WO1990002728A2 - 6-oxo-9-fluor-prostaglandin-derivate, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung - Google Patents

6-oxo-9-fluor-prostaglandin-derivate, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung Download PDF

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Publication number
WO1990002728A2
WO1990002728A2 PCT/DE1989/000588 DE8900588W WO9002728A2 WO 1990002728 A2 WO1990002728 A2 WO 1990002728A2 DE 8900588 W DE8900588 W DE 8900588W WO 9002728 A2 WO9002728 A2 WO 9002728A2
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hydrogen atom
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PCT/DE1989/000588
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German (de)
English (en)
French (fr)
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WO1990002728A3 (de
Inventor
Ulrich Klar
Helmut VORBRÜGGEN
Claus-Steffen Stürzebecher
Karl-Heinz Thierauch
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Schering Aktiengesellschaft Berlin Und Bergkamen
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Publication of WO1990002728A2 publication Critical patent/WO1990002728A2/de
Publication of WO1990002728A3 publication Critical patent/WO1990002728A3/de

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof

Definitions

  • the invention relates to new 6-oxo-9-fluoroprostaglandin derivatives, processes for their preparation and their use as medicaments.
  • 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.
  • 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
  • W is a free or functionally modified hydroxymethylene group or a free or functionally modified OH group, the OH group
  • 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 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 ⁇ -, ⁇ - or ⁇ -cyclodextrin clathrates of the compounds of the formula I and also compounds of formula I encapsulated with liposomes
  • alkyl groups R 2 straight or branched chain alkyl groups with 1-10 C atoms are meant, such as methyl, ethyl, propyl, isopropyl, butyl,
  • 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
  • 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,
  • Suitable aryl groups R 2 are both substituted and unsubstituted aryl groups, such as phenyl, ⁇ - or ⁇ -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.
  • 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 ⁇ - or ⁇ -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, the ⁇ yl-dimethylsilyl and ⁇ -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.
  • 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.
  • R 2 H
  • 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
  • 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
  • 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.
  • diethylaminosulfur trifluoride 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
  • 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.
  • 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.
  • an organic acid e.g. Acetic acid, propionic acid, citric acid u. a.
  • an inorganic acid e.g. Hydrochloric acid
  • tetrahydropyranyl ethers using pyridinium p-toluenesulfonate preferably in alcohols as a solvent or using anhydrous magnesium bromide, preferably in diethyl ether as a solvent.
  • a water-miscible inert solvent is advantageously added when using aqueous-acidic reaction conditions.
  • 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 tetrabutylamm ⁇ nium 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.
  • 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
  • Diazole alkanes are either known or can be prepared by known methods [Org. Reactions Vol. 8, pp. 389-394
  • 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.
  • the 1-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohe ⁇ ylcarbodiimide 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.
  • a suitable base such as pyridine, dimethylaminopyridine, triethylamine
  • 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,
  • 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.
  • suitable amounts of 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.
  • 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.
  • a suitable solvent e.g. Ethanol, acetone, diethyl ether or benzene
  • 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.
  • a carboxylic acid derivative e.g. Acid chloride, acid anhydride, etc.
  • 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.
  • 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.
  • 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 ⁇ g / kg / day when administered to the human patient.
  • the unit dose for the pharmaceutically acceptable carrier is 10 ⁇ g to 100 ⁇ g.
  • 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.
  • auxiliaries known and customary in galenics, for example for the production of hypotensive agents, platelet aggregation inhibitors or cytoprotectants.
  • Example 1a 45 mg (81.7 ⁇ mol) 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 ⁇ mol, 73%) of the title compound were isolated as a colorless oil.
  • Example 1b 48 mg (85 ⁇ mol) 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 ⁇ mol, 96%) of the title compound as a colorless oil.
  • Example 1c 280 mg (498 ⁇ mol) of the compound shown in Example 1c was dissolved in 8.5 ml of anhydrous toluene, 395 ⁇ l of anhydrous pyridine were added, the mixture was cooled to -70 ° C. under an atmosphere of dry argon and 297 ⁇ l 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.
  • 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.
  • Example 2a 48 mg (90 ⁇ mol) of the compound shown in Example 2a were reacted analogously to Example 1 and, after working up and chromatographic purification, 25 mg (65 ⁇ mol, 72%) of the title compound were isolated as a colorless oil.
  • Example 2e 550 mg (811 ⁇ mol) of the compound shown in Example 2e were reacted analogously to Example 1b and, after workup and chromatographic purification, 330 mg (485 ⁇ mol, 60%) of the title compound were isolated as a colorless oil.
  • Example 2j 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 ⁇ l of glacial acetic acid and concentrated in a water jet vacuum.
  • Example 2 11 mg (29 ⁇ mol) of the compound shown in Example 2 was esterified analogously to Example 3 and, after purification, 8.5 mg (21 ⁇ mol, 74%) of the title compound was isolated as a colorless oil.
  • Example 5a 37 mg (66 ⁇ mol) of the compound shown in Example 5a were reacted analogously to Example 1 and, after workup and purification, 17 mg (43 ⁇ mol, 65%) of the title compound were isolated as a colorless oil.
  • Example 5b 41 mg (73 ⁇ mol) of the fluorine compound shown in Example 5b is saponified in analogy to Example 1a and, after workup and purification, 37 mg (66 ⁇ mol, 90%) of the title compound are isolated as a colorless oil.
  • Example 5c 243 mg (422 ⁇ mol) of the compounds shown in Example 5c were reacted analogously to Example 1b and, after working up and chromatographic separation, 45 mg (81 ⁇ mol, 19%) of the title compound A and 41 mg were isolated
  • Example 6a 35 mg (62 ⁇ mol) of the compound shown in Example 6a was reacted analogously to Example 1 and, after workup and purification, 19 mg (48 ⁇ mol, 77%) of the title compound were isolated as a colorless oil.
  • Example 6b 61 mg (108 ⁇ mol) of the compound shown in Example 6b were reacted analogously to Example 2a and, after workup and purification, 35 mg (62 ⁇ mol, 57%) of the title compound were isolated as a colorless oil.
  • Example 6c 99 mg (152 ⁇ mol) of the compound shown in Example 6c were reacted analogously to Example 2b and, after workup and purification, 61 m (108 ⁇ mol. 71%) of the title compound were isolated as a colorless oil.
  • Example 6d 105 mg (158 ⁇ mol) of the compound shown in Example 6d were reacted analogously to Example 1a and, after working up and purification, 99 mg (152 ⁇ mol, 96%) of the title compound were isolated as a colorless oil.
  • IR film 3600-2500, 2960, 2920, 2860, 2230, 1730, 1710, 1445, 1130, 1080,
  • Example 6e 107 mg (164 ⁇ mol) of the compound shown in Example 6e were reacted analogously to Example 1b and, after workup and purification, 61 mg (92 ⁇ mol, 56%) of the title compound were isolated as a colorless oil.
  • Example 6f 150 mg (198 ⁇ mol) of the compound shown in Example 6f were reacted analogously to Example 2e and isolated after workup and purification
  • Example 6g 142 mg (217 ⁇ mol) of the compound shown in Example 6g were reacted analogously to Example 2f and, after workup and purification, 155 mg (204 ⁇ mol, 94%) of the title compound were isolated as a colorless oil.
  • Example 6i 468 mg (719 ⁇ mol) of the compound shown in Example 6i were reacted analogously to Example 2h and, after workup and purification, 425 mg (561 ⁇ mol, 78%) of the title compound were isolated as a colorless oil.
  • Example 6j 550 mg (848 ⁇ mol) of the compound shown in Example 6j were reacted analogously to Example 2i and, after workup and purification, 473 mg (727 ⁇ mol, 86%) of the title compound were isolated as a colorless oil.
  • Example 6j
  • Example 5c 518 mg (900 ⁇ mol) of the compound shown in Example 5c was reacted analogously to Example 2j and, after workup and purification, 562 mg (866 ⁇ mol, 96%) of the title compound was isolated as a colorless oil.
  • Example 5 6.5 mg (16.4 ⁇ mol) of the compound shown in Example 5 was reacted analogously to Example 3 and, after workup and purification, 4.8 mg (11.7 ⁇ mol, 717.) of the title compound was isolated as a colorless oil.
  • Example 6 9 mg (22.7 ⁇ mol) of the compound shown in Example 6 was reacted analogously to Example 3 and, after workup and purification, 6.5 mg (15.9 ⁇ mol, 70%) of the title compound were isolated as a colorless oil.
PCT/DE1989/000588 1988-09-09 1989-09-10 6-oxo-9-fluor-prostaglandin-derivate, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung WO1990002728A2 (de)

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DE19883831222 DE3831222A1 (de) 1988-09-09 1988-09-09 6-oxo-9-fluor-prostaglandin-derivate verfahren zu ihrer herstellung und ihre pharmazeutische verwendung
DEP3831222.0 1988-09-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008959A1 (en) * 1992-10-20 1994-04-28 Taisho Pharmaceutical Co., Ltd. Prostaglandine derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0069696A2 (de) * 1981-07-03 1983-01-12 Schering Aktiengesellschaft 9-Fluor-prostaglandinderivate, Verfahren zur Herstellung und Verwendung als Arzneimittel

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3708537A1 (de) * 1987-03-13 1988-09-22 Schering Ag 6-oxoprostaglandin-e-derivate, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0069696A2 (de) * 1981-07-03 1983-01-12 Schering Aktiengesellschaft 9-Fluor-prostaglandinderivate, Verfahren zur Herstellung und Verwendung als Arzneimittel

Non-Patent Citations (1)

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Title
Tele Systems, File Server, Databasis W.P.I.L. (Derwent), Nr. 88-271929 (39), siehe die Zusammenfassung & ZA 8801777 (Schering AG) 9. September 1988 & DE, A, 3708537 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008959A1 (en) * 1992-10-20 1994-04-28 Taisho Pharmaceutical Co., Ltd. Prostaglandine derivative

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