoro-11,15-dihydroxy-16-methyl-18,18,19,19-tetradehydro-13-prostate acid methyl ester:

10 mg (26 μmol) of the compound shown in Example 1 was esterified at 5-10 ° C. by adding an ethereal diazomethane solution. The homogeneous solution formed after about 15 minutes was concentrated in a water jet vacuum and purified by chromatography on half an analytical thin-layer plate. A mixture of n-hexane / ethyl acetate served as the eluent and diethyl as the eluent ether. 7.6 mg (19 μmol, 74%) of the title compound were isolated as a colorless oil.

IR (film): 3600-3200, 2960, 2930, 2860, 1740, 1720, 1410, 1380, 1095 and 975 cm ^-1 .

Example 4

(9S, 11R, 13E, 15S, 16S) -6-oxo-9-fluoro-11,15-dihydroxy-16-methyl.18,18.19,19-tetradehydro-13-prostonic acid methyl ester:

11 mg (29 μmol) of the compound shown in Example 2 was esterified analogously to Example 3 and, after purification, 8.5 mg (21 μmol, 74%) of the title compound was isolated as a colorless oil.

IR (film): 3600-3200. 2960, 2940, 2850, 1735, 1715, 1410, 1375, 1090 and 975 cm ^-1 .

Example 5

(9R, 11R, 15S, 16S) -6-oxo-9-fluoro-11,15-bis-hydroxy-16,20-dimethyl-13,14,18,18,19, 19-hexadehydro-13-prostic acid:

37 mg (66 μmol) of the compound shown in Example 5a were reacted analogously to Example 1 and, after workup and purification, 17 mg (43 μmol, 65%) of the title compound were isolated as a colorless oil.

IR (film): 3600-2500. 2970, 2230, 1730, 1710, 1410, 1275, 1020 and 970 cm ^-1 . Example 5a

(9R, 11R, 15S, 16S) -6-oxo-9-fluoro-11,15-bis- (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14,18,18,19,19- hexadehydro-13-prostic acid:

41 mg (73 μmol) of the fluorine compound shown in Example 5b is saponified in analogy to Example 1a and, after workup and purification, 37 mg (66 μmol, 90%) of the title compound are isolated as a colorless oil.

IR (film): 3600-2500, 2960, 2920, 2850, 2230, 1715, 1435, 1135, 1030, 1020, 970, 870 and 815 cm ^-1 .

Example 5b

(11R, 15S, 16S) -6-oxo-11,15-bis- (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14, 18, 18,19,19-hexadehydro-8,13- methyl prostadienes (A) and (9R, 11R, 15S, 16S) -6-oxo-9-fluoro-11,15-bis (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14, 18,18 , 19,19-hexadehydro-13-prostenic acid methyl ester (B):

243 mg (422 μmol) of the compounds shown in Example 5c were reacted analogously to Example 1b and, after working up and chromatographic separation, 45 mg (81 μmol, 19%) of the title compound A and 41 mg were isolated

 (71 µmol, 17%) of the title compound B as a colorless oil.

IR (film) from W: 2960, 2920, 2860, 2230, 1735, 1715, 1440, 1200, 1130, 1030, 1020, 970, 875 and 810 cm ^-1 .

Example 5c

(9R, 11R, 15S, 16S) -6-oxo-9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14,18,18,19,19- Heκadehydro-13-prostic acid methyl ester:

4.6 g (6.7 mmol) (5RS, 6RS.16S) -5-iodine-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-prostaglandin-I ₁ -11.15 bis (tetra hydropyra nyl ether) methyl ester (see DE3708537 for representation) was reacted in analogy to Example 1c and isolated after working up and chromatographic purification, 3.5 g (6.1 mmol, 91%) of the title compound as a colorless oil.

IR (film): 3600-3200. 2960, 2920, 2850, 2230, 1730, 1710, 1435, 1200, 1130, 1030, 1020, 970, 870 and 815 cm ^-1 .

Example 6

(9S, 11R, 15S.16S) -6-oxo-9-fluoro-11.15-dihydroxy-16.20-dimethyl-13,14,18,18,19, 19-hexadehydro-13-prostatic acid:

35 mg (62 μmol) of the compound shown in Example 6a was reacted analogously to Example 1 and, after workup and purification, 19 mg (48 μmol, 77%) of the title compound were isolated as a colorless oil.

IR (film): 3700-2500. 2960, 2920, 2850, 2230, 1715, 1410, 1380, 1090, 1035, 1020, 930 and 915 cm ^-1 .

Example 6a

(9S, 11R, 15S.16S) -6-oxo-9-fluoro-11.15-dihydroxy-16.20-dimethyl-13,14,18,18,19,19-hexadehydro-13-prostatic acid:

61 mg (108 μmol) of the compound shown in Example 6b were reacted analogously to Example 2a and, after workup and purification, 35 mg (62 μmol, 57%) of the title compound were isolated as a colorless oil.

IR (film): 3600-2500, 2960, 2920, 2850, 2230, 1730, 1715, 1440, 1130, 1030, 1020, 970, 870 and 815 cm ^-1 . Example 6b

(6RS, 9S, 11R, 15S, 16S) -6-hydroxy-9-fluoro-11,15-bis- (tetrahydropyran-2-yloxy) - 16,20-dimethyl-13,14,18,18,19, 19-hexadehydro-13-prostic acid:

99 mg (152 μmol) of the compound shown in Example 6c were reacted analogously to Example 2b and, after workup and purification, 61 m (108 μmol. 71%) of the title compound were isolated as a colorless oil.

IR (film): 3600-2500, 2960, 2930, 2850, 2230, 1720, 1440, 1130, 1025, 970 and 835 cm ^-1 .

Example 6c

(6RS, 9S, 11R, 15S, 16S) -6-hydroxy-9-fluoro-11,15-bis- (tetrahydropyran-2-yloxy) - 16,20-dimethyl-13,14,18,18,19, 19-hexadehydro-13-prostic acid:

105 mg (158 μmol) of the compound shown in Example 6d were reacted analogously to Example 1a and, after working up and purification, 99 mg (152 μmol, 96%) of the title compound were isolated as a colorless oil.

IR (film 3600-2500, 2960, 2920, 2860, 2230, 1730, 1710, 1445, 1130, 1080,

1030, 1020, 970, 840 and 770 cm- ¹ .

Example 6d

(6RS, 9S, 11R, 15S, 16S) -6-tert-butyldimethylsilyloxy-11,15-bis (tetrahdropyran-2-yloxy) -16.20-dimethyl-13,14,18,18,19,19-hexadehydro -13-methyl prostate:

107 mg (164 μmol) of the compound shown in Example 6e were reacted analogously to Example 1b and, after workup and purification, 61 mg (92 μmol, 56%) of the title compound were isolated as a colorless oil.

IR (film): 2960, 2930, 2860, 2230, 1740, 1440, 1245, 1130, 1080, 1030, 1020, 970, 840 and 770 cm ^-1 . Example 6e

(6RS, 9R, 15S, 16S) -6-tert-butyldimethylsilyloxy-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14,18,18,19 , 19-hexadehydro-13-prostonic acid methyl ester:

150 mg (198 μmol) of the compound shown in Example 6f were reacted analogously to Example 2e and isolated after workup and purification

110 mg (168 μmol, 85%) of the title compound as a colorless oil.

IR (film): 3600-3200, 2940, 2850, 2230, 1735, 1440, 1355, 1250, 1200, 1130, 1030, 1020, 970, 860, 840, 815 and 775 cm ^-1 .

Example 6f

(6RS, 9R, 15S, 16S) -6-tert-butyldimethylsilyloxy-9-benzoyloxy-11,15-bis- (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14,18,18.19,19 -hexadehydro-13-prostonic acid methyl ester:

142 mg (217 μmol) of the compound shown in Example 6g were reacted analogously to Example 2f and, after workup and purification, 155 mg (204 μmol, 94%) of the title compound were isolated as a colorless oil.

IR (film): 3050, 2960, 2920, 2860, 2230, 1740, 1715, 1435, 1355, 1240, 1200, 1110, 1030, 1020, 970, 865, 835, 810, 775 and 735 cm ^-1 .

Example 6g

(6RS, 9S, 15S, 16S) -6-tert-butyldimethylsilyloxy-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14,18,18,19 , 19-hexadehydro-13-prostenic acid methyl ester: 419 mg (552 μmol) of the compound shown in Example 6h were reacted analogously to Example 2g and, after workup and purification, 352 mg (506 μmol, 92%) of the title compound were isolated as a colorless oil.

IR (film): 3600-3200, 2960, 2920, 2850, 2230, 1740, 1435, 1355, 1250, 1200, 1030, 1020, 970, 835 and 775 cm ^-1 .

Example 6h

(6RS, 9S, 15S, 16S) -6-tert-butyldimethylsilyloxy-9-benzoyloxy-11,15-bis- (tetrahydropyran-2-yloxy) -16,20-dimethyl-13,14,18,18,19 , 19-hexadehydro-13-prostonic acid methyl ester:

468 mg (719 μmol) of the compound shown in Example 6i were reacted analogously to Example 2h and, after workup and purification, 425 mg (561 μmol, 78%) of the title compound were isolated as a colorless oil.

IR (film): 3060, 2950, 2860, 2230, 1740, 1715, 1600, 1445, 1355, 1260, 1200, 1110, 1030, 1020, 970, 865, 830, 810, 770, 735 and 710 cm ^-1 .

Example 6i

(6RS, 9S, 15S, 16S) -6-hydroxy-9-benzoyloxy-11,15-bis- (tetrahydropyran-2-yloxy) - 16,20-dimethyl-13,14,18,18,19,19- hexadehydro-13-prostonic acid methyl ester:

550 mg (848 μmol) of the compound shown in Example 6j were reacted analogously to Example 2i and, after workup and purification, 473 mg (727 μmol, 86%) of the title compound were isolated as a colorless oil.

IR (film): 3600-3200, 3060, 2950, 2860, 2230, 1735, 1715, 1600, 1450, 1360, 1200. 1110, 1030, 1020, 970, 870, 820 and 710 cm ^-1 . Example 6j

(9S, 11R, 15S, 16S) -6-oxo-9-benzoyloxy-11,15-bis- (tetrahydropyran-2-yloxy) -16.20- dimethyl-13,14,18.18,19,19-hexadehydro-13- methyl prostate:

518 mg (900 μmol) of the compound shown in Example 5c was reacted analogously to Example 2j and, after workup and purification, 562 mg (866 μmol, 96%) of the title compound was isolated as a colorless oil.

IR (film): 3050, 2960, 2920, 2860, 2230, 1735, 1715, 1600, 1450, 1375, 1260, 1200, 1110, 1020, 970, 865, 815 and 710 cm ^-1 .

Example 7

(9R, 11R, 15S.16S) -6-Oxo-9-fluoro-11.15-dihydroxy-16.20-dimethyl-13,14,18,18,19,19-hexadehydro-13-prostonic acid methyl ester:

6.5 mg (16.4 μmol) of the compound shown in Example 5 was reacted analogously to Example 3 and, after workup and purification, 4.8 mg (11.7 μmol, 717.) of the title compound was isolated as a colorless oil.

IR (film): 3600-3200, 2960, 2920, 2850, 2230, 1735, 1715, 1410, 1375, 1095 and 980 cm ^-1 .

Example 8

(9S, 11R, 15S, 16S) -6-Oκo-9-fluoro-11.15-dihydroxy-16.20-dimethyl-13,14,18.18,19. 19-hexadehydro-13-prostenic acid methyl ester:

9 mg (22.7 μmol) of the compound shown in Example 6 was reacted analogously to Example 3 and, after workup and purification, 6.5 mg (15.9 μmol, 70%) of the title compound were isolated as a colorless oil.

IR (film) 3600-3200, 2960, 2920, 2850, 1735, 1715, 1410, 1375, 1095 and 980 cm ^-1 .

Claims

P a t e n t a n s p r u c h e 1.6-Oxo-9-fluor-prostaglandin derivatives of the formula I,

 wherein

R ^{1 is} COOR ² or CONHSO ₂ R ² with R ² as C ₅ -C ₆ cyclo

5 6 alkyl or a C ₆ -C ₁₂ aryi group or a 5- or 6-glιedrιgen heterocyclic radical or, if R ¹ is COOR, R ^{2 has} the meaning of a hydrogen atom or a free or substituted by 1-3 halogen atoms Phenacyls can have

A is an E-confgured CH = CH or a -C≡C group,

W is a free or functionally modified hydroxymethylene group or a free or functionally modified C (CH ₃ ) OH group, the OH group

 can be α- or ß-permanent,

D is a straight-chain or branched-chain alkylene group with 1-5 C atoms or a direct bond,

E is a - C≡C group, a C ₂ -C ₄ AI kenyl en group or a group,

R ^{2 is} a hydrogen atom, a C ₁ -C ₁₀ alkenyl, C ₃ -C ₁₀ cycloalkyl or an optionally substituted C ₆ - C ₁₂ aryl group or a 5- or 6-membered heterocyclic group, R ^{4 is} a Represent hydrogen atom, a methyl group or a free or functionally converted hydroxy group and, if R ^{2 has} the meaning of a water atom, its salts with physiologically compatible bases, the α-, β- or y-cyclαdextrin clathrates of the compounds of the formula I and the compounds of the formula I encapsulated with liposomes

2. A process for the preparation of the compounds of formula I, characterized in that a compound of formula II,

 wherein

X is a C = 0 or CH (R ⁵ ) group,

R ^{5 is} a hydroxyl group and R ¹ , R ³ , R ⁴ , A, W, D and E have the above-mentioned explanations and free OH groups in R ⁴ , R ⁵ and W are protected with diethylaminosulfur trifluoride or other fluorinating agents and protected hydroxyl groups released in X and oxidized to ketone, protected hydroxyl groups in R ⁴ and W released and / or free

Hydroxy groups are esterified, etherified and / or an esterified carboxy group is saponified or a carboxyl group is converted into a salt with a physiologically compatible base or reacted with α-, β- or γ-cyclodextrin to form a clathrate or encapsulated with liposomes.

3. Medicament from one or more compounds of the formula I and customary auxiliaries, carriers and additives.