DK155317B - 13,14-DEHYDRO-PROSTAGLANDIN-F2ALFA DERIVATIVES FOR USE IN ANIMALS WITH AN ABORTIVE ACTIVITY - Google Patents

Description

1 DK 155317 B

The present invention relates to novel, optically active or racemic 13,14-dehydro-prostaglandin F2a derivatives for use in agents of abortion-inducing activity which have the general formula (I)

H COOR

7 “(i) \ -. 2 4 r \? r 35 0H C <? C - fi -C t. (ch,) -R6 i k r3 r5 2

DK 155317B

wherein R represents a hydrogen atom, a -12 alkyl group or the cation of a pharmaceutically useful base, represents hydroxy, acetoxy, 2,3 propioxyloxy or benzoyloxy, one of R and R represents 45 hydroxy and the other hydrogen, R and R independently of each other 05 6

is hydrogen or C 1-4 alkyl, n is zero, 1, 2 or 3 and R is

represents a group (CH 2) wherein m represents 2, 3, 4 or 5, / r Å m

-CH, I

CH 2 g or R represents 1-adamantyl or 2-norbornyl.

In the formulas of the present description, the broken dashes ("hmhi) indicate that the substituents are in α configuration, i.e. below the plane of the ring or chain, while the thick black dashes (-") indicate that the substituents are in β configuration. i.e., above the plane of the ring or chain, the wavy line (|) indicates that the groups may be either in α-configuration, i.e. below the plane of the ring, or in β-configuration, i.e. over the plane of the ring.

As can be seen from Formula (I), the hydroxy group attached to the carbon atom at the 15 position can be either in α configuration 20 15 15 ("C -: 15 S oils) or in β configuration (- C -: 15R-ols).

4 c · '\

H OH H OH

When there is only one C 1 -C 4 alkyl group on the carbon atom at the 16-position, said substituent can be either a 16 S-alkyl (α-configuration) or a 16-R-alkyl (β-configuration) or a 16 (S, R ) -alkyl, i.e.

the mixture of the two 16S and 16R diastereoisomers.

The alkyl groups may be branched or straight-chain groups.

When R represents a C1-6 C2 alkyl group, it is preferably a methyl, ethyl or heptyl group; n is preferably 1.

When R and / or R are C --C - alkyl, the alkyl group is preferably methyl.

(CH)

The group "qj / i 2 m preferably represents cyclopentyl,

- \ I

XCH2 is hexyl or cycloheptyl.

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

DK 155317 B

3

The compounds of this invention may be more specifically referred to as ω-nor-cycloalkyl-13,14-dehydro-prostaglandin-F2a derivatives. The Nor compounds are those wherein n is 3; the dinor compounds are those wherein n is 2; the trinor compounds are those in which n is 1 and the tetra-noran compounds are those in which n is zero.

05

Examples of preferred compounds of the invention are the following: 5c-9a, 11a, 15S-trihydroxy-20,19,18-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9a, 11a, 15S-trihydroxy-20,19,18-trinor-17-cycloheptyl prost-5-en-13-acid acid; 5c-9a, 11a, 15S-trihydroxy-20,19,18-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid, 5c-9a, 11a, 15S-trihydroxy-20,19,18-trinor 17-cyclohexyl prost-5-en-13-ynoic acid 9a-propionate; 5c-9a, 11a, 15S-trihydroxy-20,19-dinor-18-cyclohexyl-prost-5-en-13-yne-acid; 5c-9a, 11a, 15S-trihydroxy-20,19,18,17-tetranor-16-cyclohexyl-prost-5-en-13-acid.

20 From the specification of Danish patent application No. 1935/73, it is known that certain 13,14-dehydro-PGF2a derivatives possess biological effects indicating an abortion-inducing activity. The compounds thus known do not contain, as the compounds of the present invention, a ω-nor-cycloalkyl group and, surprisingly, it has been found that the presence of such a group exerts a stronger abortifacient effect.

The compounds of general formula (I) can be prepared by reacting an optically active compound, or a racemic mixture of compounds, of the general formula (II) 30 1 '· ti r · 2 / {in 35 - C - <CH 2 ) n-R6 hyki Ac R 'J R3

DK 155317B

4

wherein X

A is -CSC- or -CH = C- wherein X represents bromine, chlorine or iodine, and wherein R, R, R and n have the meaning given above, 2 3 represents one of R1 and R 'optionally etherified hydroxy, and the other is a hydrogen atom, and Y optionally represents etherified-05 hydroxy, with a Wittig reagent containing a group of the formula - (CH 2) 4-COOR 'wherein R 1 represents a hydrogen atom or a C 2. -12 alkyl group, to give a compound of the general formula (III)

10 IL PH

V ^ \ - / V \ COOR

/ Ί y, (IlD

/ R'2 R4 S C - a - C - (CH2) n-R6 Η Ϊ il A.

r '3 R 5 wherein R', Y, R '^, R1 ^, R ^, R ^, R ^ and n have the meaning given above, which compound when Y is etherified hydroxy and one of 2 3 R 'and R 1 are etherified hydroxy and the other represents hydrogen, 20 can be esterified to give corresponding compounds substituted at the 9a position with acetoxy, propionyloxy or benzoyloxy, then deetherifying a compound so prepared and, if desired, reacting a compound of the general formula (I) thus prepared, wherein R represents a hydrogen atom, with a base to give a compound of the general formula (I) wherein R is a cation, or esterifies a compound thus prepared with the general formula (I) wherein R represents a hydrogen atom to give a compound of the general formula (I) wherein R represents C 1-6 alkyl or hydrolyzing a compound thus prepared with the general formula (I) ), wherein R represents C1-2 alkyl, to give a compound otherwise having the general formula (I), wherein R represents a hydrogen atom.

The protective ether groups must be capable of being converted to hydroxy groups under mild reaction conditions, e.g. acid hydrolysis. Examples are acetal ether, enol ethers and silyl ethers. The preferred groups are the following: 5

DK 1 553 1 7 B

O · Alk LX ^ O «- · Q ^ .- O · OAlk 05 CH, \ ^ Si - O CH3 c 10 CI * 3 ^ CH3 jch3 wherein W represents -O- or -CH9-, and Alk is a lower alkyl group.

Δ X

When A in the lactol of formula (II) is -C = C- or n "Jx wherein Ί5" tn-L "f X represents bromine or iodine, the Wittig reaction can be carried out using two moles of Wittig reagent per ml. mole of lactol and it is sufficient for the reaction to take 10 to 20 minutes. When A in the lactol

X

of formula (II) is -CH = C-, where X represents chlorine, it is necessary to extend the reaction time up to ten hours, e.g. using 1.5 to 2.5 moles of Wittig reagent per moles of lactol; if shorter reaction times are desired, a large excess of Wittig reagent is required (at least 5 moles of Wittig reagent per mole of lactol for reaction times of about 30 minutes).

25

X

When A in the lactol of formula (II) is -CH = C- wherein X represents bromine, chlorine or iodine, the hydrogen atom bonded to the carbon atom in the 13-position and the halogen atom bonded to the carbon atom may be in the 14 position , be either in the trans position (geometric trans isomers) or in the cis position (geometric cis isomers). They are preferably in trans position.

The Wittig reaction is carried out under the conditions commonly followed by reactions of this kind, i. in an organic solvent, e.g. diethyl ether, hexane, dimethylsulfoxide, tetrahydrofuran, dimethylformamide or hexamethylphosphoramide, in the presence of a base, preferably sodium hydride and potassium tert-butoxide, at a temperature of the reaction mixture of 0 ° C to reflux temperature, before stirring at room temperature or below.

6

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The term "Wittig reagent" encompasses compounds of the general formula: (-) (Ra) 3 - P - CH2 - CH2 - CH2 - CH2 - COOR * Half 1 wherein R represents aryl or alkyl, Hal is bromine or chlorine, and RA is α 05 hydrogen or C 1-6 alkyl. When Ra is alkyl, it is preferably ethyl.

The preparation of the Wittig reagent is described in detail by Tripett in Quart. Rev., 1963, XVII, Nos. 4, 406.

It is obvious that for financial reasons, A is in the lactol

X

of formula (II) preferably an R in which X is preferably cn-y group 10 is bromine or iodine, since both the triple bond formation and the alkylation with the Wittig reagent take place rapidly at the same time, in only one step.

χ When A in the lactol of formula (II) is wherein X is bromine, chlorine or iodine, during the reaction with Wittig reagent, the dehydrohalogenation occurs just as easily, whether the hydrogen atom is mixed to the carbon atom at the 13 position and the halogen atom which is is bonded to the carbon atom at the 14-position, is in the trans position, or is in the cis position.

The optional acylation of the 9a-hydroxy group in the compound of formula (III) with a carboxylic acid may e.g. is carried out by treatment with an anhydride or with a chloride of a corresponding carboxylic acid in the presence of a base, i. in accordance with the usual methods of organic chemistry.

The deetherization reaction is carried out under mild acid hydrolysis, e.g. with mono- or polycarboxylic acid, e.g. formic, acetic, oxalic, citric or tartaric acids, and in a solvent, e.g. water, acetone, tetrahydrofuran, dimethoxyethane or lower aliphatic alcohols.

Preferably 0.1N to 0.25N polycarboxylic acid (eg oxalic or citric acid) is used in the presence of a suitable low boiling water-miscible solvent which can be easily removed in vacuo at the end of the reaction.

The lactol of formula (II) can be prepared by a multi-step process using as an starting material an optically active or racemic lactone of formula (V): 7

DK 155317 B

ISLAND

05 «» _ 05 jX ^ §'4 <v> η Γ-, XH = CCC- (CH0) -R'6 Y 'il Ae 2 n O R5 wherein ln 4 Y' represents hydroxy, acyloxy or etherified hydroxy, X , R, 5 6 R, R and n are as defined above and wherein the hydrogen atom attached to the carbon atom at the 13 position and the halogen atom attached to the carbon atom at the 14 position (prostaglandin numbering) may be either in trans position or in cis position.

The multi-step process for preparing the compound of 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 obtaining a mixture of 15S and 15R oils having the following formulas (Via) and (VIb):

ISLAND ISLAND

25 Λ Λ L— x I4 w X R4 30 HY · 'H CH = C-.C - | - (CH2) n-R6 HO H Rb H HO R5 (Via) (15S-ol) (VIb) (15R- ol) 4 5 6 wherein Y *, X, R, R, R and n are as defined above, followed by separation of the 15S oil from the 15R oil and, if desired, by dehydrohalogenation of the separated alcohols to give a compound of formula (Vila): 35 8

DK 155317B

Λ ((Vila)? 4 H γ. A VV c- <ch2) n-R6 OH H kc R5 05 or a compound of formula (Vllb): Λ • «r

** "V

} ['(Vllb) 10 Jh *. t H Y1 A - C - S- (CH,) -R6 4 \ k 2 n OH H r5 15 wherein Y'f R4r R5, R6 and n have the meaning given above.

If desired, the 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, and using e.g. metal borohydrides, in particular sodium borohydride, lithium borohydride, zinc borohydride and sodium trimethoxy borohydr id.

The separation of the 15S oil from the 15R oil can be carried out by chromatography, e.g. silica gel chromatography, or by fractional crystallization. The dehydrohalogenation can be carried out in a solvent preferably selected from the group consisting of dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, in the presence of a base such as e.g. may be an alkaline metal amide, potassium tert.butylate or the anion 0,.

CH 2 -S -OH 2 b) Conversion of a compound of formula (VIII): 9

DK 155317 B

ISLAND

(VIII) (In R2 R4

Hff ^ t "i" (cH2) n'R6 R3 r 5 wherein Y ', R, R, R, Aogn have the meaning given above, and 2 3 one of R and R represents a hydrogen atom and the other a 05 hydroxy group , for a compound of formula (IX): Λ Λ (ix) R "2 R4" Υ "AS - é- (CH2) n-R6 R" 3 r5 wherein 4, 5 6 A, R, R, R and n have the meaning given above, Y "is an etherified hydroxy group, and one of R" and R "is an etherified hydroxy group and the other is a hydrogen atom.

Prior to the etherization of the compound of formula (VIII) to give a compound of formula (IX), when Y 'in the compound of formula (VIII) represents an acyloxy group, a hydrolysis, e.g. by mild treatment with an alkali, to give a compound of formula (VIII) wherein Y 'represents a hydroxy group.

The etherization is preferably carried out with a vinyl ether of the formula, 0 ~ Λ, wherein W represents -O- or -CH ~ -, in the presence (>

\ _W

of catalytic amounts of e.g. phosphorus oxychloride, jo-toluene sulfonic acid or benzenesulfonic acid, or with a silyl ether, e.g. by reacting a trisubstituted chlorosilane in the presence of an acceptor base (e.g., a trialkylamine) of the formed hydrochloride.

DK 155317B

ίο gene halide, or with an enol ether, e.g. by reaction in the presence of an acid catalyst with a 1,1-dialkoxy-cyclopentane or -cyclohexane at reflux temperature in an inert solvent, and by distilling the alcohol formed to obtain mixed dialkoxy ethers or enol ethers, depending on the amount used. catalyst or by the heating time.

c) Reduction of the compound of formula (IX) to give a lactol derivative of formula (X):

.OH

X

(x) (R "2 R4 - 9- (CH2> n-R6 R" 3 r 5 10 wherein Y ", &, r" r "3 ^ r r 5 / r6 0g n has the meaning given above).

The reduction may be effected by treatment with diisobutyl aluminum hydride or sodium bis- (2-methoxyethoxy) aluminum hydride in an inert solvent such as e.g. toluene, n-heptane, n-hexane or benzene or mixtures thereof, at below 30 ° C.

d) Optional deetherization of the compound of formula (X) to give a compound having free 11 and 15 hydroxy groups. The deetherization can be carried out by mild acidic hydrolysis in a water-miscible solvent with a solution of a mono- or polycarboxylic acid.

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

The lactone of formula (V) can be prepared in only one step by reaction of an aldehyde of formula (XI):

u DK 155317 B

o Λ Λ

-yl CHO

wherein Υ 'has the meaning given above, with a halogen phosphonate of formula (XII): R, 0? f? £ <„_ _.

05 - C - CO - C - (CH2) -R6 (XIIJ

V (-) i5 2 n

R

wherein R 1 is lower alkyl and 4 d 5 6 X, R, R, R and n are as defined above.

The reaction can be suitably carried out in a solvent which is preferably dry benzene, dimethoxyethane, tetrahydrofuran, dimethylformamide or mixtures thereof, and using a suspension of 1.1-1.2 molar equivalent of the halogen phosphonate carbonate anion.

When Y * in the aldehyde of formula (XI) is an acyloxy group, it may e.g. be acetoxy, propionyloxy, benzoyloxy or p-phenylbenzoyloxy. When Y 'is an etherified hydroxy group, it may e.g.

15 be one of the above.

The aldehyde of formula (XI) can be prepared essentially as described by E.J. Corey et al., Ann. of New York Acad, of Sciences, 180, 24 (1971).

The halogen phosphonate carbonate of formula (XII) can be prepared by reacting a halogen phosphonate of formula (XIII): R η $ X R4 r> \ tis r ^ P-C-C-C- (CH0) -R6 (XIII) R I II Ας 2 n b HOR5 wherein

Rj, X, R4, R ^, R R and n have the meaning given above, with an equivalent of a base, preferably selected from the group 25 consisting of sodium hydride, lithium hydride, calcium hydride,

12 DK 155317 B

The halogen phosphonate of formula (XIII) can be obtained by halogenating a phosphonate of formula (XIV): R. OS f? 4 _ 0> i-si- (cH2> n-E6 <XIV> DU HOR5 wherein R ^, R4, R5 , R6 and n have the meaning given above.

The halogenation may be carried out in a conventional manner, proceeding in substantially the same manner as in the halogenation of 3-ketoesters. The phosphonate of formula (XIV) can be prepared by known methods, e.g. according to E.J. Corey et al., J. Am. Chem. Soc. 9, 3247 (1968) and E.J. Corey and G.K. Kwiatkowsky, J. Am. Chem. Soc., 88, 56 10 (1966). Preferably, the phosphonate of formula (XIV) is prepared by reaction of lithium methyl phosphonate 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 appropriate aliphatic acid can be prepared by known methods. Eg. For example, ethyl β-cyclobutyl propionacet can be prepared by condensing cyclobutyl formate with a compound of the formula:

ISLAND

C2H5 °. f - CH2 - COOC2H5 C2H5o / 20 and then reduce the resulting ethyl β-cyclobutyl acrylate by e.g. Pd / C. The ethyl ester of γ-cyclobutyl butyric acid may e.g. is prepared from the corresponding ester of cyclobutyl acetic acid after reduction to alcohol and conversion to halide, by malone synthesis, as is known in the organic chemistry, followed by esterification of the acid obtained.

The esters, e.g. the ethyl esters of the unsubstituted propionic acids (e.g., cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-adamantyl or 2-norbornylpropionic acid) can be prepared, starting from the corresponding substituted acetic acids by known methods, Fe.

30 by reducing the substituted acetic acids to primary alcohols, conversion ai 13

DK 155317 B

the alcohols to mesylates and then to halides, and finally by reaction with a cyanide, e.g. an alkaline cyanide, to obtain the nitriles of the substituted propionic acids, which are then converted to the substituted propionic esters by conventional methods in organic chemistry, the α-methylation of the enolates of the above esters which can be obtained by reaction of the esters with lithium diisopropylamide in tetrahydrofuran (according to the procedure described in Org. Synthesis, J50, 58 and in Tetrahedron Letters, 2425 (1973)) gives the α-methyl-substituted esters of the above acids, which may optionally be dissolved into the optical antipodes to obtain of the 2S-methyl and 2R-methyl derivative. Further methylation of the above esters gives the α, α-dimethyl-substituted esters of the above acids.

Alternatively, the halogen phosphonate carbon anion of formula (XII) can be prepared by reacting a phosphonate carbon anion of formula (XIVa): R o OH R-4 b> PC “C-é- (CH9) -R6 (XIVa) <-> 5 r5 in which

Λ C C

Rto, R, R, R and n are as defined above, with a halogenating compound selected from the group consisting of pyrrolidone hydrotribromide (PHTB), dioxane dibromide, N-chloroacetamide, N-chloro-succinimide, N-bromosuccinimide, N- bromoacetamide, N-bromocaprolactam and N-iodosuccinimide.

Using the imides as halogenating compounds, the carbanion of the halogen phosphonate of formula (XII) is obtained directly using only one equivalent base; otherwise, it would be necessary to use another equivalent base to obtain the carbanion of the halogen phosphonate.

14

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The phosphonate carbon anion of formula (XlVa) can be obtained by treating the phosphonate of formula (XIV) with one equivalent base, e.g. sodium, lithium or calcium hydride.

The halogen lactone of formula (V), wherein X represents bromine, can also be obtained by a multistage process, starting from a lactone of formula (XV): Λ / Ί (XV)

We r4 H ^ CH = CH-C-C- (CH_) -R 6 γ. II 1 2 n OR 5 wherein 4 5 6 Y ', R, R, R and n have the meaning given above, which lactone can be prepared essentially as described by E.J. Corey et al., Annals of the New York Acad, of Sciences, 180, 24 (1971).

This multi-step process comprises the following steps: a ') reduction of the lactone of formula (XV) to give a mixture of the 15S and 15R oils of formulas (XVIa) and (XVIb): A Λ u ϋ ί, CH = CH -CV- Å- (CH2) n-R6 OH Η ^ 5 H OH R 5 (XVIa) (15S-ol) (XVIb) (15R-ol) wherein Y ', R ^, R ^, and n have the above significance.

The reduction may be carried out in an organic solvent such as acetone, diethyl ether and dimethoxyethane using e.g. sodium borohydride, zinc borohydride or lithium borohydride.

15

DK 155317 B

b ') Halogenation of the mixture of the two 15R and 15S oils to give a mixture of 13j, 14j-dibromo alcohols of formulas (XVIIa) and (XVIIb): Λ Λ P) p 1 \ Is R4 Br R4? | 7 ^ CH- £ hC - ^ - (CH2) n-R6 H CH-CH-PV-C- (CH2) n-R6

Br OH H Y Br H OH 5 05 (XVIIa) (15S-01) (XVIIb) (15R-01) wherein Y ', R4, R5, R6 and n have the meaning given above.

The halogenation is carried out in an inert solvent, preferably selected from the group consisting of a halogenated solvent, e.g. dichloromethane, dichloroethane, CC14 and a linear or cyclic ether, e.g. tetrahydrofuran, dioxane, dimethoxyethane or mixtures thereof, using a molar equivalent of halogenating compound or an excess of the same compound, e.g. may be Br 2, dioxane dibromide, pyrrolidone hydrotri bromide.

C) Oxidation of the mixture of the 13, 14j-dibromo alcohols to give a 13I, 14j-dibromo-15-oxo derivative of formula (XVIII): Å / - (XVIII) (_ Br R 4 H , CH-CH-C - C- (CH-) -R 6 YS II i, 2 "

Br 0 R b wherein Y ', R4, r5, r6 and n have the meaning given above.

The oxidation is carried out at a temperature in the range of -25 ° C

to room temperature, using a dichloromethane-16

DK 155317 B

solution of the pyridine-chromohydride complex or a sulfur solution of chromohydride in acetone (Jones reagent), or a carbodiimide, working in dimethyl sulfoxide in the presence of an appropriate acid.

05 d ') Dehydrohalogenation of the 13 j, 14 µ-dibromo-15-oxo derivative to give the halogen lactol of formula (V) wherein X is bromine. The dehydrohalogenation can be carried out using an organic base e.g. a tertiary amine in an inert solvent, or alternatively using an inorganic base, e.g. potassium acetate in a solvent such as methanol, ethanol or the like.

A further alternative process for preparing the halogen lactol of formula (V) wherein X is bromine is the reaction of the lactone of formula (XV) in an ethereal anhydrous solvent such as tetrahydrofuran or dimethoxyethane with a halogenating compound such as bromophenyltrimethylammonium tribromide. in particular pyrrolidone hydrotribromide (1.1 - 1.3 molar equivalents) to directly obtain the 131,14j-dibromo-15-oxo derivative of formula (XVIII), which is then dehydrohalogenated as described above, to give the halogen lactone of formula (V ), wherein X represents bromine.

Also in the alternative methods of preparing the halo gene lactone of formula (V), all of the compounds may be either optically active compounds or racemic mixtures thereof.

In the preparation of the halogen lactone of formula (V) in accordance with the methods described above, both bonding compounds are obtained wherein the hydrogen atom bonded to the carbon atom at the 13 position and the halogen atom bonded to the carbon atom at the 14 position (prostaglandin numbering}, is in trans position (geometric trans isomer) and compounds wherein said atoms are in cis position (geometric cis isomer), The geometric trans isomer is obtained in much higher percent yield (92- 95%), while the geometric cis-isomers are obtained in much lower percent yield (5-8%).

The geometric trans isomers of the formula: 0 Λ «« ** / hb \ U X R4 H ^ Iv.Voc-C-t! - (CEL ·) -R6 17

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can be easily distinguished from the geometric cis-isomers of the formula: 0 Λ 9: (Ί As ηΛ \ »Ϊ4 6 Y 'C = C-C - C - (CH_) - R5 II As 2 n

Ha X R

in that the H-vinylic protons of the two isomers produce resonance ri in different positions, and that the coupling-phase constants of the HA-vinylic proton with the H₂ proton are quite different (9 Hz for the trans isomer and 10.2 Hz for cis isomer).

In any case, both the trans isomers and the cis isomers are intermediates in the synthesis of the 13,14-dehydro-prostaglandins of the invention.

The lactol of formula (II) wherein A represents -C = C- can also be obtained

is dehydrohalogenated by the lactol of formula (II) wherein X

A represents -CH = 0-, wherein X represents bromine, chlorine or iodine. The dehydrohalogenation may be carried out in an aprotic solvent preferably selected from the group consisting of dimethylsulfoxide, dimethylformamide and hexamethylphosphoramide, by treatment with a base preferably selected from the group consisting of potassium tert.butylate, an alkali metal amide and the anion CH 2 -SO-C ^^

Of the intermediates mentioned in this specification, the following are believed to be novel: 1) the halogen phosphonate carbonate of formula (XII); 2) the lactol of formula (II); 3) the lactone of formula (XIX): Λ ΓΊ A (xix) \? 4

HfT> A-C-C- (CH,) -R6 Y1 h i / n O „5

18 DK 155317 B

wherein Y ', A / R4, R5, R6 and n are as defined above; 4) a compound of formula (XX): 0 Λ

H

Br R \ '2 | 4 6

H ^ v. CH-Ϊη - C - C- (CH-) -R

\ i 3K

Br R "'R

4 5 6 05 wherein Y ', R', R, R and n are as defined above, 2 3 and one of R "1 and R" 1 represents hydroxy and the other 2 3 is hydrogen, or R "1 and R "1 together forms an oxo group; 5) a compound of formula (XXI): R3

COOR

R 2 is R 4 C = C - C 0 - (CHO) -R 6 (XXI) p 4.5 wherein R represents hydrogen or C 1-6 C 1-4 alkyl, Y ", R" 2, R "2, R 4, R 2, R 2 and n have the meaning given above, 3 and R are hydroxy, acetoxy, propionyloxy or benzoyloxy.

All of the intermediates mentioned under 1) to 5) are optically active or racemic compounds.

The compounds of formula (I), relative to natural prostaglandins, do not have the advantage of being substrates for the enzyme 15-prostaglandin dehydrogenase, which, as is well known, rapidly inactivates natural prostaglandins, and they are further characterized by a more selective biological effect.

19 DK 155317 B

Furthermore, the compounds of formula (I) inhibit the enzyme's use of natural prostaglandins as a substrate.

Using 15-hydroxy-prostaglandin dehydrogenase derived from human placenta showed in vitro tests performed with e.g.

13,14-dehydro-17-cyclohexyl-20,19,18-trinor-PGF2a (5c-9a, 11a, 15S-trihydroxy-20,19,18-trinor-17-cyclohexyl-prost-5-en-13 -ynoic acid) that while the inhibition with respect to PGE2 is of a non-competitive nature (K ^ = 468 μΜ), the inhibition becomes partially competitive with respect to PGF2α (K ^ = 152 μΜ).

The same compound (13,14-dehydro-17-cyclohexyl-20,19,18-trinor-PGF2a) was compared with PGF2a and with the olefin analog 5c, 13t-9a, 11a, 15S-trihydroxy-20,19,18 -trinor-17-cyclohexyl-prosta-5,13-diacetic acid (17-cyclohexyl-20,19,18-trinor-PGF2a) by the following in vitro tests: guinea pig ileum test, rat uterus test, rat gastric fundus. The results are given in the following table, in which the activity of PGF ^ is arbitrarily added to the value 1 in all tests. The three tests refer to the determination of the spasmogenic activity.

Guinea pig Rat rat stomach Compound ileulyt uterus fundus PGF2a 1 1 1 17-cyclohexyl-20,19-18- 0,60 3,23 1,86 trinor-PGF2a 13,14-dehydro-17-cyclohexyl-20, 19.18-Trinor 0.17 15.7 1.96 PGF 2a,

13.14-dehydro-17-cyclo-I

hexyl-20,19,18-trinor-I

PGF2α methyl ester 0.05 6.8 0.2b_J

3q For the guinea pig ileum test, a 10 ml thermostatic bath maintained at 35 ° C containing an ileum from a male guinea pig for a duration of 0.5 g and was carbohydrated in a "Tyrode" solution. The solution was allowed to stabilize for 30 minutes before the compounds were tested. The rash was recorded using an isotonic frontal bar 35 long enough to amplify the rash 4.5 times.

For the rat uterus test, a 10 ml thermostatic bath maintained at 29 ° C was used in which estrogenated rat uteri for a stretch of 0.5 g were carbohydrated in a "Dejalon" saline solution. Experimental 20 was allowed

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des. The rash was measured using an isotonic frontal bar that was long enough to amplify the rash 4.5 times.

The rat stomach fundus test was performed as follows: male albino rats of the Sprague-Dawley strain weighing 200 - 250 g were used.

The gastric fundus strip was prepared according to Vane (J. R. Vane, Brit. J. Pharmacol. 12, 344, (1957)). The strip was placed in a 10 ml organ bath containing "Tyrode" solution aerated with a mixture of O 2 and CC> 2 (95: 5%). The contractions of the strip were recorded using an isotonic frontal bar, as in the previous 0 tests.

It is clear from the comparison of the activities of the three in vitro tests that regardless of the nature of the animals used, a remarkable increase in the selective effect on myometrium was obtained, as well as a decreased effect on the 5 muscles of the gastroenteric apparatus. i.e. a decrease in the gastrointestinal side effects that are always present when natural prostaglandins are administered. In fact, the comparison of the uterus / ileum and uterus / gastric fundus ratios shows that these ratios are much more favorable when the 13,14 dehydro analogs are used: 0 Compound Uterus / ileum Uterus / gastric fundus PGF2a 1 1 17- cyclohexyl-20,19,18-5,4,7 trinor-PGF2a 13,14-dehydro-17-cyclo-91 8 5 hexyl-20,19,18-trinor-PGF2a 13,14-dehydro-17-cyclohexyl-20 The 19,18-trinor PGF2a methyl ester 136 27 13.14 dehydro compounds' selectivity of action on myometrium 0 and on the reproducer is also shown by the remarkable increase in luteolytic activity in the pregnant rat on the 9th to 10th day of pregnancy. Specifically, if the luteolytic activity of PGF2a is added to an arbitrary value of 1, the luteolytic activity of 17-cyclohexyl-20,19,18-trinor-PGF2a 5 must be added to the value 30, and the luteolytic activity of 13.14 -dehydro-17-cyclohexyl-20,19,18-trinor-PGF2a is added to the value 200. In addition, the compounds of formula (I) t, e.g. 13,14-dehydro-17-cyclohexyl-20,19,18-trinor-PGF2 capable when tested against PGF2 at

21 DK 155317 B

The compound 13,14-dehydro-17-cyclohexyl-20,19,18-trinor-PGF2a and its methyl ester, as well as 13,14-dehydro-17- (2'-nor-boryl) -20,19,18-trinor PGF2a and 13,14-dehydro-17- (1'adamantyl) -20,19,18-trinor-PGF2a according to the invention were compared with the compound 05 13,14-dehydro-PGF2a (Danish Patent Application No. 1935/73) and with PGF2a in terms of abortion-inducing effect.

-i ————--——— -— -

Compound Number of ahorts / number of rats PGF2a 0/20 13.14-dehydro-PGF2a 5/20 10 13,14-dehydro-17-cyclohexyl-20,19,18-trinor-PGF2a 20/20 13,14-dehydro-17-cyclohexyl-20 , 19,18-15 trinor-PGF2a methyl ester 20/20 13.14-dehydro-17- (2'-nor-bornyl) -20,19,18-trinor-PGF2a 18/20 13.14-dehydro-17-20 (1 (-adamantyl) -20,19,18-trinor-PGF2a 20/20

The number of hortices was determined as follows.

The oestral cycle of virgin rats weighing 200 to 250 g was followed by vaginal scraping for several days. On proestrus day 25, the females were placed in cages with fertile males and mating was confirmed by findings of spermatozoa in vaginal scraping the following morning. This day was designated as the first day of pregnancy. Pregnancy was confirmed on day 9 by laparatomy during ether anesthesia and the number and position of the fetus in the two uterine horns was recorded.

Thirty groups of '20 rats were treated with the test compounds. These were administered subcutaneously at a dose of 2000 micrograms per kg body weight on the 9th and 10th days of pregnancy. Autopsy was performed on day 20 and the number of living and dead fetuses, placentae and resorbing fetal placental units was recorded. The abortion was considered "complete", 35 when the uterus was empty.

The presence of just one placental residue was considered pregnancy. As can be seen from the table, the compounds of nnf in nrlol con naacfan were 1 o fnT H cf-iPnd 1 ΓΓ OCT 13.14 —d eh VdrO—

22 DK 155317 B

17-cyclohexyl-20,19,18-trinor-PGF2a and its methyl ester showed the same efficacy (20 complete abortions in 20 pregnant rats) even at a dose of 400 micrograms over kg.

The compounds of formula (I) may be administered orally, parenterally or in an intravenous or intrauterine (extra-amniotic or intra-amniotic) manner, by rectal suppositories or by inhalation.

For example, they can is administered by intravenous infusion of a sterile isotonic saline at a rate of 0.01 to 10, preferably 0.05 to 1, µg / kg body weight per day. minute.

The agents may be prepared by conventional methods and may e.g.

be in the form of tablets, capsules, pills, suppositories or bougies, or in liquid form, e.g. solutions, suspensions or emulsions.

Examples of compounds which can serve as carriers or diluents include water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oil, benzyl alcohol and cholesterol.

The invention is illustrated by the following Examples, in which Examples 6-21 illustrate the preparation of the subject compounds, while Examples 1-5 illustrate the preparation of the starting materials and in which the abbreviations "DIOX", "DMSO", "THF" and "DIBA" refer to -dioxanyl, dimethylsulfoxide, tetrahydrofuran and diisobutylaluminum hydride, respectively.

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23

Example 1

To a solution of 13.1 g of dimethyl (2-oxo-4-cyclohexyl) -butyl-phosphonate in 200 ml of tetrahydrofuran was added 27.28 g of pyrrolidone-2-hydrodribromide (PHT). The reaction mixture was allowed to stand overnight with stirring. The precipitate which separated was filtered off, the THF was evaporated in vacuo (bath temperature below 30 ° C) and the residue was collected in ethyl ether which was washed to neutral.

After drying and evaporating the ether, the residue was chromatographed on silica gel, eluting with cyclohexane-ethyl ether to give 9.32 dimethyl (1-bromo-2-oxo-4-cyclohexyl) -butylphosphonate. Bromine: found 23.18, calculated 23.42.

Example 2 a) Under inert air, 72 mg of NaH (80% dispersion in mineral oil) was heated in 3 ml of DMSO with stirring to 60 ° until no more hydrogen was developed.

The solution was cooled to 10-12 ° and diluted with 20 ml of benzene. Over a 15 minute period, a solution of 0.75 g of dimethyl (1-bromo-2-oxo-4-cyclohexyl) phosphonate was added dropwise. After stirring for 30 minutes more, a solution of 0.7 g of 5β-formyl-2α, 4β-dihydroxy-cyclopentane-10β-acetic acid-y-lactone-4-β-phenyl-benzoate was added in 15 ml of benzene. After 30 minutes, it was diluted with 30 ml of benzene and 30 ml of a 5% aqueous solution of NaH 2 PO 2. The organic layer was separated, washed to neutral, dried and the solvent was evaporated. After chromatographic purification on silica gel (eluent CH₂Cl₂ ether 90:10) and recrystallization from ethyl ether, 0.82 g of 5β- (2, -bromo-3, -oxo-5, -cyclohexyl-pent-1) were obtained. , -trans-1,1-enyl) -2of, 4a-dihydroxy-cyclopentane-1a-acetic acid-y-lactone-4-p-phenylbenzoate, m.p. 155-157 ° C.

B) To a suspension of 104 mg of NaH (80% dispersion in mineral oil) in 30 ml of benzene was added dropwise a solution of 904 mg of dimethyl (2-oxo-4-cyclohexyl) -butyl-phosphonate in 10 ml of benzene. and stirred for 1 hour. A jelly-like suspension was formed to which -614 mg of finely divided N-bromo-succinimide was added at once. After stirring for 15 minutes, a solution of 1.05 g of 5β-formyl-2cf, 4of-dihydroxy-cyclopentan-1α-acetic acid β-lactone-4-p-phenylbenzoate in 20 ml of benzene was added. The mixture was stirred for 20 minutes and then diluted with 20 ml of 6% water

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you NaH ^ PO ^. The organic phase was separated, washed to neutral, dried and the solvent removed by evaporation.

After purification in silica gel column, 1.17 g of 5β- (2'-bromo-3'-oxo-5'-cyclohexyl-pent-1'-trans-1'-enyl) -cyclopentane-2α, 4α-dihydro-5-oxide were obtained. -la-acetic acid-y-lactone-4-p-phenylbenzoate, mp 154-156 ° C.

c) A solution of 2.6 g of 5β-hydroxymethyl-2α, 4α-dihydroxy-cyclopentane-1α-acetic acid Y-lactone-4-β-phenylbenzoate in 38 ml of benzene DMSO (75:25) was reacted with 4 , 6 g of dicyclohexylcarbodiimide and 7.5 ml of a solution of trifluoroacetate and pyridine (2 ml of pyridine - 1 ml of trifluoroacetic acid in 25 ml of benzeneDMSO 75:25).

After 3 hours, the excess reagent was destroyed by reaction with 2.8 g of oxalic acid in 6 ml of methanol and then diluted with 80 ml of water and 80 ml of benzene. After filtration, the filtrate was washed to neutrality, dried and concentrated in vacuo to 15 ml (aldehyde solution).

To a suspension of 334 mg of 80% sodium hydride in 80 ml of benzene was added three times a solution of 3.92 g of dimethyl (2-oxo-4-cyclohexyl) -butyl-phosphonate in 15 ml of benzene. This was stirred for 2 hours, after which the aldehyde solution was added. After further stirring for 20 minutes, the mixture was filtered and the filtrate washed with 5% NaH 2 PO 3 and sodium chloride to neutrality and evaporated to dryness. After crystallization from hexane, 2.38 g of 5β- (3'-oxo-5'-cyclohexyl-pent-1'-trans-1'-enyl) -2α, 4α-dihydroxy-cyclopentane-1α-acetic acid γ-lactone were obtained. 4-p-phenylbenzoate, mp 104-106 ° C.

25 g of this compound were dissolved in 20 ml of dimethoxyethane and 40 ml of ethyl ether and added dropwise to 250 ml of 0.0511 zinc borohydride in ethyl ether. After 30 minutes, the excess reagent was destroyed with 2N sulfuric acid. The organic phase was separated, washed to neutrality and evaporated to dryness to give 2.1 g of crude 5β- (3 '(S, R) -hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl) ) -2a, 4a-dihydroxy-cyclopentane-1a-acetic acid-y-lactone-4-p-phenylbenzoate.

This compound was dissolved in 30 ml of anhydrous THF and reacted with 4.78 g of pyrrolidone-2-hydrotribromide, relieving constant stirring and at room temperature overnight. It was diluted with 120 ml of ethyl ether, filtered and the filtrate washed with saturated ammonium sulfate for neutrality. After drying over MgSO 4, it was evaporated in vacuo on a water bath below 40 ° C. The crude 5β- (1'2 '' / -dibromo-3 '(S, B) -hydroxy-5' - 25

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cyclohexyl-pentanyl-2-chloro-4α-dihydroxy-cyclopentanalea-acetic acid γ-lactone-4-p-phenylbenzoate (about 3 g) was dissolved in 150 ml of acetone, cooled to 0 ° and oxidized by addition of 8.2 ml Jones reagent.

After 5 minutes, 7 volumes of benzene were diluted and washed to neutrality with a saturated ammonium sulfate solution, dried over RgSO4 and concentrated in vacuo to% volume. Then 2.5 ml of triethylamine was added and the mixture was allowed to stand overnight at room temperature. The mixture was washed with 40% citric acid solution (3 times 8 ml), then with ammonium sulfate to neutrality, dried 10 and evaporated to give 2.6 g of the crude product which crystallized from ethyl ether to give 1.2 g of 5β- (2). , -Bromo-3, -oxo-5'-cyclohexyl-pent-1 * -trans-1'-enyl) -2a, 4a-dihydroxy-cyclopentane-1-acetic acid-y-lactone-4-p-phenylbenzoate, m.p. 154-156 ° C.

Example 3

A solution of 53- (2, -bromo-3'-oxo-5'-cyclohexyl-pent-1,1-trans-1'-enyl) 2a, 4a-dihydroxy-cyclopentane-1a-acetic acid-y-lactone-4 -p-phenylbenzoate (2 g) in 20 ml of dimethoxyethane and 80 ml of ethyl ether was poured onto a 0.14M ZnCBH 3 ethereal solution (150 ml).

After 30 minutes, the transenone lactone was completely reduced. A saturated aqueous sodium chloride solution was added to decompose excess reagent, then 2N H 2 SO 2 to adjust the mixture to pH 3.5.

The organic phase was washed to neutral and evaporated to dryness. The residue was chromatographed on 100 g of silica gel, eluting with cyclohexane-ethyl acetate 80:20 and then 60:40, yielding 1,245 g of 5β- (2, -bromo-3, 5-hydroxy-5'-cyclohexyl-pent-1'-, respectively). trans-1'-enyl) -cyclopentane-2a, 4a-dihydroxy-1-acetic acid-y-lactone-4-p-phenylbenzoate, m.p. 124-126 ° C and 0.485 g of the corresponding 3'R-hydroxy epimer , mp 177-179 ° C.

Example 4

A stirred solution of 0.9 g of 5β- (2'-bromo-3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-11-enyl) -cyclopentane-2a, 4a-dihydroxy-1a vinegar -35 acid-γ-lactone-4-p-phenylbenzoate in 30 ml of anhydrous methanol was treated with 210 mg of E 2 CO 2 at room temperature for 4 hours and then neutralized by the addition of 15% aqueous acetic acid. The methanol removed- 26

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in vacuo and the residue is partitioned between ethyl acetate and 10% aqueous sodium chloride. The organic layer was separated, washed to neutrality, dried and the solvent was evaporated to give the free dihydroxy-lactone [M + m / e 388,386]. To a solution of this compound in 20 ml of anhydrous benzene was added 0.35 g of 2,3-dihydropyrone and a solution in benzene of 2.5 mg of p-toluenesulfonic acid. The mixture was kept at room temperature for 3 hours, then washed with 3% aqueous potassium carbonate and then with water for neutrality. After removal of the solvent in vacuo, the residue was chromatographed on silica gel and eluted with cyclohexane-ethyl acetate-pyridine 80: 20: 0.1 to give pure 5β- (2'-bromo-3'S-hydroxy-5'-cyclohexyl-pent -1'-trans-1 '-enyl) -2a, 4'-dihydroxy-cyclopentane-1a-acetic acid-y-lactone-3' S-4or-bis-THP-ether. To a stirred solution of this compound (0.57 g) in toluene, cooled to -60 ° C, was added a 0.5 M solution of DIBA in Ιοί 5 luen (4.4 ml) over a period of 15 minutes. Stirring was maintained for 30 minutes, the reaction mixture was then treated with 2N-isopropanol in toluene and heated after 10 minutes to 0-2 ° C and treated with 1 ml of water, 2 g of anhydrous sodium sulfate and 2.5 g of celite and then filtered. The filtrate was evaporated to dryness under vacuum to give 0.57 g of 5β- (2'-bromo-3'S-hydroxy-5'-cyclohexyl-pent-1 '-trans-1'-enyl) -2cr, 4of-dihydroxy cyclopentane-10i-ethanal-γ-lactol-3'S, 4-bis-THP-ether, M + -H 2 O = m / e 540,438. In analogous manner to the 3'R-hydroxy-epimeric lactone obtained in Example 3, the 3'R-hydroxy-epimeric lactol-3'S, 4-bis-tHP-ether [M + -H 2 O = m / e 25 540.538] was obtained.

Example 5

A solution of 5β- (2 * -chloro-3'S-hydroxy-5'-cyclopentyl-pent-1 '-trans-1' -enyl) -2a, 4a-dihydroxy-cyclopentane-1a-acetic acid-y-lactone 30 ( (G), obtained by a process analogous to that described in Examples 1-4, in anhydrous benzene, was reacted with 0.4 g, 4-diox-2-ene and 4 mg anhydrous p-toluenesulfonic acid for 3 hours. at room temperature. The organic phase was washed with 5% potassium carbonate and with water for neutrality, dried and evaporated to dryness to give 0.4 g of 5β- (2'-chloro-3'S-hydroxy-5'-cyclopentyl-pent-1'-trans -1'-enyl) -2a, 4a-dihydroxy-cyclopentane-acetic acid-y-lactone-3,4'-bis-DIOX ether.

This compound was reduced by DIBA as described in Example 4-27

DK 155317 E

process for obtaining 5β- (2'-chloro-3'S-hydroxy-5'-cyclo-pentyl) -pent-1 '-trans-1'-enyl) -2a, 4a-dihydroxy-cyclopentane-1a-etha nal-γ-lactol-3 ', 4-bis-DIOX ether, M + -H 2 O m / e 486,484.

Example 6

Under a nitrogen atmosphere, a slurry of 80% NaH (dispersion in mineral oil) (0.48 g) in dry DMSO (12 ml) was heated with stirring at -60 ° C until no more hydrogen was developed (about 3 hours). . The in stirred mixture of methylsulphinylcarbanide, CH₂SOCH ^ ^ 10 was cooled at 5-8 ° and treated with crystalline triphenyl (4-carboxybutyl) phosphonium bromide (3.42 g) and stirring was continued until this compound was completely dissolved. The deep orange-red (-) solution of the ylid: (CgH 2 - ^ - P-CH-iCH 2 -g-CO 2 J was then treated with a solution of 5β- (2'-bromo-3'S-hydroxy-5'-cyclohexyl) pent-1'-trans-11-enyl) -2a, 4c-dihydroxy-cyclopentane-1a-ethanal-y-lactol-3 ', 4-bis-THP-ether (0.6g) in dry DMSO (8ml After stirring overnight under nitrogen atmosphere at room temperature, the reaction mixture was diluted with water (20 mL) and the alkaline phase was repeatedly extracted with ether 20 to remove the triphenylphosphoxide; the ethereal extracts were combined, countercurrent washed with 0.5N NaOH and discarded The alkaline wash liquors were combined with the original alkaline phase, acidified to pH 4.8 and extracted repeatedly with 1: 1 ethyl ether pentane. The combined organic extracts were washed with saturated (NH solution, dried on Na 2 SO 4 and evaporated to dryness to give 0.55 g of 5c-9a, 11a, 15S-trihydroxy-18,19,20-fcrinor-17-cyclohexyl-prost-5-en-13-ynoic acid -11,15-bis-THP-ether (u) -trinor-17-cyclohexyl-13, 1,4-dehydro-PGF 2 Cl-11, 15-bis-TSDP ether), an oil having [α] D = -7.8 °. Under similar conditions and starting from the 15-epimeric lactol: 5β- (2β-bromo-3'R-hydroxy-51-cyclohexyl-pent-1'-trans-1'-enyl) -2α, 4α-dihydroxy cyclopentane-1a-ethanal-γ-lactol-3 ', 4'-bis-THP-ether, the product 5c-9a, 11a, 15R-trihydroxy-18,19,20trinor-17-cyclohexyl-prost-5-ene-13 was obtained. -acetic acid 11,15-bis-THP-ether (u) -trinor-17-cyclohexyl-13,14-dehydro-15-epi-PGF-β-bis-THP-ether), [α] β = +4 ° (CHCl 3).

Separately, 250 mg of each of the two compounds was dissolved in 12 ml of acetone and refluxed with 0.2N oxalic acid (10 ml) for 3 hours.

28

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The acetone was evaporated and the aqueous phases were extracted with ethyl acetate. The organic extracts from each product were combined, dried over Na2 SO4 and the ethyl acetate removed in vacuo.

The resulting crude products were chromatographed on deacidified silica-05 gel (12 g) diluted with methylene chloride containing 15% ethyl acetate and then 20% ethyl acetate to give 151 mg of 5 c-9ci, 11a, 15S-trihydroxy-18,19,20 trinor-17-cyclohexyl-prost-5-en-13-ynoic acid (u) -trinor-17-cyclohexyl-13,14-dehydro-PGF2a), [α] D = + 78 ° (EtOH) and 142 mg of 5c 9or, chloro, 15R-trihydroxy-18,19,20-trinor-17-cyclo-10-hexyl-prost-5-ene-13-ynoic acid (u) -trinor-17-cyclohexyl-13,14-dehydro-15 epi-PGF2a), [<x] D = + 17.6 ° (EtOH).

Example 7 In humid room and under nitrogen atmosphere, a solution of triphenyl (4-carboxy-butyl) phosphonium bromide (2.66 g) in 5 ml of dry DMSO was added at 5-10 ° C with stirring to a suspension in DMSO. of the carban ion CH₂SOCH ^ obtained by heating at 60 ° for 3 hours of the suspension of 0.365 g of 80% NaH in 10 ml of dry DMSO. To the dark red solution of the ylide was then added 5 ml of DMSO solution of 425 mg of 5β-20 (21-chloro-3'S-hydroxy-4 '(S, R) -methyl-5'-cyclohexyl-pent-1'-trans). 1'-Enyl) -20i, 4'-dihydroxy-cyclopentanloro-ethanal-y-lactol-3 ', 4-bis-DIOX ether. The reaction mixture was stirred for 12 hours at room temperature.

After dilution with water, it was extracted with ethyl ether to remove the triphenyl phosphoxide. The ethereal extracts were countercurrently diluted with dilute alkali (0.5N NaOH) and then discarded. The combined aqueous alkaline fractions were acidified to pH 4.8 with 2N sulfuric acid and extracted with a 1: 1 mixture of pentane: ethyl ether.

These extracts were washed until neutral and the solvent was evaporated to give 0.428 g of 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-16 (S, R) -methyl-prost-5 en-13-ynoic acid-ll, 15-'bis-DlOX ether. 0.128 g of this product was deacetallized by the method described in Example 6 which, after chromatography on deacidified silica gel diluted with C ^C ^-ethyl acetate 70:30 gave 62 g of 5c-9a, 11a, 15S-35 trihydroxy-18.19, 20-trinor-17-cyclohexyl-16 (S, R) -methyl-prost-5-en-13-ynoic acid (io-trinor-17-cyclohexyl-16 (S, R) -methyl-13,14-dehydro-1 PGF2q) [a] D = + 13 ° (EtOH).

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29

Example '8

Under an inert gaseous atmosphere, a solution of cooled (about 12-14 ° C) triphenyl (4-carboxy-butyl) -phosphonium bromide (3.1 g) in DMSO was added a solution of potassium tert-butoxide (1.58 g ). Stirring was continued until a strongly colored solution of the ylide was obtained, then 0.573 g of 5β- (2'-bromo-3'-hydroxy-4'-methyl-5'-cyclohexyl-pent-1 '-trans-1') was added. -enyl) -2a, 4a-dihydroxy-cyclopentane-1a-ethanal-γ-lactol-3'S, 4-bis-THP-ether dissolved in a minimal amount of dry DMSO. The reaction mixture was stirred for 3 hours at room temperature, then placed on an ice bath and diluted with an equal volume of water. The alkaline aqueous phase was extracted with ethyl ether to remove (C ^H ,.)) = = 0. The ethereal extracts were rinsed with N NaQH and then discarded.

The aqueous alkaline phases were combined, acidified to pH 5 and extracted with ethyl ether-pentane 1: 1 to give 0.52 g of 5c-9a, 11a, ISB trihydroxy-ie, 19,20-trinor-17-cyclohexyl -16S-methyl-prost-5-and-13-acid-11, 15-bis-THP-ether.

A solution of 0.25 g of this compound in 6 ml of tetrahydrofuran was refluxed for 3 hours with 5 ml of 0.2N oxalic acid. The THP is removed in vacuo and the residue is extracted with ethyl acetate. The combined ethyl acetate extracts were washed until neutral with a saturated (NH ^ I₂SO ^ solution, dried and the solvent removed by evaporation. The residue was chromatographed on silica gel (9g) eluted with CH2 Cl2 and with CH2 Cl2 ethyl acetate 75:25 to give 120 5c-25 9a, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-16S-methyl-prost-5-en-13-ynoic acid (u) -trinor-16S-methyl-17-cyclohexyl -13.14-dehydro-PGF2α), [α] D = + 14 ° (EtOH).

Example 9 Using the procedures described in Examples 7 and 8 by reacting a DMSO solution of the ylidene of triphenyl (4-carboxybutyl) phosphonium bromide (6 moles) with a mole of 2α, 4α-dihydroxy-cysteine. clopentane-1a-ethanal-γ-lactol of a 3 ', 4-bis-tetrahydropyranyl ether selected from: 5β- (21-bromo-31S-hydroxy-4'S-methyl-51-cyclohexyl-pent-1'-trans). 1'-enyl) -3 ', 4-bis-THP ether, M + -H 2 O m / e 554.552; 5β- (2'-bromo-3'S-hydroxy-4'R-methyl-5'-cyclohexyl-pent-1'-30

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trans-1'-enyl) -3 ', 4-bis-THP-ether, M + -H 2 O m / e 554,552; 5β- (2 * -bromo-3'R-hydroxy-4'S-methyl-5'-cyclohexyl-pent-1'-trans-1'-enyl) -3 ', 4-bis-THP-ether, M + -H 2 O m / e 554,552; 5β- (2'-bromo-3'R-hydroxy-4 * R-methyl-5'-cyclohexyl-pent-1'-trans-05-11-enyl) -3,4-bis-THP-ether, M + - H 2 O m / e 554.552; the 11,15-bis-THP ethers of the corresponding prost-5-ene-13-amino acids were obtained, which were then deacetalled to give respectively: 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17 -cyclohexyl-16S-methyl-prost-5-and-13-acid, [or] jj = + 14 ° (CHCl4); 5c-90t, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-16R-methyl-prost-5-en-13-acid, [a] + = + 16 ° (CHCl4); 5c-90i, 11oT, 15R-trihydroxy-18,19,20-trinor-17-cyclohexyl-16S-methyl-prost-5-en-13-acid, [a] + = + 12 ° (CHCl4); 5c-9a, 1010, 15R-trihydroxy-18,19,20-trinor-17-cyclohexyl-16R-15-methyl-prost-5-en-13-acid, [α] D = + 11 ° (CHCl ^).

Similarly, starting from one of the 3 ', 4-bis-acetal ethers of the 20i, 4a-dihydroxy-cyclopentane-10β-ethanal-γ-lac tolerances listed below: 5β- (2 * -bromo-3 * S-hydroxy -5'-cycloheptyl-pent-1'-trans-1 * -enyl) -20 3 ', 4-bis-DIOX ether, M + -H 2 O m / e 558,556; 5β- (2'-bromo-3'S-hydroxy-5 '- (1'-adamantyl) -pent-1'-trans-1'-enyl) -3 *, 4-bis-DIOX ether, [α] β = 12 ° (CHCl3); 5β- (2 * -bromo-3 * 5-hydroxy-61-cyclohexyl-hex-1 * -trans-1'-enyl) -3 ', 4-bis-THP-ether, M + -H 2 O m / e 556,552; 5β- (2 * -bromo-3'S-hydroxy-4 * -cyclohexyl-but-1'-trans-1 * -enyl) -3 ', 4-bis-THP-ether, M + -H 2 O m / e 526,524; 5β- (2 * -bromo-3 * S-hydroxy-4'-cyclopentyl-but-1 * -trans-1 * -enyl) -3 *, 4-bis-DIOX ether, M + -H 2 O m / e 516,514 ; 5β- (2'-bromo-3 * 5-hydroxy-5 * -cyclopentyl-pent-1 * -trans-1 * -enyl) -30 3 *, 4-bis-THP-ether, M + -H 2 O m / e 526524; 5β- (2 * -bromo-3'S-hydroxy-4'R-methyl-5 * -cyclopentyl-pent-1 * -trans-1'-enyl) -3 ', 4-bis-DIOX ether, M + -H 2 O m / e 544,542; 5β- (2 * -bromo-3 * 5-hydroxy-4 * - (1'-adamantyl) -but-1'-trans-1'-enyl) -3 ', 4-bis-THP-ether, [a = -2 ° (CHCl 3); 35, the 11,15-bis-acetal ethers (11,15-bis-DIOX ethers or 11,15-bis-THP ethers) were obtained from the corresponding prost-13-amino acids, which were then deacetalled to give the following free acids:

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31 5c-90i, ίοί, 15S-trihydroxy-18,19,20-trinor-17-cycloheptyl-prost-5-en-13-acid, [α] 25 = + 22 ° (EtOH); 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17- (1'-adamantyl) -prost-5-en-13-acid acid, [a] + = + 19 ° (CHCl4); 5c-9a, 11a, 15S-trihydroxy-I9,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid, [aj ^ = + 18 °; [a] 365 ° + 44 ° (EtOH); 5c-9a, 11a, 15S-trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-acid, [α] 2 = + 18 °; = + 38 ° (EtOH); 5c-9a, 11a, 15S-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-10-prost-5-en-13-acid, [α] 2 = + 19 ° (EtOH); 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid, [α] 25 = + 20 ° (EtOH); 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclopentyl-16R-methyl-prost-5-en-13-acid, [a] + = + 29 ° (CHCl4); C-9a, 11a, 15S-trihydroxy-17,18,19,20-tetranor-16- (1'-adamantyl) -prost-5-en-13-acid, [α] 2 = + 21 ° ( CHCI ^) ·

Example 10

To a stirred solution of the ylide obtained by treating a solution of triphenyl (4-carboxybutyl) phosphonium bromide (2.4 g) in dry DMSO (8 ml) with 1.21 g of potassium tert-butoxide cooled to 5 8 ° under inactive air, 0.42 g of 5β- (2'-bromo-3'S-hydroxy-5 '- (2'-nor-benzyl) -pent-11-trans-1'-enyl) -2a, 4a was added. dihydroxy-cyclopentane-la-etha-Nal-y-lactol-3 ', 4-bis-dioxide-ether. After stirring for 8 hours at room temperature, the mixture was diluted with water (13 ml) and after extraction of the alkaline solution with ethyl ether to remove the triphenylphosphoxide, countercurrent washing of the ethereal extracts with 0.5N NaOH and discarding the etheric phase. the combined aqueous phases were acidified to pH 4.6. Subsequent extraction with ethyl ether-pentane 1: 1 gave 0.39 g of 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17- (2'-nor-benzyl) -prost-5. en-13-ynoic acid-11,15S-bis-DI0X ether. 100 mg of this compound was deacetated in acetone -0.2 N oxalic acid to give 48 mg of U) -trinor-17- (2'-norbornyl) -13,14-dehydro-PFG2cf, [α] β = +19 ° (EtOH).

35 32

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Example 11

A solution of 0.395 g of 5β- (2, -chloro-3, 5-hydroxy-4, 5-methyl-5, -cyclopentyl-pent-1 * -trans-1'-enyl) -2a, 4a-dihydroxy-cyclopentane -la-ethanal-γ-lactol-3 ', 4-bis-THP-ether in 4 ml of DMSO was reacted with a solution of the ylide obtained by the procedure described in Example 1 starting from 0.34 g NaH (80% dispersion in mineral oil), 9 ml of DMSO and 2.4 g of triphenyl (4-carboxybutyl) phosphonium bromide. The reaction mixture was allowed to stand for 8 hours at room temperature and for 2 hours at 38 ° C.

It was then cooled and diluted with 13 ml of water and extracted with benzene-ethyl ether 70:30 to remove the triphenylphosphoxide. The organic extract was countercurrent washed with 0.8N NaOH and discarded. The aqueous alkaline fractions were combined, acidified to pH 4.6, and extracted with ether-pentane to give 0.34 g of 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinorecyclopentyl-16S methyl prost 5-and-13-acid-11, 15 "bis-THP ether.

When 0.17 g of this compound was deacetalled in THP-0.2N oxalic acid 98 mg of iu-trinor-17-cyclopentyl-16S-methyl-13,14-dehydro-PGF20 was obtained [α] D = + 16 ° (EtOH ).

20

Example 12

A solution of 0.34 g of 5β- (2'-bromo-3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1 * -enyl) -cyclopentane-2α, 4α-dihydroxy-1α-ethanal-γ -lac-tol in 5 ml of trimethyl orthoformate and 25 ml of benzene was heated with 1.9 25 g of p-toluenesulfonic acid for 2 hours at 40 ° C. Next, 30 mg of anhydrous potassium carbonate was added and stirred for 10 minutes, after which the material was transferred to a separatory funnel, washed with 8% NaHCO 3 and with water to neutral, dried and evaporated to dryness.

The residue of 5β- (2 * -bromo-3′s-hydroxy-5′-cyclohexyl-pent-1′-trans-1′-enyl) -cyclopentane-2α, 4α-dihydroxy-1α-ethanal-γ-lactolmethyl ether was thoroughly dried and dissolved in 3 ml of DMSO. This solution was added to a solution of 150 mg of potassium tert-butoxide in DMSO. After 3 hours at room temperature, it was diluted with water and extracted with ethyl ether to give 0.24 g of 5β- (3 * -hydroxy-5-cyclohexyl-pent-1 * -ynyl) -cyclopentane-2α, 4α-dihydroxy -la ethanal-γ-lactol methyl ether deacetalled with acetone and 0.2N oxalic acid (10 ml -8 ml for 2 hours, reflux) to give 0.24 g of 5β- (3'8-hydroxy-5 cyclohexyl-pent-11-ynyl) -cyclopentane-2a, 4a-dihydroxy-1a-ethanal-y-lactol

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33

A solution of this compound in DMSO was combined with a solution of the ylid of triphenyl (4-carboxybutyl) phosphonium bromide prepared from NaH (80% dispersion in mineral oil, 150 mg), 5 ml of DMSO and 1.1 g of triphenyl ( 4-carboxybutyl) -phosphonium bromide. The reaction mixture was stirred for 45 minutes and then diluted with water. The triphenyl phosphoxide was extracted with ethyl ether which was countercurrent washed with 0.8N NaOH. The combined alkaline phases were sewn with 2N sulfuric acid to pH 4.8 and extracted with 1: 1 ethyl acetate-pentane.

After percolation through a silica column, 0.21 g of U) -trinor-17-cyclohexyl-13,14-dehydro-PGF2a, [α] + = + 23.9 °, = 78.1 ° (EtOH) was obtained.

Example 13 0.53 g of 5β- (2'-chloro-3'S-hydroxy-5'-cyclopentyl-pent-1'-trans-1'-enyl) -2a, 4a-dihydroxy-cyclopentane-10-ethanal-y -lactol-3 ', 4-bis-D10Ox ether in 8 ml of acetone and 8 ml of 0.2N oxalic acid was refluxed for 1 hour and 30 minutes. After evaporation of the acetone in vacuo and extraction with ethyl acetate, 0.36 g of 5β- (2'-chloro-3'-hydroxy-5'-cyclopentyl-pent-1'-trans-1'-enyl) -2a, 4a dihydroxy-cyclopentanalof-ethanal-v-lactol.

By treatment with 3 mg of p-toluenesulfonic acid in benzene and 3 ml of methyl orthoformate under the conditions described in Example 12, 0.34 g of lactol methyl ether was obtained.

Under nitrogen, a solution of 90 mg of 80% NaH in my crude oil was heated in 4 ml of DMSO at 60 ° C for 3 hours until all hydrogen was developed. To the cooled solution of the carbanion CH 2 -SO-OB 2 obtained in this way was added a solution of the above-mentioned lactol methyl ether in 1.5 ml of DMSO. This was allowed to stand for 12 hours at room temperature and then heated for 2 hours to 40 ° C, cooled and diluted with water. It was then extracted with ethyl ether.

The organic phases were washed to neutral, dried and the solvent removed by evaporation to give 0.29 g of 5β- (318-hydroxy-5 '-cyclopentyl-pent-1' -ynyl) -cyclopentane-20 (, 4'-dihydroxy-35 la-ethanal-y-lactol methyl ether.

This compound was deacetallized with refluxing THF 0.2N oxalic acid to give 0.24 g of the free lactol, then 34

DK 155317 B

reacted with 2.5 mole equivalent of the ylide of 5-triphenyl- (4-carboxy-butyl) -phosphonium bromide in DMSO to give, after chromatography on silica gel, 0.21 g of + [α] β = + 20 ° (EtOH).

05

Example 14

A solution of U) -trinor-17-cyclohexyl-13,14-dehydro-PGF2a “11,15-bis-THP-ether-propyl ester (0.15 g) in acetone (10 g) was refluxed with 0.2N aqueous oxalic acid (8 ml) for 1 hour and 30 minutes.

The acetone was removed in vacuo and the aqueous phase was repeatedly extracted with ether.

The combined organic layers were washed to neutral, dried and evaporated to dryness, which after chromatographic purification on silica gel using methylene chloride-ethyl acetate 80:20 as eluent gave iu-trinor-17-cyclohexyl-13,14-dehydro -PGF2a “propyl ester (Olp = + 19 ° (CHCl3), 95 mg).

Example 15

A solution of 0.28 g of m-trinor-17-cyclohexyl-13,14-dehydro-20 PGF-11,15-bis-THP-ether in dry pyridine (1.8 ml) was treated with 145 mg of propionic anhydride overnight. at room temperature. The reaction mixture is partitioned between ethyl ether and a 30% aqueous solution of citric acid.

The organic phases were combined, washed to neutral and evaporated to dryness. The resulting U) -trinor-17-cyclohexyl-13,14-dehydro-PGF2a? 9-propionate-11, 15-bis-THP ether was then deacetallized in acetone-0.2N oxalic acid, extracted with ethyl acetate, and The reaction product was chromatographed on silica gel (10 g: g acid) eluted with cyclohexane-ethyl ether to give 185 mg of io-trinor-17-cyclohexyl-13,14-dehydro-PGF20; -9-propionate, [a] + = + 1 ° (CHCl ^).

30

Example 16

To a solution of 18,19,20-trinor-13,14-dehydro-17-cyclohexyl-PGF2ff (0.510 g) in 25 ml of a mixture of ethanol and water (1: 1) cooled in a bath of ice and water an equivalent amount (13 ml) of 0.1 normal aqueous sodium hydroxide solution was added.

The mixture was then concentrated to a residue of the sodium salt of 18,19,20-trinor-13,14-dehydro-17-cyclohexyl-PGF2cf (0.530 g) [cr] D = +24 [tt] 365 = +78 C 1: 1.

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35

Example 17

A solution of 18,19,2Q-trinor-13,14-dehydro-17-cyclohexyl-PGF2a methyl ester {[of] = +31, CH2 OH] (0.660 g) in 7 ml of a mixture of 9 ml of water and ethanol (2: 8) was treated with 0.100 g of lithium hydroxide and stirred for 5 hours. The solution was then neutralized with 3 normal sulfuric acid and extracted twice with 30 ml of ethyl ether.

The organic phase was washed out to neutrality and evaporated to dryness. Data for the oil obtained as residue of 18,19,20-trinor-13,144-dehydro-17-cyclohexyl-PGF2a (0.620 g) were in accordance with data for the product obtained in Example 6.

Example 18 Dry potassium carbonate (0.959 g) was added to a solution of 20.19.18- [alpha] -trinor-17-cyclohexyl-13,14-dehydro-PGF2 [beta] -11,15-bis-THP-15 ether (2.69 g) in dry dimethylformamide (10 ml) and then CH 2 J (0.985 g) was added dropwise the stirred mixture.

After further stirring for 3 hours at room temperature, the solid was filtered off and shaken with diethyl ether (50 ml). The organic phase was washed with water to neutrality, dried over 20 Na 2 SO 4, and the solvent was evaporated in vacuo to give 20.19.18-U) -trinor-17-cyclohexyl-13,14-dehydro-PGF2a-11, bis-THP ether methyl ester (2.7 g); [.alpha.] D = -6.2 (CHCl3).

20,19,18-m-trinor-17-cyclohexyl-13,14-dehydro-PGF20f-11,15-bis-THP-ether methyl ester (2.7 g) was dissolved in acetone (50 ml); 0.2N aqueous oxalic acid (40 ml) was added and the reaction mixture was stirred at 50 ° C for 4 hours. The acetone was evaporated under vacuum and the water extracted with diethyl ether. The combined organic layers were washed with water to neutrality, dried and evaporated in vacuo to give 9a, 11a, 15 (S) -trihydroxy-20,19,18-U) -trinor-17-cyclohexyl-prost -13-ynoic acid methyl ester (2.6 g) as a crude product. After chromatographic purification on a silica gel column (eluent: ethyl acetate: hexane = 80:20), 1.73 g of 2Q, 19,18-u) -trinor-17-cyclohexyl-13,15-dehydro-PGF4 oily product; [or] + = +31 (C 2 H 5 OH), mass spectra: M + 406, 388 (M + -H 2 O), 370 (M + -2H 2 O), 357 (M + -2H 2 O-CH 3 .

36

DK 155317 B

Example 19

A solution of 18,19,20-tris-nor-17-cyclohexyl-13,14-didehydro-PGF2a (390 mg) in methanol (17 ml) was treated with dried "Amberlyst 15" resin (30 mg).

The mixture was stirred for 12 hours at room temperature and after removal of the resin, the solution was diluted with water (10 ml) and extracted with diethyl ether, 20 ml (3 times). The combined organic phases were washed with water, dried over Na 2 SO 4 and evaporated to dryness to give 18,19,20-tris-nor-17-cyclohexyl-13,14-dide-hydro-PGF as pure oil (392 mg); [a] + = +31 (C2H, -0H), mass spectra: M + 406, 388 (M + -H2 O), 370 (M + -211 + O), 357 (M + -2H2-OCH3O +), 344 (M + -2H2O) C2H40 +).

Example 20 To a solution of 18,19,20-tris-nor-17-cyclohexyl-13,14-didehydro-PGF2cf (175 mg) in dry dimethylformamide (2 ml) was added dry potassium carbonate (96 mg) , and then methyl iodide (96 mg) was added dropwise.

The mixture was stirred for 3 hours at room temperature, after which the solid was filtered off and washed with diethyl ether.

The organic phase was washed with water to neutrality and dried in Na 2 SO 4 · The solvent was evaporated in vacuo to give 18,19,20-tris-nor-17-cyclohexyl-13,4-didehydro-PGF2a methyl ester as pure oil (170 mg); = +31 ((1H + OH), mass spectra: M + 406, 388 (M + -H 2 O), 370 (M + -2H 2 O), 357 (M + -2H 2 O-CH 3 O +), 344 (M + -2H 2 O-C 2 H 4 O +).

Example 21

To a solution of 18,19,20-tris-nor-17-cyclohexyl-13,14-dide-hydro-PGF2a (200 mg) in 10 ml of methanol was added p-toluenesulfonic acid (20 mg), the reaction mixture was stirred for 3 h. hours at room temperature.

The solution was diluted with a 1: 1 mixture of water and methanol (10 ml) and evaporated under reduced pressure.

The aqueous phase was extracted with diethyl ether (20 ml) (3 times) and the organic extracts were washed with water and then with dilute aqueous solution of NaHCO 3, again with water, and finally dried over Na 2 SO 4 · After evaporation of the solvent, 198 mg was pure oil 18,19,20-tris-nor-17-cyclohexyl-13,14-didehydro-PGF₂O (methyl ester recovered, [α] D = +31 (C = 1 ethanol), mass spectra: M + 406, 388 (M + - H2O), 370 (M + -2H2O), 357 (M + -2H2O-CH3O +), 344 (M + -2H + O-CJBLO +).

Claims (1)

Optically active or racemic 13,14-dehydro-prostaglandin F 20 derivatives for use in agents of abortion-inducing activity, CHARACTERISTIC in that they have the general formula (I): R1 _ / \ / \ COOR / ~ \ ( I) V \ f2 R4 OH- C ^ c _ é -i - (CH7) -R6 kk B? R5 wherein R represents a hydrogen atom, a C1-12 alkyl group or the cation of a pharmaceutically useful base, R5 represents hydroxy, acetoxy, propionyloxy or benzoyloxy, one of R and R represents hydroxy and the other is hydrogen , R and R independently represent hydrogen g or C 1-4 alkyl, n is zero, 1, 2 or 3, and R represents a group (CH 2) m · wherein m represents 2, 3, 4 or 5, or R 6 -CH <^CH₂₂-adamantyl or 2-norbornyl.