SE431090B - OPTICAL ACTIVE OR RACEMIC FLUOR-PROSTAGLAND INCORPORATION FOR USE AS A LUTEOLYTIC AND ABORTIVE AGENT - Google Patents

Description

7908642-7 or acyloxy or R 1 and R 2 together form an oxo group; A is trans-CH = CH- or -CÉC-; one of R 4 and R 5 is hydroxy and the other is hydrogen; R 6 is hydrogen, methyl or fluorine; n is zero or an integer of 1-6; R 7 is, when A is trans -CH = CH-, a cycloalkyl group having 3-7 ring carbon atoms, while, when A is -CEC-, R 7 is methyl, cycloalkyl having 3-7 ring carbon atoms or phenyl unsubstituted or optionally substituted with a or more substituents selected from halogen, C 1 -C 6 alkoxy and trihalomethyl.

The double bond in the 5 (6) position is a cis double bond. In the formulas in this description, the dashed lines ("" U indicate that the substituents are in the d-configuration, i.e. below the plane of the ring or chain, while the solid lines (- IEE) indicates that the substituents are in B-configuration, ie above the plane of the ring or chain, the waveguide connections (É) indicate that the groups can be either in d-configuration, ie below the plane of the ring or chain, or in B-configuration, ie above the plan of the ring or chain.

As shown in formula (I), the hydroxy group attached to the carbon atom in the 15-position may be either in the α-configuration (-C 1: 158-ols) or in the B-configuration (: Cab: 15R-ols). When there is only one fluorine atom at the carbon atom in the 16-position, this substituent can be either a 16S-fluorine (α-configuration) or a 16R-fluorine (B-configuration) or a 16 (S, R) -fluorine , i.e. a mixture of the two 16S and 16R diastereoisomers.

Analogously, when there is only one methyl group at the carbon atom in the 16-position, this substituent is either a 16S-methyl or a 16R-methyl or a 16 (S, R) -methyl. It is also obvious that when the symbol: _: ¿: represents a double bond and therefore R3 is a hydrogen atom, this hydrogen atom is bound to a carbon atom which is no longer asymmetric and thus this hydrogen atom can only have a fixed position, i.e. in the plane of the ring, and therefore it can be neither in the u-position (ie below the plane of the ring) nor in the B-position (ie above the plane of the ring).

The alkyl and alkoxy groups may be branched or straight chain groups. When R is a C 1 -C 12 alkyl group, it is preferably a methyl, ethyl, propyl or heptyl group. Preferably one of R 1 and R 2 is hydrogen and the other hydroxy or R 1 and R 2 together form an oxo group. When one of R 1 and R 2 is acyloxy, it is preferred that it be an alkanoyloxy having up to 6 carbon atoms, a benzoyloxy or p-phenylbenzoyloxy group. When R 7 is methyl, n is preferably 3 or 4; when R 7 is cycloalkyl or phenyl n is preferably 1. When R 7 is a cycloalkyl group it is preferably cyclopentyl, cyclohexyl or cycloheptyl. When R 7 is a trihalomethyl substituted phenyl, the trihalomethyl group is preferably trifluoromethyl or trichloromethyl.

Examples of cations of pharmaceutically acceptable bases are either metallic cations such as sodium, potassium, calcium and aluminum or organic amine cations such as trialkylamines.

Specific examples of compounds of the invention are the following: 18,19,2O-trinor-17-cyclohexyl-16 (S, R) -fluoro-PGFZG, 18,19,2O-trinor-17-cyclohexyl-16 (S, R) -fluoro-PGE2, 18,19,20-trinor-17-cyclohexyl-1GS-fluoro-PGF2a, 18,19,20-trinor-17-cyclohexyl-16R-fluoro-PGF2a, and 16-fluoro-18,19, 20-Trinor-17-cyclopentyl-PGF2α, and 16-fluoro-18,19,2O-trinor-17-cyclopentyl-PGE2,18,19,20-trinor-17-cyclohexyl-16,16-difluoro-PGFZU, 18 , 19,2O-trinor-17-cyclopentyl-16,16-difluoro-PGF2α, and 16-fluoro-13,14-dehydro-PGF2u, and 16-fluoro-13,14-dehydro-PGE2, and 16-fluoro-PGF2α 13,14-dehydro-PGA2, and 16-fluoro-13,14-dehydro-PGF2B, 16S-methyl-16R-fluoro-13, 14-dehydro-PGE2, 16R-methyl-16S-fluoro-13,14-dehydro -PGE2, 168,20-dimethyl-16R-fluoro-13,14-dehydro-PGE2, 16R, 20-dimethyl-16S-fluoro-13,14-dehydro-PGE2, and 16-methyl, 16-fluoro-13, 14-dehydro-PGF2α, and 16-methyl, 16-fluoro-13,14-dehydro-βF2B, and 16-methyl, 16-fluoro-13,14-dehydro-PGA2, 16,16-difluoro-13,14 -dehydro-PGE2, 16,16-difluoro-13,14-dehydro-PGF2a, 16,16-difluoro-13,14-dehydro-PGA2, 18,19,2O-t rhinor-17-cyclohexyl-16 (R, S) -fluoro-13,14-dehydro-PGF2α, 18,19,2O-trinor-17-cyclohexyl-16R-fluoro-lä, 14-dehydro-PGF2u, 18,19 1,2-Trinor-17-cyclohexyl-16S-fluoro-13,14-dehydro-PGF2α, 18,19,2O-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGF2U, 7908642-7 - a 16-fluoro-18,19,2Q-trinor-17-cyclopentyl-13,14-dehydro-PGF2u, and a 16-fluoro-18,19,20-trinor-17-phenyl-13,14-dehydro-PGF2u , and 16-fluoro-18,19,2O-trinor-17-cyclopentyl-13,14-dehydro-PGE2, and 16-fluoro-18,19,2O-trinor-17-cyclohexyl-13,14-dehydro-PGE2 , and 16-fluoro-18,19,20-trinor-17-phenyl-13,14-dehydro-PGE2,1 18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro -PGFZU, 18,19,2O-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGF2a, 18,19,20-trinor-17-phenyl-16,16-difluoro-13,14 -dehydro-PGE2, 18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGE2, 18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13 , 14-dehydro-PGE2.

The compounds of formula (I) are prepared by a process which comprises reacting an optically active compound, or a racemic mixture of compounds, of formula (II) in which n, R 6 and R 7 are the same as as defined above, A 'is -CEC- or -CH = CX-, where X is hydrogen or halogen, Y is hydroxy or a known protecting group attached to the ring by an ether oxygen atom, and one of R'4 and R'5 is hydroxy or a known protecting group attached to the chain by an ether oxygen atom and the other is a hydrogen atom, with a Wittig reagent comprising the group of the formula - (CH 2) 4 -COOR, where R is a hydrogen atom or a C 1 -C 12 alkyl group, to give a compound of the formula (III) QH ._ ~ °. '- \ -' x -__ / \ / \ co R '- _ ° _ _ un) F - "' _ t \\\\ \ R 'R' In which R, Y, A, R'4, R'5, R6, R7 and n are the same as defined above, which, when Y is a known protecting group as defined above and one of R'4 and R'5 is a known protecting group as defined above and the other is a hydrogen atom, optionally itt can be esterified to give the 9u or 98 acyloxide derivative, and then the compound of formula (III) is de-etherified in which Y is a known protecting group as defined above and / or one of R'4 and R'5 is a known protecting group as defined above and the other is hydrogen, or the 9d4 or 9B acyloxy derivative of the compound of formula (III) is deeterified, whereby a compound of formula (I), wherein R 3 is a hydroxy group, is the symbol: a single bond, one of R 1 and R 2 is hydrogen and the other is hydroxy or acyloxy and one of R 4 and R 5 is a hydroxy group and the other is hydrogen, is obtained, or optionally oxidized, the 9α- or 9β-hydroxy group in a compound of the formula (IIIa) RI R '1 .Z - e “u \\ ¿=;, / \\ /” \\ CQ0R- _ å' - (ina) 7 / / - 1,7 HY 'Rncx _ In which R, A, R 6, R 7 and n are the same as defined above, one of R '1 and R' 2 is hydrogen and the other is hydroxy, Y 'is a known protecting group as defined above and the one of R "4 and R" 5 is a known protecting group such as m is defined above and the other is hydrogen, to give a compound of formula (IV) o the '_ ° - cøoR' (IV) 7908642-7 'where R, Y', A, R "4, R , R6, R7 and n are the same as defined above, the fold is in turn deeterified in the II and 15 positions to give, depending on the reaction conditions used, either a compound of formula (I), in which the symbol ~ - - ~ is a single bond, R 5 is a compound of formula (I), in which the symbol - - - - is a double bond, R 3 is hydrogen and R 1 and R 2 together form an oxo group is hydroxy and R and R together form an oxo group, or And / or optionally reacting a compound of formula (I) in which R is a hydrogen atom and the hydroxy group in the 11 and / or 15 position is optionally protected as described above, with a base, followed, if necessary, of deeterification, to give a compound of formula (I), in which R is a cation, or esterification of a compound of formula (I), in which R is a hydrogen atom and the hydroxy group of II- the ch / or 15 position is optionally protected as indicated above, followed, if necessary, by deeterification to give a compound of formula (I), wherein R is C 1 -C 12 alkyl, or hydrolysis of a compound of formula (I), in which R is C 1 -C 12 alkyl and the hydroxy group in the 11 and / or 15 position is optionally protected as indicated above, followed, if necessary, by deeterification to give a compound of formula (I), in which R is a hydrogen atom.

Hydrolysis of a compound of formula (I) in which R 1 and R 2 together form an oxo group and R is a C 1 -C 12 alkyl group, to give a compound of formula (I) in which R 1 and R 2 together form an oxo group and R is hydrogen, can also be carried out enzymatically, for example by using a yeast esterase.

The known protecting groups (ie the ether groups) should be convertible to hydroxy groups under mild reaction conditions, eg acid hydrolysis. Examples are acetal ethers, enol ethers and silyl ethers.

The preferred groups are: cH I ïshw Aik CH3 | . , (cH3) 3si-_o-, - -. »You? In Odåïßuk, (Üíçläu-'ï 79086 42-7 where W is -O- or -CH 2 - and Alk is a lower alkyl group. When in the lactol of formula (II) A 'is -CH = CH-, it is a trans- -CH = CH- When in the lactol of formula (II) A 'is -CH = CX-, where X is halogen, preferably chlorine, bromine or iodine, the hydrogen atom bound to the carbon atom in the 13-position and the hydrogen atom which are attached to the carbon atom in the 14-position are either in the trans-position (geometric trans-isomers) or in the cis-position (geometric cis -isomers). Preferably they are in the trans-position. When in the lactol of the formula ( II) A 'is trans -CH = CH-, compounds of formula (III) are obtained, where A is trans -CH = CH-f in this case the Wittig reaction can be carried out using about 2-3 moles Wittig reagent per mole of lactol and the reaction lasts about 1 hour.

When in the lactolene compound (II) A 'is -C§C- or -CH = CX1 where X is halogen, compounds of formula (III) are obtained where A is -CÉC-.

When A 'is -CEC- or -CH = CX-, where X is bromine or iodine, the Wittig reaction can be carried out using about 2 moles of the Wittig reagent per mole of lactol and it is sufficient that the reaction proceeds in 10- 20 min.

When A 'is -CH = CX-, where X is chlorine, it is necessary to use, for example, 1.5 to 2.5 moles of Wittig reagent per mole of lactol to prolong the reaction time up to 10 hours or, if shorter reaction times times desired, it is necessary to utilize a larger excess of Wittig reagent (at least 5 moles of Wittig reagent per mole of lactol for reaction times of about 30 minutes).

The Wittig reaction is carried out using the conditions generally used for this type of reaction, ie in an organic solvent, eg diethyl ether, hexane, dimethylsulfoxide, tetrahydrofuran, dimethylformamide or hexamethylphosphoramide, in the presence of a base, preferably sodium hydride and potassium tert-butoxide, at 0 ° C to the reflux temperature of the reaction mixture, preferably at or below room temperature.

The term "Wittig reagent" includes compounds of the formula W <-> (Ra) 3 - P - CH2 "CH2" CH2 - CH2 _ COOR Holes in which Ra is aryl or alkyl, Hal is bromine or chlorine and R is hydrogen or alkyl When Ra is alkyl it is preferably ethyl Preparation of the Wittig reagent is discussed in detail by Tripett, Quart.

Rev., 1963, XVII, no. 4, 406. 790864-2-7 When in the lactol of formula (II) A 'is -CH = CX-, where X is bromine, chlorine or iodine, the dehydrohalogenation takes place during the reaction with the Wittig reagent just as easily when the hydrogen atom bound to the carbon atom in the β3 position and the halogen atom attached to the carbon atom in the 14 position are in the trans position as when in the cis position.

The optional acylation of the 9a4hydroxy group in the compound of formula (III) may be carried out in a conventional manner, for example by treatment with an anhydride or a chloride of a carboxylic acid in the presence of a base. In this case, the 9α-acyloxide derivative is obtained. Conversely, the acylation of the Quehydroxy group in the compound of formula (III) is carried out with a carboxylic acid in the presence of a compound of formula MVY3, wherein MV is a metalloid from the group V and Y is an alkyl, dialkylamino or aryl group , and from a hydrogen acceptor agent a 9B-acyloxide derivative is obtained, i.e. in the latter case the esterification g means complete inversion of the configuration of the hydroxy group in the 9-position.

This reaction is preferably carried out at room temperature in an inert anhydrous solvent, which is preferably selected from aromatic hydrocarbons such as benzene and toluene, linear or cyclic ethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane.

All of the reagents used, i.e., the compounds of formula MVY3, the esterifying carboxylic acid and the hydrogen acceptor, were used in proportions of at least 1.5 moles per mole of alcohol; 2-4 moles of the reagents per each mole of alcohol are preferably used.

In the compound of formula MYY3, MV is preferably P, As, Sb and especially P. When Y in the same compound is alkyl, it is preferably methyl, while when Y is aryl it is preferably phenyl; when Y is dialkylamino it is preferably dimethylamino. The compound of the formula MVY3 arsine, triphenylstibine and hexamethyltriaminophosphine of the formula is preferably selected from triphenylphosphine, triphenylphenyl. The hydrogen acceptor used is preferably an ester or an amide of azodicarboxylic acid, 5,6-tetrachlorobenzoquinone, 2,3-dicyano-5,6-dichlorobenzoquinone or azobisformamide.

The deeterification reaction of the compound of formula (III) - or of the 9a- or 9B-acyloxide derivative of this compound - wherein Y and / or one of R'4 and R'5 is a known protecting group as defined above 7908642-7 is carried out under mild conditions. acid hydrolysis conditions, eg with mono- or polycarboxylic acids, eg formic acid, acetic acid, oxalic acid, citric acid and tartaric acid, and in a solvent, eg water, acetone, tetrahydrofuran, dimethoxyethane and lower aliphatic alcohols. Preferably, 0.1 ~ 0.25n of polycarboxylic acid (eg, oxalic or citric acid) is used in the presence of a suitable low-boiling co-solvent which is miscible with water and which can be easily removed in vacuo upon completion of the reaction.

The oxidation of the 9d4 or 98-hydroxy group to give an oxo group can be performed with, for example, Jones reagent or Moffatt reagent. As stated above, the deeterification of the compound of formula (IV) may give, depending on the reaction conditions used, either a compound of formula (I), wherein the symbol: _: _: is a single bond, R 3 is hydroxy and R and R 2 together form an oxo group, or a compound of formula (I), wherein the symbol; _; _: is a double bond, R 3 is hydrogen and R 2 and R 3 together form an oxo group.

The foregoing compound can be obtained as the only product by working at temperatures ranging between about 25 ° C and about 35-38 ° C, while by working at higher temperatures, for example at reflux temperature for about 3 hours, the latter compound as the only product.

The lactol of formula (II) can in turn be prepared by a multi-step process using, as starting material, an optically active or racemic lactol of formula (V) .Q, "i'- .R i. _ H n" (iecx - in which Y "is hydroxy, acyloxy or a known protecting group attached to the ring by an ether oxygen atom, X, R6, R7 and n are the same as defined above; and in which the hydrogen atom bonded to the carbon atom in the 13-position and the halogen atom bonded to the carbon atom in the 14-position (prostaglandin numbering) can either be in the trans-position 7908642-7 or in the cis-position. - the general formula (II) starting from the lactone of formula (V) comprises the following steps: a) reduction of the 15-oxo group (prostaglandin numbering) in the lactone of formula (V) to give a mixture of the 15S and 15R-oils of the formulas (V) VIa) and (VIb) O 0 2 / 9. s ° = than ï -, = _ _ '_) -R', cn = ox - \ - C 4GB) R - CH CX yc c (GHz n 7 H Yu í 2 7 H Yu H \ HQ à R6 _ _ P - 5 kvíaí) ü (15s - <> 1) I '(VIB) (BR-d) where Y ", X, R6, R7 and n are the same as defined above, followed by separation of the 15S-olene from the 15R-olene and, if desired, by dehydrohalogenation of the separated alcohols, where X is halogen, to give a compound of formula (VIIa) '(mia) or a compound of the formula (VIIb) 7908642-7 il _ o (_- '(vm) F _ i. 2 cec-c, _ c_ (cn) -Rï.

H Yu 0/9 "z n where Y", R 6, R 7 and n are the same as defined above.

If desired, reduction may follow the dehydrohalogenation.

The reduction of the 15-oxo group may conveniently be carried out in an organic solvent, such as acetone, diethyl ether, dimethoxyethane, dioxane or benzene or mixtures thereof, using, for example, metal borohydrides, especially sodium borohydride, lithium borohydride, zinc borohydride or sodium trimethoxyborohydride. The separation of the 15S-ol from the 15R-ol can be carried out by chromatography, for example silica gel column chromatography, or by fractional crystallization. The dehydrohalogenation can be carried out in a solvent, preferably selected from dimethylsulfoxide, dimethylformamide and hexamethylphosphoramide in the presence of a base, which may be, for example, an alkali metal amide, potassium tert-butylate or the anion CH 3 -ge-CH 2 (-). b) Conversion of a compound of formula (VIII). 0/2: a, 'f' Q- i i (YlII) ål? u IIIY »Auš. in which Y ", R 6, R 7, A 'and n are the same as defined above and one of R 4 and R 5 is a hydrogen atom and the other is a hydroxy group, to a compound of formula (IX) 7908642 -7 12 KÄ R "F 54 1 1 '_ (U f, v" i' 2 'WI- "1' - RR \ nF ox in which A ', R6, R7 and n are the same as defined above, Y' is a known protecting group attached to the ring by an ether oxygen atom and one of R "4 and R" 5 is a known protecting group attached to the chain by an ether oxygen atom and the other is a hydrogen atom. Eterification of the compound of formula (VIII) to give a compound of formula (IX) is preceded, when in the compound of formula (VIII) Y "is an acyloxy group, of saponification, for example by mild treatment with an alkali, to give a compound of formula (VIII), wherein Y" is a hydroxy group.

The etherification is preferably carried out with a vinyl ether in which W 'is -O- or -CH 2 -, in the presence of catalytic amounts of, for example, the phosphorus oxychloride, p-toluenesulfonic acid or benzenesulfonic acid, or with a silyl ether, for example by substituting a trisubstituted chlorosilane react in the presence of an acceptor base (eg a trialkylamine) of the hydrogen halide formed, or with an enol ether, for example by reaction, in the presence of an acid catalyst, with a 1,1-dialkoxy-cyclopentane or cyclohexane at reflux temperature in a inert solvent and distillation of the obtained alcohol to obtain mixed dialkoxy ethers or enol ethers, depending on the amount of catalyst used or on the heating time. c) Reduction of the compound of formula (IX) to give a lactol derivative of formula (X) 7908642-7 13 in øH š - x Q m? “'I n H hu? (ï: “(cH2)„ _ R7 i '.

R in which Y ', A', R "4, R" 5, R6, R7 and n are the same as defined above.

The reduction can be carried out by treatment with diisobutylaluminum hydride or sodium bis- (2-methoxyethoxy) aluminum hydride in an inert solvent such as toluene, n-heptane, n-hexane or benzene or mixtures thereof, at a temperature below 3000. d Optional deeterification of the compound of formula (X) to give a compound having free II and 15 hydroxy groups. The deeterification can be carried out by mild acid hydrolysis, in a water-miscible solvent, with a solution of a mono- or polycarboxylic acid.

All of the compounds mentioned in a) to d) may be either optically active compounds or racemic mixtures thereof.

The lactone of formula (V) can in turn be prepared in only one step by reacting an optically active or racemic aldehyde of formula (XI) - (x1) in which Y "is the same as defined above, with an optically active or racemic phosphonate carbonate of the formula (XII) 51.63 J: 4 å. '(111) _ P _ c - co ~ ä: -. (cu2) n-R7 / (_) _ nho H6 7908642-7 14 in which Rb is lower alkyl and X, R 6, R 7 and n are the same as defined above. The reaction is conveniently carried out in a solvent, which is preferably dry benzene, dimethoxyethane, tetrahydrofuran, dimethylformamide or mixtures thereof, and using a suspension of 1,11, 2 molar equivalents of the halophosphonate carbonate.

When Y "in the aldehyde of formula (XI) is an acyloxy group it may be, for example, acetoxy, propionyloxy, benzoyloxy and p-phenylbenzoyloxy.

When Y "is a known protecting group attached to the ring by an ether-oxygen atom, it may be, for example, one of the above-mentioned ether protecting groups. The aldehyde of formula (XI) may be prepared essentially as described by EJ Corey et al., Ann. of New York Acad. of Sciences, Low, 24 (1971).

The phosphonate carbonate of formula (XII) can in turn be prepared by reacting a phosphonate of formula (XIII) 2 nx F clrcf fl cn) R '"à-l ä. 7 -' mm in which Rb, X, R6, R7 and n is the same as defined above, with one equivalent of a base, preferably selected from sodium hydride, lithium hydride, calcium hydride, an alkyllithium derivative and the anion cH3-so2-cH2 M.

The phosphonate of formula (XIII), wherein X is halogen, can be obtained by halogenation of a phosphonate of formula (XIV) R \ __ 0 u \ ï É '- ~ / Pgš-lcjšš- (cußn-R? _ _ (XIV) J 350 H 0 n 6 in which R b, R 6, R 7 and n are the same as defined above.

The halogenation can be carried out in a conventional manner, operating essentially as in the halogenation of β-ketoesters. The phosphonate of formula (XIV) can be prepared by known methods, for example according to E. J. Corey et al., J. Am. Chem. Soc. 29, 3247 (1968) and E. J. Corey and G. K. Kwiatkowsky, J. Am. Chem. Soc., §§, 5654 (1966). Preferably, the phosphonate of formula (XIV) is prepared by reacting lithium methylphosphonate with a lower alkyl ester of the optionally substituted aliphatic acid. When the aliphatic acid contains asymmetric carbon atoms, it is possible to use either the racemic acid or one of its optical antipodes. The lower alkyl ester of the optionally substituted aliphatic acid can be prepared by conventional methods. Alternatively, the phosphonate carbonate of formula (XII), where X is halogen, can be prepared in situ by reacting a phosphonate carbonate of formula (XII). wherein X is hydrogen and Rb, R6, R7 and n are the same as defined above, with one equivalent of a halogenating agent selected from N-chloroacetamide, N-chlorosuccinimide, N-bromosuccinimide, N-bromoacetamide, N-bromocaprolactam and N -iodosuccinimide.

In the preparation of the halo-lactone of formula (V), in which A 'is -CH = CX, according to the procedures described above, both compounds are obtained in which the hydrogen atom bonded to the carbon atom in the 13-position and the halogen atom bonded to the carbon atom in the 14-position the position (prostaglandin numbering) is in the trans position (geometric trans isomers) and compounds where said atoms are in the cis position (geometric cis isomers).

The geometric trans isomers are obtained in a much higher yield (92-95%), than the geometric cis isomers, which are obtained in a much lower yield (5-8%).

The geometric trans isomers of the formula ffs' H: eßš- š zc = cc-.c- (ca) a HY: h fl 211 fl A 016 790864-2-7 f- 16 _ i dezatt HA * vinyl protons for the two the isomers are in resonance at different positions and the coupling constants of the HA vinyl proton with the HB proton are sufficiently different (9 Hz for the trans isomer and 10.2 Hz for the cis isomer).

Both the trans isomers and the cis isomers are intermediates for the synthesis of the 13,14-dehydroeprostaglandins of the invention.

The lactol of formula (II), where A 'is -CEC- can also be prepared by dehydrohalogenation of the lactol of formula (II), where A' X I. is -CH = è-, where X is bromine, chlorine or iodine. The dehydrohalogenation can be carried out in an aprotic solvent, which is preferably selected from dimethylsulfoxide, dimethylformamide and hexamethylphosphoramide, by treatment with a base, preferably selected from potassium tert-butylate, an alkali metal amide and the anion_CH 3 -SO-CH 2 (_). as described in this specification, the following compounds are new: l) a compound of formula (XV) ä 'i I e ° f * å * (C fi ålf fi q g - m) R. in which Z is \ C = O or Cx fl. , one of R 1 and R 2 is hydrogen and the other is hydroxy or a known protecting group attached to the carbon atom through an ether oxygen atom or, when Z is> C = O, R "'4 and R"' 5 together form an oxo group, in which Y, A ', R 6, R 7 and n are the same as defined above. 2) a compound of the formula (XVI) R1§2 "x _ '_. \ _ \\ ==; // ^ \\ // ^ \\ c0OR '_. (xyl) _ F _ - H ey A - - å - (cH) _11 Q å 2 n RII R | In which Y is hydroxy or a known protecting group attached to the ring by an ether oxygen atom, one of R "4 and R" 5 is a known protecting group attached to the chain by an ether oxygen atom and the other is hydrogen, the one of R 1 and R 2 is hydrogen and the other is hydroxy or acyloxy or R 1 and R 2 together form an oxo group and R 1, R 6, R 7, A and n are the same as defined above.

The compounds of formula (I) may be used for the same therapeutic indications as natural prostaglandins, in view of which, however, they offer the advantage that they are not substrates of the enzyme 15-prostaglandin dehydrogenase, which, as is known, rapidly inactivates natural prostaglandins, and further the compounds of the invention are characterized by a more selective therapeutic action.

In addition, the compounds of the formula (If) competitively inhibit the use of the same enzyme by natural prostaglandins as substrates.

In particular, the compounds of formula (I), wherein R 2 and R 3 are hydroxy, possess an excellent luteolytic activity, i.e. they are useful as abortifacients, as shown in Table 1, from which it appears that the presence of a fluro atom in C16 maintains the luteolytic activity unchanged. and at the same time it reduces the contractional activity of the uterine muscles, whereby the two activities can be separated, while the compounds of formula (I), wherein R 1 and R 2 together form an oxo group and R 3 is hydroxy, in particular possess remarkable luteolytic activity, as shown in Table 2, which shows that the presence of a fluorine atom in C16 causes good luteolytic activity, while reducing the ability to stimulate smooth muscle, such as the uterus of rats. 7903642-7 18 fššil U Å Potency ratio Abortion in rats fx) 0 F ° renln9 _ L _ _. . . . . . _. , (number of abortions / number of rat uterus. rats) PGFZ q 'i 1 _ 0/10 l8, 19,20-trinor-17- -cyclohexyl-PGF2a 3,22 7/10 l8, 19,20-trinor-l7- - cyclohexyl-16 (S, R) - '-fluoro-PGF2Q I 0.33 6/12 18, 19,20-trinor-17- -cyclohexyl-1α, 14--dehydro-PGF2α 10.59 10/10 18, 19,20-Trinor-17- -cyclohexyl-13,14- -dehydro-16 (S, R) -fluoro-PGFZG 3.29 10/10 In this and subsequent antifertility experiments, all compounds were administered subcutaneously at a dose of 2 mg / kg body weight (0.2 ml / 10 g body weight) for female rats on the 10th day of pregnancy after examination of the uterus, and implanted fetuses were counted on the same day. The animals were killed on the 2nd day of pregnancy and the presence of any fetal fragment was counted as no abortion. 7908642 ~ 7 19 Compound å _ Potency ratio Number of abortions / number '' ^ '' '' '' "" "'rat tüterüsÃ', '_. \ Rats PGEZ l O / lO l8, l9,20-trinor-l7- -cyclohexyl -PGE2 0.75 O / 10 18,19,20-Trinor-17- -cyclohexyl-16 (S, R) -Fluoro-PGE2 No, 55 _ 10/12 Comparative experiments- The compound 18,19,20-Trinor -17-cyclohexyl-13,14-dehydro-16 (S, R) -fluoro-PGEZQ, according to the present invention was compared with the compound 13,14-dehydro-PGE1 according to DE Offenlegungsschrift 2,318,595 and the compounds 16-fluoro-PGFZQ and 16-fluoro-PGE2 according to DE Offenlegungsschrift 2 320 368 in the case of uterine stimulating activity in rats (in vitro) and abortifacient activity in rats and hamsters.

MÉÉ9§Éš¿ _ H The contraction of ¿åtr§tergs = Rat turetus was suspended in a 10 ml bath of de Jalon, at 29 ° C, which contained only 1/3 of the usual Ca ++ concentration.

Both uterine horns were removed from virgin rats weighing 250-300 g 24 hours after pretreatment with diethylstilbestrol 1 mg / kg s.c. and sesame oil.

For comparison, contractions were recorded with an isotonic frontal writing arm, fed with 0.5 g of joint dose-response curves of the tested compounds, and data were expressed as potency ratios.

Abortion in rats: The Austrian cycle in virgin rats, which weighed 200-250 g, was followed by examination of the vaginal secretion for several days.

On the day of proestrus, the females were caged with fertile males, and mating was verified by detection the following morning of spermatozoa in the vaginal secretions. This day was considered day 1 of pregnancy. The pregnancy was verified on day 9 by laparotomy under ether anesthesia, and the number of fetuses and their position in the two uterine horns were recorded. On the tenth day of pregnancy, the tested compounds were administered as a single treatment, subcutaneously at a dose of 2 mg / kg U body weight.

On day 20, autopsy was performed, and the number of living and dead fetuses, placenta and resorbing fetal placenta units were recorded. The abortion was considered "complete" when the uterus was empty. The presence of even a single placental remnant was considered pregnancy. 7 7 Maple; hamsters: Adult female hamsters weighing 110-130 g were used for the experiment. The day sperm was detected in the vaginal secretion was defined as day 1 of pregnancy. The tested compounds were administered subcutaneously at a dose of 50 pg / animal, 2 times a day, with a time difference of 6 hours between the two injections.

Appropriate controls treated with physiological saline were maintained. Hamsters were treated between days 1-3, and autopsy was performed on day 7. At autopsy, the number of living, dead and resorbed fetuses was recorded. The results of the comparisons are given in Table 3. 7908642-7 21 Tißl-BdELlfï-3_ Pf fi ensföfhål- Éfšïršnlåšïeíåt- 'šaïïtšššr- Föreningen _l llande råttf »abortions / number of ter (1-3 .uretusv l rat * _ 10 days) o PGF2a 3.5 O / 10 O 13,14-dehydro-PGE1 0.6 - 0/10 0 16-fluoro-PGF2Q 1.8 3/10 25 16-fluoro-PGE2 1.3 2/10 15 l8, 19,20-Trinor-17-cyclohexyl-1,3,14-dehydro-16 (S, R) -fluoro- -PGFM A9 Women in 100 The compounds of formula (I) may be administered orally, parenterally or on by intravenous or intrauterine (extra amniotic or intra-amniotic) route, by rectal suppositories or by inhalation. They can be administered, for example, by intravenous infusion of a sterile isotonic saline solution at a ratio of 0.01 to 10, preferably 0.05 to 1.0 pg / kg mammalian body weight per minute.

The active compound is suitably administered in the form of a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. 79ase42-vi 22 The compositions may be prepared by conventional methods and may be, for example, in the form of tablets, capsules, pills, suppositories or bougainvillea, or in liquid form, for example solutions, suspensions or emulsions.

Examples of substances that can serve as carriers or diluents are water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, benzyl alcohol and cholesterol.

The invention is illustrated by the following examples, in which the abbreviations THP, DIOX, DMSO, THF, DM, DIBA, HMA, Et 2 O and DM refer to tetrahydropyranyl, dioxanyl, dimethylsulfoxide, tetrahydrofuran, dimethylformamide, diisobutylaluminum hydride, hexamethylenephosphorus or dimethoxyethane.

Tißëëßßs fi l- 1 One suspension of 1.220 g NaH (80% dispersion in mineral oil) in 30 ml dry DMSO, under a nitrogen atmosphere and in the absence of moisture, was heated at 58-65 ° C until hydrogen no longer developed. After cooling to 4-8 ° C, 8.92 g of triphenyl- (4-carboxybutyl) -phosphonium bromide was added and the mixture was stirred until everything had dissolved, whereby a dark red solution of the ylide was formed, and the temperature was maintained at about 10-122 ° C. by external cooling. To this mixture was added a solution of 1.2 g of 2- {3α, 5α-dihydroxy- (3α-THP-ether) -26 - [(3S) -3-hydroxy- (3-THP-ether) -4- R, S) -fluoro-5-cyclohexyl-trans-1-pentenyl] -cycloplopyl} -ethanal-γ-lactol in 5 ml of anhydrous DMSO. The mixture was stirred for 4 hours, then diluted with 30 ml of water and extracted repeatedly (16 x 5 ml) with ethyl ether to remove the triphenylphosphoxide formed. The combined ether extracts were re-extracted with 0.5N NaOH (5 x 5 mL) and discarded. The combined aqueous alkaline extracts were acidified to pH 4.5 with 2N sulfuric acid and extracted with ethyl ether-pentane 1: 1. These organic extracts were combined, washed to neutrality and evaporated to dryness, after drying over Na 2 SO 4, to give 1.3 g of 7- {3a, 5urdihydroxy- (3-THP-ether) -25 - [(3S) -3- hydroxy- (3-THP-ether) -4lR, S) -fluoro-5-cyclohexyl-trans-1-pentenyl] -1β-cyclopentyl} -5-cis-heptenoic acid [18,19,20-trinoric acid 17-cyclohexyl-16 (R, š) -fluoro-PGF2a-11,15- -bis-THP-ether1, [α] D = + 7.5 (acetone).

By the same procedure and starting from the individual 16S-fluorine and 16R-fluorine isomers and from one of the following aldehydes: 2- {3a, 5-dihydroxy- (3arTHP-ether) -2B ~ [(3S) -3-Hydroxy- (3-THP--ether-4 (R, S) -fluoro-5-cyclopentyl-trans-1-pentenyl] -lacyclopentyl} -ethanal-γ-lactol; {3a, 5ardihydroxy- (3arTHP-ether) -2B - [(3S) -3-hydroxy- (3-THP- -ether) -4,4'-difluoro-5-cyclopentyl-trans-1-pentenyl] -1a- cyclopentyl} -ethanal-γ-lactol; 2- {3α, 5-dihydroxy- (3arTHP-ether) -2B - [(3S) -3-hydroxy- (3-THP-ether) -4,4'-difluoro -5-cyclohexyl-trans-1-pentenyl-1-cyclopentyl} -ethanal-γ-lactol, the following compounds were obtained: 18,19,20-trinor-17-cyclohexyl-16S-fluoro-PGF2qf11, 15-bisfTHP- -ether, [u] D = +90 (acetone); 18,19,2O-trinor-17-cyclohexyl-16R-fluoro-PGF2qf11, 15-bis-THP- -ether, [a] D = +80 (acetone 18,19,2O-trinor-17-cyclopentyl-16 (R, S) -fluoro-PGF2qf11, 15-bis- -THP-ether, [α] D = + 7.5 ° (acetone); 18, 19,20-trinor-17-cyclopentyl-16,16-difluoro-PGF2α-11,15-bis- -THP-ether, [q] D = + 12 ° (acetone); 18,19,20-trinor-1 7-cyclohexyl-16,16-difluoro-PGF -11,15-bis-2a -THP-ether, [α] D = + 10.5 ° (acetone). EXAMPLE 2 To a solution of the ylide, prepared as described in Example 1, starting from 612 mg of NaH (80% dispersion in mineral oil) and 4.52 g of triphenyl- (4-carboxybutyl) -phosphonium bromide in 25 ml of anhydrous DMSO was added a solution of 934 mg of 2- {3α, 5α-dihydroxy- (3-THP-ether) -2B- [2-bromo- (3S) -3-hydroxy- (3-THP-ether) - 4 (R, S) -fluoro-trans-1-nonenyl] -la-cyclopentyl-ethanal-γ-lactol in 8 ml of DMSO. The mixture was kept at room temperature for 10 hours, after which it was diluted with 30 ml of water and extracted with ether to remove the triphenylphosphoxide. The combined ether phases were re-extracted with 0.5N NaOH and then discarded. The combined alkaline aqueous phases were acidified to pH 4.5 and extracted with ethyl ether pentane 1: 1. These organic extracts were combined, washed to neutrality with saturated aqueous ammonium sulfate solution, dried over sodium sulfate and evaporated to dryness. The yield was 860 mg of 13,14-aeyarO-1β (R, s) -fluoro-zo-methyl-11,15-bis-THP-ether-P <; F +40 (acetone). 2a '[u] D EXAMPLE 3 To a solution of 0.5 g of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGFZG-11,15-bis-THP-ether in 8 ml of acetone were added to 10 ml of a 0.25 N aqueous solution of oxalic acid, and the mixture was refluxed for 2 hours. The excess acetone was evaporated in vacuo and the aqueous phase was extracted with ethyl ether. The organic extracts were combined, washed to neutrality with a saturated ammonium sulfate solution, dried and evaporated to dryness. The residue was chromatographed on an acid washed silica gel eluting with methylene chloride-ethyl acetate 8: 2 to give 320 mg of pure 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGF [F EwH = + 1s, 1 °; [QUEWH = + 46.8 °. za * n 2 3650 The dioxanyl ethers were deacetalized in the same manner. EXAMPLE 4- A solution of 1.75 g of potassium ether-butylate, recently sublimated, in anhydrous DMSO was added to a solution of 3.46 g of triphenyl- (4-carboxybutyl) -phosphonium bromide in 25 ml of DMSO whereby the temperature was maintained at about 15 ° C, and the mixture was stirred continuously under inert gas. To the dark red solution of the ylide which was formed was added a solution of 770 mg of 2- {3α, 5α-dihydroxy- (3α-DIOX-ether) -2B- [2-bromo- (3S) -hydroxy- (3- DIOX-ether) -4,4'-difluoro-5-phenyl-trans-1-pentenyl] -1α-cyclopentyl} -ethanal-γ-lactol in 10 ml of a 1: 1 mixture of DMSO: THF.

The mixture was stirred for 10 hours, after which it was diluted with 30 ml of water and the aqueous phase was extracted with ethyl ether to remove the triphenylphosphoxide. The ether extracts were re-extracted with 0.5N NaOH and then discarded. The alkaline aqueous phases were combined, acidified to pH 4.5 with 2N H 2 SO 4 and extracted with ethyl ether / pentane 1: 1. These organic extracts were washed to neutrality with saturated ammonium sulfate solution and evaporated to dryness to give 700 mg of 18,19,20--trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGP Gf11, 15- bis- -DIOX-ether, [α] D = -0.6 ° (acetone).

Following the procedures of Examples 2 and 3 and 2 starting from the following aldehydes: 2- {3a, 5grdihydroxy-2β- [2-bromo- (3S) -3-hydroxy-4 (R, S) -fluoro- -trans- 1-octenyl] -dicyclopentyl} -ethanal-γ-lactol; 2- {3d, 5-dihydroxy-Z6; [2-bromo- (38) -3-hydroxy-4R-fluoro-4S -methyl-trans-1-octenyl] -gryclopentyl} -ethanal-γ-lactol and its 4R-methyl -4S-fluoro isomer; 2-Ba, 5-Chydrohydroxy-2B- [2-bromo- (3S) -3-hydroxy-4,4-difluoro-trans- -1-octenyl] -gyclopentyl} -ethanal-γ-lactol; 2- {3α, 5-dihydroxy-2B- [2-bromo- (3S) -3-hydroxy-4 (R, S) -fluoro--trans-1-nonenyl] -gycyclopentyl} -ethanal-γ-lactol; 2- {3d, 5-dihydroxy-2B- [2-bromo- (3S) -3-hydroxy-4S-fluoro-4R-methyl-trans-1-nonenyl] -larcyclopentyl} -ethanal-γ-lactol and its 4S- methyl 4R-fluoro isomer; 79O863f2- 26 2- {3a, 5a-dihydroxy-2B> ε-bromo- (3S) -3-hydroxy-4,4-difluoro-trans-1--onenone; 7α-cyclopentenyl} -ethanal- γ-lactol; 2- {3u, 5u-dihydroxy-23-α: -bromo (3S) -3-hydroxy-4 (R, S) -fluoro-trans- -1-decenyl; 7α-cyclopentyl} -ethanal-Y- lactol; 2- {3u, 5u-dihydroxy-2B-β-β-bromo- (3S) β-hydroxy-4,4-difluoro-trans-1--denkenyl} 7α-cyclopentyl} -ethanal-γ-lactol; 2- {3a, 5u-Dihydroxy-2B-β-bromo- (3S) -3-hydroxy-4S-fluoro-S-cyclopentyl-trans-1-pentenyl; 7α-cyclopentyl} -ethanal-Y lactol; 2- {3a, 5a4-dihydroxy-2B-β-bromo- (38) -3-hydroxy-4,4-difluoro-5-cyclopentyl-trans-1-pentenyl] -laa-cyclopentyl} -ethanal-γ-lactol; 2- {3a, 5a4-Dihydroxy-28-β-bromo-(3S) -3-hydroxy + 4 (R, S) -fluoro-5-cyclohexyl-trans-1-pentenyl-7α-cyclopentyl} -ethanal-Y lactol and the individual 4S-fluorine and 4R-fluoroisomers; 2- {3α, 5β-dihydroxy-2B-1β-bromo- (3S) -3-hydroxy-4,4-difluoro-5-cyclohexy] -trans-1-pentenyl-7-cyclopentyl} -ethanal-γ-lactol; 2- {3u, 5u4dihydroxy-2B> ¿§4bromo- (38) -3-hydroxy-4 (R, S) -fluoro-5-phenyl- -trans-1-pentenyl] ¥ lu-cyclopentyl} -ethanal-Y -lactol; 2- {3a, 5a4-dihydroxy-2B> β-bromo- (3S) -3-hydroxy-4,4-difluoro-5-phenyl--trans-1-pentenylsulfluecyclopentyl} -ethanal-γ-lactol; 2- {3a, 5u4-Dihydroxy-2B-β-bromo- (38) -3-hydroxy-4 (R, S) -fluoro-4- (4'-fluoro) -phenyl-thanes-1-pentenylphela4cyclopentyl} -ethanal-Y -lactol; 2- {3a, 5a% dihydroxy-2β-β-bromo- (3S) -3-hydroxy-4 (R, S) -fluoro-4- (3'-chloro) -phenyl; -trans-1- pentenylphelaecyclopentyl} -ethanal-γ-lactol; 2- {3u, 5a4-dihydroxy-2B-β-bromo- (35) -3-hydroxy-4 (R, S) -fluoro-4- (3'-trifluoromethyl) -phenyl-trans-1-penteny; 11α-cyclopentyl} -ethaneL--γ-lactol, the following compounds were obtained, either as the 11,15-bis-THP-ether or as the 11,15-bis-DIOX-ether: 13,14-aehyarO-1s (1z, s) -fluoro-PGF 2 a, as THF-acer MD = + z °; 13,14-dehydro-165-methyl-16R-fluoro-PGF2Q and its 16S-fluoro-1-dimethyl-isomer, [α] D = + 1.8 ° and + 3.2 °, respectively, as DIOX-ether; 13, lzz-aehyaro-ls, _16-aif1uQr-PGF2Q, tall) = -1s ° as THP-ether; 13,14-dehydro-16,16-difluoro-20-methyl-PGF2a, [u] D = -120 as THP-ether; . 13,14-dehydro-16S-fluoro-16R, 20-dimethyl-PGFZG and its 16R-fluoro--165-methyl isomer, [alu = -14 ° and -13.5 ° as THP- ether; 13,14-anhydro-16 (ms) -fluoro-zo-motyl-Porza, [oln = + 2 ° as mox- -ether; 13,14-dehydro-16 (R, S) -fluoro-20-ethyl-PGF2Q, ldln = -4 ° as DIOX- -ether; 13-, 14-enyaro-1e, 1s-aifluoro-zo-eayl-Psrza, IoJD = -12 ° as THP-ether; 18,19,20-trinor-17-cyclopentyl-168-fluoro-13,14-dehydro-PGF 2, [α] D = -6 ° as THP-ether; e '18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro- -Psrzw IaJD = -s ° as' rnP-ether; - 18,19,20-trinor-17-cyclohexyl-15 (R, S) -fluoro-13,14-dehydro-PGF2G, [α] D = -4 ° as THP-ether; and the individual 16S-fluorine and 16R-fluoroisomers, [river = -7 ° and -6 ° respectively as THP-ether; 1,8,19,20-Trinor-17-cyclohexyl-1,6,16-difluoro-13,11-dehydro-PGF2Q, [alu = -12 ° as DIOX-ether; 18,19,20-trinor-17-phenyl-16 (R, S) -fluoro-13,14-dehydro-PGF2Q, [a] D = -14 ° as DIOX-ether; 18,19,2O-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGF2α, [α] D = + 1 ° as DIOX-ether 1 §, 19,20-trinor-16 (R , S) -fluoro-17- (4'-fluoro) -phenyl-13,14-dehydro- -PGF2G, [a] D = -2 ° as DIOX-ether; 18,19,20-trinor-16 (R, S) -fluoro-17- (3'-chloro) -phenyl-1,3,14-dehydro- -PGF2G, IQID = -4 ° as DIOX-ether; 18,19,20-trinor-16 (R, S) -fluoro-16- (3'-trifluoromethyl) -phenyl-13,14-dehydro-PGF2a, [a] D = -6 ° as DIOX-ether; which were then deacetalized by the procedure described in Example 3 to give the following free hydroxy acids, with the values for [alu (c = 1, EtOH) given below: 13,14-dehydro-16 (R, S) -fluoro- PGF -anzo = 316 m / e; IoID = +21.2; . 13,14-dehydro-16S-methyl-16R-fluoro-PGFZG [a] D = +29, and its 16S-fluoro-16R-methyl isomer, [a] D = + 22.4, M * = 384 nVe ; + _ + _ __ + zwm -avom Hzo-aszu 7993642-7 za 13,14-dehydro-16,16-difluoro-PGFZQ, M + = 388 m / e; [α] D = + 21.9; 13,14-dehyaro-16,16-difluoro-zo-methyl-PGF2a, M * 402 mye; IQJD 19.5; 13β-4-dehydro-168-fluoro-16R, 20-dimethyl-PGF2Qγ [a] D = +27, and its 16R-fluoro-16S-methyl isomer, [Q] D = + 188.1 M + 398 m / e; 13,14-aeyaro-16 (R, s> -fluoro-zo-methyl-PGF, M * 384 m / e; [q] D +20,2; _ 13,14-dehydro-16 (R, S) -Eluoro-20-ethyl-PGF + 17.7; 13,14-dehydro-16,16-difluoro-20-ethyl-PGF2a, Mf 416 m / e; [α] D = + 18.2; 18.19.20 -trinor-17-cyclopentyl-16S-fluoro-13,14-dehydro-PGF M * 396 m / e; [α] D = +35; 18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13 1,4-dehydro- -PGF2Q, M * 414 m / e; [a] D = +31; 18,19,2O-trinor-17-cyclohexyl-16 (R, S) -fluoro-13,14-dehydro- PGF2Q, [a] D = + 25, 1; 2a, M + 398 m / e; la] = 2a D 2a 'and the individual 16S-fluorine; [Q] D = + 12.3, and the 16R-fluoroisomers, [ a] D = +38.4, M + 410 m / e; 18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-1-PGF2Q, M * 428 mye; [a ] D = +22; 18,19,20-trinor-17-phenyl-16 (R, S) -fluoro-13,14-dehydro-PGP M * 404 mye; [a] D = +26.2; 18 , 19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGFZG, M * 422 mye; [a] D = +19; 18,19,20-trinor-16 (R, S) -fluoro-17- (4'-fluoro) -phenyl-13,14-dehydro--PGF2α, mf 422 m / e; [α] D = + 1s, s; 18,19,20-trinor-16 (R , S) -fluoro-17- (3'-chloro) -phenyl-1,3,14-dehydro- -PGF2Q, M * 440, 438 m / Q; [α] D = + 1s, 1; 18,19,20-Trinor-16 (R, S) -fluoro-16- (3'-trifluoromethyl) -phenyl-13,14--dehydro-PGF2Q, M * 472 m / e, [a] D = + 16.3. EXAMPLE 5 A solution of 0.37 g of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGF2Qf11,15-bis-THP-ether in 10 ml of acetone was cooled to -15 ° C 29 and 0.9 ml of Jones reagent were added. The mixture was kept at -10 to -12 ° C for 30 minutes, after which it was diluted with 70 ml of benzene and washed repeatedly with saturated aqueous solution of ammonium sulfate to neutrality (10 x 5 ml). It was then dried over sodium sulfate and evaporated to dryness. * The crude reaction product was dissolved in 60 ml of acetone and combined with 80 ml of an aqueous 0.1 ml of sodium oxalate solution.

This mixture was kept at 40 ° C for 10 hours. The acetone was evaporated in vacuo and the aqueous phase was extracted with ether. The combined organic extracts were washed to neutrality, dried and evaporated to dryness. The residue was chromatographed on acid-washed silica gel eluting with methylene chloride-ethyl acetate to give 0.2 g of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGE 2, δ L] B = -47, s °, ¿E_7365 ° = -291 ° (ston).

Using the above procedure and starting from compounds prepared as described in Examples 1, 2 and 3, the following PGE2 derivatives were obtained in the form of 11,15-bis-acetals having the values given below for [u] D (c = 1, EtOH), after oxidation with Jones reagent and subsequent deacetalization. 18,19,20-trinor-17-cyclopentyl-16 (R, S) -fluoro-PGE2, M + 396 M + -2H2O 360 m / e; [α] D = -39.2; 18,19,2O-trinor-17-cyclopentyl-16,16-difluoro-PGE2, M + -2H2O 378 m / e; taln = fav; 18,19,20-trinor-17-cyclohexyl-16 (R, S) -PGE 2, [α] D = -47.8, and the individual 16S-, [α] D = -59.2, and 16R- the isomers, [α] D = -39.6, M * -zuzo 374 m / e; 18,19,20-trinor-17-cyclohexyl-16,16-difluoro-PGE = 392 m / e; [α] D = -37.9; 13,4-dehydro-16 (R, S) -fluoro-PGE 2, [α] D = -3.60 (EtOH), M + -2H 2 O = 332 m 2; 13,14-dehydro-16S-methyl-16R-fluoro-PGE 2, [u] D = -17.2, and its 16R-methyl-16S-fluoro-isomer, IGID = -12.5, M + -2H 2 O = 346 m / e; 13,14-dehyaro-16,16-aifluoro-PGE2, M * = sas M * -zazo =: so m / e; [α] D = -18.7; 13: 14'd9Hydro-16 (R, S)'luoro-20-methyl-PGE 2, M + -2H 2 O [u] D = -6.7: + 2, M -znzo 346 m / e; CO o -PGE2, M * -7 CH ephene 13,14-dehydro-165-fluoro-16R, 20-dimethyl-PGE2, [GID = -5.7 and -15, M + -2920 = 360 m / e; 400 m / e; its 16S-methyl-16R-fluoro-isomer, [α] 13,14-ahyaro-16,16-aifluoro-20-methyl-PGE2, M * [a] D = -9.8; 13,14-dehydro-16 (R, S) -fluoro-20-ethyl-PGE 2, [α] D = -7.1; 13,14-dehydro-16,16-difluoro-20-ethyl-PGE2, = 396 M * -z2 = 378 m / e; [alu = -9.2; 18,19,20-Trinor-17-cyclopentyl-16 (R, S) -fluoro-13,4-dehydro- -PGEZ, M? -znzo = ass m / e; [α] D = -22.5; 18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro- -Pssz, M * -znzo = 316 m / e; number = -13.7; 18,19,20-trinor-17-cyclohexyl-16 (R, S) fluoro-13,14-dehydro-PGE2, [u] D = 49.2; M + -2H o = 360 m / e; 2 M * = 414 M * -H o 2 and the individual 16S-fluoro-, [u] D -33.5, and the 16R-fluoroisomers, [a] D = -59.6, M * -znzo = 372 m / e; 18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGE2, M * -2320 = 390 myel; [α] D = -23; 18,19,20-trinor-17-phenyl-16 (R, S) -fluoro-13,14-dehydro-PGE 2, * -zuzo 366 m / e, [α] D = -55.7; M 18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGE 2, M -znzo = 384 m / e; [α] D -30.5; 18,20,20-trinor-16 (R, S) -fluoro-17- (4'-fluoro) -phenyl-1,3,14-dehydro- -PGE2, M * -zino 384 m / e; [α] D = -29.1, and 18,19,20-trinor-16 (R, S) -fluoro-16- (3'-chloro) -phenyl-13,4-dehydro--2H 2 O = 402, 400 m / e; [a] D -21.

+ EXAMPLE 6 A solution of 0.59 g of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGE2-11,15-bis-THP-ether in 80 ml of acetone was refluxed with SO ml of an aqueous 0.25N solution of oxalic acid for 6 hours. The acetone was evaporated in vacuo and the residue was extracted repeatedly with ethyl ether. The combined ether extracts were washed with saturated aqueous ammonium sulfate solution and allowed to evaporate. The residue was chromatographed on an acid-washed silica gel eluting with cyclohexane-ethyl acetate 80:20 to give 300 mg of 18,19,20-trinor-17-cyclohexyl-16 (R, SL-fluoro-PGA2, M + -H 2 O = 374 m / e and as bis-disilyl ether, M + = 536 m / e.

Using the above procedure and starting from compounds prepared as described in Example 5, either in the form of the free alcohols or of 1,5,15-bis-THP- ethers or 11,15-bis-DIOX ethers, the following compounds: 18.19, zo-trinor-17-cyclopentyl-16 (R, s) -fluoro-PGAZ, M * -H 2 O = 360 m / e; 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGA2, M + -H2O = 374 m / e; 13,14-aenyaro-16 (R, s) -fluoro-PGAZ, M * -H 2 O = 332 m / e; 13,14-ahyaro-les-methyl-16R-fluoro-PGA2, M * -H2O = 346 m / e; 13,14-aenyaro-is, 1s-aifluoro-PGAZ, M * -H 2 O = sso m / e; 13,14-denyaro-1s (R, s) -fluoro-20-methyl-PGAZ, MF -H 2 O = 346 m / e; 13,14-dehydro-16S-fluoro-16R, 20-dimethyl-PGA2, M + -H2O = 360 m / e; 13,14-dehydro-16,16-difluoro-20-methyl-PGA2; M + -H 2 O = 364 m / e; 13,14-aenyaro-16 (R, s) -fluoro-zo-ecyl-PGAZ; M * -azo =: so m / e; 13,14-dehydro-16,16-difluoro-20-ethyl-PGA2; M + -H 2 O = 378 m / e; 18,19,20-trinor-17-cyclopentyl-16 (R, S) -fluoro-13,4-dehydro--PGA2, M * -H 2 O = 358 m / e; 18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro- -PGA2; M + -H 2 O = 376 m / e; 18,19,20-trinor-17-cyclohexyl-16S-fluoro-13,14-dehydro-PGA2 and its 16R-isomer, M + -H 2 O = 372 m / e; 18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGA2, M * -H2O = 390 N / e; 18,19,20-Trinor-17-phenyl-16 (R, S) -fluoro-13,14-dehydro-PGA2, M + -H 2 O = 366 m / e and 18,19,20-Trinor-17-phenyl- 16,16-difluoro-13,14-dehydro-PGA2, M * -nzo = 384 m / e.

EXAMPLE 7 To a solution of 0.58 g of 18,19,20-trinor-17-cyclohexyl-16- (R, S) -fluoro-PGF2aff1,15-bis-THP-ether in 12 ml of HMPA was added 44 mg of NaOH 7908642 -7 32 dissolved in ml of water. The mixture was stirred for 1 hour. Then 150 mg of 1-bromopropane was added and stirring was continued for 12 hours. Then 25 ml of water were added and the mixture was extracted with ethyl ether.

The combined organic phases were washed with saturated aqueous ammonium sulfate solution, dried and evaporated to dryness to give 600 mg of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGF 2 -bis-THP-ether-n-propyl ester, [u] D = -4 °. By this procedure and starting from the 11,15-bis-acetal ethers described in Examples 1, 2 and 3, and by using another haloalkyl compound instead of 1-bromopropane (e.g. methyl iodide, ethyl iodide, bromobutane, The bromooctane, or bromodecane) was prepared to give the methyl, ethyl, butyl, octyl and decyl esters of the corresponding 11,15-bis-acetal ethers, which could then be deacetalized by the procedure of Example 3 to give the free hydroxy- estrarna.

Human 8, To a solution of 0.6 g of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGF2a-11,15-bis-THP-ether-n-propyl ester in 15 ml of anhydrous THF were added 1.05 g of triphenylphosphine and 0.79 g of p-phenylbenzoic acid.

The reaction mixture was kept at 20-22 ° C and stirred while a solution of 0.7 g of ethyl azadicarboxylate in 6 ml of THF was added dropwise during the Szüza period. After a further 10 minutes, the mixture was evaporated to dryness and the residue was taken up in 75 ml of ethyl ether, washed with a saturated aqueous carbonate aqueous solution, then with water, and then evaporated to dryness. The residue was dissolved in 25 ml of acetone, and 18 ml of 0.2N aqueous oxalic acid solution was added. The mixture was refluxed for 30 minutes, concentrated in vacuo to remove the acetone, extracted with ethyl acetate and the organic phase evaporated to dryness. The residue was chromatographed on silica gel eluting first with cyclohexane-ethyl ether 6: 4 and then with ethyl ether to give 0.5 g of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGFZB-9 -p-phenylbenzoate-n-propyl ester, IQID = -12 °. A solution of this compound in 10 ml of anhydrous propanol was treated with 140 mg of anhydrous potassium carbonate and the mixture was refluxed for 1.5 hours. Then it was neutralized and the solvent was evaporated, after which the residue was partitioned between methylene chloride and water. The organic phase was dried and evaporated to dryness, after which the residue was chromatographed on silica gel, eluting first with ethyl ether and then with ethyl ether-ethyl acetate 1: 1. The yield was 340 mg of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGF2β-n-propyl ester, M + in an 8: 2 mixture of methanol and water, and 215 mg of potassium carbonate. nat was added. The mixture was refluxed for 1 hour. After evaporation of the solvent, the residue was taken up in water, acidified to pH 4.5 and extracted with ethyl acetate. After evaporation of the organic phase, 280 mg of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-PGF2B, M + = 412 m / e were obtained. Using the procedures of Examples 7 and 8 and starting from compounds prepared as described in Examples 1, 2 and 3, the following compounds were prepared as free acids or as alkyl estersz = 454 m / e. This compound was dissolved is, 19,2o-trin ° r-17-cyclapentyl-16 (R, s) -fluoro-Psrzß, M * sea m / e; is, 19, zo-trinor-17-cyclopentyl-16,1s-afluoro-Psrzß, M * 416 m / e; 18,19, zo-trinor-11-cyclohexyl-16 (R, s) -fluoro-PGPZB, M * 412 m / e; 18,19,20-trinor-17-cyclohexyl-16,16-difluoro-PGF2B, M + 430 m / e; 13,14-aeyaro-16 (R, s--fluoro-Pcrzß, M * 370 m / e; 13,14-dehydro-16S-methyl-16R-fluoro-PGF2B and its 16R-methyl-16S-fluoroisomer, M + 384 m / e; 13,14-aehyaro-1s, la-aifluoro-PGPZB, m * ses m / e; 13,14-aehyaro-16 (R, s) -fluoro-zo-methyl-Psrzß, M * 384 m / e; 13,14-dehydro-16S-fluoro-16R, 20-dimethyl-PGF2B and its 16S-methyl-16R-fluoro-isomer, M + 398 mYe; 13,14-dehydro-16,16-difluoro -20-methyl-PGF2β, M + 402 m / e; 13,14-dehydro-16 (R, S) 'fluoro-20-ethyl-PGF2B, M + 398 m / e; 13,14-dehydro-16,16 -difluoro-20-ethyl-PGF2B, M + 416 m / e; 18,19,20-trinor-17-cyclopentyl-16 (R, S) -fluoro-13,14-dehydro- -PGFZW M * 396 m / e 18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro- -PGF2W m * 414 m / e; 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro-1,3,14-dehydro- -PGF2B, Mf 410 m / e and 7993642-7 34 18,19,20-trinor-17-phenyl-16 (R, S) -fluoro-13,14-dehydro -PGFZB, M * 404 m / e.

EXAMPLE 9 In an inert gas phase and in the absence of moisture and with constant stirring, a solution of 3.82 g of dimethoxy-β-oxo was added dropwise to a suspension of 410 mg of NaH (80% dispersion in mineral oil) in 10 ml of anhydrous benzene. -3-fluoro-4-cyclohexyl7-butylphosphonate in 10 ml of anhydrous benzene. The mixture was stirred for 1 hour, then a solution of 2 g of 2-β-formyl-α, α-dihydroxy- (Ba-p-phenylbenzoethyl-lu-cyclopentyl-acetic acid-1,5-7-lactone in anhydrous benzene was added. Then stirred for 15 minutes and then 100 ml of a saturated aqueous solution of monobasic sodium phosphate were added, after which the organic phase was separated, washed to neutrality, dried and evaporated to dryness, the residue was chromatographed on silica gel and eluted with cyclohexane-ethyl acetate. : 2 to give 2.1 g of 2- [3α, 5u-dihydroxy- (3α-p-phenylbenzoate) -2B-β-keto-4-fluoro-5-cyclohexyl-trans-1-pentenyl] -la -cyclopentyl} -acetic acid 1,5-γ-lactone, mp 127-129 ° C. EXAMPLE 10 To a suspension of 410 mg of NaH (80% dispersion in mineral oil) in 140 ml of anhydrous THF was added dropwise a solution of 3.82 g of dimethyl-β-oxo-3 (R, S) -fluoro-cyclohexyl-7-butyl-phosphonate in 10 ml of THF, then stirred for 1 h until hydrogen no longer developed, then 2.432 g of N-bromo-succinimide were added all over once. was stirred for 15 minutes and then a solution of 2 g of 2- {β §B-formyl--3u, 5u-dihydroxy- (3α-p-phenylbenzoateβ7-1α-cyclopentyl} -acetic acid--1,5-γ- lactone and THF. The mixture was stirred for 1 hour, then diluted with 200 ml of a 6% aqueous solution of monobasic sodium phosphate. The organic phase was separated, washed to neutrality, dried and evaporated to dryness. After chromatography on a silica gel column, 1.9 g of 2- {3α, 5u-dihydroxy- (3α-p-phenylbenzoate) -28-ε-bromo-3-keto-4 (R, S) -fluoro-S-cyclohexyl were obtained -trans-1-pentenyl7-1u- -cyclopentyl} -acetic acid-1,5-γ-lactone, M * 584, 582 m / e.

Following the procedures of Examples 9 and 10, the following acid-1,5-γ-lactones were obtained: 2- {3a, 5urdihydroxy- (3ufp-phenylbenzoate) -25- [3-keto-4 (R , S) -fluoro--5-cyclopentyl-trans-1-pentenyl-lafcyclopentyl} -acetic acid-1,5-γ-lactolh M + 49o m / e; 2- {3α, 5-Dihydrohydro- (3-urp-phenylbenzoate) -2B- [3-keto-4,4-difluoro--5-cyclopentyl-trans-1-pentenyl] -lu-cyclopentyl} -acetic acid-1,5- Γ-lactone, M + 508 m / e; 2- {3α, 5H-dihydroxy- (3α-p-phenylbenzoate) -25- [3-keto-4 (R, S) -fluoro--5-cyclohexy-trans-11-pentene-ethyl] -lurocyclopentyl} -acetic acid-1,5-yl -lactone, M 504 m / e; 2- {3α, 5-Dihydroxy- (3H-p-phenylbenzoate) -2B- [3-keto-4,4-difluoro--5-cyclohexyl-trans-1-pentenyl] -larcyclopentyl} -acetic acid-1,5- lacquer, m * 522 m / e; 2- {3α, 5-dihydroxy- (3α-p-phenylbenzoate) -26- [2-bromo-3-keto-4 (R, S) -fluoro-trans-1-octenyl] -1α-cyclopentyl} -acetic acid 1,5-7-lactone, m + 544, 542 m / e; 2- {3α, 5-Dihydrohydro- (3α-p-phenylbenzoate) -2B- [2-bromo-3-keto-4,4-difluoro-trans-1-octenyl] -urocyclopentyl} -acetic acid-1,5-Y- lactone, m * 552, sso m / e; 2- {3α, 5-Dihydrohydro- (3crp-phenylbenzoate) -2B- [2-bromo-3-keto-4S--methyl-4R-fluoro-trans-1-octenyl] -1-cyclopentyl} -acetic acid-1,5-S-Y- lactone and its 4R-methyl-48-fluoro isomer, M + 558, 556 m / e; 2- {3a, Acid-hydroxy- (3α-p-phenylbenzoate) -2β- [2-bromo-3-keto-4 (R, S) -fluoro-tranS-1-nonenyl] -1α-cyclopentyl} -acetic acid-1 , 5-γ-lactone, m * 558, 556 m / e; 2- {3α, 5-Dihydroxy- (3α-p-phenylbenzoate) -2B- [2-bromo-3-keto-4S-fluoro-4R-methyl-trans-1-nonenyl] -lucyclicpentyl} -acetic acid-1,5-yl lactone and its 48-methyl-4R-fluoro isomer, Mf 572, 570 m / e; 2- {3α, 5α-Dihydroxy- (3β-p-phenylbenzoate) -2β- [2-bromo-3-keto-4,4--difluoro-trans-1-nonenyl] -la-cyclopentyl} -acetic acid-1,5 -Y-1ak- con, M 516, 514 m / e; 2- {3u, 5-urdihydroxy- (3urp-phenylbenzoate) -2β- [2-bromo-3-keto-4- (R, S) -fluoro-trans-1-decenyl] -10-cyclopentyl} -acetic acid-1,5 -y- -1-actone, M 572, 57o m / e; 7908642-7 see 2- {3α, 5-ureahydroxy- (3-arp-phenylbenzoate) -2B- [2-bromo-3-keto-4,4--difluoro-trans-1-dekenyl] -1α-cyclopentyl} -acetic acid-1 , 5-7- -lactone, M * sso, sas m / e; 2- {3u, 5-dihydroxy- (3ufp-phenylbenzoate) -2β- [2-bromo-3-keto-4- - (R, S) -fluoro-5-cyclopentyl-trans-1-pentenyl] -1arcyclopentyl} - - acetic acid 1,5-Y-lactone, M * s7ø, sea m / e; 2- {3α, 5-Dihydrohydro- (3α-p-phenylbenzoate) -2B- [2-bromo-3-keto-4,4--difluoro-5-cyclopentyl-trans-1-pentenyl] -la-cyclopentyl} -acetic acid - syra-1,5-y-lakcon, M * sas, ses m / e; 2- {3α, 5-Dihydrohydro- (3-crp-phenylbenzoate) -2β- [2-bromo-3-keto--4 (R, S) -fluoro-cyclohexy; -trans-1-pentenyl] -locyclopentyl} -acetic acid-1 , 5-γ-lactone and the individual 4Rf and 4S isomers, M + 584, 582 m / e; 2- {3α, 5-urodydroxy- (3uβ-phenylbenzoate) -2B- [2-bromo-3-keto-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl] -lurocyclopentyl} -acetic acid-1 , 5-γ-lactone, M + 602, 600 m / e; 2- {3a, Surdihydroxy- (3a-p-phenylbenzoate) -2β- [2-bromo-3-keto--4 (R, S) -fluoro-5-phenyl-trans-1-pentenyl] -lorocyclopentyl} -acetic acid acid-1,5-γ-lactone, M + 578, 576 m / e; 2- {3a, cycloharyloxy- (cyclo-phenylbenzoate) -2β-bromo-3-ket-4,4-difluoro-5-phenyl-trans-1-pentenyl-1-cyclopentyl} -acetic acid 1,5-γ-lactone, M + 596, 594 m / Q; 2f {3α, 5-dihydroxy- (3α-p-phenylbenzoate) -2β '[2-bromo-3-ketoE4- (R, S) -fluoro-5- (4'-fluorine) -phenyl-trans-1-pentenyl] -la-cyclopentyl} -acetic acid-1, γ-lactone, MT see, 594 m / e; 2- {3α, 5-urdihydroxy- (3orp-phenylbenzoate) -2β- [2-bromo-3-keto--4 (R, S) -fluoro-5- (3'-chloro) -phenyl-trans-1-pentenyl -larcyclo-phenyl} -acetic acid-1, sv-lactone, M * 614, 612, 61o lot; a 2- {3α, 5-urdihydroxy- (3u-p-phenylbenzoate) -2B- [2-bromo-3-keto--4- (R, S) -fluoro-5- (3'-trifluoromethyl) -phenyl-trans -1-pentenyl] -lucyclopentyl} -acetic acid-1,5-γ-lactone, M * 646, 644 m / e. EXAMPLE 11 2.03 g of 2- {3a, safainydrox1- (sa-p-phenylbenzoate) -2β- [3-keto--4 (R, S) -fluoro-5-cyclohexy] -trans-1- pentenyl-1α-cyclopentyl} -acetic acid 1,5-β-lactone was dissolved in 120 ml of a 5: 1 mixture of anhydrous ethyl ether: DM, and 280 ml of a 0.07M solution of Zn (BH4) were added dropwise with stirring. ) 2 1 ethyl ether, at room temperature. The mixture was stirred for 30 minutes, after which 40 ml of a saturated aqueous solution and then 55 ml of 2N H 2 SO 4 were added. The organic phase was separated and washed to neutrality, after which it was dried and evaporated to dryness. the residue was chromatographed on a silica gel column and eluted with methylene chloride 9: 1. There was thus obtained 1.18 g of 2 * {3u, 5α-dihydroxy- (Bofp-phenylbenzoate) -28 - [(3S) -3-hydroxy-4 (R, S) -fluoro-5-cyclohexyl-trans- 1-pentenyl] -lur -cyclopentyl} -acetic acid-1,5-γ-lactone Mf 506 m / e and 780 mg of 2- {3α, 5-ordihydroxy- (3ufp-phenylbenzoate) -Zβ - [(3R) -3-hydroxy -4 (R, S) - -fluoro-5-cyclohexyl-trans-1-pentenyl-1-cyclopentyl} -acetic acid--1,5-γ-lactone, mp 116-11s ° c, Pain = -1øs ° (cnc13) .

Exarmzt. 1.18 g of 2 (3u, 5a-dihydroxy- (3a-Q-phenylbenzoate) -28-AlIES) -3-hydroxy-4 (R, S) -fluoro-5-cyclohexyl-trans-1-pentenyl7-1a -cyclopentyl} -acetic acid-1,5-Y-action was dissolved in 60 ml of anhydrous methanol. 360 mg of anhydrous KZCO3 were added, after which the mixture was stirred for 4 hours.

It was then diluted with a saturated solution of monobasic sodium phosphate and filtered. The filtrate was concentrated to a small volume, taken up in water and extracted with ethyl acetate. The combined organic phases were washed to neutrality, dried and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of cyclohexane and ethyl acetate.

There was thus obtained 750 mg of 2- (3α, 5α-dihydroxy-26-ÅTBS) -3-hydroxy-4- (R, S) -fluoro-5-cyclohexyl-trans-1-pentenyl] -1α-cyclopentyl} -acetic acid-1 , 5-v-lactone, M * 326 M * -H 2 O aos m / e.

EXAMPLE 13 310 mg of 2- (Su, sa-ainyaroxy-za-β) -3-nyaroxy-4 -5-cyclohexyl-trans-1-pentenylyela-cyclopentyl] -acetic acid-1,1-Sy-7-lactone dissolved in 50 ml of anhydrous benzene. Then 2 mg of p-toluenesulfonic acid and 0.3 ml of 1,2-dihydropyran were added. The mixture was allowed to stand at room temperature for 4 hours, after which it was washed with 3% aqueous potassium carbonate and with water to neutrality. Then dried and evaporated. There was thus obtained 560 mg of 2- {3α, 5α-dihydroxy- (3α-THP-ether) -2B-β3S) -3-hydroxy- (3-THP-ether) -4 (R, S) -fluoro-5 -cyclohexyl-trans-1-pentenyl] -la-cyclopentyl} -acetic acid-1,5-γ-lactone, n * 494 m / e. - ExEnPEL 14 4eo mg 2- {zmsu-aihyroxy- (sa-ænP-ether) -zß- [as) -s-nyaroxy- (s- -THP-ether) -4 (R, S) -fluoro-5- cyclohexyl-trans-1-pentenyl-7α-cyclopentyl-acetic acid 1,5-γ-lactone was dissolved in 20 ml of anhydrous toluene. This solution was cooled to -70 ° C and kept at temperatures not exceeding -60 ° C while a solution of 7.21% DIBA in toluene was added dropwise.

When all had been added, the mixture was stirred for another 30 minutes.

Then 3.2 ml of 2M isopropanol in anhydrous toluene were added and the temperature was allowed to rise to 0 ° C, after which 2 ml of water were added. Stirring was continued for about 20 minutes, after which 500 mg of celite and 1.0 g of anhydrous sodium sulfate were added. Then it was filtered and the filtrate was evaporated to give 400 mg of 2- {3α, 5α-dihydroxy- (3-THP-ether) -2β-βK3S) -3-hydroxy- (3-THP-ether) -4 ( R, S) -fluoro-5-cyclohexyl-trans-1--pentenyl1-chlorocyclopentyl} -ethanal-1,1SY-lactol, M + -H 2 O = 41s m / e.

Following the procedures of Examples 11-13 and starting from compounds prepared according to the procedures of Examples 9 and 10, the following compounds were obtained (either as bis-THP ethers or as bis-DIOX ethers): 2- {3a , 5α-dihydroxy-25 - [(38) -3-hydroxy-4 (R, S) -fluoro-5-cyclopentyl-trans-1-pentenyl] -1α-cyclopentyl} -ethanal-γ-lactol, M + -H 2 O = 464 m / e as THP-ether; 2- {3α, 5α-Dihydroxy-2β - [(35) -3-hydroxy-4,4-difluoro-5-cyclopentyl-trans-1-pentenyl] -1α-cyclopentyl} -ethanal-γ-lactol, M + - H 2 O = 482 as TH 2 ether; 2- {3a, 5u-dihydroxy-25-I (35) -3-hydroxy-4 (R, S) -fluoro-5-cyclohexy-79os642-7 39 -trans-1-pentenyl] -la-cyclopentyl} - ethanal-γ-lactol and the individual 48- and 4R-isomers, M + -H 2 O = 478 m / e as THP-ether; 2- {3α, 5 -ardihydroxy-2β - [(38) -3-hydroxy-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl] -lacyclopentyl} -ethanal-γ-lactol, M + -H 2 O = 500 m / e as DIOX-ether; 2- {3u, 5a-Dihydroxy-2B- [2-bromo- (35) -3-hydroxy-4 (R, S) -fluoro-trans- -1-octenyl] -1α-cyclopentyl} -ethanal-γ-lactol , M + -H 2 O 518, 516 “Ye as THP-ether, 2- {3a, 5-dihydroxy-2B- [2-bromo- (3S) -3-hydroxy-4S-methyl-4R-fluoro--trans-1-octenyl] -lurocyclopentyl} -ethanal-γ-lactol and the 4S-fluoro--4R-methyl isomer, NU'-H 2 O 532, 530 m / e as THP-ether; 2- {Ba, Sa-dihydroxy-Z B-1Z-bromo- (35) -3-hydroxy-4, d-difluoro-trans- -1-octonyl] -10-cyclopenzycinnic-γ-lactol, m * -Hzo 540, saa “Ye as DIOX-ether; - 2- {3α, 5-urdihydroxy-2B- [2-bromo- (35) -3-hydroxy-4 (R, S) -fluoro- -trans-1-nonenyl] -larycyclopentyl} -ethanal-7-lactol, M + -H 2 O sas, 534 m / o as oOox-ecor; 2- {3α, 5-urdihydroxy-2β- [2-bromo- (3S) -3-hydroxy-4S-fluoro-4R-methyl-trans-1-nonenyl] -1α-cyclopentyl} -ethanal-V-lactol and 4S -methyl- -4Rfluoroisomer, M + -H 2 O = 546, 544 m / e as THP-ether; 2- {3a, 5a-Dihydroxy-2B- [2-bromo- (3S) -3-hydroxy-4,4-difluoro-trans--1-nonenyl] -la-cyclopentyl} -ethanal-γ-lactol, M + -H 2 O = 550, 548 m / e as THP-ether; In 2- {3α, 5-dihydroxy-2β- [2-bromo- (38) -3-hydroxy-4 (R, S) -fluoro-trans- -1-dekenyl] -1α-cyclopentyl} -ethanal-γ-lactol , M + -H 2 O = 546, 544 m / e as THP-ether; 2- {3α, 5-dihydroxy-2β- [2-bromo- (3S) -3-hydroxy-4,4-difluoro-trans- -1-aoxonylo] -m-cyclopontyn-otanal-γ-acetol, α * -azo = 564, 562 m / e as THP ether; 'z-íso, so-ainyaroxy-z ß- lz-bromo- (ss) -s-hyaroxy-fz (ms) -f1 nor-s- -cyclopentyl-trans-1-pentenyl-1-cyclopentyl} -ethanal-Y -lactol, M * -H 2 O = 544, 542 m / s as Tap-stor; 2- {3α, 5-dihydroxy-2β- [2-bromo- (38) -3-hydroxy-4,4-difluoro-S--cycopentyl-trans-1a-pentenyl] -cyclopentyl} -ethanal-γ-lactol, n * -nzo = 562, sso m / o as Tas-stor; 7908642-7 40 2- {3α, 5-ordihydroxy-2B- [2-bromo- (35) -3-hydroxy-4 (R, S) -fluoro--5-cyclohexyl-transdspentenyl] -lacyclopentyl} -ethanal-γ-lactol and the individual 48- and 4R-isomers, M + -H 2 O = 558, 556 m / e as THP-ether; 2 {3a, Sardihydroxy-26- [2-bromo (35) -3-hydroxy-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl-1-cyclopentyl] -ethanal-γ-lactol, M + -H 2 O = 580, 578 m / e as DIOX ether; 2- {3α, 5-Dihydrohydroxy-2B- [2-bromo- (3S) -3-hydroxy-4 (R, S) -fluoro-5-phenyl-trans-1-pentenyl] -lacyclopentyl-1-ethanal-γ-lactol , M + -H 2 O = S 52, 550 m / e as THP ether; 2- {3α, 5-Dihydroxy-2β- [2-bromo (3S) -3-hydroxy-4,4-difluoro-5-phenyl-trans-1-pentenyl] -larcyclopentyl} -ethanal-γ-lactol, M * -H 2 O = 570, 568 “Ye sem THP-ecer; 2- {3α, 5-dihydroxy-2β- [2-bromo- (3S) -3-hydroxy-4 (R, S) -fluoro-5- - (4'-fluoro) -phenyl-trans-1-pentenyl] - lafcyclopentyl} -ethanol-Y- -lactol, M + -H 2 O = 570, 568 “Ye as THP-ether; 2- {3α, 5-dihydroxy-2β- [2-bromo- (38) -3-hydroxy-4 (R, S) -fluoro-5-- (3'-chloro) -phenyl-trans-1-pentenyl] - air cyclopentyl} -ethanal-Y- -lactol, M * -H 2 O = ses, ses, 584 m / e as Tap-ether and 2- {3a, 5-ordihydroxy-2B- [2-bromo- (35) -3-hydroxy- 4 (R, S) -fluoro-5- - (3'-trifluoromethyl) -phenyl-trans-1-pentenyl] -larcyclopentyl} -ethanal-γ-lactol, M + -H 2 O = 620, 618 m / e as THP -ether.

These compounds can be deacetalized as shown in the following examples (whether they are bis-THP ethers or bis-DIOX ethers). common 0.5 g 2- {3α, 5α-dihydroxy- (3α-THP-ether) -2B- (38) -3-hydroxy- (3-THP-ether) -4 (R, S) -fluoro -5-cyclohexyl-trans-1-pentenyl7F1a-cyclopentyl} -ethanal-γ-lactol in 10 ml of acetone was treated with 5 ml of 0.25n aqueous oxalic acid and refluxed for 90 minutes. The solvent was evaporated in vacuo and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous ammonium sulfate, dried and evaporated to dryness. The residue was chromatographed on silica gel eluting with ethyl acetate to give 320 mg of 2- (3u, Su-dihydroxy-28-βTS) -3-hydroxy- (R, S) -fluoro-5-cyclohexyl- trans-1-pentenyl7-1a-cyclopentyl} -ethanal- -Y-lekeel, vf = 328 M * -H2O = 310 me.

EXAMPLE 16 0.18 g of z-Phsenyl-aminearexy- (se-p-phenylbenzene) -2β-ethyl) -3--hydroxy-48-fluoro-5-cyclohexyl-trans-1-pentenyl-7α-cyclopentyl} - Acetic acid 1,5-γ-lactone in 25 ml of anhydrous methanol was reacted for 2 hours at room temperature with 150 mg of anhydrous K 2 CO 3.

The mixture was then neutralized and treated with Amberlite IR 120 resin (H +), filtered and the filtrate evaporated to dryness. The residue was taken up in 10 ml of dichloroethane and treated with 0.8 ml of 2,3-dihydropyran and 4 mg of p-toluenesulfonic acid. After 2 hours at room temperature, 0.3 ml of pyridine was added and the mixture was evaporated to dryness to give 0.9 g of 2- {3u, 5a-dihydroxy- (3d-THP-ether) -2B-βTR) -Hydroxy- (3-THP-ether) -48-fluoro-5-cyclohexyl-trans-1-pentenyl-7H-lurocyclopentyl} -acetic acid 1,5-γ-lactone, M + 494 m / e. This was dissolved in 10 ml of toluene, cooled to -60 ° C and treated under a nitrogen atmosphere with 6.5 ml of man (man 1 thiu). after so min at -so ° c the excess reagent was destroyed with 7 ml of a 2M solution of isopropanol in toluene to give 0.88 g of 2- {3a, 5dfdihydroxy- (3af -THP-ether) -2ß - [(3R) -3-hydroxy- (3-THP) -48-fluoro-5-cyclohexyl-trans- -1-pentenyl-1α-cyclopentyl-1-ethanal-1,5-γ-lactol, M + -H 2 O 478 m / e. This compound was then reacted according to the procedure of Example 1 with the ylide, which was derived from 0.92 g of NaH and 6.7 g of triphenyl- (4-carhoxy-butyl) -phosphonium bromide in 20 ml of DMSO, to give 0 96 g 18,19,20-trinor-17-cyclohexyl-16S-fluoro-15- -epi-PGF2qf11, 15-bis-THP-ether, M + 580 m / e. This compound was deacetalized in acetone with aqueous oxalic acid, as described in Example 3, to give 18,19,20-trinor-17-cyclohexyl-16S-fluoro--is-epi-pcrza, [din = + 4, s ° (meon).

In an analogous manner, by oxidation of the 11,15-bis-tetrahydropyranyl ether derivatives with Jones reagent, according to the procedure of Example 5, followed by deacetalization, 18,19,20-trinor-1-eyklehexyi-les- fiuer-is-epi-Pcrz, ¿E_7D = -s3,2 °, ¿E_7365e = -32s ° (atom. 7908642-7 42 EXAMPLE 17 8 ml of 0,2n oxalic acid was added to a solution of 380 mg of 18,19,20 - -trinor-17-cyclohexyl-16 (R, S) -fluoro-13,14-dehydro-PGF2af11, 15-bis- -THP-ether, [a] D = + 9 °, [a] 365o = + 102 ° (acetone) in 10 ml of acetone.

After 12 hours at 38 ° C, the acetone was evaporated in vacuo and the residue was extracted with ethyl ether. The organic extracts were evaporated to dryness and the residue was chromatographed on silica gel eluting with 50:50 methylene chloride: ethyl acetate to give 120 mg of 18,19,20-trinor-17-cyclohexyl-16 (S, R) -fluoro-13, 14-dehydro-PGF2α, [GID = + 38 ° (EtOH).

EXAMPLE 18 0.65 g of 18,19,20-trinor-17-cyclohexyl-16 (S, R) -fluoro-13,14-dehydro-PGF2Q-11,15-bis-THP-ether was dissolved in 20 ml of acetone . The solution was cooled to -15 ° C and 1.3 ml of Jones reagent was added. After 15 minutes, the mixture was diluted with 100 ml of benzene and washed to neutrality with 20% ammonium sulfate solution. Then dried over sodium sulfate and evaporated to dryness to give 0.52 g of 18,19,20--trinor-17-cyclohexyl-16 (S, R) -fluoro-13,14-dehydro-PGE 2 -11,5 -bis- -THP-ether, [α] D = -23 ° (acetone). This compound was dissolved in 15 ml of acetone and 12 ml of 0.1N oxalic acid was added, after which the mixture was allowed to stand for 12 hours at 37 ° C. The acetone was distilled off in vacuo and the residue was extracted with ethyl acetate, after which the ethyl acetate extracts were evaporated to dryness. The residue (0.39 g) was chromatographed on 12 g of silica gel eluting with methylene chloride-ethyl acetate (80:20) to give 0.2 g of 18,19,20-trinor-17-cyclohexyl-16 (R, S) -fluoro -1,4,14- -aehydro-PGE2, {a] D = -6.2 ° (ston). EXAMPLE 19 In the absence of moisture and under a nitrogen atmosphere, 1.4.21 g of 2-oxo-3 (R, S) -fluoro-4- were added dropwise to a slurry of 1.413 g of NaH (80% dispersion in mineral oil) in 250 ml of dry benzene. cyclohexyl butyl dimethyl phosphonate in 100 ml of dry benzene. After stirring for 15 minutes, 8.41 g of N-bromo-succinimide were added all at once, after which stirring was continued for 15 minutes and a solution of 16 g of 2- (12B--formyl-3a, 5-dihydroxy4urbenzoate) -1-1α-cyclopentyl} -acetic acid-1,5,5-I-lactone in 50 ml of dry benzene was added. The mixture was stirred for 11 h and then 4 ml of acetic acid were added dropwise; the organic phase was washed to neutrality with water, dried and the solvent was removed to give 18.5 g of 2- (Ba, 5 -ardihydroxy% 3u-benzoate) -2β- [2-bromo-3- oxo-4 (R, S) -fluoro-5-cyclohexyl-trans-1--pentenyl-1-cyclopentyl-acetic acid-1,5-6-lactone.

The mixture was separated by preparative HPLC using ethyl acetate, ethyl ether 60:40 on silica gel and 7.08 g of para--2- {3d, 5α-dihydroxy- (3α-benzoate) -26- [2-bromo-3-oxo -4 (S) -fluoro--5-cyclohexyl-trans-1-pentenyl} -acetic acid-1,5-X-lactone, [a] D = -36.2 (c = 1 CHCl 3) and 6.5 g of pure 2- {3α, 5α-Dihydroxy- (3α-benzoate) -26- [2-bromo-3-oxo-4 (R) -fluoro-5-cyclohexyl-trans-1-pentenyl] -la-cyclopentyl } -acetic acid-1,5-lactone, [α] D = -65.9 (c = 1 CHCl 3) was obtained. Following the same procedure and starting from 2-oxo--3-fluoro-heptyl-dimethyl-phosphonate, 2- {3α, 5α-dihydroxy- (3-arbenzoate) -2β- [2-bromo-] were collected and separated by preparative HPLC. 3-oxo-4 (S) -fluoro-trans-1-octenyl] -lurocyclopentyl-acetic acid-1,5-β-lactone, IQID = -43.5 (c = 1 CHCl 3), and 2- {3g, 5-dihydroxy- - (3α-benzoate) -2β- [2-bromo-3-oxo-4 (R) -fluoro-trans-1-octenyl] -1α-cyclopentenylβ-acetic acid 1,5-klactone, [a] D = -66.5 ° (c = 1 CHCl 3).

EXAMPLE 20 A solution of 2.64 g of 2-oxo-3 (R) -fluoro-4-cyclohexyl-butyl-dimethylphosphonate in 25 ml of dry benzene was dropped into a mixture of 0.283 g of NaH (80% dispersion in mineral oil) in 50 ml. ml of dry benzene under a dry nitrogen atmosphere.

The mixture was stirred for about 20 minutes, after which 1.685 g of N-bromosuccinimide were added. After stirring for 15 minutes, a solution of 3.2 g of 2 - {[2β-formyl-3α, 5α-dihydroxy- (3α-benzoate) 1--aircyclopentyl] -acetic acid-1,5-β-lactone in 20 ml of dry benzene. The solution was stirred for 1 h, then 0.8 ml of acetic acid was added dropwise and the organic phase was washed to neutrality with water, dried and the solvent removed to give 3.65 g of 2- {3α, 5α-dihydroxy- (3α-benzoate) 2β- [2-bromo-3-oxo-4 (R) -fluoro-5-cyclohexyl-trans-1-pentenyl] -1α-cyclopentylβ-acetic acid-1,5-β-lactone, [α] D = - 65.9 ° (c = 1 CHCl 3).

EXAMPLE 21 A Solution of 2- {3α, 5 -ardihydroxy- (3α-benzoate) -2B- [2-bromo--3-oxo-4 (R) -fluoro-5-cyclohexyl-trans-1-pentenyl] -1α-cyclopentyl } - v! 7908642-7 44 -acetic acid-1,5-X-lactone (4.6 g) in 40 ml of dry methanol was cooled to -25 ° C, then it was dropped with stirring into a solution of 0.89 g of sodium borohydride in 90 ml of dry methanol cooled to -25 ° C; during the instillation, the temperature was kept between -20 ° C and -25 ° C.

The solution was stirred for 30 minutes while cooling at -25 ° C, then 7 ml of a 20% solution of H 2 SO 4 in methanol was added.

The cooling bath was removed and the solution was diluted with 100 ml of saturated NaCl solution and 200 ml of ethyl acetate. The organic phase was washed to neutrality with water, dried and evaporated to dryness. A mixture of 4.5 g of 2- [3α, 5u-dihydroxy- (3α-benzoate) -2B- [2-bromo-3 (R, S) -hydroxy-4 (R) -fluoro-5-cyclohexyl- -trans-1-pentenyl-1α-cyclopentyl] -acetic acid-1,5-β-lactone was obtained; The mixture was separated by preparative HPLC to give 2.36 g of pure 2- (3a, 5a-dihydroxy- (3ufbenzoate) -2β- [2-bromo- - 3 (R) -hydroxy-4 (R) -fluoro-S - cycldxem-trans-1-pentenyl] -loc-cyclopentyl) - -acetic acid-LS-β-lactone [δJD = -31.4 (c = 1 cHc13), NMR JHF 10 Hz corresponding to the erythro structure, and 1.2 g 2 - (3a, 5a-Dihydroxy- (3-benzoate) -2β- [2-bromo-3 (S) -hydroxy-4 (R) -fluoro-5-cyclohexyl-trans-1-pentenyl] -la- cyclopentyl) -acetic acid-1,5-β-lactone [a] D = -27.8 (c = 1 CHCl 3), NMR JHF 18 Hz corresponding to the threostructure.

Using the same procedure as described above and starting from 2- {3α, 5-dihydroxy- (3α-benzoate) -2β- [2-bromo-3-oxo-4 (S) -fluoro-5-cyclohexyl-trans-1-pentenyl ] -la-cyclopentyl} acetic acid-1,5-¥? lactone the mixture of the 3 (R, S) -alcohol was obtained. The mixture was separated by liquid chromatography (HPLC) to give pure 2- (3a, 5a-dihydroxy- (3urbenzoate) -2B- [2-bromo-3 (S) -hydroxy-4 (S) -fluoro-5- cyclohexyl-trans-1-pentenyl] -la-cyclopentyl) -acetic acid--1,5-gllactone, amp sa-100 ° c, [α1D = -52.9 (C = 1 cHc13), NMR JHF 9 Hz corresponding to the erythro structure and pure 3 (R) -hydroxypimes, mp 153-15s ° c, [alu = -57 (C = 1 cHc13), NMR JHF 17 Hz corresponding to the threostructure.

Starting from 2- {3a, salicaroxyl- (safbenzoate) -2β- [2-bromo-3-oxo [4 (S) -fluoro-trans-1-octenyl] -cyclopentyl} -acetic acid-1,5-silica Pure 2- {3a, Surdihydroxy- (3a-benzoate) -2B- [2-bromo--3 (S) -hydroxy-4 (S) -fluoro-trans-1-octenyl] -lacyclopentyl} -acetic acid- 1,5-Ulactone, [α] D = -45.4 (c = 1 CHCl 3), NMR JHF 9 Hz corresponding to the erythroform and 2- {3a, 5a> dihydroxy- (3a-benzoate) - 2β- - [2-bromo-3 (R) -hydroxy-4 (S) -fluoro-trans-1-octenyl] -1α-cyclopentyl} -acetic acid-1,5-β-lactonylene = -52, 2, NMR JHF 17 Hz corresponding to the threo fi henmene phenoxy-3-oxo-4 (R) -fluoro derivative was obtained pure 2- {3α, 5-dihydroxy- (3-arbenzoate) -26- [2-bromo-3 (R) -hydroxy-4 (R) -fluoro-trans-1-octenyl-1α-cyclopentyl} -acetic acid-1,5-6-lactone [α] D = -29.2 (c = 1 CHCl 3), NMR JHF 11 Hz for erythro and 2- { 3α, 5α-Dihydroxy- (3α-benzoate) -2β- [2-bromo-3 (S) -hydroxy-4 (R) -fluoro-trans- -1-octenyl] -1α-cyclopentyl] -acetic acid-1,5 β-lactone [α] D = -28.7 (c = 1 CHCl 3), NMR JHF 18 Hz corresponding to the threoisomer.

EXAMPLE 22 A solution of 1.1 g of 13,14-dehydro-18,19,20-trinor-17-cyclohexyl-16 (R) -fluoro-15 (S) -hydroxy-PGF2a was reacted with 3 ml of a 1 M solution of diazomethane. After 10 minutes, the reaction mixture was evaporated to dryness and the methyl ester was purified by preparative chromatography on silica gel using 20 ml of ethyl ether to give ethyl acetate, hexane 60:40. There was thus obtained pure 1,3,14-dehydro- -18,19,20-trinor-17-cyclohexyl-16 (R) -fluoro-15 (S) -hydroxy-PGF2Gf -methyl ester (1,94 q), [QID = + 12.3 (c = 1 EtOH).

Following the same procedure and starting from the different 15-hydroxy- and 16-fluoro-epimers, the following methyl esters were obtained: 13,14-dehydro-18,19,20-trinor-17-cyclohexyl-16 (R) -fluoro- (R) - -Hydroxy-PGF2qmethyl ester, [α] D = +17.5, (c = 1 EtOH), 13,14-dehydro-18,19,20-trinor-17-cyclohexyl-16 (S) - fluoro-15 (R) -hydroxy-PGF2ufmethyl ester, [α] D = +38.3, (c = 1 EtOH), 13,14-dehydro-18,19,20-trinor-17-cyclohexyl-16 (S ) -fluoro-15 (S) -hydroxy-Psvza-methyl ester, [α] D = +34.9, (c = 1 ston), and the corresponding PGE2 analogs: 13,14-dehydro-18,19, 20-Trinor-17-cyclohexyl-16 (R) -fluoro-15 (S) -hydroxy-PGE 2 methyl ester, [u] D = -51.2, (c = 1 EtOH), I 13,14-dehydro -18,19,20-trinor-17-cyclohexyl-16 (R) -fluoro-15 (R) -hydroxy-PGE2-methyl ester, [α] D = -53.2 (c = 1 EtOH), 13, 14-dehydro-18,19,20-trinor-17-cyclohexyl-16 (S) -fluoro-15 (S) -hydroxy-PGE 2 methyl ester, [α] D = -40.7, (c = 1 EtOH ), 13,14-dehydro-18,19,20-trinor-17-cyclohexyl-16 (S) -phenor-15 (R) -7908642-7 46-hydroxy-PGE2-methyl ester, [a] D = -38 , (c = 1 Et 0H).

EXAMPLE 23 'is now a solution of 13,14-ethylhex -1s, 19,2o-trifluoro-11-cyclohexyl-16 (R) -fluoro-15 (R, S) -hydroxy-PGF2 510 g) in 5 ml of dry dimethylformamide were added 0.12 ml of methyl iodide and 0.260 g of dry K 2 CO 3.

The slurry was stirred for 4 hours, then filtered and the organic phase was diluted with 20 ml of ethyl ether and washed to neutrality with water, dried and evaporated to dryness. The crude methyl ester was purified on silica gel using preparative HPLC in isocratic process with ethyl acetate, hexane 60:40.

There was thus obtained 0.49 g of pure 13,14-dehydro-18,19,20-trinor-17- -cyclohexyl-16 (R) -fluoro-15 (R, S) -hydroxy-PGF2qmethyl ester, [a] D = + 14.2 (c = 1 EtOH).

Following the same procedure starting from 13,4-dehydro- -18,19,20-trinor-17-cyclohexyl-16 (S) -fluoro-15 (R, S) -hydroxy- -PGF2α, 13,14- dehydro-18,19,20-trinor-17-cyclohexyl-16 (S) -fluoro-15 (R, S) -hydroxy-PGF 2 -methyl ester, [α] D = +37.6 (c = 1 EtOH).

Claims (1)

1. 7908642- 7 47 CLAIMS Optically active or racemic fluoroprostaglandin compound for use as a luteolytic and abortifacient agent, characterized in that it has the formula (I) RI _.52§ .- "\ ______ / \ / \ wherein (R) is hydrogen, a C1-C12-alkyl group or a cation of: (C2-C1-alkyl or a cation of a pharmaceutically acceptable base; the symbol - - - - represents a single or double bond, in which, when the symbol: _- - - is a double bond, R 3 is a hydrogen atom and R 1 and R 2 together form an oxo group, while, when the symbol - - - - is a single bond, R 3 is hydroxy and one of R 1 and R 2 is hydrogen and the other is hydroxy or acyloxy or R 1 and R a together form an oxo group; A is trans-CH = CH- or - Cfc-; one of R4 and R5 is hydroxy and the other is hydrogen; R6 is hydrogen, methyl or fluorine; n is zero or an integer of 1-6; R7 is, when A is trans-CH = CH-, a cycloalkyl group having 3-7 ring carbon atoms, while, when A is -CfC-, R7 is methyl, cy chloroalkyl having 3 to 7 ring carbon atoms or phenyl, unsubstituted or optionally substituted by one or more substituents selected from halogen, C 1 -C 6 alkoxy and trihalomethyl.