CA2036386A1

CA2036386A1 - 9-fluoroprostaglandin derivatives, process for their production and their pharmaceutical use

Info

Publication number: CA2036386A1
Application number: CA002036386A
Authority: CA
Inventors: Ulrich Klar; Hartmut Rehwinkel; Helmut Vorbruggen; Karl-Heinz Thierauch; Claus-Steffen Sturzebecher
Original assignee: Individual
Current assignee: Bayer Pharma AG
Priority date: 1989-07-14
Filing date: 1990-07-13
Publication date: 1991-01-15
Also published as: DK0434833T3; EP0434833B1; JPH04502329A; WO1991001302A1; ES2055925T3; DE3923797A1; ATE106076T1; DE59005819D1; EP0434833A1

Abstract

ABSTRACT
The invention relates to 9-fluoroprostaglandin derivatives of formula I, (I), in which R1 means --- , , COOR4 or CONHR5, R2 and R3 each mean a hydrogen atom or a free or functionally modified hydroxy group, X means a CH2 group, an O or S atom, W means hydrogen, -OR6, halogen, -CN-, -NO2, trifluoromethyl or COOR6, and, if R4 means hydrogen, their salts with physiologically compatible bases, the alpha-, beta- or gamma-cyclodextrin clathrates, as well as the compounds of formula I
encapsulated with liposomes, process for their production and their pharmaceutical use.

Description

~,'f~ ~ 8 9-Fluoroprostaglandin Derivatives, Process for their Production and their Pharmaceutical Use The invention relates to 9-fluoroprostaglandin derivatives, process for their production as well as their use as auxiliary agents for pharmacological analyses and as pharmaceutical agents.
It has been found, surprisingly, that chemically and metabolically stable prostaglandin analogs, whose pharmacological properties are comparable to those of unstable thromboxane A2(TXA2) or PGH2, are obtained by the introduction of a fluorine atom in 9 position in connection with an aromatic substituent in 17 position.
The compounds of this invention therefore are suitable as auxiliary agents for pharmacological characterizations as well as for selective treatment of diseases, which are attributable to a deficiency in endogenous TXA2/PGH2.
The invention relates to 9-fluoroprostaglandin derivatives of formula I, (I), ~J'J',~

in which Rl can be ~ < ~ , CooR4r in whi.ch R4 can mean hydrogen or a Cl-C10alkyl radical optionally substituted by halogen, phenyl, CI~C4 alkoxy or di-(CI-C4) alkylamino, a C3-C10cycloalkyl radical, a C7-C16aralkyl radical, a phenacyl radical substituted by W, a C6-C12aryl radical or a 5- or 6-member heterocycli~
radical with at least one N, O or S atom, or Rl can be a C~NHR5 radical with R5 meaning hydrogen, Cl-Cl0alkanoyl or Cl-Cl0 alkanesulfonyl, R2 and R3 each mean a hydrogen atom or a free or functionally modified hydroxy group, and the OH ~roup can be respectively in alpha- or beta-position, X means a CH2 group, an O or S atom, W means hydrogen, -oR6, halogen, -CN-, -NO2, trlfluoromethyl or COOR6, R6 can be hydrogen, Cl-C10alkyl, C6-C12aryl or C7-C16aralkyl substituted by halogen, and, if R4 means hydrogen, their salts with physiologically compatible bases, as well as the alpha-, beta- or gamma-cycl~dextrin clathrates, as well as the compounds of formula I encapsulated with liposomes.
The definition of 5- or 6-membered heterocyclic radical relates to heterocycles, which contain at least one heteroatom, ~1 S ~ rJ ~ .J ~i preferably nitroyen, oxygen or sulfur~ For example, there can be mentioned 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl.
As alkyl groups R4 and R6, straight-chain or branched--chain alkyl groups with 1-10 C atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl, are to be considered.
Alkyl groups R4 and R6 can be substituted by halogen atoms, hydroxy groups, Cl-C4 alkoxy groups, C6-CI2aryl groups, whi~h can be substituted by halogen, di-(CI-C4)-alkylamines and tri-(CI-C4)-alkylammonium. Those alXyl groups which are singly substituted are preferred.
As substituents, for example, there can be mentioned fluorine, chlorine or bromine atoms, phenvl, dimethylamino, diethylamino, methoxy, ethoxy.
As preferred alkyl groups R4 and R6, those with 1-4 C atoms, such as, for example, methyl, ethyl, propyl, isobutyl, butyl, can be mentioned.
As aryl groups R4 and R6, for example, phenyl, diphenyl;
1-naphthyl and 2-naphthyl, which can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 C
atoms, a chloromethyl group, fluoromethyl group, carboxyl group, Cl-C4 alkoxy group or hydroxy group, are suitable. The substitution in 3- and 4-position on the phenyl ring is preferred, for example, by fluorine, chlorine, Cl-C4 alkoxy or trifluoromethyl or in 4-position by hydroxy.

3 f ',~

Cycloalkyl groups R4 can contain 3-10 carbon atoms, preferably 3-6 carbon atoms, in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, methylcyclohexyl.
Especially preferred cycloalkyl groups are cyclopentyl and cyclohexyl.
As C7-C16aralkyls, the following radicals are meant:
phenyl-substituted alkyl radicals (straight-chain and bra~ched~
with 1-10 C atoms, such as, for example, benzyl, phenylmethyl, alpha-phenylethyl, 3-phenylpropyl, etc. But 1- or 2-naphthyl with a suitably shorter alkyl chain are also suitable as Ar.
The alkyl groups or alkoxy groups with 1-4 C atoms mentioned as substituents are to be straight-chain or branched-chain.
The hydroxy groups in R2 and R3 can be functionally modified, for example, by etherification or esterification, and the free or modified hydroxy groups can be in alpha- or beta-position, and free hydroxy groups are preferred.
As ether and acyl radicals, the radicals known to one skilled in the art are suitable. Easily cleavable ether radicals, such as, for example, the tetrahydropyranyl radical, tetrahydro~uranyl radical, tert~butyldimethylsilyl radical, tert-butyldiphenylsilyl radical, tribenzylsilyl radical, are preferred. As acyl radicals, for example, acetyl, propionyl, butyryl, benzoyl are suitable.

iJ ~J ~ ,J ~ ,JI~

Halogen in the definitions for R4, R6 and W means fluorine, chlorine and bromine.
Radicals ''Cl-ClOalkanoyl'' or ''Cl-C10-alkanesulfonyl''for RS
correspond to the already mentioned alkyl groups of the same length with the difference that they are bound on a carboxyl group. Cl C4 alkanoyl or Cl-C4 alkanesulfonyl are preferred.
Inorganic and organic bases are suitable for salt formation with the free acids (R4 = H), as they are known to one skilled in the art for forming physiologically compatible salts. Fo~
example, there can be mentioned: alkali hydroxides, such as sodium hydroxide or potassium hydroxide, alkaline earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, n-methylglucamine, morpholine, tris-(hydroxymethyl)methylamine, etc~
Preferred compounds of formula I are compounds in which Rl means the group CooR4, R2 means hydrogen or hydroxyl, R3 means hydrogen or hydro~yl, R4 means hydrogen or Cl-C6 alkyl, ~~
R5 means methanesulfonyl, X means oxygen or CH2, W means hydrogen or fluorine.
The invention further relates to a process for the production of co~pounds of formula I, which is characterized in rl ~ ~, f~ r~ ~ ~

~ that a compound of formula II
..~

~Z ~ ~ ~

in which ;f R4 exhibits a hydroxy group and Rl, R2, R3, X and W have the above-indicated meanings and free OH groups in R2, R3 and W are protected, is reacted with diethylaminosulfur trifluoride [M.
Sharma, Tetrahedron Lett. 573 (1977); W. J. Middleton, J. Org.
Chem. 40, 574 (1975)] or other ~luorinating agents, such as, e.g., (HF~n--pyridine [G. A. Olah, Synthesis 786 (1973)] or SeF4-pyridine [G. A. Olah, J. Am. Chem. Soc. 96, 925 (1974)] and protected hydroxy groups optionally in R2, R3 and W are released and/or free hydroxy groups are esterified, etherified, and/or an esterified carboxy group is saponified or a carboxy group~with a physiologically compatible base is converted to a salt or reacted to a clathrate with alpha-, beta- or gamma-cyclodextrin or encapsulated with liposomes.
The reaction of the compounds of general formula II to the compounds of general formula I is performed with diethylaminosulfur trifluoride at -80C to +40C, preferably at 7 ;'~ '3 -70C to +25C. As a solvent, dichloromethane, 1.1.2-trifluorotrichloroethane, pyridine, toluene, benzene, ethylene chloride, i.a., preferably toluene and pyridine, are suitable.
The release of functionally modified hydroxy groups R2, R3 and W takes place according to the methods known to one skilled in the art. For example, the cleavage of the ether protecting groups is performed in an aqueous solution of an organic acid, such as, e.g., acetic acid, propionic acid, citric acid, i.a., or in an aqueous solution of an inorganic acid, such as, é~g., hydrochloric acid, or in the case of tetrahydropyranyl ethers with use of pyridinium-p-toluene sulfonate, preferably in alcohols as a solvent or with use of anhydrous magnesium bromide, preferably in diethyl ether as a solvent.
To improve the solubility, a water-miscible inert solvent is suitably added with use of aqueous-acid reaction conditions. For example, alcohols, such as methanol and ethanol, ethers, such as dimethoxyethane, dioxane and tetrahydrofuran have proved to be suitable, and tetrahydrofuran is preferably used.
The cleavage of silylether protecting groups takes place, for example, with tetrabutylammonium fluoride according to the meth~ds known to one skilled in the art. As a solvents, for example, tetrahydrofuran, diethyl ~ther, dioxane, methylene chloride, etc., are suitable. The cleavage is performed preferably at temperatures between 20 and 80C.
The saponification of the acyl groups and prostaglandin ester is performed according to the methods known to one skilled in the art, such as, for example, with basic catalysts, such as, e.g., with alkali or alkaline-earth carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol. As alcohols, aliphatic alcohols, such as, e.g., methanol, ethanol, butanol, etc., but preferably methanol, are suitable. As alkali carbonates and alkali hydroxides, there can be mentioned lithium, sodium and potassium salts. The lithium and potassium salts are preferred. As alkaline-earth carbonates and alkaline-earth hydroxides, for example, calcium carbonate, calcium hydr~ide and barium carbonate are suitable. The reaction generally takes place at -10 to +70C, but preferably at +25C.
The introduction of the ester groups C02~4 for Rl or CO~R6 for W, in which R4 or R6 represents an alkyl group with 1-10 C atoms, takes place according to the methods known to one skilled in the art. The l-carboxy compounds (R4 = H or R6 = H) are reacted, for example, with diazohydrocarbons in a way known in the art. The esterification with diazohydrocarbons takes place, e.g., in that a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, is mixed with the 1-carboxy compound, dissolved in the same or in another inert solvent, such as, e.g., methylene chloride. After completion of the reaction within 1 to 60 minutes, the solvent is removed and the ester is purified in the usual way. Diazoalkanes are either known or can be produced according to known methods (Org. Reactions, Vol. 8, pages 389-39~ (1954)~.

The introduction of the ester group Co2R4 for Rl or C02R6 for W, in whi~h R4 or R6 represents a substituted or an unsubstituted aryl group, takes place according to the methods known to one skilled in the art. For example, the 1-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, such as, e.g., pyridine, dimethylaminopyridine, triethylamine, in an inert solvent, such as, e.g., methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, but preferably with chloroform. The reaction is performed at temperatures between -30C and ~50C, preferably at +10C.
The prostaglandin derivatives of formula I with R4 or R6 meaning a hydrogen atom can be converted to salts with suitable amounts of the corresponding inorganic bases with neutralization.
For example, by dissolving the corresponding prostaglandin acids in water, which contains stoichiometric amounts of the base, the solid inorganic salt is obtained after evaporation of the water or after the addition of a water-miscible solvent, e.g., alcohol or acetone.
The production of the amine salts takes place in the usual way. For this purpose, the prostaglandin acid is dissolved in a suitable solvent, such as, e.g., ethanol, acetone, diethyl ether or benzene and 1 to 5 equivalents of the respective amine of this solution is added to this solution. In this case, the salt usually accumulates in solid form or is isolated in the usual way after the evaporation of the solvent~

l o The functional modification of the free hydroxy groups ta~es place according to the methods known to one skilled in the art.
For the introduction of the ester protecting groups, it is reacted, for example, with dihydropyran or methyl vinyl ether in methylene chloride or chloroform with use of catalytic amounts''o'f an acidic condensing agent, such as, e.g., toluenesulfonic acid.
The respective enol ether is added in excess, preferably in 1.2 to 10 times the amount of the theoretical requirement. The reaction normally takes place at -10C to +30C and is comp-eted after 2 to 45 minutes. - '-For the introduction of the silylether protecting groups, it is reacted, for example, with t-butyl-diphenylchlorosilane or t-butyl-dimethylchlorosilane in dimethylformamide with use of a base such as, e.g., imidazole. The respective silyl chloridQ is added in excess, preferahly in ~.05 to 4 times the amount of the theoretical requirement. The reaction normally takes place at 0C to 30C and is completed after 1 to 24 hours.
The introduction of the acyl protecting groups takes place by a compound of formula I being reacted in a way known in the art with a carboxylic acid derivative, such as, e.g., acid chloride, acid anhydride, etc.
The new chemicaLly and metabolically stable 9 fluoroprostaglandin derivatives have pharmacological properties which are comparable to those of the unstable thromboxane A2(TXA2) or PGH2. Thus as TXA2~PGH2 rec~ptor agonists, they represent a valuable diagnostic instrument for characterizing ] ]

prostaglandin receptors or TXA2/PGH2 receptor subtypes, with which the importance of the TXA2/PGH2-dependent stimulation of platelets and vessels can be established. This applies both for in vitro tests, such as, e.g., receptor characterization or displacement on the receptor, platelet aggregation inhibiting tests, vessel layer constriction, etc, and for pharmacological tests on the animal.
The ~XA2/PGH2 receptor agonists can be used for specific weakening or elimination of the action of cyclooxygenase;~
inhibitors, of TXA2-synthetase inhibitors as well as of TXA2/PGH2 receptor blockers. Another possibility of use exists in the partial downward adjustment of the TXA2/~GH2 action in clinical pictures with increased sensitivity to or production of thromboxane, such as, e.g., those of coronary arteries or vessels with arteriosclerotic lesions.
In combination with a TXA2/PGH2 receptor antagonist, the TXA2/PGH2 receptor agonist can be used for diagnostic clarification o f the involvement of the TXA2/PGH2-dependent process in those clinical pictures which require no systemic dose of a TXA2/PGH2 receptor agonist for this diagnosis but also in the case of other clinical pictures, provided that undesirable effects of the TXA2/PGH2 receptor agonist can be counteracted by an antagonist.
The TXA2/PGH2 receptor agonists are further suitable for local control of hemorrhage in the case o f defects of the ~ J

platelet function, which are based on an impairment of the TXA2/PGH2 formation and/or action.
The fluoroprostaglandin derivatives of this invention can also be used in combination, e.g., with beta-blockers, diuretics, phosphodiesterase inhibitors, Ca antagonists or nonsteroidal antiinflammatory agents.
The dose of the compounds is 1-1000 micrograms/kg/per day, if it is administered to the human patient. The unit dose for the pharmaceutically acceptable vehicle is 10 microgram~ to 100 micrograms. -For parenteral administration, sterile, injectable aqueousor oily solutions are used. For oral administration, for example, tablets, coated tablets or capsules are suitable. The ., invention thus also relates to pharmaceutical-agents based on compounds of formula I and usual auxiliary agents and vehicles including cyclodextrin clathrates and encapsulation of liposomes.
The active ingredients according to the invention are to be used in combination with the auxiliary agents known and usual in galenicals, for example, for the production of pharmaceutical agents.

, ",~

(5Z,9R,13E,15R)-9-Fluoro-15-hydroxy-16-phenoxy-17,18,1g,20-tetranor-5,13-prostadienoic acid methyl ester:
The solution of 47 mg (75 micromol) of (5Z,9R,13E,15R)-9-fluoro-15-t-butyl-diphenylsilyloxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester [cf. Dr. U. Klar et al~, German patent application, file number P....... ] is dissolved in 870 microliters of anhydrous tetrahydrofuran, mixed with 170 microliters of a 1 M tetrabutylammonium fluoride~
solution in tetrahydrofuran and allowed to stir for three hours under an atmosphere of dry argon. It is poured on ice water, extracted with diethyl ether, rewashed with a saturated sodium chloride solution and dried on magnesium sulfate. The crude oil obtained after removal of the solvent in the water jet vacuum is purified by chromatography on two analytic thin-layer slabs. A
mixture of n-hexane and ethyl acetate is used as a mobile solvent, diethyl ether is used as an eluant. 26 mg (67 micromol, 89%) of the title compound is isolated as a colorless oil.
IR (film): 3600-3200, 3060, 3030, 3010, 2930, 2870, 1735, 1600, 1585, 1495, 1245, 1040, 970, 750 and 690 cm~l.

(SZ,9R,13E,lSR)-9-Fluoro-l5~hydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid:

26 mg (67 micromol) of the compound produced in example 1 is dissolved in 970 microliters oi methanol, mixed with 324 ~
.

.

. 1 r~- r~ ~ r, microliters of an 8~ potassium hydroxide solution and stirred for 5 hours at 25C. It is poured in ice water, adjusted to a pH of 4 to 5 by adding a saturated citric acid solution, extracted several times with dichloromethane, washed with water and dried on magnesium sulfate. 25 mg (66 micromol, 99%) of the title compound is isolated as a colorless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2930, 2870, 1710, 1600, 1585, 1495, 1245, 1040, 970, 755 and 690 cm~l.

,: .

(5Z,9R,13E,15S)-9-Fluoro-15-hydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester:
41 mg (65 micromol) of (5Z,9R,13E,15S)-9-fluoro-15-t-butyl-diphenylsilyloxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester [cf. Dr. U. Klar et al., German patent application, file number P....... ] is reacted analogously to example 1 and, after working up and purificationl 25 mg ~64 micromol, 98%) of the title compound is isolated as a colorless oil.
IR (film): 3600-3200, 3060, 3020, 2940, 2870, 1740, 1600, 1590, 1245, 1040, 970, 755 and 695 cm~l.

~ ~ C:, 3 ~, /,. '~

:

(5Z,9R,13E,15S)-9-Fluoro-15-hydroxy-16-phenoxy-17,18,15,20-. tetranor-5,13-prostadienoic acid:
25 mg (64 micromol) of the compound produced in example 3 is reacted analogously to example 2 and, after working up, 24 mg (64 micromol, 100%) of the title compound is isolated as a colorless ; oil.
IR (film): 3600-2400, 3060, 3010, 2940, 2870, 1710, 1600, 1590, 1500, 1245, 1080, 1040~ 970, 755 and 690 cm~l.

~ (5Z,9R,llS,13E,15R)-9-Fluoro-11,15-dihydroxy-16-phenoxy-: 17,18,19,20-tetranor-5,13-prostadienoic acid:
54 mg (106 micromol) of the compound produced in example 5a is saponified analogously to example 2 and, after working up and ~ purification, 36 mg (92 micromol, 87%) of the title compound is :~ isolated as a colorless oil.
IR (film): 3600-2400, 3090, 3060, 3040, 3010, 2930, 2870, 1710, 1600, 1585, 1495, 1245, 1085, 1040, 975, 755 and 690 cm l a) (5Z,9R,llS,13E,15R)-9-Fluoro-ll-henzoyloxy-15-hydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl : ester:
86 mg (115 micromol) o~ the compound produced in example 5b - is reacted analogously to example 1 and, after working up and O, puri~ication, 54 mg (106 micromol, 92%) of the title compound is isolated as a colorless oil.

' ~ ~-' ~J J
IR (filmJ: 3600-3200, 3060, 3020, 2950, 2870, 1735, 1710, 1600, 1495, 1445, 1245, 1110, 1065, 1025, 970, 755, 715 and 695 cm~l.
b) (5Z,9R,].lS,13E,15R)-9-Fluoro-11-benzoyloxy-15-t-butyl-diphenylsilyloxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester:
78 mg (121 micromol) of the compound produced in example 5c is dissolved in 3 ml of anhydrous toluene, mixed with 65 mg of triphenylphosphine, 30 mg of benzoic acid and 39 microli~ers of azodicarboxylic acid diethyl ester (DEAD). It is stirred for 2.5 hours at 25C under an atmosphere of dry argon, mixed with water, extracted several times with diethyl ether, dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on about 30 ml of fine silica gel. A
mixture of ethyl acetate and n-hexane is used as a mobile solvent. 86 mg (115 micromol, 95%) of the title compound is isolated as a colorless oil.
IR (film~: 3070, 3020, 3000, ~940, 2B60, 1735, 1715, 1600, 1590, 1490, 1445, 1425, 1270, 1245, 1110, 970, 820, 745 and 700 cm~l.
c) (5Z,9R,llR,13E,15R)-9-Fluoro-ll-hydroxy-15-t-butyl-diphenylsilyloxy-16~phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester:
93 mg (128 micromol) of (5Z,9R,llR,13E,15R)-9-fluoro~
(tetrahydropyran-2-yloxy)-15-t-butyl-diphenylsilyloxy-16-phenoxy-17,18,19,20-tetranor-5,8(9),13-prostatrienoic acid methyl ester , ' ' , , ~ ' ~ ~ ~S ~, ~ ,r1 [cf. Dr. U. Klar et al., German patent application, file number P........ ] is dissolved in 2 ml of anhydrous methanol, mixed with 11 mg of pyridinium-p-toluenesulfonate (PPTs) and heated under an atmosphere of dry argon for 2 hours to 55C. After the cooling, it is mixed with dichloromethane, washed with water and saturated sodium chloride solution, dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on four analytic thin-layer slabs. A mixture of n-hexane and ethyl acetate is used as a mobile solvent, ethyl acetate is used as an eluant. 78 mg (121 micromol, 95~) of the title compound is isolated as a colorless oil.
IR (film): 3600-3200, 3070, 3030, 3000, 2940, 2850, 1735, 1600, 1590, 1495, 1450, 1245, 1110, 970, 815, 750, 740 and 705 cm~l.

(5Z,9R,llS,13E,15R)-9-Fluoro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester:
12 mg (31 micromol) of the acid produced in example 5 is dissolved in 0.5 ml of dichloromethane, cooled to 5C and mixed with an ethereal solution of diazomethane. It is allowed to stir for 15 minutes, excess reagent and solvent are removed by distillation in the water jet vacuum and 12 mg (30 micromol, 97%) of the title compound is isolated as a colorless oil.

' ~` :
: , ~ J ~J 5'~

IR (film): 3600-3200, 3090, 3060, 3030, 3010, 2930, 2870, 1735, 1600, 1590, 1495, 1245, 1085, 1040, 975, 760 and 690 cm~l.

(5Z,9R,llS,13E,15S)-9-Fluoro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic aeid:
139 mg t272 micromol) of (5Z,9R,llS,13E,15S)-9-fluoro-11-benzoyloxy-15-hydroxy-16-phenoxy-17,18,19,20-tetranor-5,8(9),13-prostadienoic acid methyl ester [ef. Dr. U. Klar et al., German patent application, file number P....... ] is saponified~
analogously to example 2 and, after working up and chromatographic purification, 88 mg (224 mieromol, 82%) of the title eompound is isolated as a colorless oil.
IR tfilm): 3600-2400, 3070, 3050, 3010, 2940, 2870, 1710, 1600, 1590, 1495, 1445, 1245, 1080, 1040, 980, 755 and 695 em~l.

(5Z,9R,llS,13E,15R)-9-Fluoro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor~5,13-prostadienoic aeid methyl ester:
16 mg (41 mieromol) of the eompound produeed in example 7 is esterified analogously to example 6 and, after working up and purifieation, 16 mg (39 mieromol, 96~) of the title eompound is isolated as a colorless oil.
- IR (film): 3600-3200, 3070, 3050, 3010, 2940, 2870, 1740, ~ 1600, 1585, 1500, 1245, 1080, 1040, 980, 755 and 695 em~l.

'~, ~' ';

(5Z,9R,llS,13E,15R)-9-Fluoro-11,15-dihydroxy-17-phenyl-18,19,20-tri-nor-5,13-prostadienoic acid methyl ester:
360 mg (629 micromol) of (5Z,9R,llR,13E,15R)-9-fluoro-11,15-bis-(tetrahydropyran-2-yloxy)-17-phenyl-18,19,20-tri-nor-5,13-prostadienoic acid methyl ester [cf. Dr. U. Klar et al., German patent application, file number P........ ] is mixed with 15 ml of a vinegar/water/tetrahydrofuran (65:35:10) mixture and allowed to stir for 16 hours at 23C. It is concentrated by evaporation in the water je-t vacuum and the residual acetic acid is removed azeotropically hy repeated addition of toluene. 238 mg ~587 micromol, 93%) of the title compound is isolated as a colorless oil, which is further reacted without purification.
IR ~film): 3600-3200, 3070, 3040, 3010, 2940, 2870, 1740, 1600, 1585, 1495, 1245, 1080, 1040, 980, 760 and 695 cm~l.

(5Z,9R,llR,13E,15R)-9-Fluoro-11,15-dihydroxy-17-phenyl-18,19,20-tri-nor-5,13-prostadienoic acid:
238 mg t587 micromol) of the compound produced in example 9 is reacted analogously to example 2 and, after working up, 176 mg (452 micromol, 77%) of the title compound is isolated as a colorless oil.
IR (KBr); 3600-2400, 3090, 3070, 3030, 3010, 2960, 2930, 2870, 1715, 1605, 1500, 1455, 1410, 1355, 1225, 1205, 1165, 1105, 1085, 1060, 1050, 980, 870, 825, 755 and 700 cm~l.

, " j ~, J ., (5Z,9R,llR,13E,15S)-9-Fluoro-11,15-dihydroxy-17-phenyl-18,19,20-tri-nor-5,13-prostadienoic acid methyl ester:
314 mg (549 micromol) of (5Z,9R,llR,13E,15S)-9-fluoro-11,15-bis-(tetrahydropyran-2-yloxy)-17-phenyl-18,19,20-tri-nor-5,13-prostadienoic acid methyl ester [cf. Dr. U. Klar ~t al., German patent application, file number P....... ] is reacted analogously to example 9 and, after working up and purification, 221 mg (538 micromol, 98~) of the title compound is isolated as a colorless oil.
IR (film): 3600-3200, 3080, 3060, 3030, 3010, 2940, 2860, 1735, 1600, 1495, 1450, 1410, 1245, 1085, 1045, 970, 750 and 700 cm~l.

, .

(5Z,9R,llR,13E,15S)-9-Fluoro-11,15-dihydroxy-17-phenyl-18,19,20-tri-nor-5,13-prostadienoic acid:

; 221 mg (538 micromol) of the compound produced in example 11 is reacted analogously to example 2 and, after working up, 145 mg (372 micromol, 69%) of the title compound is isolated as a colorless oil.

IR (film): 3600-2400, 3080, 3050, 3030, 3010, 2940, 2860, 1710, 1600, 1550, 1495, 1450, 1435, 1410, 1245, 1090, 1045, 1030, 970, 750 and 700 cm 1.
:' .'

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. 9-Fluoroprostaglandin derivatives of formula I, (I), in which R1 can be --- , , COOR4, in which R4 can mean hydrogen or a C1-C10alkyl radical optionally substituted by halogen, phenyl, C1-C4 alkoxy or di-(C1-C4) alkylamino, a C3-C10cycloalkyl radical, a C7-C16aralkyl radical, a phenacyl radical substituted by W, a C6-C12aryl radical or a 5- or 6-membered heterocyclic radical with at least one N, O or S atom, or R1 can be a CONHR5 radical with R5 meaning hydrogen, C1-C10alkanoyl or C1-C10 alkanesulfonyl, R2 and R3 each mean a hydrogen atom or a free or functionally modified hydroxy group, and the OH group can be respectively in alpha- or beta-position, X means a CH2 group, an O or S atom, W means hydrogen, -OR6, halogen, -CN-, -NO2, trifluoromethyl or COOR6, R6 can be hydrogen, C1-C10alkyl, C6-C12aryl or C7-C16aralkyl substituted by halogen, and, if R4 means hydrogen, their salts with physiologically compatible bases, as well as the alpha-, beta- or gamma-cyclodextrin clathrates, as well as the compounds of formula I encapsulated with liposomes.

2. 9-Fluoroprostaglandin derivatives of formula I according to claim 1, wherein R1 means the radical COOR4 with R4 as hydrogen or C1-C6 alkyl or R1 means the radical CONHR5 with R5 as methylsulfonyl, X means a CH2 group or an O atom, R2 and R3 mean hydrogen or hydroxy and W means hydrogen or fluorine.

3. Process for the production of compounds of formula I, wherein a compound of formula II

(II), in which R4 exhibits a hydroxy group and R1, R2, R3, X and W have the above-indicated meanings and free OH groups in R2, R3 and W are protected, is reacted with diethylaminosulfur trifluoride or other fluorinating agents and protected hydroxy groups in R2, R3 and W are released and/or free hydroxy groups are esterified, etherified, and/or an esterified carboxy group is saponified or a carboxyl group with a physiologically compatible base is converted to a salt or reacted to a clathrate with alpha-, beta-or gamma-cyclodextrin or encapsulated with liposomes.

4. Pharmaceutical agents of one or more compounds according to claim 1 and usual auxiliary agents, vehicles and additives.

5. Use of 9-fluoroprostaglandin derivatives of formula I
according to claim 1 as diagnostic auxiliary agents for the characterization of prostaglandin receptors and TXA2/PGH2 receptor subtypes.