FI56678C - EFFECTIVE EFFECTS FOR THERAPEUTIC EFFECTIVE 9ALFA- AND 9BETA-HYDROXIPROSTANSYRADERIVAT - Google Patents

Description

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Patent neddelat • * • ^ 5 («) ^ T ^ (51) Kv.lk. '/ Int.CI. * © 07C 177/00 SUOMI FINLAND (21) Patent application - PatentansAknlng 1061/73 (22) Hakemlspllvl - AnsAknlngsdag 06 .Oi.73 ^ ^ ^ (23) Start Date - Glltighetsdag 06.Oi.7 3 (41) Become public - Bllvlt offentllg 2.1 # 2.0.73

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Patent · och registerstyrelsen 'Ansökan utlagd och utUkrlften published by JJ-X ·' y (32) (33) (31) Pyydetty etuoikeus —Begird prlorltet! 3 · Oi. 72

It ali a-Itali en (IT) 23063 A / 72 - (71) Farmitalia Carlo Erba S.p.A., Via Carlo Imbonati 2l, 20159 Milan,

Italia-Italien (IT) (72) Carmelo Gandolfi, Milan, Gianfederico Doria, Milan, Pietro Gaio,

Belluno, Italy-Italy (IT) (7l) Munsterhielm, S.A.

This invention relates to a process for the preparation of prostanoic acid derivatives. The present invention relates to a process for the preparation of prostanoic acid derivatives. The present invention relates to a process for the preparation of prostanoic acid derivatives.

Natural prostaglandins are C-20-unsaturated non-aromatic hydroxyl-containing carboxylic fatty acids in which C8 and I are joined together to form a five-membered ring. The basic carbonic acid backbone has the following structure:

tooh

VJ. . CH 2 11 13 15 1719 ^ 20

In the body, prostaglandins are formed from essential C-20 fatty acids by a microsomal enzymatic system.

Natural prostaglandins are known to have a variety of 56678 physiological properties, i. hypertensive, hypotensive and smooth muscle stimulating activity. They also prevent and reverse platelet adhesion and aggregation, which is the initial stage of a blood clot. In general, therefore, the effect of prostaglandins is based on the fact that they regulate smooth muscle activity, blood circulation and secretion (including the secretion of some endocrine glands). Through these effects, they are able to affect human physiology in a number of ways: in particular, they can be effective in preventing peptic ulcers, asthmatic seizures, hypertension, nasal congestion, and in abortion, menstrual inducing used in childbirth to facilitate labor.

However, natural prostaglandins are rapidly converted in the body to pharmacologically inactive metabolites; their short half-life (approximately 10 minutes) precludes the use of natural prostaglandins as therapeutic agents. Dehydrogenation of the allylated hydroxy function at the C-15 atom of all naturally occurring prostaglandins by 15-hydroxy-prostaglandin dehydrogenase (NAD-dependent enzyme) is the first and more important metabolic step: A A Λ A Λ

Il * D "B OH ° In this first degradation step to form Δ 2-2-keto-prostaglandins, prostaglandins are converted to pharmacologically inactive metabolites ^ Anggard E., Acta Physiol. Scand., 66, 509 (1966); Kloeze J ., Biochim. Biophys. Acta, 187, 285 (1969) 1 ·

Thus, new prostaglandin-type compounds have now been synthesized with some modifications in the molecule in order to obtain a beneficial effect on biological parameters and to maintain prostaglandin-type activity.

In particular, the invention provides pure optically active or racemic prostanoic acid derivatives, all of which have a lower metabolic rate of 35,6678 compared to natural prostaglandins, thus providing an effective therapeutic effect at lower doses.

The prostanoic acid derivatives prepared according to the present invention can be used for the same purposes as the above-mentioned natural prostaglandins.

The general formula of the compounds according to the invention is R, R2 /

^ R1-000R

A, m 16 A ^ A-C-CH- (CHO) -CH, H ÖH / \ 2n 3 (!) R5 R1! and racemates thereof, wherein R is a hydrogen atom, a pharmaceutically acceptable cation or a C 1-6 alkyl group or a trichloroethyl group, R 1 is -C 1-6 CH 8 -, one of R 6 and R 2 is a hydrogen atom and the other is a hydroxy-S 1 hydroxy group, A is -CH = C- or -C = C-, one of R1 is hydrogen and the other is hydroxy, R1 is hydrogen or methyl, n is 3 or α, and in the formula in the 8-position and 12-position the chains attached to the existing carbon atoms have a trans configuration. The double bond at the 5 (6) position is a cis double bond. In the group i1, the -CH = C- double bond is a trans double bond.

In the formulas of this specification, dashed lines indicate that the substituents have the oi, configuration, i. they are below the plane of the ring or chain, respectively, while the bond (* ^) marked with a wavy line means that the groups can have either the r <configuration, i. they are below the plane of the ring or have the p-configuration, i. they are above the level of the tire.

As mentioned above, the chains attached to the carbon atoms in the 8-position and 12-position must have the trans configuration, i. both of these chains cannot simultaneously have the β-configuration, nor both have the β-configuration, but when one has the β-configuration, the other must have the β-configuration, and vice versa. As shown in formula (I), the hydroxy group attached to the carbon atom at the 15-position may have either the o (-configuration) or the /'-configuration (-, C-; 1 H-ol). you were).

H OH H OH

As mentioned above, the invention relates to a process for the preparation of either optically active or racemic compounds.

The compounds according to the invention are thus either optically active compounds of the general formulas r2 R2 R, X V'3

<X R, -COOR \ R ·, -COOR

V_ (^ 6 1 V- <> 1 h / 0H 'H / qh U-C-CH- (CH2) n-CH3

R5 ^ r5 K

and their racemates.

Examples of specific preferred compounds of formula (I) of the invention include the following; 5c, 13t-11 + -chloro-9o> (, 11o (, 15S-trihydroxy-prostadienoic acid $ 5c, 13 ^ 1 * + -chloro-9o (, 11 <? (, 15S-trihydroxy-8,12-di -iso-prostadienoic acid; 5c, 13t-11 + -chloro-9 / 3,11K, 15S-trihydroxy-8,12-di-iso-prostadienoic acid; 5c-9β, 10 (15S-trihydroxy-prosten -13-ynoic acid; 5c-16-methyl-9,110 (1,5S-trihydroxy-prosten-13-ynoic acid; 5c-9 ° <, 11,15S-trihydroxy-20-homo-prosten-13-ynoic acid; 5c -9 °, 11 °, 15R-trihydroxy-prosten-13-ynoic acid, 5c, 9X, 11c, 15S-trihydroxy-8,12-diisopropopr-13-ynoic acid, 5c-16-methyl -9X, 11X, 15S-trihydroxy-8,12-di-iso-prosten-13-ynoic acid 5c-9,11,15S-trihydroxy-20to-homo-8,12-di-iso-prosten-13 5C-9β, 1,1X, 15S-trihydroxy-8,12-diisoproposten-13-ynoic acid (.0-homo compounds are those in which n is b.

The capped compounds of general formula (I) may be prepared by a process wherein the optically active or racemic compound of general formula (II) is $ 667.

Λ yOH

n6-6 (II) NA-O-CH- (CH2) n-CH3 R'j wherein R1, n and A have the same meaning as above, one of R'4 "and R'4 is hydroxy or one of the known a protecting group bonded to the ether via its oxygen atom and the other being a hydrogen atom, Y is a hydroxy or known protecting group bonded to the ring via an ether oxygen atom, and wherein the lactol ring has the trans configuration relative to the hydroxy-aliphatic side chain is reacted with CH2 With a Wittig reagent containing -RpCOOR, wherein R1 is as defined above and R1 is a hydrogen atom or a C1-6 alkyl group, to form a compound of general formula (III) R2 is R3

-— '"' Νΐη -C00R

Λλ i6 cun HY AC-CH- (CH2) n-CH3 r'5'h \ wherein R, Rp Y, A, R '^, R ^, R ^ and n have the same meaning as above and wherein one of R2 and R R 2 is a hydroxy group and the other is a hydrogen atom, after which the compound of formula (III) is de-etherified at the 11- and / or 15-position, in which formula Y is a known protecting group as defined above and / or one of R 1 and R 2 is a known protecting group as defined above and the other is a hydrogen atom. ^

Compounds of formula (III) in which A is -C = C- may be converted to compounds of formula (III) in which A is -C = C-. The conversion may be carried out using, for example, an excess of tert.-BuOK S6676 (e.g. 2.1 to 3 moles) in a suitable organic solvent, for example dimethyl sulfoxide. Compounds in which R is a hydrogen atom may be esterified or reacted with a pharmaceutically acceptable base, according to methods commonly used in organic chemistry, to form compounds in which R is a C 1-6 alkyl group, a pharmaceutically acceptable cation or a trichloroethyl group, respectively.

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

Compounds of formula (I) wherein one of R 1 and R 2 is a hydrogen atom and the other a hydroxy group and wherein R is a C 1-8 alkyl group may be hydrolysed to form compounds of formula (I) wherein R 1 and R 2 are as defined for above and R is a hydrogen atom. The reaction can be carried out according to methods commonly used in organic chemistry and obvious to those skilled in the art.

In the compound (III), which may be either an optically active or a racemic compound, the chains attached to the carbon atoms in the 8-position and the 12-position always have the trans configuration.

As mentioned above, either optically active or racemic lactol can be used as the starting material of formula (II).

In the lactol of formula (II), the bond indicated by the two wavy lines (\) of the lactol ring has the cis configuration i.e. they are both simultaneously below the level of the cyclopentane ring or both above the level of the cyclopentane ring, whereas as mentioned above the side chain has a trans configuration with respect to the lactol ring, i.e. it is below the level of the cyclopentane ring while the lactol ring is above the level of the cyclopentane ring and vice versa. The lactol hydroxy group may have either the K configuration, i. it is below the level of the lacquer ring or may have the -configuration i.e. it is above the level of the lactol ring.

The starting material can thus be either a compound of formula

? Y 0H

6 (IIa) H A -C-CH- (CHO) -CH, n y / \ ^ n 3 R'5 7 56676 or a compound of formula

OH

V- <r (iib) H 1 'A-C-CH- (CH 2) n -CH 3 or a racemate thereof.

When a slight compound of formula (IIa) is used as a starting material, a compound of formula (III) in which R 2 is a hydrogen atom and is a hydroxy group is obtained. When a compound of formula (Hb) is used as a starting material, a compound of formula (III) is obtained in which R 2 is a hydroxy group and R 1 is a hydrogen atom.

Known protecting groups (i.e., ether groups) should be convertible to hydroxy groups under mild reaction conditions, e.g., by hap-Pamella hydrolysis. Examples are acetal ethers, enol ethers and silyl ethers. The most preferred groups are (CH) S10-, [} (OAlk. O ° -, - / O-OAlk where W is -O- and -CH2-, and Alk is a lower alkyl group. The Wittig reaction is preferably carried out using at least one mole, preferably 2 to 10 moles, of Wittig reagent per mole of lactol.

The reaction is generally carried out in an organic solvent, for example diethyl ether, hexane, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, hexamethylphosphoramide, in the presence of a base, preferably sodium hydride and potassium tert-butoxide at room temperature or below, at 0 ° C and at room temperature. . The reaction time may be from a few minutes to several days depending on the temperature and concentration of the reaction mixture and the Wittig reagent specifically used.

The phrase "Wittig reagent" encompasses compounds of the general formula

0 O

(aryl) -P-CH2-CH2-C00R Hai 8 5667 «where Hal is bromine or chlorine and R and R4 are as defined above. It also includes other phosphorus derivatives, e.g. diethyl derivatives. Tripett is in Quart. Rev. 1963 XVII, no k, ^ 06 explained in detail the preparation of these reagents.

Depending on the reaction conditions used, it is possible, starting from a compound of general formula (II) in which A is? -C = C-, to give either a compound of formula (III) wherein A is -C = C-,

Cl or a compound of formula (III) wherein A is -C = C-.

f1

In fact, a compound of formula (III) wherein A is -C = C- can be obtained as the sole product using, for example, 1.5 to 2.5 moles of Wittig's reagent per mole of compound (II) and using reaction times of 10 to about 30 minutes. .

The compound of formula (III) wherein A is -C = C- can in turn be obtained as the sole product using, for example, 1.5 to 2.5 moles of Wittig reagent per mole of compound (II) and using reaction times of about 2 to about 10 hours. Similarly, a compound of formula (III) wherein A is -CeC- can be prepared using reaction times of about 30 minutes and at least 5 moles of Wittig reagent per mole of compound (II).

Cl • 1

The starting material A of formula (II) is preferably -C = C-.

The de-etherification of compound (III) is carried out under mild acid hydrolysis conditions, for example with mono- or polycarboxylic acids, e.g. formic, acetic, oxalic, citric and tartaric acid, and in a solvent, e.g. water, acetone, tetrahydrofuran, dimethoxyethane. and lower aliphatic alcohols. Preferably, 0.1N to 0.25N polycarboxylic acid (e.g. oxalic or citric acid) is used with a suitable low boiling solvent which is miscible with water and can be easily removed in vacuo upon completion of the reaction.

Separation of 9β-hydroxy and 9β-hydroxy-11 ethers from their δ 56678 and / or free 11,15-diols can be performed using, for example, chromatographic methods, preferably column chromatography.

Subsequent de-etherification can be performed as described above under mild acid hydrolysis conditions, for example with oxalic acid in acetone.

The compounds of the general formula (II) can in turn be prepared in a multi-step process using as starting material an optically active or racemic lactone of the general formula (IV) of 0-6 -V (A) (O) (iv) A-O (CH2) n-CH3 in which and n has the same meaning as above and Y 'is a hydroxy group or an aliphatic, aromatic or cycloaliphatic acyloxy group or a known protecting group attached to the cyclopentane ring via an ether oxygen atom and wherein the lactone ring has the trans configuration with respect to the keto-aliphatic side chain.

The lactone used as starting material can thus be either a compound of formula (IVa), o-f °

Av - 1 * 6 (CVn-OTj (IVa) y * 0 or a compound of formula (IVb) is

Af0 yy r6 Y_ / i (ivb) H '(CH2) -CH, Y' 0 ^ n ö or a racemate thereof.

10 S6676

The compound of formula (IVa) can be prepared essentially from E.J. In Corey et al., Annals of N.Y. Ac. of Sciences, l80.

2k (1971). The compound of formula (IVb) can be prepared essentially by the method described in our BE Patent No. 792,803.

Racemates can be prepared essentially by the same methods.

The multi-step process for preparing a compound of general formula (II) comprises the following steps: 1) Reaction of a compound of formula (IV) with a halogenating agent to form a compound of formula (V) 0- ^ 0

/ J

/ V ^ ci r6 (CH) -CH (V) Y 'O ^ n j in Y', and n have the same meaning as above. A suitable halogenating agent is, for example, sulfonyl chloride, preferably the SO 2 Cl 2 reaction can be carried out in a solvent, preferably pyridine, acetone, acetic acid, toluene, diethyl ether, benzene, water or mixtures thereof; 2) Reduction of the 15-oxo group (prostaglandin numbering) of a compound of formula (V) to form a mixture of 15S and 15R ols having the formulas / "f °

Cp} 36 Cff-, R6 / \ - (CH,) -CH, (CH,) -CH, Y 'OH' H 2 n 3 γ. OHX Ή 2 n 3 (Via) (15S-ol) (VIb) (15R-ol) where Y ', R1 and n have the same meaning as above, after which 15S - was separated from the 15R-ol and the separated compounds are then, if desired, de -hydrohalogenated to form a compound of formula (Vila) SS678 11

j / P

/ Ϋ r6 γΑ ι6 K C = C-p-CH- (OH2) n-CH3 Y '0¾ H (Vila) (15S-011) or to form a compound of formula (VIIIb)

O-O W "6 H Y = C-C-CH- (CH 2) -OH, Y '/ \ 2 n 3 (VIIIb) (15R-ol)

OH H

in which formulas Y ', R 1 and n have the same meaning as above, if desired, the reduction can be carried out after 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 sodium borohydride, lithium borohydride or zinc borohydride. Separation of the 15S-ol from the 1R-ol can be accomplished by chromatography, preferably column chromatography, or fractional crystallization. The dehydrohalogenation can be carried out in a solvent, preferably dimethyl sulfoxide, dimethylformamide, benzene, hexamethylphosphoric triamide, or mixtures thereof, using a base such as 1,5-diazabicyclo [b] -3, o-non-5 -ene, or an alkali metal hydride, carbonate or alkoxide.

3) For compounds of formula (VIII) h / Y / AC-CH-CCH 2 -CH 2 (VIII) r 5 ri + wherein Y ', A, and n have the same meaning as above and one of the groups and R 1 is a hydrogen atom and the other a hydroxy group , to compounds of formula (IX) 56678 12 H 'r, A-O-CH- (CH2) n-OH3 CIX).

R 5 R 1 wherein R 1 and n are as defined above and Y "is a known protecting group attached to the cyclopentane ring via an ether of its oxygen atom, and one of the groups and R 1 'is a known protecting group attached to the ether of its oxygen atom. When Y 'in the compounds of general formula (VIII) is an aliphatic, aromatic or cycloaliphatic acyloxy group precedes etherification of compounds (VIII) to compounds (IX), saponification, for example by treatment with mild alkalis to form compounds of formula (VIII) in which Y 'is a hydroxy group.

The etherification is preferably carried out according to formula o

\ -W

in which W is -O- or using catalytic amounts of, for example, phosphorus oxychloride, p-toluenesulphonic acid or benzenesulphonic acid or a silyl ether, for example by reaction with a tri or with cyclohexanone diacetal in the presence of an acid catalyst at reflux temperature in an inert solvent and distilling off the alcohol formed to obtain mixed acetals or enol ethers, depending on the amount of catalyst or heating time used.

M-) Reduction of a compound of general formula (IX) to form lactol derivatives of general formula (X)

° H

A7 i6 H ϊ „A ^ -CH- <CH2) n-CH3 <« R'j n \ $ 6678 13 where A, Y ", n, R ^, R '^ and R' ^ have the same meaning as above. The reduction can be performed by treatment with diisobutylaluminum hydride or sodium bis- (2-methoxyethoxy) aluminum hydride in an inert solvent, for example toluene, n-heptane, n-hexane or benzene or mixtures thereof, at a temperature below -30 ° C.

5) Possible de-etherification of a compound of general formula (X) to form a compound having free 11- and 15-hydroxy groups; the de-etherification can be carried out by mild acid hydrolysis in a water-miscible solvent, a solution of a mono- or polycarboxylic acid.

All of the compounds mentioned in 1) to 5) above, which may be either optically active or racemic compounds, have a trans configuration with respect to the side chain on the lactol ring or the lactone ring, respectively.

As mentioned above, the prostanoic acid derivatives of formula (I) can be used for the same purposes as natural prostaglandins, but they have the advantage of having a slower metabolic degradation rate and, in addition, a more selective therapeutic effect.

Pharmacological experiments have shown that, for example, 5c-9c <, 11o (15S-trihydroxy-prosten-13-ynoic acid) has excellent spasmogenic activity "in vitro" in the rat uterus.

In addition, for example, compounds 5c-9β, 11 ° (15R-trihydroxy-prosten-13-ynoic acid, 5c-13t-1β-chloro-9β, 11β, 15S-trihydroxy-prostadienoic acid and 5c-13β- -1 + -chloro-9β, 11β, 15R-trihydroxy-prostadienoic acid has excellent anti-wounding activity, as can be demonstrated in "in vivo" experiments in rats.

The compounds of general formula (I) may be administered orally, parenterally or intravenously using rectal suppositories or by inhalation. They can be administered, for example, by intravenous administration of sterile isotonic saline at a rate of 0.01 to 10, preferably 0.05 to 1 / ug per kg of mammalian body weight per minute.

The compositions may be prepared by conventional methods and may be in the form of, for example, tablets, capsules, pills, suppositories or suppositories, or in liquid form, e.g. as solutions, suspensions or emulsions.

Examples of substances which can serve as carriers or diluents are water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohol and cholesterol.

5667 · l '+

The invention is illustrated by the following examples in which the abbreviations "THP", "DIOX", "DMSOr" and "DI3A" mean tetrahydropyranyl, dioxanyl, dimethyl sulfoxide and diisobutylaluminum hydride, respectively.

Comparative Experimental Description: The compound 13,1β-dehydro-PGF204 prepared according to the present invention proved to be a good muscle muscle stimulant when compared to the compounds of the PGFβ1 series. When tested on estrogenized rat uterus in vitro, the following relative potency values were obtained: PGF2r>, 100, 3, β-dehydr ° -pGF2Cx 109 The compounds of this invention are also excellent luteolytic agents. This activity was tested as follows:

Female rats that were confirmed to be pregnant (by examining the fallopian tubes and counting the number of clots) were given the test compound subcutaneously at a single dose of 2000 on day 10 of gestation f / kg - later, on day 20, surviving fetuses and reabsorbed clots were counted. Although administration of PGF2rβ failed in all cases (100% of pregnancies), the compounds of the invention showed significant activity, as shown by the values shown in the following table:

Table Number of animals used Pregnant Not pregnant PGF2c ^ IfO IfO 0 13, 11f-dehydro-PGF2c ^ 16 9 7 20- (o-homo-1β-dehydro-pgf2o <16 0 16 15 56678

Example 1 A ^) Freshly sublimed potassium tert-butoxide (1.1 * g) in dry (by distillation from calcium hydride, H 2 O $ 0.02) in DMSO (20 ml) under nitrogen is added 13t-lif-chloro-9 cs <, 11,15S-triol-pentanor-prost-13-en-6-alpha-X-lactol-11,5,5-bis-ether (1.18 g) and triphenyl- (4-carboxybutyl) -phosphonium bromide (2.8 g) in a stirred solution in dry DMSO (20 ml) and cooled in an ice-water bath so that the temperature of the reaction mixture does not rise above 20 ° C. The dark red solution is further stirred for 30 minutes at room temperature diluted with ice water (70 ml).

The aqueous phase is repeatedly extracted with ether until all triphenylphosphoxide has been removed, and the combined organic layers are re-extracted with 5% sodium bicarbonate. The pH of the combined aqueous phases is adjusted to b, 5-7 with sulfuric acid, followed by extraction with ether-pentane (1: 1). The organic layers are combined, washed with saturated ammonium sulfate solution, dried (Na 2 SO 4) and evaporated in vacuo to give 5c-13t-1β-chloro-9β, 11® <, 15S-trihydroxy-Prosta-5,13-diene-1 -acid - 11,15S-bis-THP-ether (1. ^ 1 g), \ p <1D = Jfl.7 ° (CHCl 3), i.e. 1 * f - chloro-PGF 4 -11 ° bis-THP ether.

A2) A suspension of dry dimethyl sulfoxide (23 ml) in $ 80 sodium hydride (0.78 g) is heated with stirring at 60 ° C until hydrogen evolution has ceased (3 hours).

The methylsulfinylcarbanide mixture, cooled to 5-10 ° C and stirred, is treated with triphenyl- (N-carboxybutyl) -phosphonium bromide (5.78 g) in dry DMSO (23 ml); the dark orange-red ylide solution is then treated with 13t-11f-chloro-90? (10S-trihydroxy-pentanor-prost-13-en-6-alpha-β-lactol-11,15-bis-THP-ether). (1.35 g) in dry DMSO (10 ml), the mixture was further stirred for 5 minutes and diluted with ice-water (50 ml) and repeatedly extracted with ether until all triphenylphosphoxide was removed and the combined organic layers were re-extracted for $ 5: The pH of the combined aqueous phases is adjusted to * f, 5 - * +, 7 * + N with sulfuric acid, followed by extraction with ether-pentane (1: 1).

The organic layers are combined, washed with saturated (NH 4 -SO 4) solution, dried (Na 2 O 2) and evaporated to dryness to give 5c, 13t-IL-chloro-9.11 ° (15S-trihydroxy-Prosta-5 , 13-diene-1-acid-11,15S-bis-THP-ether, i.e. 11+ -chloro-PGF2c-11,15-bis-16 SS676 -THP-ether, and 5c-9 ° -11. 15S-trihydroxy-prost-5-en-13-yn-1-acid-11,15-bis-THP-ether, i.e. a mixture of 13,11 + -dehydro-PGF2O (-11,15-bis-THP-ether ( 80:20).

This mixture was absorbed onto an acid-washed silica gel column (180 g) and eluted with cyclohexane-ethyl acetate to give 13,11-dehydro-PGF20 <> - bis-THP-ether (0.21 g) in the following order, \ d = 3 D = -18 ° (CHCl 3) and 1+ -chloro-PGF 2 O <-bis-THP-ether (0.98 g),

Hd = - * + 1.7 ° (CHCl3).

The starting materials for the above reactions are 13t-1'+ chloro-9,11,15S-triol (or trihydroxy) -pentanor-prost-13-en-6-allyl-γ-lactol-11,15-bis-THP ethers were prepared as follows: a) A solution of 0.002 moles of 5-hydroxymethyl-2H-β-dihydroxy-cyclopentane-1-acetic-β-lactone β-lactone * + ester (acetate, propionate, p-phenylbenzoate) and β-acetal ether (t-tetrahydropyranyl ether (THP ether), dioxanyl ether (DIOX ether)], either in optically active or racemic form, in $ 25 ml of dimethyl sulfoxide (DMSO) in benzene (e.g. dl-5- [3-hydroxymethyl-11-20 (, 1 + O (solution of 1-dihydroxy-cyclopentane-1 H -acetic acid γ-lactone-β-propionate (U-, 56 g)], with dicyclohexylcarbodiimide ( 12.5 g) and pyridine trifluoroacetate (19.25 ml) in 25% DMSO in benzene, obtained from pyridine (2 ml) and trifluoroacetic acid (1 ml) in 25 ml of 25% DMSO in benzene. ].

The mixture is stirred for one hour at room temperature and then treated with oxalic acid (5. * + 6 g) in methanol (30 ml) to remove excess carbodiimide. Further stir for * + 5 minutes, then dilute the mixture with water (100 mL) and benzene (150 mL).

The precipitate is filtered off and the organic layer is separated, washed with 5% sodium bicarbonate and saturated ammonium sulphate solution until neutral, dried and evaporated to 20 ml of 5/3-formyl-2-diol-cyclopentane-> (--acetic acid-γ-lactone). to form a solution (about 0.02 moles) of an ester (acetate, propionate, p-phenylbenzoate, formate) or V-acetic ether (THP ether, DIOX ether), either in optically active or racemic form, for example a solution containing about 0.02 moles of dl-5- [3-formyl-2 ° (N, N-dihydroxy-cyclopentane-1H-acetic acid-Y-lactone-1-propionate].

a2) A stirred solution of dry pyridine (3.6 ml) in dry methylene chloride (90 ml) cooled to 5 ° C, 17 5667 β is treated with chromic anhydride (3.6 g); stirring is continued for 15 minutes at 18-20 ° C to form a dark red solution.

A solution of 0.06 mol of 5β-hydroxymethyl-20- (N-dihydroxy-cyclopentane-1 H -acetic acid-γ-lactone β-ester (acetate, propionate, p-phenylbenzoate, formate) is added. or N-acetal ether (THP-ether, DIOX-ether), either in optically active or racemic form, e.g. a solution of 2.11 g of 5H-6-hydroxymethyl-2 °, 1,1'-dihydroxy-cyclopentane- Lo <- acetic acid γ-lactone - β - p-phenylbenzoate, mp 129.5-131 ° C,, HL = -87.5¾, in dry methylene chloride in one portion, followed by vigorous stirring for 15 minutes. decant and the inorganic materials are washed with methylene chloride and combined with the first organic layer obtained.

ν '_

After evaporation of the solvent to 5-8 ml in vacuo, the residue is diluted with benzene (U-0-50 ml), treated with decolorizing carbon (1.5 g), filtered to give, after evaporation in 20 ml of vacuum, a benzene solution of about 0 ml. .06 moles of 5/3-foryl-2o (, · · ο (-dihydroxy-cyclopentane-lacto-acetic acid γ-lactone? -Ester (acetate, propionate, p-phenylbenzoate, formate) or -acetal ether (THP-ether, DIOX-ether), in either optically active or racemic form, e.g. 5/3-formyl-2 o (? l-o (-dihydroxy-cyclopentan-lo) -acetic acid-β-lactone M-p-tert-nyylibentsoaattiaj.

Alternatively, the benzene solution can be evaporated to dryness in vacuo, whereupon the crude 5/3 formyl derivative is then dissolved in dimethoxyethane (20 ml).

a) Using one of the methods described in a ^) and described in 5/3 -hydroxymethyl-2 -, - dihydroxy-cyclopentane-1-acetic acid γ-lactone L-ester or * + - acetal ether (dl- or optically active compounds) is oxidized to form the following 5/3-formyl derivatives (dl- or optically active compounds): 5/3-formyl-20 (R-dihydroxy-cyclopentane-lot-acetic acid N-lactone-L-formate, oil; -formyl-2-ol, .beta.-dihydroxy-cyclopentane-.beta.-acetic acid .beta.-lactone-.beta.-acetate, oil; 5,3-formyl-2H-dihydroxy-cyclopentane-.beta.-acetic acid lactone N-propionate, oil; 5R-formyl-2-s (-dihydroxy-cyclopentane-1 H -acetic acid β-lactone-β-phenylbenzoate, oil; 5667 (18 5/3-formyl) 2-Dihydroxy-cyclopentane-10β-acetic acid-γ-lactone-β-DIOX-ether, oil, 5,3-formyl-2-ol-β-dihydroxy-cyclopentan-10-acetic acid-γ-lactone -THP ether, oil.

b- ^) A stirred suspension of a $ 80 dispersion of sodium hydride (NaH) in mineral oil (0.58 g) in dry benzene (70 ml) is slowly treated with dimethyl (2-oxoheptyl) phosphonate (1 +, 5 ml) in absolute in benzene (15 ml).

When the formation of hydrogen has ceased (1 hour), a solution of 0.02 mol of the above-described (cf. a-^), a2) and a ^)) is added to the benzene suspension of the sodium salt of phosphonate with vigorous stirring. -2 ° (-dihydroxy-cyclopentane-1 - (-acetic acid γ-lactone β-ester or β-acetal ether in e.g. benzo-propionate) benzene. After 20 minutes, a 10% sodium dihydrogen phosphate solution is added and the organic layer is separated. and washed twice with 10% sodium dihydrogen phosphate. Each aqueous washing solution is re-extracted with benzene and combined with the first layer obtained. The organic phase is washed neutral with water, dried and evaporated to dryness with 5 / 3- (3-oxo-oct-1 "trans). -1 "-yl) -2-c, 1,1'-dihydroxy-cyclopentane-1c-acetic acid) (- lactone N + ester (formate, acetate, propionate, p-phenylbenzoate) or * f - acetal ether (DIOX ether or THP ether), for example 5.15 g of the corresponding dl-β-propion are obtained. azo derivative, ^ mlks 226 Ψ 9,800 · b2) A stirred suspension of 80 # dispersion of NaH mineral oil (198 mg) in dry dimethoxyethane (30 ml) is slowly treated with dimethyl (2-oxooctyl) phosphonate (1 , 32 ml) in dry dimethoxyethane to give a fine suspension of the sodium salt of the phosphonate (1 hour).

A solution of 0.006 mol of 5β-formyl-2 ° (, N, N -dihydroxy-cyclopentane-10 (-acetic acid-Y-lactone) ester (e.g. * + p-phenylbenzoate) is then added. ) in dimethoxyethane.

After one hour, the reaction mixture is diluted with benzene (2 vol.), The organic layer is washed with saturated sodium dihydrogen phosphate solution and saturated ammonium sulfate solution until neutral, and dried over sodium sulfate.

Removal of the organic solvents in vacuo gives 1 "-trans-5- [3- (1" -non-1 "-en-3" -one) -2 ° (, M -dihydroxy-cyclopentan-10 (acetic acid). cacetic γ-lactone ester or β-acetal ether (e.g. β-phenylbenzoate), mp 60-61 ° C.

Starting from 5/3 -formyl-2-diol-cyclopentane-1-acetic acid-1-lactone β-esters (acetate, propionate, p-phenylbenzoate) using the method described above, 5 / 3- (3 "- oxo-non-1 "-trans-en-1" -yl) -2H, N'-dihydroxy-cyclopentane-10β-acetic acid γ-lactone corresponding β-esters (acetate, propionate, p (Phenylbenzoate) (optically active or racemic) The acetate and propionate esters are oils, = 225 np, ί = 9 900, b ^) By giving 5/3-formyl-2 σt, 1,1-c-dihydroxy -Cyclopentane-10- (acetic acid-1-lactone ester (acetate, propionate, p-phenylbenzoate) in benzene (b. b) or dimethoxyethane (b2) (3-methyl-2-oxoheptyl) dimethoxyphosphonate with sodium salt, prepared 5/3 - (^ "- methyl-3" -oxo-oct-1 "-trans-en-1" -yl) -2o (N, N-dihydroxy-cyclopentane-1-acetic acid) - - The corresponding ester of γ-lactone, in the form of an optically active or racemic compound, β-phenylbenzoate sulphate .p. 105 ° C.

c ^) Sulfuryl chloride (13.5 nil) is added dropwise with stirring to a solution of dl-5 / 3- (3 "-oxo-oct-1" -trans-en-1 "-yl) -2 <= ( N - (- dihydroxy-cyclopentane-N-acetic acid N-lactone-N-p-phenylbenzoate (m.p. 120-122 °; ^ 8 g) in dry pyridine (95 ml) cooled 0-5 ° C, then stirring is continued for 16 hours at 0-2 ° C.

The reaction mixture is then poured into cold 2N H 2 O 2 (500 ml) and extracted several times with ethyl acetate (300 ml). The combined organic layers are washed with U-N H 2 SO 4, water with 5% NaHCO 3 and again with water until neutral, dried over sodium sulfate and evaporated to dryness in vacuo.

The crude residue (* +, 6 g) is then purified by filtration through a short column of silica gel (^ -0 g); eluting with methylene chloride; pure dl-5 / 3- (2 "-chloro-3" -oxo-3 "-oct-1" -trans-en-1 "-yl) -2- (N, N-dihydroxy-cyclopentane-1-yl) is obtained. -acetic acid γ-lactone-β-p-phenylbenzoate (m.p. 1 DEG-9 DEG-150 DEG C.; 3.2 g) i.e. dl-13t-11f-chloro-pentanor-911-dihydroxy- prost-13-ene-15-oxo-6-acid-γ-lactone-10 (p-phenylbenzoate).

c2) A mixture of isocyanuric chloride (0.9 g), acetic acid (9 ml), 5/3 - (3 "-oxo-non-1" -trans-en-1 "-yl) -2-dihydroxy - S6678 20 -cyclopentane-1H-acetic acid β-lactone-β-acetate and acetone (90 ml), refluxed under cooling for 2 hours, evaporated in vacuo to a small volume (25 ml) and then poured into cold 10% sodium carbonate solution The aqueous phase is repeatedly extracted with ether and the combined organic layers are washed with water, dried over sodium sulfate and evaporated in vacuo to give a crude chlorine derivative which is adsorbed onto a silica gel column.

Elution with methylene chloride gives 5/3 - (2 "-chloro-3" -oxo-non-1n-trans-en-1 "-yl) -2c <, L | -c> (- dihydroxy - cyclopentane-1 o (-acetic acid β-lactone-β-acetate (1.06 g), λmax = 2 ^ 2 sec, Έ = 9,300.

c) A solution of 5/3 - (3 "-oxo-oct-1" -trans-en-1 "-yl) -2 ° (N, N-dihydroxy-cyclopentane-1-acetic acid-Y β-lactone-β-p-phenylbenzoate (m.p. 80-82 ° C, = -1 * + 6 °; 1.2 g) in acetone (80 ml), treated with isocyanuric chloride (0.85 g) using the accompanying 10 perchloric acid (8 ml) and reflux for two hours.

The reaction mixture is concentrated in vacuo to a small volume, diluted with water and repeatedly extracted with ether.

The combined organic layers are washed with 5% NaHCO 3 and water until neutral, dried (Na 2 SO 4) and evaporated to dryness to give 5 / 3- (2M-chloro-3 "-oxo-oct-1 '' - trans). -luyl) -2-dihydroxy-cyclopentane-1 '(-acetic acid β-lactone-β-p-phenylbenzoate (0.85 g), mp 150-151 ° C, m.p. ] D = - 126.5 ° (chci3).

c) Sulfuryl chloride (10.5 ml) is added dropwise to a stirred solution of 5 ° (- (3 "-oxo-oct-1n-trans-en-1" -yl) -2H), * + ° C-dihydroxy-cyclopentane-1,3-acetic acid γ-lactone-β-p-phenylbenzoate (6.52 g) in dry pyridine (80 ml) cooled to 0-2 ° C, and stirring is continued at this temperature for 12 hours.

The reaction mixture is then poured into ice-water, acidified and repeatedly extracted with ethyl acetate. The combined organic layers are washed neutral, dried (£30%) and evaporated to dryness to give, after crystallization from methanol-ether, 5 ° (- (2 "-chloro-3" - oxo-oct-1 "-trans-en-1). "-yl) -2,3-dihydroxy-cyclopentane-1/3-acetic acid β-lactone - β-p-phenylbenzoate (5.8 g), i.e. 13β-chloropentanor-9/3 , 11-dihydroxy-8,12-diisoisor-prost-13-ene-15-one-6-acid-X-lactone-11-p-phenylbenzoate, mp 101-102 ° C.

c ^) Using 5o (- (1 + n-methyl-3 "-oxo-oct-trans-1" -en-1 "-yl) -2/3, * + o (-dihydroxy-cyclopentyl-1/3) In the process according to c), the following compound is obtained: 5 ° (- (2 "-chloro-1 +" - methyl-3 "-) - acetic acid β-lactone-5667- α-p-phenylbenzoate (1.2 g) oxo-oct-trans-1 "-en-1" -yl) -2/3, * + ° (-dihydroxy-cyclopentyl-1/3-acetic acid-α-lactone-Up-phenylbenzoate (0.93 g) i.e. 131-1β-chloro-16-methyl-pentanor-9,3,11-dihydroxy-8,12-diisoprost-13-en-15-one-6-acid -X-lactone-11-p-phenylbenzoate, mp 10U-106 ° C.

Cg) A stirred solution of 5 (3, f-oxo-non-trans-1 "- en-1" -yl) -2/3, * + o-dihydroxycyclopentyl-1/3-acetic acid Toni-Up phenyl benzoate (0.97 g) in dry pyridine (15 ml) cooled to 0 ° C is treated with sulfuryl chloride (1.6 ml) and kept at 0 ° C for 12 hours with stirring.

The reaction mixture is then poured into ice-water, acidified with U-N-H 2 SO 4 and extracted with ethyl acetate. The organic extracts are washed neutral, dried (Na 2 SO 4) and evaporated to dryness to give, after crystallization, 5 (2'-chloro-3 "-oxo-non-trans-1" -en-1 "-yl) - 2/3, Uo (-dihydroxycyclopentyl-1/3 -acetic acid-X-lactone-Up-phenylbenzoate (0.6 U g) i.e. 131-1 ^ -chloro-9 / 3,11 (diol-20 Ui - homo-pentanor-8,12-diisoisor-prost-13-en-15-one-6-acid-N-lactone-11-p-phenylbenzoate, mp 132-13 ° C, = - 17.6 ° (dec. 3).

Cy) To a stirred solution of dl-5 / β- (U "-methyl-3" -oxo-oct-1 "-en-1" -yl) -2 o (, U o (-dihydroxycyclopentyl-lo) -acetic acid β-lactone β-formate (2.3 g) in dry pyridine, sulfuryl chloride (2.5 molar equivalents) is added dropwise, and the reaction mixture is allowed to stand at 0 ° C for 10 hours with stirring. with water, acidified to pH 3 * + with NH 4 SO 4 and extracted with ether-methylene chloride (U: 1) The combined organic extracts are washed neutral, dried (Na 2 O 4) and evaporated to dryness, whereupon after crystallization dl-5 / 3- (2 "-chloro-Li-'' - methyl-3 '- oxo-oct-1" -en-1 "-yl) -2o (-dihydroxycyclopentyl-10 (acetic acid) is obtained -3β-lactone-U-formate (2.05 g) or dl-13t-11 + -chloro-16-methyl-9 ° (,? -> - dihydroxy-pentanor-prost-13-ene-15- oni-6-acid-X-lacto-ni-11-formate, oil, \ max ~ mP '& ~ 9 100.

Cg) Using the trans-enone lactones prepared in b), b2) and b), the 11-esters of the following compounds (acetates, p-phenylbenzoates, formates, propionates) are prepared in the process according to c) and Cy) and 11-acetal ethers (11-THP-ethers, 11-DIOX-ethers) all of which, with the exception of their p-phenylbenzoates, have a peak in the UV spectrum of 2 ^ 0-2 ^ -1 m /. = 9,000-10,000: 22 56676 13t-1α-chloro-9,11 ° -dihydroxy-pentanor-prost-13-en-15-one-6-acid-β-lactone; 13t-11 + -chloro-9 o (, 11c <-dihydroxy-20 (d-homo-pentanor-prost-13-ene-15-one-6-acid-β-lactone; 13t-11-chloro-16 -methyl-9β, 11β-dihydroxy-pentanor-prost-13-ene-15-one-6-acid-γ-lactone.

d- (1) -dl-1H-chloro-13t-9 o (, 11- (dihydroxy-pentanor-prost-13-ene-15-one-6-acid-X-lactone-11-p-phenylbenzoate ( 2.55 g) in dry dimethoxyethane (39.5 ml) is added to an ethereal solution of 0.065 M zinc borohydride (220 ml) with vigorous stirring, stirring is continued for 2.1 / 2 hours, the excess reagent is then discarded by careful addition of 2N H 2 SO 4) and the organic layer is separated and washed with 2N 2 SO 4 and water until neutral.Each aqueous washing solution is re-extracted with ether and combined with the organic phase.After drying (Na 2 SO 4) and removal of the solvents, the residue consisting of both epimeric 15S and 15R alcohols is absorbed in vacuo. eluting with ethyl ether to give dl-13t-11 + -chloro-9o (.11- (15S-trihydroxy-pentanor-prost-13-ene-6-acid-V). -lactone-11-p-phenylbenzoate (1.6 g) as an oil and dl-13t-11f-chloro-9 o (? 10 (15R-trihydroxy-pentanor-prost-13-ene) -6-acid-Y- lactone-II-p-tert nyl benzoate (0.9 g, m.p. 126-128 ° C).

d2) To a stirred solution of 0.05 M zinc borohydride in ether (500 ml) is added a solution of 13t-11L-chloro-90 <, 10 <-dihydroxy-pentanor-prost-13-en-15-one-6-acid - ^ - lactone-11-p-phenylbenzoate (* +, 8 g) in dry dimethoxyethane. After 15 minutes, the excess reagent is discarded by careful addition of saturated sodium chloride solution.

The zinc hydroxide precipitate is dissolved by adding 2N 2 SO 4, and the organic layer is separated and washed with 2N 2 SO 4 and water until neutral. Each aqueous wash is re-extracted with ether and combined with the organic phase.

After drying (Na 2 SO 4 [f]) and removal of the solvents in vacuo, the residue is absorbed onto a silica gel column (0.9 kg). Elution with ether gives 13t-1 * f-chloro-9β, 11S, 5S-trihydroxy-pentanor-prost-13-ene-6-acid-β-lactone-11β-phenylbenzoate ^ 2.7 gj = -79.5 ° (0Η01. ^ Γ \ and 13t-li + -chloro-9 ° (, 11 ((15R-trihydroxy-pentanor-prost-13-ene-6-acid-lactone-11-p-phenylbenzoate) 2.2 g, mp 83-85 ° C, tf <[D = -89 °.

d ^) Using the chloro-trans-23 S6678 enone lactones prepared in cg) above in the process according to d- ^) and dg), the 11-esters (acetates, formates, propionates, p-phenylbenzoates) and 11 -acetal ethers (11-THP-ethers, 11-DIOX-ethers): 13t-11L-chloro-90 (11,11 <, 15S-trihydroxy-pentanor-prost-13-ene-6-acid-β-lactone; 13t-1 * + -chloro-9β, 11β, 15S-trihydroxy-pentanor-20β-homo-prost-13-ene-6-acid-γ-lactone, with p-phenylbenzoate = -60 ° (CHCl 3) 13) -13 + -chloro-16-methyl-9,10 ° (15S-trihydroxy-pentanor-prost-13-ene-6-acid-γ-lactone, with p-phenylbenzoate = -70 ° (CHCl 3); ); 13t-1H-chloro-9c <, 11M, 15R-trihydroxy-pentanor-prost-13-ene-6-acid-γ-lactone, with p-phenylbenzoate = -83.5 ° (CHCl3); t-1M-chloro-9? -, 11β, 15R-trihydroxy-pentanor-20? -homo-prost-13-ene-6-acid-β-lactone, D = - 82 ° (CHCl 3) p 13β-11+ -chloro-16-methyl-9,10 (1,15R-trihydroxy-pentanor-prost-13-ene-6-acid-Y1 acton, D = -91 ° (CHCl 3) p-phenylbenzoate.

e) Sodium borohydride (MD mg) is added to a stirred solution of 13β-11,4-chloro-9β, 11β-dihydroxy-pentanor-8,12-diiso-prost-13-en-15-one-6- acid Y-lactone-Mp-phenylbenzoate (0.1 U · g) in methanol (10 ml) and methylene chloride (5 ml) cooled to 0-5 ° C. Stirring is continued for 30 minutes, the excess reagent is discarded by adding saturated NaHgPO 4 solution (1.5 ml) and the mixture is evaporated to near dryness in vacuo. After dilution with ethyl acetate, the organic layer is washed with water until neutral, dried (NagSO 4) and evaporated to dryness to give a crude product which is absorbed onto a silica gel column (80 g).

Elution with isopropyl ether-ethyl ether (75:25) gives 13β-1H-chloro-9,3,11,11R-trihydroxy-pentanor-8,12-diisoprost-13-ene-6-acid -Y-lactone-11-p-phenylbenzoate (0.15 g) and 13t-11-chloro-9/3, H, 15S-trihydroxy-pentanor-8,12-di-iso-prost-13-ene-- 6-acid γ-lactone-11-p-phenylbenzoate, i.e. 5 ° (- (2n-chloro-oct-trans-1 "-en-1" -yl) -2/2, *? 3 "S- trihydroxycyclopentyl-1,3-acetic acid γ-lactone-β-p-phenylbenzoate, m.p., m.p. = -25.2 ° (CHCl3) The above compounds have an OH band of 3 x 90 cm-1. .

Using the chloro-trans-eno-nl-lactones prepared in c) and c), d2) and d2) (reduction with zinc borohydride in dimethoxyethyl ether) e) (reduction with sodium borohydride in methanol-methylene chloride) was prepared : 2b 56678 13t-1H-chloro-9,11 c <, 15S-trihydroxy-pentanor-20β-homo-8,12-di-iso-prost-13-ene-6-acid-γ-lactone- 11-p-phenylbenzoate, oil, I ° * 3d -21.2 ° (CHCl 3); 13β-1U-chloro-9/3,11c *, 15S-trihydroxy-pentanor-16-methyl-8,12-diisopro-13-ene-6-acid-β-lactone-11-β -phenyl benzoate, oil, Ho = -23.5 ° (CHCl 3); 13β-1U-chloro-9,3,11β, 15R-trihydroxy-pentanor-20 M-homo-8,12-di-iso-prost-13-ene-6-acid-β-lactone-11-β -phenyl benzoate, oil, = -27.9 ° (CHCl 3); 13t-1H-chloro-9 / 4,11,15R-trihydroxy-pentanor-16-methyl-8,12-di-iso-prost-13-ene-6-acid Y-lactone-11-p-phenylbenzoate , oil, = 29.2 ° (CHCl 3).

All of these compounds have an OH band of 3 ^ 90 cm- · * ·.

f) A solution of 13t-1U-chloro-9 ° (, 11 ° 4, 15S-trihydroxy-pentanor-prost-13-ene-6-acid-X'-lactone-11-p-phenylbenzoate (1 , 6 g) in methanol, treated with 758 ml of $ 20 aqueous potassium carbonate, refluxed for 1 hour, cooled to room temperature and treated with UN HgSO 4 (6 ml), stirred for 3 hours at room temperature, the separated salts filtered off and the filtrate The residue is diluted with ethyl acetate and the organic phase is separated, the aqueous layer is repeatedly extracted with ethyl acetate (5 x 25 mL) and then the organic layers are combined, washed first with saturated sodium bicarbonate and brine to remove p-phenylbenzoic acid (then evaporated to dryness in vacuo to give 13t-1U-chloro-9α, 11,15S-trihydroxy-pentanor-prost-13-ene-6-acid-β-lactone or 5 / 3- (3 "-chloro- oct-l-trans "en- 1 "-yl) -2 ° (, Uo (> 3" S-tri-hydroxy-cyclopentyl-1 c <-acetic acid-β-lactone, as oil: = -17.8 ° (CHCl 3); 0.93 g (92% yield).

This compound is refluxed in benzene (30 ml) to collect the aqueous azeotrope in a water trap, the cooled solution is treated with 2,3-dihydropyran (1.2 ml) and p-toluenesulphonic acid (10 mg) in benzene (3 ml).

After 6 hours at room temperature, the benzene layer is washed with 5% sodium bicarbonate and water until neutral, and the solvent is evaporated in vacuo to give the crude product, 566788, which is absorbed onto a silica gel column (30 kg). Elution with cyclohexane-ethyl acetate (80:20) gives pure 13t-19-chloro-9 ° *, 11 ° * v, 15S-trihydroxy-pentanor-prost-13-ene-6-acid-N-lactone as an oil. -9 ° (15S-bis-THP-ether (1, * + 1 g); = -58.6 ° (CHCl 3 or 5/2 - (2 "-chloro-oct-trans-1" -en -1 "-yl) -2 ° <9,9-c> (.3" S-trihydroxy-cyclopentyl-1 ° <-acetic acid β-lactone-9-o (3 "S-bis-THP- ether.

f2) 13t-11 + -chloro-9 // 3.11 ° (, 15S-trihydroxy-pentanor-8,12-diisoprost-13-ene-6-acid-lactone-11-p-phenylbenzoate ( 2.9- g) in dry methanol (30 ml) is treated with anhydrous potassium carbonate (0.77 g) with stirring for 9-0 minutes at 10. The reaction mixture is neutralized with 15% aqueous acetic acid, evaporated to near dryness and diluted with ether. .

The organic layer is washed repeatedly with 5% NaHCO 3 and water until neutral, dried (Na 2 SO 4) and the solvent is evaporated off under vacuum to give 13t-19-chloro-9 / 3.11 «=> (15S-trihydroxy-Penta). -nor-8,12-diisoisor-prost-13-ene-6-acid-β-lactone (1.9-5 g), oil,

If3D = - ^ 1 ° (chci3).

This compound is treated in dry benzene (30 ml) with 1,9-dioxo-2-ene (2.2 ml) and p-toluenesulfonic acid (9.5 mg) in benzene (9 ml).

After 6 hours at room temperature, the organic phase is washed with 5 N NaHCO 3 and water until neutral and the solvents are evaporated to dryness in vacuo to give a crude product which is absorbed onto a silica gel column (60 g). Elution with cyclohexane-ethyl acetate (80:20) gives pure 13t-19-chloro-9β, 11β, 15S- -trihydroxy-pentanor-8,12-diisoprost-13-ene-6- acid γ-lactone - 11,15S-bis-DIOX ether (2.12 g) or 5 ° (- (2 "-chloro-oct-trans-1" -en-1 "-yl) -2 (2,9 - (? 3, 3'-S-trihydroxy-cyclopentyl-1H-3-acetic acid) -? - lactone (.beta. - .beta.-Bis-dioxa-1 ", 9 -" - nyl ether, = - 89- ° (CHCl 3).

f) Starting from 13β-19-chloro-9,11,15-trihydroxy-pentanor-prost-13-ene-6-acid-β-lactone 11-ester (acetate, propionate, formate, p-phenylbenzoate) and using the methods described in f- (2) and (f)), the free hydroxy derivatives, 11,15-bis-THP ethers and 11? (15-bis-DIOX-ethers of the following compounds were prepared: 13t-19-chloro-9 ° ( , 11 ° {., 15S-trihydroxy-pentanor-prost-13-ene-6-acid-β-lactone 13β-19-chloro-9 ° (, 11 ° <.15S-trihydroxy-pentanor-20 td- homo-prost-13-ene-6-acid-β-lactone, = -16 ° (CHCl 3)} 26 S6676 13t-1L-chloro-16-methyl-9β, 11β, 15S-trihydroxy-pentanor- prost-13-ene-6-acid-β-lactone, = "13 ° CCHCl 3); 13t-1H-chloro-9,5,5,10 (15R-trihydroxy-pentanor-prost-13-ene-6-acid - β-lactone, λmax = + 9 (CHCl 3); 13t-11 + -chloro-9 o <, 11,15R-trihydroxy-pentanor-20 (N-homo-prost-13-ene-6 -acid-β-lactone, = + 16 ° (CHCl 3) β 3 -1-chloro-16-methyl-9β, 11R *, (15R-trihydroxy-pentanor-prost-13-ene-6- acid-β-lactone, p = + 7 ° (C ^ HCl); 13t-11 + -chloro-9 / J 11 o (, 15S-trihydroxy-pentanor-8,12-di-iso-prost-13-N, N-ene-6-acid γ-lactone, oil, = “ 6.5 (CHCl 3); 13β-1H-4β, 3,11,15S-trihydroxy-pentanor-20-homo-8,12-di-iso-prost-13-ene-6-acid -X-lactone, oil, = -7.2 ° (CHCl 3); 13t-1-chloro-16-methyl-9 / 3.11 ° <, 15S-trihydroxy-pentanor-8,12-di- iso-prost-13-ene-6-acid-β-lactone, oil, ta D = -6.1 ° (CHCl 3; 13t-t1-chloro-9β, 3,11,15R-trihydroxy-pentanor-8 , 12-diisoiso-β-13-ene-6-acid-γ-lactone, 1β, <<= <JD = + b- ° (CHCl3) ^ 13t-11 + -chloro-9,11 o {, 15R-Trihydroxy-pentanor-20β-homo-8,12-di-iso-prost-13-ene-6-acid-β-lactone, oil, D = + 3.9 ° (CHCl 3) 13t-1+ -chloro-16-methyl-9H, 3,11,15R-trihydroxy-pentanor-8,12-di-iso-prost-13-ene-6-acid-γ-lactone, oil, = + 3.9 ° (CHCl 3).

f) Lithium borohydride (200 mg) is added portionwise to a stirred solution of 13t-11+ -chloro-9β-dihydroxy-pentanor-prost-13-en-15-one-6-acid-γ-lactone 11o ( acetal ether (11α-THP ether, 11c <-DIOX ether) (2.2 g) in methanol (* + 0 ml), stirring is continued for 30 minutes, then the excess reagent is discarded by adding saturated sodium dihydrogen phosphate solution and the reaction mixture is concentrated to a small volume. After drying (Na 2 SO 4) and removal of the solvents in vacuo, the residue is absorbed onto a column of silica gel (^ 00 g) and eluted with isopropyl ether-ethyl ether (50:50) to give 1.05 and 0, respectively. , 95 g of 13t-11l-chloro-9o (, 11 ((15-trihydroxy-pentanor-prost-13-ene-6-acid-β-lactone-10β-monoacetal ether (11β-THP-ether, 11-DIOX ether) both 15S and 15R epimers, which are reacted with 2,3-dihydropyran and 1,2-diox-2-ene if desired. to form the corresponding 11,15-bis-THP ether and 11,15-bis-DIOX ether.

27 56678 g ^) A stirred solution of 13t-1+ -chloro-9,11,11S-triol-pentanor-prost-13-ene-6-acid-γ-lactone-11 ' X ', 15S-bis-THP - ether (1, * + 1 g) in dry toluene (^ 3 nil) cooled to -60 ° C is treated with 0.5 M diisobutyl under nitrogen for 20 minutes. -aluminium hydride solution (15.8 ml). The mixture is further stirred for 30 minutes at -60 ° C and then treated with 12 ml of a 2 M solution of isopropanol in toluene. After 10 minutes, the mixture is warmed to 0-2 ° C, treated with water, sodium sulfate (2.8 g) and celite (1.2 g), then filtered. The filtrate is evaporated to dryness in vacuo to give 13t-1-chloro-9α, 11S, 5S-triol-pentanor-prost-13-en-6-allyl-γ-lactol-11β (15S-bis) as an oil. -THP - ether (1.38 g), t-D = -62 ° (CHCl 3 or 5 / 3- (2 "-chloro-oct-1" -trans-1-yl) -2 ° (? 3 "S-trihydroxy-cyclopentyl-10? -Ethanal-β-γ-lactol-β-β (? 3" S-bis-THP-ether.

g2) Under a nitrogen atmosphere, a 70% solution of sodium bis- (2-methoxyethoxy) aluminum hydride in benzene (2.2 U · ml) and toluene (8 ml) is added dropwise to a stirred solution of 13t-11 + chloro-9 ° (11,10R-trihydroxy-prost-13-ene-6-acid-γ-lactone-11,15S-bis-THP-ether (2.6 g), 1 * 1D = + 56 ° (CHCl 3) ^) in dry toluene (60 ml) cooled to -50 to -55 [deg.] C. Stirring is continued for three hours, after which the excess reagent is discarded by careful addition of a 5% acetone solution in toluene.

After 10 minutes, the mixture is warmed to 0-2 ° C, treated with saturated sodium dihydrogen phosphonate solution (3 mL) and the crystalline inorganic precipitate is filtered off.

The filtrate is evaporated to dryness in vacuo to give 13t-11 + -chloro-9,11,15R-trihydroxy-pentanor-prost-13-en-6-allyl-Y-lactol-11 (1,515-bis-THP- ether (2.55 g),? D = + 32, + (CHCl 3), as an oil.

Using the 11,15-bis-acetal ethers prepared in f) above in the methods of g) (diisobutylaluminum hydride reduction) and g2) (sodium bis- (2-methoxyethoxy) aluminum hydride reduction), 11,15-bis-acetal ethers (bis-THP-ether, bis-DIOX-ether) of the following lactol compounds were prepared, which were found to lack the IR band of γ-lactone at 1775 cm-1, while on the other hand the hydroxyl IR band is observed at 3 * + 0 cm-1: 13t-11 + -chloro-9β, 11,15S-trihydroxy-pentanor-prost-13-en-6-alpha-γ-lactol, oil; 28 56678 13t-1M-chloro-9 <= *, 11 c <, 15S-trihydroxy-pentanor-20k) -homo-prost-13-ene-6-alpha-γ-lactol, oil;

N, N-chloro-1b-methyl-N, N-S-trihydroxy-pentanor-prost-4-en-6-alpha-γ-lactol, Oil; 13β-chloro-9α, 11β, 11β-trihydroxy-pentanor-prost-13-en-6-allyl-γ-lactol, oil; 13t-yl + -chloro-9 o (1,1'-R'-trihydroxy-pent Anor-20-homo-prop-13-ene-6-alpha-γ-lactol, oil; 13t-lif-chloro -1,6-methyl-9β-1,1,15H-trihydroxy-pentanor-prost-13-ene-6-alpha-γ-lactol, oil, 13β-chloro-9β, 11,11 ° -trihydroxy-pentanor-8,12-di-iso-prost-13-ene-6-alpha-γ-lactol, Oil; 13t-11 + -chloro-9H, 3,11c -20-1H-homo-8,12-di-iso-prost-13-en-6-allyl-γ-lactol, oil, 13t-yl + -chloro-16-methyl-9 / 3,11,15R-trihydroxy -pentanor-8,12-di-isoprost-13-ene-6-alpha-γ-lactol, oil; 13t-1+ -chloro-9H, 1,1,11,5S-hydroxyhydro-pentanor-8 , 12-dl-10-prost-13-en-6-allyl-γ-lactol, oil; 13t-11 + -chloro-9,3,11 (15S-trihydroxy-pentanor-20-tert-homo-8 , 12-di-iso-prost-13-en-6-allyl-γ-lactol, oil, 13t-11 + -chloro-16-methyl-9/3, H, 15S-trihydroxy-pentanor-8,12- di - iso-prost-13-ene-6-alpha-γ-lactol, Oil.

Example 2 To a stirred solution of 5c, 13t-1H-chloro-9Y, 11β, 15S-trihydroxy-Prosta-5,13-diene-1-acid-11,15-bis-THP-ether in dry DMSO: (3 ml), a solution of potassium tert-butoxide (0.075 g) in dry DMSO (6 ml) is added under a nitrogen atmosphere and stirring is continued for 2 hours.

The reaction mixture is then diluted with water (10 ml), acidified to pH * f, 5 and repeatedly extracted with ether. The combined organic layers are washed with saturated ammonium sulfate solution until neutral, dried and evaporated to dryness in vacuo to give 5c-9 °, 11β (15S-trihydroxy-prost-5-en-13-yn-1-acid-11,15-bis). -THP-ether (0.118 g), J 1 = -18 ° (CHCl 3).

Example 3

A solution of triphenyl- (4-carboxybutyl) -phosphonium bromide (2.5b g) in dry DMSO (10 ml) is added at 5-10 ° C to a suspension of methylsulfinylcarbide starting from 80 overnight NaH (0.35 g) and from dry DMSO (10 mL) using the procedure described in Example 1 (A). The dark orange red ylide solution is then treated with 13t-11H-chloro-9β, 11,15R-trihydroxy-pentanor-8,12-diisoisor-prost-13-en-6-alpha-β-lactol-11,15 -bi s-DIOX-ether (0.6 g) dissolved in dry DMSO (13 ml) The mixture is stirred for only 12 minutes and then rapidly diluted with water (33 ml).

Extract with ether until all triphenylphosphoxide is removed, then re-extract the combined organic layers with 5% sodium bicarbonate. The pH of the combined aqueous phases is adjusted to α, --5- * f, 7 2N 2 SO 2, followed by extraction with ether-pentane (1: 1).

These organic layers are combined, washed neutral, dried (^ 230 ^) and evaporated to dryness to give 5c, 13t-11 + -chloro-9,11,15R-trihydroxy-8,12-diisoprost-5,13-diene - N-1-acid-11β, 15R-bis-DIXX ether (0.55 g) i.e. 11+ -chloro-15-epi-8,12-diisoiso-PGF2β-11,15R-bis-DI0X ether, oil.

Example * + a) A 7.2% solution of diisobutylaluminum hydride in toluene (16 ml) is added over 15 minutes to a stirred solution of 13t-1H-chloro-9,10 (1,5S-trihydroxy-pentanor). -prost-13-ene-6-acid X-lactone-11-p-phenylbenzoate (1.15 g) in dry toluene cooled to -60 ° C and stirring is continued for 30 minutes. isopropanol in toluene and after 10 minutes is warmed to 0-2 ° C, treated with water (1 ml), anhydrous sodium sulphate (2 g) and Celite (2.5 g) and filtered.

- The filtrate is evaporated to dryness in vacuo to give a crude product which is absorbed onto a silica gel column (30 g). Elution with cyclohexane-ethyl acetate * +: 6 gives 13t-11 + -chloro-9,11,15S-trihydroxy-pentanor-prost-13-en-6-alpha-β-lactol.

Starting from 13β-11+ -chloro-9β, 11β, 15-trihydroxy-pentanor-prost-13-ene-6-acid-γ-lactone 11-ester by corresponding reduction with diisobutylaluminum hydride, the following compounds were prepared; having the absence of an IR line of β-lactone at 1770 cm -1, while the IR band of hydroxyl has been found to be 3 ^ 50 cm -1; in: 13β-1β-α-9β, 11,15,15R-trihydroxy-pentanor-prost-13-en-6-allyl-X-lactol; 13β-11+ -chloro-16-methyl-9 ° 1,1,15S-trihydroxy-pentanor-prost-13-en-6-alpha-β-lactol; 3ο S6678 13β-11β-chloro-16-methyl-9β, 11β, 15R-trihydroxy-pentanor-prost-13-ene-6-alpha-β-lactol-13β-11+ -chloro-9β, 11c N, 15S-trihydroxy-pentanor-20-to-homo-prost-13-ene-6-alpha-X-lactol; 13β-1H-chloro-9,11,15R-trihydroxy-pentanor-20β-homo-prost-13-ene-6-alpha-γ-lactol 13β-1H-chloro-9β, 11, L5R-pentanor-trihydroxy-8,12-di-iso-prost - 13-ene-6-bellows-V-lactol; 13β-1H-chloro-9,3,11,10,15S-trihydroxy-pentanor-8,12-diisopro-13-ene-6-allyl-lactol; 13t-1 * + -chloro-16-methyl-11-9β / 3,11 ° 4,15S-trihydroxy-pentanor-8,12-diisoprost-13-en-6-alpha-β-lactol ; 13t-15 + -chloro-16-methyl-9 / 3.11 ° (15R-trihydroxy-pentanor-8,12-diisoprost-13-en-6-alpha-β-lactol; 13t-lLt - chloro-9,11 ° -15S-trihydroxy-pentanor-20β-homo-8,12-di-iso-prost-13-en-6-alpha-γ-lactol; 9β, 3,11 ° (15R-trihydroxy-pentanor-20 M-homo-8,12-diisoisor-prost-13-ene-6-α-β-lactol.

b) A stirred suspension of a $ 80 dispersion of sodium hydride mineral oil (1.08 g) in dry DMSO is heated under a nitrogen atmosphere at 60 ° C to form a DMSO solution of methylsulfinylcarbide (about 3 hours).

This mixture, cooled to 5-10 ° C and stirred, is treated with triphenyl- (α-carboxybutyl) -phosphonium bromide (7.98 g) in DMSO (2b ml). A solution of 5 turaman orange red ylides is then treated with 13t-11 + chloro-9.11 ° C. (15S-Trihydroxy-pentanor-prost-13-en-6-alpha-β-lactol (0.5-5 g) in DMSO (20 mL).

After 8 minutes, 26 ml of a red solution are removed from the reaction mixture, diluted with ice-water (26 ml) and repeatedly extracted with ether until all triphenylphosphoxide has been removed. The combined organic layers are re-extracted with 5N NaHCO 3; the pH of the combined aqueous phases is then adjusted to α, --5-7.7 with 2N H2SO4, followed by extraction with ether.

These combined organic layers are washed with 10% ammonium sulfate, dried (Na 2 SO 4) and evaporated to dryness in vacuo to give the crude product (0.15 g) which is absorbed onto an acid washed silica gel column (15 g).

Elution with cyclohexane-ethyl acetate (1: 1) and ethyl acetate gives pure 5c, 13t-11 + "chloro-9 ° (, 11 ° (15S-trihydroxy-31 56678-prosta-5,13-dien-1-acid (0.131 g ), = -6.9 ° (ethanol), i.e. 11+ -chloro-PGF 2 O. After 12 hours, the remainder of the reaction mixture (2/3 of the original mixture) is diluted with water (50 ml).

The aqueous phase is extracted with ether to remove triphenylphosphoxide and, after extraction with 0.5N NaOH, the organic layer is discarded.

The combined basic extracts are acidified with 2N E 2 SO 4 to pH and extracted with ether, the combined organic layers are washed neutral, dried and evaporated to dryness in vacuo.

Absorbing the residue (310 ml) on an acid-washed silica gel column (30 g) followed by elution with ethyl acetate gave 5c-9 ° (, - 11,15S-trihydroxy-prost-5-en-13-yn-1-acid (0.22 g). ), H 2 D = + 28 ° (ethanol), i.e. N-dehydro-PGF 2.

Using the same procedure, the N-chloro-lactol derivatives of Example 1 (g2) are reacted with a Wittig reagent derived from (N-carboxybutyl) triphenylphosphonium bromide to give the following compounds: 5c, 13t-IL (-chloro-9o ( , 11β, 1,5R-trihydroxy-prosta-5,13-dienoic acid, H1d = -25.5 ° (chci3) 5 5c, 13t-11 + -chloro-16-methyl-9 o <, 11ö <, 15S -trihydroxy-Prosta-5,13-dienoic acid,? -dis = -10O (CHCl3); 5c, 13t-11 + -chloro-9 DEG, -5,13-dienoic acid, δ = -8 ° (CHCl 3) $ 5c, 13t-1+ -chloro-9.11 ° (, 15R-trihydroxy-20k) -homo-Prosta-5.13 "- dienoic acid, Hd = -18 ° (CHCl3); 5c, 13t-1H-chloro-16-methyl-9,5R-trihydroxy-Prosta-5,13-dienoic acid, = -21 ° (CHCl3); 5c, 13t -lä - chloro-9 {Z, 11 ° E, 15S-trihydroxy-8,12-diisoiso-Prosta-5,13-dienoic acid, ^ = -17 ° (CHCl3) $ ^ 5c, 13t-1 N-chloro-9/8, H <= A, 15R-trihydroxy-8,12-diisoiso-Prosta-5,13-dienoic acid, [.alpha.] D @ 20 -11 DEG (CHCl3); 1H-chloro-16-methyl-9,3,11 <= 1,15S-trihydroxy-8.1 2-diiso-Prosta-5,13-dienoic acid, 1 D = -1 ^ 5 ° (CHCl 3); 5c, 11β-1H-chloro-1-methyl-N, S, 11α, 15R-trihydroxy-8,12-diiso-Prosta-5,13-dienoic acid, D = -I30 (CHCl3) $ 5c , 13t-1+ -chloro-9β, 11,15S-trihydroxy-20β-homo-8,12-diiso-Prosta-5,13-dienoic acid, = -17 ° (CHCl3); 5c, 13t-11 + -chloro-9 / 73,11β, 15R-trihydroxy-20β-homo-8,12-diiso-Prosta-5,13-dienoic acid, = -13 ° (CHCl3); 32 56678 5c-9β, 110β, 15R-trihydroxy-prost-5-en-13-ynoic acid, YfT1D = + 310 (CHCl3); 5-cis-9 / 11,11,15S-trihydroxy-8,12-diisoisor-prost-5-en-13-ynoic acid, Hd = -15.5 ° (CHCl3); 5-cis-16-methyl-9β, 11β, 15S-trihydroxy-prost-5-en-13-ynoic acid, δ = ¾ D = + 27.5 ° (CHCl 3) and 5-cis-16-methyl -9 ° i, 11β, 15R-trihydroxy-prost-5-en-13-ynoic acid, (k) d = + 16.2 ° (CHCl 3) i 5-cis-9 ° *, 11 ° i, 15S- trihydroxy-20lo-homo-prost-5-en-13-ynoic acid, (¾ = + 30.70 (CHCl3)) 5_cis-9β, γγΛ, 15R-trihydroxy-2010-homo-prost-5-en-13 -ynic acid, = + 33.8 ° (CHCl 3), 5-cis-9 / 3.11 °, 15R-trihydroxy-8,12-dl-iso-prost-5-en-13-ynoic acid, H1d = + 1 * + ° (CHCl3); 5-cis-16-methyl-9H, 11 ° <, 15S-trihydroxy-8,12-diisoisor-prost-5-en-13-ynoic acid, jWjD = + 12 ° (CHCl 3) $ 5-cis-16-methyl-9 / 3,11 ® <, 15R-trihydroxy-8,12-diisoisor-prost-5-en-13-ynoic acid, D = + 16 ° (CHCl 3); 5-cis-9 / 3.11 ° <15S-trihydroxy-20H-homo-8,12-diisoisor-prost-5-en-13-ynoic acid, D = + 1 ^ ( CHCl 3 -cis-9 / 3,11,15R-trihydroxy-20β-homo-8,12-dl-iso-prost-5-en-13-ynoic acid, 1 H-iD = + 13 ° (CHC13).

By a similar method, the following compounds were prepared: 5c-9 rsi, 11,15S-trihydroxy-8,12-diisoisoprosten-13-ynoic acid, colorless oil, \ f <\ D = -36 ° (CHCl3); 50-9,11,11S-trihydroxy-8,12-diisoproposten-13-ynoic acid,? -? - = 36 ° (CHCl 3) $ 5c-9 ° (11C) (, 15S) -trihydroxy-20 [alpha] -homo-8,12-diisoproposten-13-ynoic acid, [.alpha.] D @ 20 = -32 DEG (CHCl3) and 5C-16-methyl-9,11β (15S-trihydroxy- 8,12-diisoisoprosten-13-ynoic acid, [α] D = -36 ° (CHCl 3) δ 5c, 13t-11+ -chloro-9β, 11β, 15S-trihydroxy-8,12-di -iso-prostadienoic acid, 1 D = -1 ° (CHCl 3); 5c, 13t-16-methyl-11 + -chloro-9-ol, 11c, 15S-trihydroxy-8,12-diiso- prostadienoic acid, [α] D = -2.2 ° + ° (CHCl3); 5c, 13t-11 + -chloro-9c * ·, 11R, 15S-trihydroxy-2010-homo-8,12-diiso- 33 & 66β-prostadienoic acid, = -7 ° (CHCl 3); 5c, 13t-lb-chloro-9 / 3.11β, 15S-trihydroxy-prostadienoic acid, i.e. lb-chloro-PGF 2+, (¾ = - 2.6 ° (EtOH); 5c, 13t-lb-chloro-9/3, 11 ° <, 15S-trihydroxy-prostadienoic acid, = -1.2 ° (EtOH); 5c, 13t-lb-chloro-16- methyl-9,3,11 ° *, 15S-trihydroxy-prostadienoic acid, = + 1.9 ° (EtOH); 5c, 13t-1b-chloro-9β, 11,15S-trihydroxy-20β- homo-prostadienoic acid, -f? 1D = + 2.9 ° (EtOH); 5 ^ -9 ^, 11 ^, 15S-trihyd roxy-prosten-13-ynoic acid, lr * 1D = + 3.7 ° (EtOH); 5c-16-methyl-9/3,11 (1,5S-trihydroxy-prosten-13-ynoic acid, = + 2.8 ° (EtOH); 5c-9β, 11,15S-trihydroxy- 20 ta-homo-prosten-13-ynoic acid, λ = + 3.2 ° (EtOH).

Example 5

By reduction at -60 ° C of 9β, 11,15R-trihydroxy-prost-13-yne-O-acid-γ-lactone-11β-phenylbenzoate (0.82 g) sodium bis- (2 -methoxyethoxy) -aluminum hydride (3.5 eq.) after chromatographic purification on a silica gel column 9 ° (11β, 15R-trihydroxy-prost-13-yn-6-alpha-β-lactol (0.31 g ).

According to the procedure described in Example b- b), a DMSO solution of this compound (10 ml) is treated with a ylide solution obtained from 5.32 g of (b-carboxybutyl) triphenylphosphonium bromide, whereby after chromatographic purification on acid-washed silica gel ( 3b- g) (cyclohexane-ethyl acetate 30:70) gives 5c- [-90- (10?) - (15R-trihydroxy-prost-5-en-13-ynoic acid, + 31.5 ° (ethanol)) as a colorless oil (0 , 27 g).

Example 6 To a stirred and cooled to 17-20 ° C mixture of dl-13t-11 + -chloro-9 ° C, 11β (15S-trihydroxy-pentanor-prost-13-ene-6-acid-β-lactol -110S-bis-THP-ether (8.28 g) and (b-carboxybutyl) -triphenylphosphonium bromide (27.6 g) in dry DMSO (120 ml) are added under a nitrogen atmosphere with potassium tert-butoxide (15 ml). .68 g) solution in dry DMSO (180 ml).

566? «3 * +

The reaction mixture is stirred for 1 * + hour at room temperature, then diluted with water (300 ml) and treated in the usual manner to give dl-5c-9,11,15S-trihydroxy-prost-5-en-13-ynoic acid. (15-bis-THP-ether (7.95 g)).

This product (1.95 g) is treated in benzene with an ethereal solution of diazomethane (1.25 eq.) And after 15 minutes the reaction mixture is evaporated to dryness in vacuo to give the crude methyl ester (2 g) which is dissolved in acetone (115 ml) and heated to 0.1 N with aqueous oxalic acid (80 ml) for 12 hours at 0 ° C.

The acetone is removed in vacuo, after which the aqueous phase is repeatedly extracted with ether, the combined organic layers are washed with saturated ammonium sulphate solution, dried (Na 2 O 2) and evaporated to dryness in vacuo to give crude dl-5c-9 ° (, 11 trihydroxy-prost-5-en-13-ynoic acid methyl ester (1.6 g).

This product was absorbed onto a silica gel column (30 g) and then eluted with cyclohexane-ethyl acetate (65:35) to give pure dl-β-dehydro-PGF 2 -methyl ester (1.22 g, m.p. , 5 ° C).

Mass spectrum: m / e 3 - -8 (M + - H 2 O), m / e 330 (M + - 2 H 2 O), m / e 317 (M + - H 2 O-OCH 3), m / e 312 (M + - 3 H 2 O) , m / e 292 (M + - CH 2 = C (OH) OCH 3).

A solution of this compound (0.6 g) in methanol (76 ml) and water (8 ml) is treated with potassium hydroxide (0.1 * fg) for two hours at room temperature, then adjusted to pH 6, 6.8 and 6.8 with saturated sodium dihydrogen phosphate solution and after removal of methanol in vacuo, the reaction mixture is diluted with 0.1 N aqueous oxalic acid.

Extract with ether and wash neutral with saturated ammonium sulfate solution to give, after drying over Na 2 O 4 and removal of the solvent in vacuo, pure dl-5c-9H, 11K, 15S-trihydroxy-prost-5-en-13-ynoic acid (0.52 g, m.p.

80-82 ° C).

Example 7 A solution of dl-5c, 13t-11 + -chloro-9,11,15S-trihydroxy-prostadienoic acid-11α, 15S-bis-THP (0.228 g) in pyridine (0.6 ml) is treated with acetic anhydride (0, 2 ml) at room temperature. After 12 hours, the mixture is poured into 20% aqueous citric acid (10 ml) and extracted repeatedly with ether (80 ml), the combined organic phases are washed with 2N citric acid, water and saturated ammonium sulphate solution until neutral, dried (Na 2 SO 4) and evaporated to dryness. -5α, 13β-11+ -chloro-9α, 11β, 15- * 667 · 35 -t trihydroxy-prostadienoic acid 11β, 15S-big-THP-ether-9-acetate (0.22 g). A solution of this compound in acetone (2 ml) is treated with 0.2 N aqueous citric acid and heated for 20 hours after removal of the acetone. After extraction in vacuo, the reaction mixture is extracted with ether.

The combined organic extracts are washed neutral, dried and evaporated to dryness in vacuo to give the crude product (0.18 g). The residue is adsorbed onto an acid-washed silica gel column (1, ½ g) and eluted with cyclohexane-ethyl acetate.

After removal of the solvents from the 150/50 eluate of cyclohexane-ethyl acetate, an oil is obtained in vacuo, in the form of dl-5c, 13t-l-chloro-9 ° (, 11.0 (,, 15S-trihydroxy-prostadienoic acid-9-acetate).

Starting from the corresponding 9 ° (, 11 (, 15-trihydroxy-11β), 15-bis-acetal ethers, treating the carboxylic acid in pyridine with the appropriate anhydride or the appropriate chloride, and then de-etherifying, the following compounds are obtained: 5c, 13t-1 β-chloro-9β, 11β, 15S-trihydroxy-propylthienic acid 9-propionate, HD = + 27.2 ° (EtOH); -trhydroxy-prostadienoic acid 9-p-phenylbenzoate, = + ½9.50 (EtOH) $ 5c, 13t-1-chloro-9 ° (, 11.0 (, 15S-trihydroxy-propionic acid-9-benzoate, = + ,56.5 ° (EtOH) and 50-9β, 11β, 15S-trihydroxy-prosten-13-ynoic acid-9-acetate, λmax + 31.3 °; © (, 15S-trihydroxy-prosten-13-yl] -acid-9-p-cellenylbenzoate, [o <5D = + 65 ° (EtOH); 55c-9® (, H ° (, 15S- trihydroxy-prosten-13-ynoic acid-9-propionate, MD - 21.5 ° 5c-9 ° (, 11S (15S-trihydroxy-prosten-13-ynoic acid-9-benzoate, "= + 5 5c, 13t-1 chloro-16-methyl-9 ° (, 11 ° (15S-trihydroxy-prostadienoic acid-9-acetate, Y_ ° <SD = + 26.7 ° (EtOH)), 5c, 13t-1-chloro-16-methyl yl-9tK, 11 ° (, 15S'-trihydroxy-prostadenoic acid-9-p-phenylbenzoate,? p (1 D = + 57 ° (EtOH)) and 5c, 13t-1'-chloro-16-methyl-9 ° (, 11β (15S-trihydroxy-prostadienoic acid -9-benzoate, IfOj) = + 55, CB ° CBtOH) f 5c, 13t-11-chloro-16-methyl-9,11 °, 15S-trihydroxy-prostadienoic acid - 9-propionate, 1 D = + 36.2 ° (E'tOH); 5c-9 ° (1,1'-trihydroxy-prosten-13-ynoic acid-9-acetate,? 5 ^ ins + 29.2 °; 36 SM7 «50-9 ^, 110 ^, 15S-trihydroxy-prosten -13-ynoic acid 9-β-phenylbenzoate, Hd = ♦ 57 ° (EtOH) and 5c-9 ° <, 11 <, 15S-trihydroxy-prosten-13-ynoic acid 9 "benzoate, \ f» < [α] 25 D = +8.8 °; 5c-9 <?, 11c »<?, 15S-trihydroxy-prosten-13-ynoic acid-9-propionate, oil, '?

Example 8 An ethereal solution of 50,13 ^ 1 ^ - ^ 00.00 -9 / 3.110 (N, S-trihydroxy-N, N-diisoiso-Prosta-dienoic acid N, N-bis-DIOX-ether is treated at room temperature with a diazoalkane (e.g. , diazomethane) solution (1.2 eq. after 30 minutes) the mixture is evaporated to dryness in vacuo to give 5c, 13t-11 + -chloro-9 / 3.11 © <, 15S-trihydroxy-8,12-di-iso-prostadiene -nic acid-11,15-bis-DIOX-ether-methyl ester IR: ester bond 1720cm “\

Using the same procedure, methyl esters and ethyl esters of 1H-chloro-Prosta-dienoic acid and prosten-13-ynoic acid were prepared.

Example 9 To a solution of 5c-9β, 11β (15S-trihydroxy-prosten-13-ynoic acid-11 * (, 15S-bis-DlOX-ether in pyridine (2.75 ml) and methylene chloride (27 ml) is added n-octanol. (0.9 g) and cyclohexylcarbodiimide (0.5 g) After 2.1 / 2 hours the reaction mixture is filtered, concentrated in vacuo to a small volume and adsorbed onto a silica gel column, then eluting with cyclohexane-ethyl acetate-pyridine (800: 200: 5). pure 5c-9 ° (, 11S-{(15S-trihydroxy-prosten-13-ynoic acid-octyl) -ester (11S-bis-DIOX-ether (0.96 g) is obtained.

An acetone solution of this compound (50 ml) is heated after the addition of 0.1N aqueous oxalic acid (* + 0 ml) for 12 hours at 35- * + 0 ° C. The acetone is removed in vacuo and the aqueous phase is extracted with ether, after which the combined ether extracts are washed with saturated sodium chloride solution, dried (Na 2 SO 4) and evaporated to dryness in vacuo. 5c-9 ° (, 11β, 15S-trihydroxy-prosten-13-ynoic acid n-octyl ester, = + 19.2 ° (CHCl3)).

Starting from the corresponding 5α, 13β-chloro-trihydroxy-Prosta-diene-11,15-bis-ether instead of the corresponding 5α-trihydroxy-prosten-13-ynoic acid-11,15-bis-ether And further treating as as described above, by esterification with a suitable alcohol and optionally with de-ethyl acetate, esters of the following compounds were prepared: 37, 46-bis-ether1- (11,15-DIOX-ether- and 11,15-THP- -ether-) and 11,15-free alcohols], the physicochemical constants listed below apply to the 11,15-free alcohols of the compounds: 5c-9 *, 11 ^ (, 15S-trihydroxy-prosten-13-ynoic acid-trihloroethyl ester, = + 20 ° (CHCl 3); 5c-9 *, 11 ° (15S-trihydroxy-prosten-13-ynoic acid n-decyl ester, 1 * 1 D = + 21 ° (CHCl 3); 5c-9 *, 11c <, 15S -trihydroxy-prosten-13-ynoic acid n-octadecyl ester, 1 * 3 D = + 17 → 2 ° (CHCl3); 5c-9?, 1,11β, 15S-trihydroxy-prosten-13-ynoic acid n-dodecyl ester, * + 20 ° (CHCl 3); 5c-9β, 11β, 15S-trihydroxy-prosten-13-ynoic acid n-hexyl ester, 1¾ = + 23 ° (CH C13); 5c-9o (, 11c> (, 15S-trihydroxy-20 (o-homo-prosten-13-ynoic acid-n-octyl ester, D = + 20 ° (CHCl3)) 5c-9o (, llo <, 15S -trihydroxy-20 (N-homo-prosten-13-ynoic acid n-decyl ester, [α] D = + 26 ° (CHCl3); 5c-9 <*, 11 * (, 15S-trihydroxy-20 (u -homo-prosten-13-ynoic acid-n-octadecyl ester,] o (] D = + 2b ° (CHCl 3) and 5c-9 <?, 11 °, 15S-trihydroxy-20Lj-homo-prosten-13- ynoic acid trichloroethyl ester,] o <] β = + 25.8 ° (CHCl3) $ 5c-9oC, 11,5 (15S-trihydroxy-20 (a) -homo-prosten-13-ynoic acid-n-hexyl ester D = + 28 ° (CHCl 3 and 5c-16-methyl-9 o (, 11S, 15S-trihydroxy-prosten-13-ynoic acid n-octyl ester,] D = + 27 ° (CHCl 3, 5C-16-methyl-9 ° (, 11β, 15S-trihydroxy-prosten-13-ynoic acid n-decyl ester, ° C = 16 ° (CHCl 3)) -9o (, 11 © (, 15S-trihydroxy-prosten-13-ynoic acid n-octadecyl ester,] c <jD s + 22.8 ° (CHCl3) j 5c-16-methyl-9 ί, 11ο (, 15S-trihydroxy-prosten-13-ynoic acid-n-hexyl ester, j * 3D = + 29 ° (CHCl3); 5c-16-methyl-90 (? 10 (15S-trihydroxy-prosten-13-ynoic acid-n -trikl oo-rethyl ester, D = + 30 ° (CHCl 3) and 5c, 13t -1H-O 2 O-90 (1,115S-trihydroxy-prostadienoic acid trichloroethyl ester, ^ *] D = - ^ ° (CHCl 3) , · 5c, 13t-11-chloro-90 ° (, 11S, 15S-trihydroxy-prostadienoic acid n-octyl ester,? = 0D = + 1 ° (CHCl3), · 5c, 13t-11 + -chloro- 9β, 1,11,15S-trihydroxy-prostadienoic acid n-hexyl ester, Mds-5Λ0 (CHCl3) and 38 * Μ7 · 5c, 13t-11 + -chloro-9,3,11,15S-trihydroxy-prostadienoic acid -decyl ester, D = - if0 (CHCl 3); 5c, 13t-11f-chloro-9,15S-trihydroxy-prostadienoic acid n-dodecyl · ester, \ * \ D = -2 ° (CHCl 3 and 5c, 13t-11f-chloro-9,11,15S-trihydroxy -prostadienoic acid n-octadecyl ester, oil δQD = + 6.1 ° (CHCl 3); 5c, 13t-11 + "chloro-9d, 11 '(15S-trihydroxy-20'-homo-prostadienoic acid trichloroethyl ester, IR : ester bond 1720 cm -1; 5c, 13t-11L-chloro-9o (, 11ö (, 15S-trihydroxy * 20l * J-homo-prostadienoic acid - n-hexyl ester, IR: ester bond 1720 cm ”1; 5c, 13t- 11β-chloro-9 ', 11,15S-trihydroxy-20β-homo-prostadienoic acid-n-octyl ester, IR: ester bond 1720 cm -1; 5ο, 131-1 ^ · - ^ οογ1-9 o (, ΙΙοί 15S-trihydroxy-20 (O-homo-prostadienoic acid - n-decyl ester, IR: ester bond 1720 cm-1 ·; 5c, 13t-11 + -chloro-9β, 11β (15S-trihydroxy-20-li-homo -prostadienoic acid - n-dodecyl ester, IR: ester bond 1720 cm-1; 5c, 13t-1β-chloro-90 ° (, 11β (15S-trihydroxy-2010-homo-prostadienoic acid - n-octadecyl ester, IR: ester bond 1720 cm-1; 5c, 13t-11 + -chloro-16-methyl-9 o (, 11 ((15S-trihydroxy-prostadiene) appo - trichloroethyl ester, IR: ester bond 1720 cm-1; 5c, 13t-11 + -chloro-16-methyl-9 ° (, 11 ((15S-trihydroxy-prostadienoic acid - n-hexyl ester), IR: ester bond 1720 cm-1; 5c, 13t-11f-chloro-16-methyl- 90 ° (11β, 15S-trihydroxy-prostadienoic acid n-octyl ester, IR: ester bond 1720 cm-1; 5c, 131-1β-chloro-16-methyl-9 <=?, 11 ^, 15S- trihydroxy-prostadienoic acid n-n-decyl ester, IR: ester bond 1720 cm-1; 5c, 13t-11 + -chloro-16-methyl-90 <, U ° <, 15S-trihydroxy-prostadienoic acid - n-octadecyl ester, IR: ester bond 1720 cm-1; 50-9 ^ / 3.11 ° ^, 15S-trihydroxy-8,12-diisoproposten-13-ynoic acid trichloroethyl ester, IR: ester bond 1720 cm-1; 5c-9 [5,11 ° (.15S-trihydroxy-8,12-diisoproposten-13-ynoic acid n-hexyl ester, IR: ester bond 1720 cm-1; 5c-9/3, H ° (.15S -trihydroxy-8,12-diisoprosten-13-ynoic acid n-octyl ester, IR: ester bond 1720 cm-1; 5c-9 / 3.11 oi, 15S-trihydroxy-8,12-di -iso-prosten-13-ynoic acid-n-decyl ester, IR: ester bond 1720 cm-15 5c-9/3, 11 ° <, 15S-trihydroxy-8,12-di-iso-prosten-13-ynoic acid n-oktade-kyylieste ri, IR: ester bond 1720 cm-1; 5c-9 / 3,11cβ, 15S-trihydroxy-20 L0-homo-8,12-diisoprost-13-ynoic acid trichloroethyl ester, IR:, ester bond 1720 cm-1; 39 SM? · 5c-9,11,15S-trihydroxy-20H-homo-8,12-diisoisoprosten-13-ynoic acid n-hexyl ester, IR: ester bond 1720 cm -1 "5c -9/3,11β, 15S-trihydroxy-20 [alpha] -homo-8,12-diisoproposten-13-ynoic acid - n-octyl ester; IR: ester bond 1720 cm-1; 5c-9 / 3,11,15S-trihydroxy-20 (j-homo-8,12-diisoprosten-13-ynoic acid - n-decyl ester, IR: ester bond 1720 cm-1 '; 5c-9 [3,11β, 15S-trihydroxy-20 (o-homo-8,12-diisoprosten-13-ynoic acid - n-octadecyl ester, IR: ester bond 1720 cm-1; 5c-16-methyl-9 [3,11c], 15S-trihydroxy-8,12-diisoisoprosten-13-ynoic acid trichloroethyl ester, IR: ester bond 1720 cm-1; 5c-16-methyl-9?, 110 (, 15S- trihydroxy-8,12-diiso-prosten-13-ynoic acid n-hexyl ester, IR: ester bond 1720 cm -1 1,5c-16-methyl-9β, 11,15S-trihydroxy-8,12-di- iso-prosten-13-ynoic acid n-octyl ester, IR: ester bond 1720 cm -1 1,5c-16-methyl-9,3,11,11S-trihydroxy-8,12-di-iso-prosten-13 -ynic acid n-decyl ester, IR: ester bond 1720 cm -1 1,5c-16-methyl-9,3,11KK, 15S-trihydroxy-8,12-diisoproposten-13-yneic acid -octadecyl ester, IR: ester bond 1720 cm-1; 5ο, 13ϊ-1β-^ οογ1-9 / 3,11οι, 15S-trihydroxy-8,12-diisoisostadienoic acid trichloroethyl ester, IR: ester bond 1720 cm-1; 5c, 13t-11 + -chloro-9,3,11,11S-trihydroxy si-8,12-di-iso-prostadienoic acid n-hexyl ester, IR: ester bond 1720 cm -1; 5c, 13t-11 + -chloro-9H, 3,10 (1,5S-trihydroxy-8,12-diiso-prostadienoic acid n-octyl ester, IR: ester bond 1720 cm-1; 5c, 13t-1 > + - chloro-9,3,11 °, 15S-trihydroxy-8,12-diisoisostadienoic acid n-decyl ester, IR: ester bond 1720 cm -1; 5ο, 131-1 ^ -ω. οοΓΐ-9 / 3,11 ° (15S-trihydroxy-8,12-diisoisostadienoic acid n-octadecyl ester, IR: ester bond 1720 cm-1; 5c, 13t-11 + -chloro-9 / 11β, 15S-trihydroxy-20-homo-8,12-diiso-prostadienoic acid trichloroethyl ester, IR: ester bond 1720 cm-1; 5ο, 13ί-1? 1οοΠ-9/3 -20 L) -homo-8,12-dl-iso-prostadienoic acid n-hexyl ester, IR: ester bond 1720 cm -1 1,5c, 13t-11 + -chloro-9 / 3,11 (5S-trihydroxy-20 ( N-homo-8,12-diisoisostadienoic acid n-octyl ester, IR: ester bond 1720 cm-1; 5c, 13t-11 + -chloro-9 / 3.11 ° (15S-trihydroxy-20k) -homo-8,12-di-iso-prostadienoic acid n-decyl ester, IR: ester bond 1720 cm-1; 5c, 13t-11f-chloro-9β, 1,1 '(1,5S-trihydroxy-20 (jd -homo-8,12-di-iso-prostadienoic acid n-octadecyl ester, IR steroids 1720 cm -1; 5c, 13t-11 + -chloro-16-methyl-9β, 11,15S-trihydroxy-8,12-diisoprostadienoic acid trichloroethyl ester, IR: ester bond 1720 cm -1; > 40 566/8 5c, 13t-11 + -chloro-16-methyl-9H, 11 °, 15S-trihydroxy-8,12-diisoprostadienoic acid n-hexyl ester, IR: ester bond 1720 cm-1 ; 5c, 13t-11 + -chloro-16-methyl·l-9 / 3,11β, 15S-trihydroxy-8,12-diiso-prostadienoic acid n-octyl ester, IR: ester bond 1720 cm-1; 5c, 13t-1H-chloro-16-methyl-9H, 3,11 °, 15S-trihydroxy-8,12-diisoprostadienoic acid n-decyl ester, IR: ester bond 1720 cm -1; 5c, 13t-l + -chloro-16-methyl-9H? , 11β, 15S-trihydroxy-8,12-di-iso-prostadienoic acid n-octadecyl ester, IR: ester bond 1720 cm -1.

Example 10

A solution of compound 13,11f-dehydro-PGF20 (> (1 g) in acetone (0.5 ml) was added to an aqueous solution of sec-n-amylamine (2-8 mg) in water (9, 5 ml) · The solution was then dispensed into ampoules, which were lyophilized so that each ampoule contained 12.3 mg of 1,3,11-dehydro-PGF 2? 2 -2-aminopentylammonium salt, = + 30 ° in ethanol.

Example 11

To a solution of sodium phosphate buffer (10 mL, 0.1 mol) prepared by mixing a solution of Na 2 HPO 4 and NaHL 2 PO 4 was added a solution of 5% 13,11-dehydro-PGF 2+ (1 mL). ) in dioxane. The solution was divided into five portions and lyophilized to give the 13,1β-dehydro-PGF2β-sodium salt. With aqueous solution '^! ^ = + 30 ° + 1 °.

Claims (1)

66678 Claim: A process for the preparation of therapeutically effective 9?, - and 9? -Hydroxy-prostanoic acid derivatives of the general formula (I): R 2 R 1 R C 00E o to, / x 1! Rj 6 (!) A AC-CH- (CHO ) -CH. H '/ Dd 0 H / R r5 X and the racemates of the formula wherein R is a hydrogen atom, a pharmaceutically acceptable cation, a C 1-6 alkyl group or a trichloroethyl group, R 1 is -Cl 2 Cl 2 -, one of R 2 and R 1 is a hydrogen atom and another Cl is a hydroxy group, A is -CH = C- or -C = C-, one of R 1 and R 2 is a hydrogen atom and the other is a hydroxy group, R 8 is a hydrogen atom or methyl, n is 3 or in which the chains attached to the carbon atoms in the 8-position and 12-position have the trans configuration, characterized in that the optically active or racemic compound of the general formula (II) is o -OH ^ 0 - j ** S - £ I6 S \ AC-CH- (CH0) -CH, (II) t / \ 2 n 3 R '? R 1 where R 9, n and A have the same meaning as above, one of R 1 and R 2 is a hydroxy or a known protecting group attached to the chain via an ether oxygen atom and the other is a hydrogen atom, Y is a hydroxy or a known protecting group bonded to the ring via an ether oxygen atom and wherein the lactol ring has the trans configuration with respect to the hydroxy-aliphatic side chain is reacted with a Wittig reagent containing the group -Cl 2 Cl 2 -R 2 -COOR, wherein R 1 is as defined above and R is a hydrogen atom or a 5667 · k2 C 1-6 alkyl group to form a compound of general formula (III) R 2 Rg SR -C00R k ~ \ * 6 H v AC-CH- (CH 2) -CH 2 - III) x / \ dn 3 R'5 b \ wherein R, R1-, Y, A, R'4, R'4, R8 and n have the same meaning as above and wherein one of R2 and R8 is a hydroxy group and the other a hydrogen atom , followed by a compound of formula (III) wherein Y is a known protecting group as defined above and / or one of R 1 and R 2 is preferred. a known protecting group as defined in the formula and a second hydrogen atom, de-etherified at the 11- and / or 15-position to form a compound of general formula (I) and / or, if desired, reacting a compound of general formula (I) wherein R is a hydrogen atom with a pharmaceutically acceptable with a base to form a compound of general formula (I) wherein R is a cation of a base and / or, if desired, a compound of general formula (I) wherein R is a hydrogen atom is esterified to form a compound of general formula (I) wherein R is a C 1-8 alkyl group , and / or, if desired, a compound of general formula (I) wherein R is a C 1-8 alkyl group is hydrolyzed to form a compound of general formula (I) wherein R is a hydrogen atom. Patent treatment For the preparation of therapeutically effective 9o <- and 9 / * - hydroxy-prostane-dehydrating compounds of the formula (I) R2 Rg R, -COOR Ae y R, 1 \ S * \ 6 (i) / \ AC-CH- (CHO -CH 2 H OH / \ 2 n 3 h5 r ^ 666/8 and a racemic compound, in which there is a pharmaceutically acceptable cation, a C 1-4 alkyl group or a trichloroethyl group, R 1 is -CH 2 C ^ -, in which the group R2 and R · ^ are in the group and in the case of the hydroxyl group, A is Cl -CH = C- or -C = C-, in which the group R ^ and R · is in the group and a hydroxyl group, Rg is a hydrogen atom or a methyl group, n is 3 or * + and is preferably formed by an 8-column and a 12-column compound of the trans configuration, which can be used as an optimum The active or racemic compounds of formula (II) OH vj- 'tr PC Η' YA; C: CH- (OH2) n-CH3 (II) r'5 i are selected from Rg, n and A in the same manner as above, in the group R ^ och R '^ är en hydroxi- eller känd skyddsgr up to a mixture with an ether-cyanide and anhydrous atomic atom, and a hydroxyl-eller at the side of the ring group with an ether-cyanide, and with a light lactol ring in the trans-configuration of the compound to the hydroxy-aliphatic The reaction group, which is a Wittig reagent group, includes the group -C ^ C ^ -R - ^ - COOR, and the same group of R- ^ betecknar samma som ovan ocr R R en en väteatom eller en C ^^ g-alkylgrupp, för bildning - av en for which all of the formulas (III) R2 R3 / R, -COOR * 6 (III) H n AC-CH- (CH0) -CH0 Y / \ 2 n 3 r'5 r \