EP0000207A1 - Prostaglandin derivatives, their preparation and pharmaceutical compositions and intermediates - Google Patents

Prostaglandin derivatives, their preparation and pharmaceutical compositions and intermediates Download PDF

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Publication number
EP0000207A1
EP0000207A1 EP78100303A EP78100303A EP0000207A1 EP 0000207 A1 EP0000207 A1 EP 0000207A1 EP 78100303 A EP78100303 A EP 78100303A EP 78100303 A EP78100303 A EP 78100303A EP 0000207 A1 EP0000207 A1 EP 0000207A1
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Prior art keywords
hydrogen
formula
hydroxy
carbon
nat
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German (de)
French (fr)
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George William Holland
Perry Rosen
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new prostaglandin derivatives of the formula I. wherein R 1 is hydrogen or lower alkyl; R 2 hydroxy; R 3 is hydrogen; or R 2 and R 3 together oxo; R 4 is hydrogen or lower alkyl; R 5 is fluorine, lower alkyl or trifluoromethyl; R 6 is hydrogen, fluorine or lower alkyl; R 7 Hydrogen; R 8 hydroxy; or R 7 and R 8 together oxo; A and B, and X and Y, on their own denote hydrogen or together a carbon-carbon bond; with the condition that R 2 and R 3 together are oxo when R 7 and R 8 are together oxo; and with the further condition that A and B represent hydrogen when R 7 is hydrogen; and with the third condition that X and Y represent a carbon-carbon bond when R 1 and R 7 are simultaneously hydrogen; their enantiomers and racemates.
  • the invention further relates to a process for the preparation of prostaglandin derivatives of the formula. I and new intermediates that occur in this process.
  • the invention further relates to new pharmaceutical preparations which contain prostaglandin derivatives of the formula I.
  • lower alkyl used here refers to straight-chain or branched alkyl groups having 1 to 7 carbon atoms, such as methyl and ethyl.
  • lower alkane carboxylic acid refers to alkane carboxylic acid with 1-7 C atoms such as formic acid and acetic acid.
  • halogen or halo refers to fluorine, chlorine, bromine and iodine.
  • all compounds with one or more asymmetric carbon atoms can be produced as Race. Mate. These racemates can be cleaved at a suitable point in the preparation by methods known per se, the corresponding optically pure enantiomers then being obtained as secondary products.
  • the optically active enantiomers of the formula I can be prepared from optically active compounds of the formula II.
  • a wedge-shaped line ( ⁇ ) means a substituent that is in the beta position (above the molecular level), a broken line (/////) denotes a substituent in the alpha position (below the molecular level).
  • aryl denotes mononuclear aromatic hydrocarbon groups such as phenyl or tolyl which are unsubstituted or can be substituted in one or more positions with alkylenedioxy, halogen, nitro or lower alkoxy, as well as multinuclear aryl groups such as naphthyl, anthryl, phenanthryl and.Azulyl, which can be substituted with one or more of the aforementioned groups.
  • Preferred aryl groups are substituted and unsubstituted mononuclear aryl groups, especially phenyl.
  • aryl, lower alkyl denotes groups in which aryl and lower alkyl are as defined above, in particular benzyl.
  • hydrolyzable ester or ether group refers to any ester or ether group that is obtained by hydrolysis. can be converted into the hydroxy group of such .
  • Ester phenomenon are those in which the acyl radical is' siner of a lower alkanoic acid Carbonic acid or aryl-lower alkanoic acid, phosphoric acid, carbonic acid or lower alkanedioic acid.
  • ester groups can be formed from acid anhydrides and acid halides, in particular chlorides or bromides, the lower alkanecarboxylic anhydrides, for example acetic anhydride and caproic anhydride;
  • Aryl-lower alkanoic anhydrides for example benzoic anhydride, lower alkanedioic anhydrides, for example succinic anhydride, and chloroformic acid star, for example trichloroethyl chloroformic acid esters, are preferred.
  • a particularly suitable ether protecting group is, for example, tetrahydropyranylaether or 4-methoxy-5,6-dihydro-2H-pyranylaether.
  • ethers are aryl methyl ethers, such as benzyl, benzhydryl or trityl ether, or a-lower alkoxy lower alkyl ethers, for example methoxymethyl or allyl ether or trialkylsilyl ether such as trimethylsilyl ether or dimethyl tert-silyl ether.
  • a group of compounds of the formula I can be represented by the formula IA wherein R 1 to R 6 , X and Y have the above meaning, with the proviso that X and Y represents a carbon-carbon bond when R 1 is hydrogen, being represented.
  • the hydrolysis of the protected hydroxyl group R9 is characterized by conventional ether and ester hydrolysis. be performed.
  • Acidic aqueous hydrolysis can be used if the hydroxyl group is protected by an ether bond.
  • the preferred methods of ether hydrolysis include treating a compound of formula II with a kissable inorganic acid.
  • the hydroxy group can be regenerated by treatment with a base in an aqueous medium. Any conventional method of ester hydrolysis can be used in this conversion.
  • Aqueous sodium hydroxide is to be mentioned among the preferred bases.
  • Ether protecting group R 9 such as tetrahydropyranyloxy.
  • Hydrogenation of a CC bond represented by X and Y following hydrolysis of R 9 in a compound of Formula II can be accomplished by any conventional hydrogenation method, such as catalytic hydrogenation.
  • the preferred hydrogenation methods include hydrogenation in the presence of a catalyst such as platinum or platinum oxides. Any conventional hydrogenation catalyst can be used here.
  • the reaction conditions are also those for ordinary hydrogenation reactions.
  • the oxidation of hydroxyl groups following the hydrolysis of R 9 in a compound of the formula II and the oxidation of hydroxyl groups in a compound of the formula III can be carried out by conventional oxidizing agents which oxidize a hydroxyl group to the keto group: preferred oxidizing agents are chromate Oxidizing agents such as chromium trioxide.
  • oxidizing agents such as chromium trioxide.
  • a compound II or III is used as the starting material, which is either a racemate or is in optically active form.
  • R 5 and R 6 have the meaning given above, and R 6 represents aryl or di (lower alkylamino) and V represents halogen, or a phosphonate of the formula XIV wherein R 5 and R 6 have the above meaning; wherein R 5 and the above meaning and R 1 represent aryl, aryloxy or lower alkoxy,
  • a compound of formula V can be obtained with a reducing agent.
  • All conventional reducing agents which selectively reduce a keto group to the hydroxyl group can be used to carry out these reactions:
  • Preferred reducing agents are hydrides, in particular aluminum hydrides such as alkali metal aluminum hydrides and borohydrides such as alkali metal borohydrides, zinc borohydride being particularly preferred.
  • Temperature and pressure are not critical in carrying out this reaction; the reaction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. In general, it is preferable to carry out the reaction at a temperature from -30 ° C to the reflux temperature of the reaction mixture.
  • the reduction can be carried out in the presence of an inert organic solvent.
  • an inert organic solvent Any conventional inert organic solvent or water can be used here, for example the above-mentioned inert organic solvents.
  • Preferred solvents are methanol, dimethoxyethylene glycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.
  • the conversion of a compound of formula VI in 'VII is a compound of formula carried out by hydrogenation.
  • the hydrogenation can be carried out under the conditions described above for the hydrogenation of a C 1 -C 4 bond following the hydrolysis of R 9 in a compound of the formula II.
  • the compound of formula VII is converted into a compound of formula VIII by esterification or etherification of the free hydroxy group with a hydrolyzable ether or ester protecting group.
  • This esterification or etherification can be carried out according to the usual esterification and etherification processes.
  • Preferred ester groups are lower alkanoyloxy, especially acetoxy, a preferred ether group is tetrahydropyranyloxy.
  • the compound of formula VIII is converted into a compound of formula IX by treatment with a reducing agent from sodium to as a base. If solvents other than hexametnylphosphoramide and bases other than sodium bis-trimethylsilylamide are used, the compound of formula II-B is obtained in poorer yield. However, conventional inert organic solvents can also be used alone or in a mixture with hexamethylphosphoramide. On the other hand, the solvent system can consist solely of hexamethylphosphoramide. In carrying out this reaction are Tem p ERA-ture and pressure are carried out is not critical, the reaction can be at room temperature and atmospheric pressure or at higher or lower temperatures. In general, it is expedient to work at temperatures of 0-50 ° C.
  • the conversion of compound of formula VI into compound of formula X can be carried out analogously to the conversion of compound of formula VIII into compound of formula IX.
  • the X ⁇ XI conversion can be carried out analogously to IX ⁇ II-A and the hydrogenation of the double bond in the conversion of XI or XII to III can be carried out as described for the reaction II-A ⁇ II-B .
  • the esterification of the carboxy group in connection with the compound XI and XII can be carried out analogously to the esterification of a carboxy group in the compound II-A.
  • the compounds of formula I; their optical antipodes and racemates are valuable as pharmaceuticals. In particular, they are valuable as bronchodilators, anti- made.
  • the compounds to be administered are administered orally in a mixture of tris (hydroxymethyl) aminomethane in 95% ethanol (5% w / v). A mixture of tris (hydroxymethyl) aminomethane in ethanol was used as placebo.
  • the compounds were tested on non-anesthetized rats with acute gastric fistula.
  • fasted female rats (medium weight 250 g) were surgically catheterized in the inferior vena cava (for the purpose of constant infusion of saline and administration of the test compounds); on the bile duct (to drain bile and pancreatic secretion, which can contaminate the stomach contents through reflux); at the stomach entrance (for the purpose of infusing a small volume of water during the experiment); and at the stomach exit (for collecting the contents of the stomach and for continuous monitoring of the pH by a microelectrode).
  • the stomach was flushed with water for 60 minutes before administration of the compounds.
  • the pH (measured at 10 minute intervals) of the secretion flow in each animal was approximately 1.5.
  • the compound to be administered dissolved in saline, was intravenously administered at a dose of 16 ⁇ g / kg, and samples were continuously collected for 60 minutes.
  • the pH, the volume, the total acidity ( ⁇ Aeq / ml) and the total acid release during 10 minutes were measured ( ⁇ Aeq / 10 minutes). The results are summarized in the table below.
  • the starting compound was prepared from 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-fluoro-3S-hydroxy-l (E) -octenyl] -5R-methyl-
  • nat-11R-Metyhl-16,16-difluoro-15-R-hydroxy-9-osoprosta-5 (z) -13 the nat-11R-methyl-16, 16-difluoro-9, 15-dioxoprosta-5 13 (E) -dienoic acid obtained.
  • nat-16 16-methyl-9S-hydroxy-15R- [2- nyloxy] -prost-5 (Z) -eklare the nat-16, 16- obtained hydroxy-9-oxoprosta-5 (Z) -enoic acid.
  • the starting compound was obtained from 3, 3aR, 4, 5, 6, 6aS-hexahydro-4R- [4R-methyl-4R-trifluoromethyl-3R-hydroxy-1 (E) -octenyl] -5R-methyl-2H-cyclopenta [b ] furan-2-one via 3.3aR, 4.5, -6.6aS-hexahydro-4R- (4R-methyl-4R-trifluoromethyl-3R-hydroxy-octanyl) -5R-methyl-2H-cyclopenta [b] furan-2-one and 3,3aR, 4,5, -6,6aS-hexahydro-4R- [4R-methyl-4R-trifluoromethyl-3R- [2-tetra-hydro- (2H) -pyranyloxy] -octanyl] -5R-methyl-2H-cyclopenta [b] -furan-2-ol.
  • the starting compound was prepared from 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-trifluoromethyl-4R-fluoro-3R-hydroxy-l (E) -octenyl] -5R-methyl-2H-cyclopenta [b ] furan-2-one via 3,3aR, -4, 5, 6, 6aS-hexahydro-4R- (4R-trifluoromethyl-4R-fluoro-3R-hydroxy-octanyl) -5R-methyl-2H-cyclopenta [b] furan-2-one and 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-trifluoromethyl-4R-fluoro-3R- (2-tetrahydro- (2H) -pyranyloxy) -octanyl] -5R- methyl-2H-cyclopenta [b] furan-2-ol.
  • nat-16,16-dimethyl-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid became nat-16,16-dimethyl-9,15-dioxoprost-5 (Z) -enoic acid receive.
  • nat-16R-trifluoromethyl-16R, 11R-dimethyl-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid was converted into nat-16R-trifluoromethyl-16R, 11R-dimethyl-9, 15- obtained dioxoprost-5 (Z) -enoic acid.
  • the active ingredient and the corn starch were mixed and sieved. This premix was then mixed with the calcium phosphate and half of the magnesium stearate, sieved and compacted. The granules thus obtained were sieved, the remaining magnesium stearate added, and pressed.

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Abstract

Prostaglandinderivate der Formel <IMAGE> worin R¹ Wasserstoff oder Niederalkyl; R² Hydroxy; R³ Wasserstoff; oder R² und R³ zusammen Oxo; R<4> Wasserstoff oder Niederalkyl; R<5> Fluor, Niederalkyl oder Trifluormethyl; R<6> Wasserstoff, Fluor oder Niederalkyl; R<7> Wasserstoff; R<8> Hydroxy; oder R<7> und R<8> zusammen Oxo; A und B, und X und Y, für sich allein Wasserstoff oder zusammen eine Kohlenstoff- Kohlenstoffbindung bedeuten; mit der Bedingung, dass R² und R³ zusammen Oxo darstellen, wenn R<7> und R<8> zusammen Oxo sind; und mit der weiteren Bedingung, dass A und B Wasserstoff darstellen, wenn R<7> Wasserstoff ist; und mit der dritten Bedingung, dass X und Y eine Kohlenstoff- Kohlenstoffbindung darstellen, wenn R¹ und R<7> gleichzeitig Wasserstoff sind; deren Enantiomere und Racemate weisen therapeutische, z.B. blutdrucksenkende und anti-ulcerogene Wirkungen auf. Die Erfindung betrifft solche Prostaglandinderivate, deren Herstellung und pharmazeutische Präparate enthaltend solche Prostaglandinderivate, sowie neue Zwischenprodukte für die Herstellung dieser Prostaglandinderivate.Prostaglandin derivatives of the formula <IMAGE> wherein R¹ is hydrogen or lower alkyl; R² hydroxy; R³ is hydrogen; or R² and R³ together oxo; R <4> is hydrogen or lower alkyl; R <5> fluorine, lower alkyl or trifluoromethyl; R 6 is hydrogen, fluorine or lower alkyl; R <7> hydrogen; R 8 hydroxy; or R <7> and R <8> together oxo; A and B, and X and Y, alone mean hydrogen or together represent a carbon-carbon bond; with the proviso that R² and R³ together represent oxo when R <7> and R <8> together are oxo; and with the further condition that A and B represent hydrogen when R <7> is hydrogen; and with the third condition that X and Y represent a carbon-carbon bond when R1 and R7 are simultaneously hydrogen; their enantiomers and racemates have therapeutic, e.g. hypotensive and anti-ulcerogenic effects. The invention relates to such prostaglandin derivatives, their production and pharmaceutical preparations containing such prostaglandin derivatives, and to new intermediates for the production of these prostaglandin derivatives.

Description

Die vorliegende Erfindung betrifft neue Prostaglandinderivate der Formel I

Figure imgb0001
worin R1 Wasserstoff oder Niederalkyl; R 2 Hydroxy; R3 Wasserstoff; oder R 2 und R 3 zusammen Oxo; R4 Wasserstoff oder Niederalkyl; R5 Fluor, Niederalkyl oder Trifluormethyl; R6 Wasserstoff, Fluor oder Niederalkyl; R7 Wasserstoff; R8 Hydroxy; oder R7 und R8 zusammen Oxo; A und B, und X und Y, für sich allein Wasserstoff oder zusammen eine Kohlenstoff-Kohlenstoffbindung bedeuten; mit der Bedingung, dass R 2 und R3 zusammen Oxo darstellen, wenn R7 und R8 zusammen Oxo sind; und mit der weiteren Bedingung, dass A und B Wasserstoff darstellen,wenn R7 Wasserstoff ist; und mit der dritten Bedingung, dass X und Y eine Kohlenstoff- Kohlenstoffbindung darstellen, wenn R1 und R7 gleichzeitig Wasserstoff sind;
deren Enantiomere und Racemate.The present invention relates to new prostaglandin derivatives of the formula I.
Figure imgb0001
 wherein R 1 is hydrogen or lower alkyl; R 2 hydroxy; R 3 is hydrogen; or R 2 and R 3 together oxo; R 4 is hydrogen or lower alkyl; R 5 is fluorine, lower alkyl or trifluoromethyl; R 6 is hydrogen, fluorine or lower alkyl; R 7 Hydrogen; R 8 hydroxy; or R 7 and R 8 together oxo; A and B, and X and Y, on their own denote hydrogen or together a carbon-carbon bond; with the condition that R 2 and R 3 together are oxo when R 7 and R 8 are together oxo; and with the further condition that A and B represent hydrogen when R 7 is hydrogen; and with the third condition that X and Y represent a carbon-carbon bond when R 1 and R 7 are simultaneously hydrogen;
their enantiomers and racemates.

Die Erfindung betrifft weiterhin ein Verfahren zur Herstellung von Prostaglandinderivaten der Formel . I und neue Zwischenprodukte, die in diesem Prozess auftreten. Weiterhin betrifft die Erfindung neue pharmazeutische Präparate,die Prostaglandinderivate der Formel I enthalten.The invention further relates to a process for the preparation of prostaglandin derivatives of the formula. I and new intermediates that occur in this process. The invention further relates to new pharmaceutical preparations which contain prostaglandin derivatives of the formula I.

Der hier verwendete Ausdruck "Niederalkyl" bezieht sich auf geradkettige oder verzweigte Alkylgruppen mit 1 bis 7 C-Atomen wie Methyl und Aethyl. Der Ausdruck "Niederalkancarbonsäure" bezieht sich auf Alkancarbonsäure mit 1-7 C-Atomen wie Ameisensäure und Essigsäure. Der Ausdruck Halogen oder Halo bezieht sich auf Fluor, Chlor, Brom und Jod.The term "lower alkyl" used here refers to straight-chain or branched alkyl groups having 1 to 7 carbon atoms, such as methyl and ethyl. The term "lower alkane carboxylic acid" refers to alkane carboxylic acid with 1-7 C atoms such as formic acid and acetic acid. The term halogen or halo refers to fluorine, chlorine, bromine and iodine.

Erfindungsgemäss können alle Verbindungen mit einem oder mehreren asymmetrischen Kohlenstoffatomen als Race- .mate hergestellt werden. Diese Racemate können an geeigneter Stelle bei der Herstellung nach an sich.bekannten Methoden gespalten werden, wobei dann als Folgeprodukte die entsprechenden, optisch reinen Enantiomeren erhalten werden. Andererseits können die optisch aktiven Enantiomeren der Formel I aus optisch aktiven Verbindungen der Formel II, hergestellt werden.According to the invention, all compounds with one or more asymmetric carbon atoms can be produced as Race. Mate. These racemates can be cleaved at a suitable point in the preparation by methods known per se, the corresponding optically pure enantiomers then being obtained as secondary products. On the other hand, the optically active enantiomers of the formula I can be prepared from optically active compounds of the formula II.

In den Strukturformeln bedeutet eine keilförmige Linie (▼) einen Substituenten der sich in Beta-Stellung (oberhalb der Molekülebene) befindet, eine unterbrochene Linie (/////) bezeichnet einen Substituenten in Alpha-Stellung (unterhalb der Molekülebene). Die Darstellung einer bestimmten Strukturformel wurde aus Gründen der Einfach-. heit gewählt und ist so zu verstehen, dass sie auch Enantiomere und Racemate einschliesst.In the structural formulas, a wedge-shaped line (▼) means a substituent that is in the beta position (above the molecular level), a broken line (/////) denotes a substituent in the alpha position (below the molecular level). The representation of a certain structural formula was made for the sake of simplicity. selected and is to be understood in such a way that it also includes enantiomers and racemates.

Der Ausdruck "Aryl" bezeichnet sowohl einkernige aromatische Kohlenwasserstoffgruppen wie Phenyl oder Tolyl die unsubstituiert oder auch in einer oder mehreren Stellungen mit Alkylendioxy, Halogen, Nitro, oder Niederalkoxy substituiert sein können, als auch mehrkernige Arylgruppen wie Naphthyl, Anthryl, Phenanthryl und.Azulyl, die mit einer oder mehreren der vorgenannten Gruppen substituiert sein können. Bevorzugte Arylgruppen sind substituierte und unsubstituierte einkernige Arylgruppen, insbesondere Phenyl. Der Ausdruck Aryl, Niederalkyl bezeichnet Gruppen worin Aryl und Niederalkyl wie oben definiert sind, insbesondere Benzyl.The term "aryl" denotes mononuclear aromatic hydrocarbon groups such as phenyl or tolyl which are unsubstituted or can be substituted in one or more positions with alkylenedioxy, halogen, nitro or lower alkoxy, as well as multinuclear aryl groups such as naphthyl, anthryl, phenanthryl and.Azulyl, which can be substituted with one or more of the aforementioned groups. Preferred aryl groups are substituted and unsubstituted mononuclear aryl groups, especially phenyl. The term aryl, lower alkyl denotes groups in which aryl and lower alkyl are as defined above, in particular benzyl.

Der Ausdruck "hydrolysierbare Ester oder Aethergruppe" bezeichnet eine beliebige Ester- oder Aethergruppe, die durch Hydrolyse. in die Hydroxygruppe übergeführt werden kann .Beispiel für solche Estergruppen sind die, in denen der Acylrest sich von einer Niederalkansäure' siner Kohlensäure oder Arylniederalkansäure, Phosphorsäure, Kohlensäure oder Niederalkandisäure ableitet. Solche Estergruppen können aus Säureannydriden und Säurehalogeniden, insbesondere Chloriden oder Bromiden, gebildet werden, wobei die Niederalkancarbonsäureanhydride, zum Beispiel Acetanhydrid und Capronsäureanhydrid; Aryl-niederalkansäureanhydride zum Beispiel Benzosäureanhydrid, Niederalkandisäureanhydride, zum Beispiel Bernsteinsäureanhydrid,und Chlorameisen- säureestar,zum Beispiel Trichloraethylchlorameisensäureester bevorzugt sind. Eine besonders geeignete Aetherschutzgruppe ist beispielsweise der Tetrahydropyranylaether oder der 4-Methoxy-5,6-dihydro-2H-pyranylaether. Andere solche Aether sind Arylmethylaether,wie Benzyl, Benzhydryl oder Trityläther, oder a-Niederalkoxyniederalkyläther, zum Beispiel Methoxymethyl oder Allyläther oder Trialkylsilyläther wie Trimethylsilylaether oder Dimethyl-tert.-silyläther.The term "hydrolyzable ester or ether group" refers to any ester or ether group that is obtained by hydrolysis. can be converted into the hydroxy group of such .Example Estergruppen are those in which the acyl radical is' siner of a lower alkanoic acid Carbonic acid or aryl-lower alkanoic acid, phosphoric acid, carbonic acid or lower alkanedioic acid. Such ester groups can be formed from acid anhydrides and acid halides, in particular chlorides or bromides, the lower alkanecarboxylic anhydrides, for example acetic anhydride and caproic anhydride; Aryl-lower alkanoic anhydrides, for example benzoic anhydride, lower alkanedioic anhydrides, for example succinic anhydride, and chloroformic acid star, for example trichloroethyl chloroformic acid esters, are preferred. A particularly suitable ether protecting group is, for example, tetrahydropyranylaether or 4-methoxy-5,6-dihydro-2H-pyranylaether. Other such ethers are aryl methyl ethers, such as benzyl, benzhydryl or trityl ether, or a-lower alkoxy lower alkyl ethers, for example methoxymethyl or allyl ether or trialkylsilyl ether such as trimethylsilyl ether or dimethyl tert-silyl ether.

Eine Gruppe von Verbindungen der Formel I kann durch die Formel IA

Figure imgb0002
worin R1 bis R6, X und Y die obige Bedeutung haben, mit der Bedingung, dass X und Y
eine Kohlenstoff- Kohlehstoffbindung darstel- lan,wenn R1 Wasserstoff ist,
dargestellt werden.A group of compounds of the formula I can be represented by the formula IA
Figure imgb0002
 wherein R 1 to R 6 , X and Y have the above meaning, with the proviso that X and Y
represents a carbon-carbon bond when R 1 is hydrogen,
being represented.

Eine andere, besonders interessierende Gruppe von Verbindungen der Formel I hat die Formel IB

Figure imgb0003
worin R1, R 4, R 5, R 6, A, B, X und Y die obige Bedeutung haben.Another, particularly interesting group of compounds of formula I has formula IB
Figure imgb0003
 wherein R 1 , R 4 , R 5 , R 6 , A , B , X and Y have the above meaning.

Die Verbindungen der Formeln I werden erfindungsgemäss dadurch hergestellt, dass man

  • a) eine Verbindung der Formel II
    Figure imgb0004
    worin R 9 eine durch eine hydrolysierbare Aether- oder Estergruppe geschützte Hydroxygruppe darstellt und R1 bis R6, X und Y
    die obige Bedeutung haben
    oder ein Enantiomer oder Racemat davon der Hydrolyse der Schutzgruppe R9 unterwirft und gewünschtenfalls eine durch X und Y dargestellte Kohlenstoff- Kohlenstoffbindung hydriert, und/oder eine Hydroxygruppe zur Oxo-
    Figure imgb0005
    Figure imgb0006
    worin R1 bis R 6 , X und Y die obige Bedeutung haben,
    oder eines Enantiomers oder Racemats davon zu einer Verbindung der Formel I,worin R 2 und R3 bzw. R 7 und R 8
    Figure imgb0007
    darstellen,oxidiert.
According to the invention, the compounds of the formulas I are prepared by
  • a) a compound of formula II
    Figure imgb0004
     wherein R 9 represents a hydroxyl group protected by a hydrolyzable ether or ester group and R 1 to R 6 , X and Y
    have the above meaning
    or an enantiomer or racemate thereof is subjected to the hydrolysis of the protective group R 9 and, if desired, hydrogenates a carbon-carbon bond represented by X and Y, and / or a hydroxyl group to form the oxo
    Figure imgb0005
    Figure imgb0006
     wherein R 1 to R 6 , X and Y have the above meaning,
    or an enantiomer or racemate thereof to a compound of the formula I, in which R 2 and R 3 or R 7 and R 8
    Figure imgb0007
    represent, oxidized.

Die Hydrolyse der geschützten Hydroxygruppe R9 kenn durch konventionelle Aether- und Esterhydrolyse-

Figure imgb0008
durchgeführt werden.The hydrolysis of the protected hydroxyl group R9 is characterized by conventional ether and ester hydrolysis.
Figure imgb0008
be performed.

Saure wässrige Hydrolyse kann verwendet werden, kenn die Hydroxygruppe durch eine Aetherbindung geschützt ist. Zu den bevorzugten Methoden der Aetherhydrolyse gehört die Behandlung einer Verbindung der Formel II mit einer kissrigen anorganischen Säure. Andererseits kann, wenn eine Estergruppe enthält, die Hydroxygruppe durch Behandlung mit einer Base in wässrigem Medium regeneriert kerden. Jede konventionelle Methode der Esterhydrolyse kann bei dieser Umwandlung verwendet werden. Unter den bevor- migten Basen ist wässriges Natriumhydroxid zu nennen.

Figure imgb0009
Aetherschutzgruppe R9, wie Tetrahydropyranyloxy verwendet werden.Acidic aqueous hydrolysis can be used if the hydroxyl group is protected by an ether bond. The preferred methods of ether hydrolysis include treating a compound of formula II with a kissable inorganic acid. On the other hand, if it contains an ester group, the hydroxy group can be regenerated by treatment with a base in an aqueous medium. Any conventional method of ester hydrolysis can be used in this conversion. Aqueous sodium hydroxide is to be mentioned among the preferred bases.
Figure imgb0009
Ether protecting group R 9 , such as tetrahydropyranyloxy.

Die Hydrierung einer durch X und Y dargestellten C-C-Bindung im Anschluss an die Hydrolyse von R9 in einer Verbindung der Formel II kann durch jede konventionelle Hydriermethode,wie katalytische Hydrierung,bewerkstelligt werden.Hydrogenation of a CC bond represented by X and Y following hydrolysis of R 9 in a compound of Formula II can be accomplished by any conventional hydrogenation method, such as catalytic hydrogenation.

Zu den bevorzugten Hydriermethoden gehört die Hydrierung in Gegenwart eines Katalysators wie Platin oder Platinoxyden. Jeder konventionelle Hydrierkatalysator kann hierbei Verwendung finden. Die Reaktionsbedingungen sind gleichfalls die für gewöhnliche Hydrier-- reaktionen.The preferred hydrogenation methods include hydrogenation in the presence of a catalyst such as platinum or platinum oxides. Any conventional hydrogenation catalyst can be used here. The reaction conditions are also those for ordinary hydrogenation reactions.

Die Oxidation von Hydroxygruppen im Anschluss an die Hydrolyse von R9 in einer Verbindung der Formel II und die Oxidation von Hydroxygruppen in einer Verbindung der Formel III können durch konventionlle Oxidationsmittel durchgeführt werden,die eine Hydroxygruppe zur Ketogruppe oxi-dieren:Bevorzugte Oxidationsmittel sind Chromat-Oxidationsmittel wie Chromtrioxid. Als Reaktionsbedingungen kommen die für diese Oxidationsreaktionen üblichen Bedingungen in Betracht.The oxidation of hydroxyl groups following the hydrolysis of R 9 in a compound of the formula II and the oxidation of hydroxyl groups in a compound of the formula III can be carried out by conventional oxidizing agents which oxidize a hydroxyl group to the keto group: preferred oxidizing agents are chromate Oxidizing agents such as chromium trioxide. The conditions customary for these oxidation reactions come into consideration as reaction conditions.

Je nachdem,welche besondere Form der Verbindung der Formel I gewünscht wird, wird als Ausgangsmaterial eine Verbindung II oder III verwendet die entweder ein Racemat ist oder in optisch aktiver Form vorliegt.Depending on which particular form of the compound of formula I is desired, a compound II or III is used as the starting material, which is either a racemate or is in optically active form.

Die Ausgangsverbindung der Formel II und III können wie nachstehend beschrieben hergestellt werden.

Figure imgb0010
Figure imgb0011
Figure imgb0012
Figure imgb0013
worin R5 und R6 die obige Bedeutung haben, and R6 Aryl oder Di(Niederalkylamino) und V Halogen darstellt,
oder einem Phosphonat der Formel XIV
Figure imgb0014
worin R5 und R6 obige Bedeutung haben; worin R5 und die obige bedeutung haben und R1 Aryl, Aryloxy oder Niederalkoxy darstellen,
Figure imgb0015
The starting compounds of formula II and III can be prepared as described below.
Figure imgb0010
Figure imgb0011
Figure imgb0012
Figure imgb0013
 wherein R 5 and R 6 have the meaning given above, and R 6 represents aryl or di (lower alkylamino) and V represents halogen,
or a phosphonate of the formula XIV
Figure imgb0014
 wherein R 5 and R 6 have the above meaning; wherein R 5 and the above meaning and R 1 represent aryl, aryloxy or lower alkoxy,
Figure imgb0015

Die Omsetzung einer Verbindung der Formel IV mit dem Phosphoniumsalz zu einer Verbindung der Formel V

Figure imgb0016
Figure imgb0017
Witting-Reaktion. Bei dieser Reaktion können
Figure imgb0018
Wittig-Reaktionen konventionellen Reaktionsbeding-
Figure imgb0019
angawandet werden.The reaction of a compound of formula IV with the phosphonium salt to a compound of formula V
Figure imgb0016
Figure imgb0017
Witting response. In this reaction you can
Figure imgb0018
Wittig reactions conventional reaction conditions
Figure imgb0019
be used.

Die umsetzung einer Verbindung der Formel IV

Figure imgb0020
mit dem phosphonat zu einer Verbindung derFormelV ist
Figure imgb0021
einen Verbindung der Formel V mit einem Reduktionsmittel erhalten werden. Für die Durchführung dieser Reaktionen können alle konventionellen Reduktionsmittel verwendet werden,die selektiv eine Ketogruppe zur Hydroxygruppe reduzieren.: Bevorzugte Reduktionsmittel sind Hydride, insbesondere Aluminiumhydride wie Alkalimetallaluminiumhydride und Borhydride wie Alkalimetallborhydride,wobei-Zinkborhydrid besonders bevorzugt ist. Bei der Durchführung dieser Reaktion sind Temperatur und Druck nicht kritisch, die Reaktion kann bei Raumtemperatur und Atmosphärendruck oder bei erhöhten oder verminderten Temperaturen und Drucken durchgeführt werden. Im allgemeinen ist es vorzuziehen, die Reaktion bei einer Temperatur von -30°C bis zur Rückflusstemperatur des Reaktionsgemisches durchzuführen. Die Reduktion kann in Gegenwart eines inerten organischen Lösungsmittels durchgeführt werden. Hierbei kann jedes konventionelle inerte organische Lösungsmittel oder Wasser verwendet werden,zum Beispiel die oben erwähnten inerten organischen Lösungsmittel. Bevorzugt sind als Lösungsmittel Methanol, Dimethoxyäthylenglykose und Aether wie Tetrahydrofuran, Diäthyläther und Dioxan.The implementation of a compound of formula IV
Figure imgb0020
with the phosphonate to a compound of the formula V
Figure imgb0021
a compound of formula V can be obtained with a reducing agent. All conventional reducing agents which selectively reduce a keto group to the hydroxyl group can be used to carry out these reactions: Preferred reducing agents are hydrides, in particular aluminum hydrides such as alkali metal aluminum hydrides and borohydrides such as alkali metal borohydrides, zinc borohydride being particularly preferred. Temperature and pressure are not critical in carrying out this reaction; the reaction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. In general, it is preferable to carry out the reaction at a temperature from -30 ° C to the reflux temperature of the reaction mixture. The reduction can be carried out in the presence of an inert organic solvent. Any conventional inert organic solvent or water can be used here, for example the above-mentioned inert organic solvents. Preferred solvents are methanol, dimethoxyethylene glycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.

Die Umwandlung einer Verbindung der Formel VI in' eine Verbindung der Formel VII wird durch Hydrierung durchgeführt. Die Hydrierung kann unter den Bedingungen die oben für die Hydrierung einer C-'.C-Bindung im Anschluss an die Hydrolyse von R9 in einer Verbindung der Formel II beschrieben sind, durchgeführt werden.The conversion of a compound of formula VI in 'VII is a compound of formula carried out by hydrogenation. The hydrogenation can be carried out under the conditions described above for the hydrogenation of a C 1 -C 4 bond following the hydrolysis of R 9 in a compound of the formula II.

Die Verbindung der Formel VII wird in eine Verbindung der Formel VIII durch Veresterung oder Verätherung der freien Hydroxygruppe mit einer hydrolysierbaren Aether-oder Esterschutzgruppe übergeführt. Diese Veresterung oder Verätherung kann nach den üblichen Veresterungs- und Ver- ätherungsverfahren durchgeführt werden. Bevorzugte Estergruppen sind Niederalkanoyloxy, insbesondere Acetoxy, eine bevorzugte Aethergruppe ist Tetrahydropyranyloxy,.The compound of formula VII is converted into a compound of formula VIII by esterification or etherification of the free hydroxy group with a hydrolyzable ether or ester protecting group. This esterification or etherification can be carried out according to the usual esterification and etherification processes. Preferred ester groups are lower alkanoyloxy, especially acetoxy, a preferred ether group is tetrahydropyranyloxy.

Die Verbindung der Formel VIII wird durch Behandlung mit einem Reduktionsmittel in eine Verbindung der Formel IX

Figure imgb0022
Figure imgb0023
Figure imgb0024
von Natrium-bis-
Figure imgb0025
als Base. Wenn andere Lösungsmittel als Hexametnylphosphoramid und andere Basen als Natrium-bis-trimethylsilylamid verwendet werden, erhält man die Verbindung der Formel II-B in schlechterer Ausbeute. Es können aber auch konventionelle inerte organische Lösungsmittel allein oder im Gemisch mit Hexamethylphosphoramid verwendet werden. Andererseits kann das Lösungsmittelsystem allein aus Hexamethylphosphoramid bestehen. Bei der Durchführung dieser Reaktion sind Tempera- tur und Druck nicht von kritischer Bedeutung, die Reaktion kann bei Raumtemperatur und Normaldruck oder bei höheren oder niederen Temperaturen durchgeführt werden. Im allgemeinen ist es zweckmässig, bei Temperaturen von O-5O°C zu arbeiten.The compound of formula VIII is converted into a compound of formula IX by treatment with a reducing agent
Figure imgb0022
Figure imgb0023
Figure imgb0024
from sodium to
Figure imgb0025
as a base. If solvents other than hexametnylphosphoramide and bases other than sodium bis-trimethylsilylamide are used, the compound of formula II-B is obtained in poorer yield. However, conventional inert organic solvents can also be used alone or in a mixture with hexamethylphosphoramide. On the other hand, the solvent system can consist solely of hexamethylphosphoramide. In carrying out this reaction are Tem p ERA-ture and pressure are carried out is not critical, the reaction can be at room temperature and atmospheric pressure or at higher or lower temperatures. In general, it is expedient to work at temperatures of 0-50 ° C.

Verbindungen der Formel II-A,in denen R4 Wasserstoff ist, können gewünschtenfalls in entsprechende Verbindungen in denen R 4 Niederalkyl ist durch konventionelle Veresterungsverfahren, zum Beispiel durch Reaktion mit Diazomethan, umgewandelt werden.Compounds of formula II-A in which R 4 is hydrogen can, if desired, be converted into corresponding compounds in which R 4 is lower alkyl by conventional esterification processes, for example by reaction with diazomethane.

Die Umwandlung von Verbindung der Formel VI in Verbindung der Formel X kann in Analogie zu Umwandlung von Verbindung der Formel VIII in Verbindung der Formel IX durchgeführt werden. In ähnlicher Weise kann die Umwandlung X→XI in Analogie zu IX→II-A durchgeführt werden und die Hydrierung der Doppelbindung in der Umwandlung von XI oder XII zu III kann,wie für die Reaktion II-A→II-B beschrieben,durchgeführt werden. Die Veresterung der Carboxygruppe in Verbindung mit der Verbindung XI und XII kann in Analogie zur Veresterung einer Carboxygruppe in der Verbindung II-A durchgeführt werden.The conversion of compound of formula VI into compound of formula X can be carried out analogously to the conversion of compound of formula VIII into compound of formula IX. Similarly, the X → XI conversion can be carried out analogously to IX → II-A and the hydrogenation of the double bond in the conversion of XI or XII to III can be carried out as described for the reaction II-A → II-B . The esterification of the carboxy group in connection with the compound XI and XII can be carried out analogously to the esterification of a carboxy group in the compound II-A.

Die Verbindungen der Formel I; deren optische Antipoden und Racemate sind als Pharmazeutika von Wert. Insbesondere sind sie wertvoll als Bronchodilatoren, anti-

Figure imgb0026
dungen vorgenommen. Die zu verabreichenden Verbindungen werden in einem Gemisch von Tris (hydroxymethyl) aminomethan in 95% Aethanol (5% Gew./Vol.) oral verabreicht. Als Placebo wurde ein Gemisch von Tris(hydroxymethyl)aminomethan in Aethanol verwendet.The compounds of formula I; their optical antipodes and racemates are valuable as pharmaceuticals. In particular, they are valuable as bronchodilators, anti-
Figure imgb0026
made. The compounds to be administered are administered orally in a mixture of tris (hydroxymethyl) aminomethane in 95% ethanol (5% w / v). A mixture of tris (hydroxymethyl) aminomethane in ethanol was used as placebo.

Die Versuchsresultate sind in der nachstehenden Tabelle angegeben:

Figure imgb0027
The test results are given in the table below:
Figure imgb0027

Die antisekretorische und antiulcerogene Aktivität wurde in folgender Versuchsanordnung ermittelt:

  • Verbindung A = Nat.11R-methyl-16R-fluor-15R-hydroxy-9-oxo- prost-(Z)-5-en-säure
  • Verbindung B = Nat.11R-methyl-16R-fluor-9 , 15-dioxo-prost-(Z)-5-en-säure.
The antisecretory and antiulcerogenic activity was determined in the following experimental setup:
  • Compound A = Nat.11R-methyl-16R-fluoro-15R-hydroxy-9-oxoprost- (Z) -5-ene acid
  • Compound B = Nat.11R-methyl-16R-fluoro-9, 15-dioxo-prost- (Z) -5-ene acid.

Die Verbindungen wurden an nicht anästhesierten Ratten mit akuter gastrischer Fistel getestet.Am Tag vor dem Experiment wurden gefastete weibliche Ratten (mittleres Gewicht 250 g) chirurgisch katheterisiert in der vena cava inferior (zwecks konstanter Infusion von Kochsalzlösung und Verabreichung der Testverbindungen); am Gallengang (um Galle und Pancreassekretion abzuleiten, die durch Rückfluss den Mageninhalt verunreinigen können); am Mageneingang (zwecks Infusion eines kleinen Volumens Wasser während des Experiments);und am Magenausgang (zum Sammeln des Mageninhaltes und zur kontinuierlichen Ueberwachung des pH durch eine Mikroelektrode). Am Tag des Experimentes wurde vor der Verabreichung der Verbindungen der Magen während 60 Minuten mit Wasser gespült. Während dieser Basisperiode betrug das pH (gemessen in 10-Minuten-Intervallen) des Sekretionsflusses bei jedem Tier etwa 1,5. Nach der Basisperiode wurde die zur verabreichende Verbindung, in Kochsalzlösung gelöst in einer Dosis von 16 ug/kg intravenös verabreicht und es wurden für die Dauer von 60 Minuten Proben kontinuierlich gesammelt. Gemessen wurde das pH, das Volumen, die Gesamt-Säure (µAeq/ml) und die gesamte Säureausschüttung während 10 Minuten µAeq/10 Minuten). Die Resultate sind in der nachstehenden Tabelle zusammengefasst.

Figure imgb0028
The compounds were tested on non-anesthetized rats with acute gastric fistula. The day before the experiment, fasted female rats (medium weight 250 g) were surgically catheterized in the inferior vena cava (for the purpose of constant infusion of saline and administration of the test compounds); on the bile duct (to drain bile and pancreatic secretion, which can contaminate the stomach contents through reflux); at the stomach entrance (for the purpose of infusing a small volume of water during the experiment); and at the stomach exit (for collecting the contents of the stomach and for continuous monitoring of the pH by a microelectrode). On the day of the experiment, the stomach was flushed with water for 60 minutes before administration of the compounds. During this base period, the pH (measured at 10 minute intervals) of the secretion flow in each animal was approximately 1.5. After the base period, the compound to be administered, dissolved in saline, was intravenously administered at a dose of 16 µg / kg, and samples were continuously collected for 60 minutes. The pH, the volume, the total acidity (µAeq / ml) and the total acid release during 10 minutes were measured (µAeq / 10 minutes). The results are summarized in the table below.
Figure imgb0028

Figure imgb0029
Figure imgb0030
Figure imgb0031
Figure imgb0029
Figure imgb0030
Figure imgb0031

Beispiel 5Example 5

In Analogie zu Beispiel 1 wurde aus nat-11R, 16, 16-Trimethyl-15R-hydroxy-9-oxoprosta-5(Z),13(E)-diensäure die nat-11R-16, 16-Trimethyl-9, 15-dioxoprosta-5(Z),13(E)-dien- säure als farbloses Oel erhalten.

  • Massenspektrum: M+ (m/e 376)
  • UV (Aethanol) λmax 235 nm (ε = 7425)
In analogy to Example 1, nat-11R, 16, 16-trimethyl-15R-hydroxy-9-oxoprosta-5 (Z), 13 (E) -dienoic acid became nat-11R-16, 16-trimethyl-9, 15 -dioxoprosta-5 (Z), 13 (E) -dien- acid obtained as a colorless oil.
  • Mass spectrum: M + (m / e 376)
  • UV (ethanol) λmax 235 nm (ε = 7425)

Beispiel 6Example 6

750 mg nat - 11R-Methyl-116R-fluor-15R-[2-tetrahydro-(2H)-pyranyloxy]-9-oxoprost-5(Z)-ensäure wurde in 15 ml eines 5:1 Gemisches von Essigsäure und Wasser 1.5 Stunden auf 49o erwärmt. Das Lösungsmittel wurde dann unter Hochvakuum entfernt und der Rückstand chromatographiert. Man erhielt 400 mg nat-11R-Methyl-16R-fluor-15R-hydroxy-9- oxoprost-5(Z)-ensäure als dickes farbloses Oel. Massenspektrum: m/4 370, 352, 332.750 mg of nat - 11R-methyl-116R-fluoro-15R- [2-tetrahydro- (2H) pyranyloxy] -9-oxoprost-5 (Z) -enoic acid was dissolved in 15 ml of a 5: 1 mixture of acetic acid and water 1.5 Heated to 49 o hours. The solvent was then removed under high vacuum and the residue was chromatographed. 400 mg of nat-11R-methyl-16R-fluoro-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid were obtained as a thick, colorless oil. Mass spectrum: m / 4 370, 352, 332.

Das Ausgangsmaterial wurde wie folgt hergestellt:

  • Ein Gemisch von 1 g 3,3aR,4,5,6,6aS-Hexahydro-4R-[4R-fluor-3R-hydroxy-l(E)-octenyl]-5R-methyl-2H-cyclopenta-[b]furan-2-on, 100 mg vorreduziertes Pt02 und 75 ml Aethylacetat wurde bei Raumtemperatur und Atmosphärendruck bis zur theoretischen Wasserstoffaufnahme hydriert. Das Gemisch wurde dann filtriert und das Lösungsmittel unter vermindertem Druck entfernt. Verreiben des Rückstandes mit Hexan lieferte 700 mg 3,3aR, 4, 5, 6,6aS-Hexahydro-4R-(4R-fluor-3R-hydroxy-octanyl)-5R-methyl-2H-cyclopenta[b]furan-2-on, Schmelzpunkt 52-55°C.
The starting material was produced as follows:
  • A mixture of 1 g 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-fluoro-3R-hydroxy-l (E) -octenyl] -5R-methyl-2H-cyclopenta- [b] furan -2-one, 100 mg of pre-reduced Pt0 2 and 75 ml of ethyl acetate was hydrogenated at room temperature and atmospheric pressure until the theoretical hydrogen absorption. The mixture was then filtered and the solvent removed under reduced pressure. Trituration of the residue with hexane provided 700 mg of 3.3aR, 4, 5, 6.6aS-hexahydro-4R- (4R-fluoro-3R-hydroxy-octanyl) -5R-methyl-2H-cyclopenta [b] furan-2- on, melting point 52-55 ° C.

Zu einer Lösung von 730 mg 3, 3aR, 4, 5, 6, 6aS-Hexahydro-4R- ( 4R-fluor-3R-hydroxy-octanyl ) -5 R-methyl-2H-cyclopenta-[b] furan-2-on in 50 ml Methylenchlorid wurden 50 mg Paratoluolsulfonsäure und 1 ml Dihydropyran gegeben. Die Lösung wurde bei Raumtemperatur 3 Stunden gerührt, danach mit 10

Figure imgb0032
Chromatographie des Rückstandes lieferte 2.4 g nat-11R-. Methyl-16R-fluor-15R-[2-tetrahydro-(2H)-pyranyloxy]-9S-hydroxyprosta-5(Z)-ensäure als dickes farbloses Oel; Massensprektrum: m/e 456, 438.To a solution of 730 mg of 3, 3aR, 4, 5, 6, 6aS-hexahydro-4R- (4R-fluoro-3R-hydroxy-octanyl) -5 R-methyl-2H-cyclopenta- [b] furan-2- 50 mg of paratoluenesulfonic acid and 1 ml of dihydropyran were added to 50 ml of methylene chloride. The solution was stirred at room temperature for 3 hours, then with 10
Figure imgb0032
Chromatography of the residue gave 2.4 g of nat-11R-. Methyl 16R-fluoro-15R- [2-tetrahydro- (2H) -pyranyloxy] -9S-hydroxyprosta-5 (Z) -enoic acid as a thick colorless oil; Mass spectrum: m / e 456, 438.

Zu einer rasch gerührten Lösung von 838 mg nat-11R-Methyl-16R-fluor-15R-[2-tetrahydro-(2H)-pyranyloxy]-9S-hydroxyprost-5(Z)-ensäure in 100 ml Aether-Aceton (5:1) wurden bei 0°C 0.6 ml Jones-Reagenz gegeben. Nach 10 Minuten wurden einige Tropfen Isopropanol zugesetzt und nach einigen Minuten 1.5 g Natriumbicarbonat und 5 ml Wasser. Sodann wurden 100 ml Aether zugesetzt, das Reaktionsgemisch wurde filtriert und die organische Phase mit gesättigter Natriumchloridlösung gewaschen. Die ätherische Lösung wurde dann getrocknet und das Lösungsmittel unter vermindertem Druck - entfernt. Man erhielt rohe nat-llR-Methyl-16R-fluor-15R-[2-tetrahydro-(2H)-pyranyloxy]-9-oxoprost-5(Z)-ensäure.To a rapidly stirred solution of 838 mg of nat-11R-methyl-16R-fluoro-15R- [2-tetrahydro- (2H) -pyranyloxy] -9S-hydroxyprost-5 (Z) -enoic acid in 100 ml ether-acetone (5 : 1) 0.6 ml of Jones reagent were added at 0 ° C. After 10 minutes, a few drops of isopropanol were added, and after a few minutes 1.5 g of sodium bicarbonate and 5 ml of water. Then 100 ml of ether were added, the reaction mixture was filtered and the organic phase was washed with saturated sodium chloride solution. The ethereal solution was then dried and the solvent was removed under reduced pressure. Crude nat-IIR-methyl-16R-fluoro-15R- [2-tetrahydro- (2H) -pyranyloxy] -9-oxoprost-5 (Z) -enoic acid was obtained.

Beispiel 7Example 7

Zu einer Lösung von 600 mg llR-Methyl-16R-fluor-15R-hydroxy-9-oxoprost-5(Z)-ensäure in 50 ml Aether/Aceton (5:1 Volumteile) wurde Jones-Reagenz gegeben. Nach Aufarbeitung wie in Beispiel 1 erhielt man llR-Methyl-16R-fluor-9,15-dioxoprost-5(Z)-ensäure als dickes farbloses Oel. Massenspektrum: m/e 385, 350, 348.Jones' reagent was added to a solution of 600 mg of IIR-methyl-16R-fluoro-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid in 50 ml of ether / acetone (5: 1 parts by volume). After working up as in Example 1, IIR-methyl-16R-fluoro-9,15-dioxoprost-5 (Z) -enoic acid was obtained as a thick, colorless oil. Mass spectrum: m / e 385, 350, 348.

Beispiel 8Example 8

In Analogie zu den Beispielen 6 und 7 wurde aus nat-11R-Methyl-16R-fluor-15S-[2-tetrahydro-(2H)-pyranyloxy]-9S-hydroxyprost-5(Z)-ensäure die nat-llR-Methyl-16R-fluor-15S-hydroxy-9-oxoprost-5(Z)-ensäure, ein dickes farbloses, Oel erhalten.
Massenspektrum: m/e 370, 352.Analogously to Examples 6 and 7, nat-11R-methyl was converted from nat-11R-methyl-16R-fluoro-15S- [2-tetrahydro- (2H) -pyranyloxy] -9S-hydroxyprost-5 (Z) -enoic acid -16R-fluoro-15S-hydroxy-9-oxoprost-5 (Z) -enoic acid, a thick colorless, oil obtained.
Mass spectrum: m / e 370, 352.

Die Ausgangsverbindung wurde aus 3,3aR,4,5,6,6aS-Hexahydro-4R-[4R-fluor-3S-hydroxy-l(E)-octenyl]-5R-methyl-

Figure imgb0033
The starting compound was prepared from 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-fluoro-3S-hydroxy-l (E) -octenyl] -5R-methyl-
Figure imgb0033

Beispiel 9Example 9

In Analogie zu Beispiel 1 wurde aus nat-11R-Metyhl- 16,16-difluor-15-R-hydroxy-9-osoprosta-5(z)-13

Figure imgb0034
die nat-11R-Methyl-16, 16-difluor-9, 15-dioxoprosta-5
Figure imgb0035
13(E)-diensäure erhalten.Analogously to Example 1, nat-11R-Metyhl-16,16-difluoro-15-R-hydroxy-9-osoprosta-5 (z) -13
Figure imgb0034
the nat-11R-methyl-16, 16-difluoro-9, 15-dioxoprosta-5
Figure imgb0035
13 (E) -dienoic acid obtained.

Beispiel 10Example 10

In Analogie zu den Beispielen 6 und.7

Figure imgb0036
nat-16, 16-methyl-9S-hydroxy-15R-[2-
Figure imgb0037
nyloxy] -prost-5 ( Z ) -esäure die nat-16, 16-
Figure imgb0038
hydroxy-9-oxoprosta-5(Z)-ensäure erhalten.
Figure imgb0039
In analogy to Examples 6 and.7
Figure imgb0036
nat-16, 16-methyl-9S-hydroxy-15R- [2-
Figure imgb0037
nyloxy] -prost-5 (Z) -esäure the nat-16, 16-
Figure imgb0038
obtained hydroxy-9-oxoprosta-5 (Z) -enoic acid.
Figure imgb0039

Beispiel 11Example 11

Figure imgb0040
Figure imgb0040

Die Ausgangsverbindung wurde aus 3, 3aR, 4, 5, 6, 6aS-Hexahydro-4R-[4R-methyl-4R-trifluormethyl-3R-hydroxy-1(E)-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-on via 3,3aR,4,5,-6,6aS-Hexahydro-4R-(4R-methyl-4R-trifluormethyl-3R-hydroxy- octanyl)-5R-methyl-2H-cyclopenta[b]furan-2-on und 3,3aR,4,5,-6,6aS-Hexahydro-4R-[4R-methyl-4R-trifluormethyl-3R-[2-tetra- hydro-(2H)-pyranyloxy]-octanyl]-5R-methyl-2H-cyclopenta[b]-furan-2-ol hergestellt.The starting compound was obtained from 3, 3aR, 4, 5, 6, 6aS-hexahydro-4R- [4R-methyl-4R-trifluoromethyl-3R-hydroxy-1 (E) -octenyl] -5R-methyl-2H-cyclopenta [b ] furan-2-one via 3.3aR, 4.5, -6.6aS-hexahydro-4R- (4R-methyl-4R-trifluoromethyl-3R-hydroxy-octanyl) -5R-methyl-2H-cyclopenta [b] furan-2-one and 3,3aR, 4,5, -6,6aS-hexahydro-4R- [4R-methyl-4R-trifluoromethyl-3R- [2-tetra-hydro- (2H) -pyranyloxy] -octanyl] -5R-methyl-2H-cyclopenta [b] -furan-2-ol.

Beispiel 12Example 12

In Analogie zu Beispiel 6 und 7 wurde aus nat-16R-Trifluormethyl-16R-fluor-15R-[2-tetrahydro-(2H)-pyranyloxy]-llR-methyl-9S-hydroxyprost-5(Z)-ensäure die nat-16R-Trifluormethyl-16R-fluor-15R-hydroxy-11R-methyl-9-oxoprost-5(Z)-ensäure erhalten. - Analogously to Examples 6 and 7, nat-16R-trifluoromethyl-16R-fluoro-15R- [2-tetrahydro- (2H) -pyranyloxy] -llR-methyl-9S-hydroxyprost-5 (Z) -enoic acid was converted into the nat- 16R-trifluoromethyl-16R-fluoro-15R-hydroxy-11R-methyl-9-oxoprost-5 (Z) -enoic acid was obtained. -

Die Ausgangsverbindung wurde aus 3,3aR,4,5,6,6aS-Hexahydro-4R-[4R-trifluormethyl-4R-fluor-3R-hydroxy-l(E)-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-on via 3,3aR,-4, 5, 6, 6aS-hexahydro-4R-(4R-trifluormethyl-4R-fluor-3R-hydroxy-octanyl)-5R-methyl-2H-cyclopenta[b]furan-2-on und 3,3aR,4,5,6,6aS-Hexahydro-4R-[4R-trifluormethyl-4R-fluor-3R-(2-tetrahydro-(2H)-pyranyloxy)-octanyl]-5R-methyl-2H-cyclopenta[b]furan-2-ol hergestellt.The starting compound was prepared from 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-trifluoromethyl-4R-fluoro-3R-hydroxy-l (E) -octenyl] -5R-methyl-2H-cyclopenta [b ] furan-2-one via 3,3aR, -4, 5, 6, 6aS-hexahydro-4R- (4R-trifluoromethyl-4R-fluoro-3R-hydroxy-octanyl) -5R-methyl-2H-cyclopenta [b] furan-2-one and 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-trifluoromethyl-4R-fluoro-3R- (2-tetrahydro- (2H) -pyranyloxy) -octanyl] -5R- methyl-2H-cyclopenta [b] furan-2-ol.

Beispiel 13Example 13

In Analogie zu Beispiel 7 wurde aus nat-16,16-Dimethyl-15R-hydroxy-9-oxoprost-5 (Z)-ensäure die nat-16,16-Dimethyl-9,15-dioxoprost-5(Z)-ensäure erhalten.Analogously to Example 7, nat-16,16-dimethyl-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid became nat-16,16-dimethyl-9,15-dioxoprost-5 (Z) -enoic acid receive.

Beispiel 14 Example 14

In Analogie zu Beispiel 7 wurde aus nat-16R-Trifluormethyl-16R, 11R-dimethyl-15R-hydroxy-9-oxoprost-5 (Z)-ensäure die nat-16R-Trifluormethyl-16R, 11R-dimethyl-9, 15-dioxoprost-5(Z)-ensäure erhalten.Analogously to Example 7, nat-16R-trifluoromethyl-16R, 11R-dimethyl-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid was converted into nat-16R-trifluoromethyl-16R, 11R-dimethyl-9, 15- obtained dioxoprost-5 (Z) -enoic acid.

Beispiel 15Example 15

Figure imgb0041
Figure imgb0041

Beispiel16Example 16

Figure imgb0042
Figure imgb0042

Beispiel 17Example 17

Figure imgb0043
Figure imgb0043

Beispiel AExample A

Kapseln wurden wie folgt hergestellt:

Figure imgb0044
Capsules were made as follows:
Figure imgb0044

Die oben genannten Bestandteile wurden gründlich gemischt und in Hartgelatinekapseln mit einem Füllgewicht von 350 mg abgefüllt.The above ingredients were mixed thoroughly and filled into hard gelatin capsules with a filling weight of 350 mg.

Beispiel BExample B

Tabletten wurden wie folgt hergestellt:

Figure imgb0045
Tablets were made as follows:
Figure imgb0045

Der Wirkstoff und die Maisstärke wurden gemischt und gesiebt. Dieser Prämix wurde dann mit dem Kalziumphosphat und der Hälfte des Magnesiumstearates vermischt, gesiebt und kompaktiert. Das so erhaltene Granulat wurde gesiebt, mit dem restlichen Magnesiumstearat versetzt, und gepresst.The active ingredient and the corn starch were mixed and sieved. This premix was then mixed with the calcium phosphate and half of the magnesium stearate, sieved and compacted. The granules thus obtained were sieved, the remaining magnesium stearate added, and pressed.

Claims (17)

1. Prostaglandinderivate der Formel
Figure imgb0046
worin R1 Wasserstoff oder
Figure imgb0047
Hydroxy: R3Wasserstoff; oder R 2 und
Figure imgb0048
sammen Oxo :R4Wasserstoff oder
Figure imgb0049
'R5 Fluor, Niederalkyloder Trifluormethyle R5Fluor,Niederalkyl oder Trifluormethyle R6 Wasserstoff, Fluor ode
Figure imgb0050
Wasserstoff;R8Hydroxy;oderR7 und Wasserstoff ; R3 Hydroxy; oder R7 und
Figure imgb0051
sammen Oxo; A und B, und X und Y, für
Figure imgb0052
Wasserstoff oder zusammen eine Kohlenstoff- Kohlenstoffbindung bedeuten; mit der Bei dingung ,dass R2und R3 zusammenooxo dir- stellen, wenn R7 und R8 zusammenOxo sind stellen, wenn R7 und R8 zusammen Oxo sind und mit der weiteren Bedingung, dass A und B Wasserstoff darstellen, wenn R7 Wasserstoff ist; und mit der dritten Bedingung, dass X und Y eine Kohlenstoff- Kohlenstoffbindung darstellen, wenn R1 und R7 gleichzeitig Wasserstoff sind;
deren Enantiomere und Racemate.1. Prostaglandin derivatives of the formula
Figure imgb0046
 wherein R 1 is hydrogen or
Figure imgb0047
Hydroxy: R 3 is hydrogen; or R 2 and
Figure imgb0048
together oxo: R 4 is hydrogen or
Figure imgb0049
'R 5 fluorine, lower alkyl or trifluoromethyl R 5 fluorine, lower alkyl or trifluoromethyl R 6 hydrogen, fluorine or
Figure imgb0050
Hydrogen; R 8 hydroxy; or R 7 and hydrogen; R 3 hydroxy; or R 7 and
Figure imgb0051
together oxo; A and B, and X and Y, for
Figure imgb0052
Is hydrogen or together a carbon-carbon bond; that R 2 and R zusammenooxo DIR filters with the case dingung 3 when R 7 and R 8 are zusammenOxo provide, when R 7 and R 8 together are oxo and with the further condition that A and B represent hydrogen when R 7 is hydrogen; and with the third condition that X and Y represent a carbon-carbon bond when R 1 and R 7 are simultaneously hydrogen;
their enantiomers and racemates. 2. Prostaglandinderivate gemäss Anspruch 1 der Formel
Figure imgb0053
worin R1 bis R 6, X und Y die obige Bedeutung haben, mit der Bedingung, dass X und Y eine Kohlenstoff- Kohlenstoffbindung darstellen, wenn R1 Wasserstoff ist.2. Prostaglandin derivatives according to claim 1 of the formula
Figure imgb0053
 wherein R 1 to R 6 , X and Y have the above meaning, provided that when R 1 is hydrogen, X and Y represent a carbon-carbon bond. 3. Prostaglandinderivate gemäss Anspruch 1 der Formel
Figure imgb0054
worin R 1, R 4, R 5, R 6, A, B, X und Y die obige Bedeutung haben.
Figure imgb0055
3. Prostaglandin derivatives according to claim 1 of the formula
Figure imgb0054
 wherein R 1 , R 4 , R 5 , R 6 , A, B , X and Y have the above meaning.
Figure imgb0055
 17. Nat. 11R, 16, 16-Trimethyl-9, 15-dioxoprosta-S(Z),-13 (E)-dien-säure .17. Nat. 11R, 16, 16-trimethyl-9, 15-dioxoprosta-S (Z), - 13 (E) -diene acid. 18. Nat. 16R-Trifluormethyl-16R, 11R-dimethyl-9, 15-dioxoprost-5-(Z)-en-säure.18. Nat. 16R-trifluoromethyl-16R, 11R-dimethyl-9, 15-dioxoprost-5- (Z) -enoic acid. 19. Nat. 16R-Trifluormethyl-16R-fluor-11R-methyl-9,15-dioxoprost-5(Z)-en-säure.19. Nat. 16R-trifluoromethyl-16R-fluoro-11R-methyl-9,15-dioxoprost-5 (Z) -enoic acid. 20. Nat. 11R-Methyl-16R-fluor-9, 15-dioxoprost-5(Z)-en-säure.20. Nat. 11R-methyl-16R-fluoro-9, 15-dioxoprost-5 (Z) -enoic acid. 2l. Verfahren zur Herstellung von
Figure imgb0056
derivaten der Formel
Figure imgb0057
Figure imgb0058
deren Enantiomeren und Racematen,dadurch gekennzeichnet, dass man a) eine Verbindung der Formel XI
Figure imgb0059
worin R 9 eine durch eine hydrolysierbare Aether- oder Estergruppe geschützte Hydroxygruppe darstellt und R1 bis R 6, X und Y die obige Bedeutung haben
oder ein Enantiomer oder Racemat davon der Hydro- lyse der Schutzgruppe R9 unterwirft und gewünschtenfalls eine durch X und Y dargestellte Kohlenstoff- Kohlenstoffbindung hydriert, und/oder eine Hydroxygruppe zur Oxogruppe oxidiert; oder b) die Hydroxygruppe(n) in einer Verbindung der Formel III
Figure imgb0060
worin R 1 bis R6, X und Y die obige Bedeutung haben,
oder eines Enantiomers oder Racemats davon zu einer Verbindung der Formel I, worin R2 und R3 bzw. R7 und R8 Oxo darstellen, oxidiert.
Figure imgb0061
Figure imgb0062
worin R1 bis R6, X und Y die obige Bedeutung haben, mit der Bedingung, dass X und Y eine Kohlenstoff- Kohlenstoffbindung
Figure imgb0063
- len, wenn R1 Wasserstoff ist,
herstellt. 2l. Process for the production of
Figure imgb0056
derivatives of the formula
Figure imgb0057
Figure imgb0058
their enantiomers and racemates, characterized in that one a) a compound of formula XI
Figure imgb0059
 wherein R 9 represents a hydroxyl group protected by a hydrolyzable ether or ester group and R 1 to R 6 , X and Y have the above meaning
or subjecting an enantiomer or racemate thereof to the hydrolysis of the protective group R 9 and, if desired, hydrogenating a carbon-carbon bond represented by X and Y and / or oxidizing a hydroxyl group to the oxo group; or b) the hydroxy group (s) in a compound of formula III
Figure imgb0060
 wherein R 1 to R 6 , X and Y have the above meaning,
or an enantiomer or racemate thereof to a compound of formula I in which R 2 and R 3 or R 7 and R 8 are oxo.
Figure imgb0061
Figure imgb0062
 wherein R 1 to R 6 , X and Y have the above meaning, with the proviso that X and Y are a carbon-carbon bond
Figure imgb0063
len when R 1 is hydrogen,
manufactures. 23. Verfahren nach Anspruch 21, dadurch
Figure imgb0064
zeichnet, dass man Verbindungen der Formel
Figure imgb0065
worin R1, R4, R5,R6, A,_, B,ä , X und Y die oblige Bedeutunghaben,
herstellt.23. The method according to claim 21, characterized
Figure imgb0064
records that compounds of the formula
Figure imgb0065
 where R 1 , R 4 , R 5 , R6, A, _, B , ä, X and Y have the required meaning,
manufactures. 24. Verfahren nach Anspruch23, dadurch gekennzeichnet, dass man Verbindungen der Formel IB herstellt, in denen A und B eine Kohlenstoff- Kohlenstoffbindung darstellen.24. The method according to claim 23, characterized in that compounds of the formula IB are prepared in which A and B represent a carbon-carbon bond. 25. Verfahren nach Anspruch23, dadurch gekennzeichnet, dass man Verbindungen der Eormel IB herstellt, in denen A und B Wasserstoff darstellen.25. The method according to claim 23, characterized in that compounds of formula IB are prepared in which A and B represent hydrogen. 26. Verfahren nach Anspruch21, dadurch gekennzeichnet, dass man nat. llR-Methyl-16R-fluor-9,15-dioxoprosta(Z)-5-(E)-13-dien-säure herstellt.26. The method according to claim 21, characterized in that nat. llR-methyl-16R-fluoro-9,15-dioxoprosta (Z) -5- (E) -13-diene acid. 27. Verfahren nach Anspruch2l, dadurch gekennzeichnet, dass man nat. llR-Methyl-16R-fluor-15R-hydroxy-9-oxo--prost- (Z ) -5-en-säure herstellt.27. The method according to claim 2l, characterized in that nat. llR-methyl-16R-fluoro-15R-hydroxy-9-oxo - prost- (Z) -5-ene acid. 28. Verfahren nach Anspruch21, dadurch gekennzeichnet, dass man nat. 11R-biethyl-16R-fluor-9,15-dioxo-prost-(Z)-5-en-säure herstellt.28. The method according to claim 21, characterized in that nat. 11R-diethyl-16R-fluoro-9,15-dioxo-prost- (Z) -5-ene acid. 29. Pharmazeutische Präparate, gekennzeichnet. durch einen Gehalt an einem Prostaglandinderivat der Formel I gemäss Definition in Anspruch 1.29. Pharmaceutical preparations, labeled. by a content of a prostaglandin derivative of the formula I as defined in claim 1. 30. Verfahren zur Herstellung pharmazeutischer Präparate, dadurch gekennzeichnet, dass man ein Prostaglandinderivat der Formel I gemäss Definition in Anspruch 1 mit nicht-toxischen, inerten, physiologisch verträglichen festen oder flüssigen, an sich in solchen Präparaten üblichen Trägerstoffen mischt.
Figure imgb0066
Figure imgb0067
worin R1 Massarstoff oder Niederalkyl, a5 Fluor, Niederalkyldear Trifluormethyl Wasserstoffe Fluor oder Niedaralkyl) und R10 gegebenenfalls geschütztes Hydroxy ist.30. A process for the preparation of pharmaceutical preparations, characterized in that a prostaglandin derivative of the formula I as defined in claim 1 is mixed with non-toxic, inert, physiologically tolerable solid or liquid carriers which are customary in such preparations.
Figure imgb0066
Figure imgb0067
 wherein R 1 is massar or lower alkyl, a 5 is fluorine, lower alkyldear trifluoromethyl hydrogen fluoride or lower alkyl) and R 10 is optionally protected hydroxy. 32. wischenprodukte zur
Figure imgb0068
gemäß Anspruch dar Formel
Figure imgb0069
Figure imgb0070
Figure imgb0071
worin R9 geschütztes Hydroxy darstellt und R1 bis R6, X und Y wie in Anspruch 1 definiert sind, wobei X und Y eine C-C-Bindung darstellen, wenn R1 Wasserstoff ist.32. wiping products for
Figure imgb0068
according to claim the formula
Figure imgb0069
Figure imgb0070
Figure imgb0071
 wherein R 9 represents protected hydroxy and R 1 to R 6 , X and Y are as defined in claim 1, wherein X and Y represent a CC bond when R 1 is hydrogen.
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EP0310305A2 (en) * 1987-10-02 1989-04-05 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Cathartics
US5204371A (en) * 1979-12-10 1993-04-20 Schering Aktiengesellschaft Pharmaceutically active 9-chloroprostaglandins
US5317032A (en) * 1987-10-02 1994-05-31 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Prostaglandin cathartic

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EP0030377B1 (en) * 1979-12-10 1984-02-22 Schering Aktiengesellschaft 9-chloro-prostaglandin derivatives, process for their preparation and use as medicines
US5204371A (en) * 1979-12-10 1993-04-20 Schering Aktiengesellschaft Pharmaceutically active 9-chloroprostaglandins
EP0310305A2 (en) * 1987-10-02 1989-04-05 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Cathartics
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