CH625236A5 - Process for the preparation of 1,3-benzodioxane-prostanoic acid derivatives - Google Patents

Description

The invention thus relates to a process for the preparation of 40 new 1,3-benzodioxane-prostanoic acid derivatives of the formula I and their antipodes and racemates

CD

wherein

Ri is a hydroxyl group, a straight or branched alkoxy group with 1-10 C atoms, a methylsulfamide group, a substituted or unsubstituted aryloxy group, a 0-CH2-UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V represents a phenyl ring substituted by one or more phenyl groups, alkoxy groups having 1-2 carbon atoms or halogen atoms, preferably bromine atoms,

A denotes a —CH2 — CH2— or a trans-CH = CH group,

B represents a cis-CH = CH group,

Z represents the hydroxymethylene group,

55 R2 denotes a hydrogen atom or an alkyl group with 1-5 C atoms,

R3 and R4 are the same or different and represent H, F, Cl, Br, J, CF3, CH3 or alkoxy groups with 1-2 C atoms and 60 if Ri represents a hydroxyl group, the salts with physiologically compatible bases.

Examples of suitable substituted or unsubstituted aryloxy groups R 1 are: phenoxy, 1-naphthoxy 65 and 2-naphthoxy, which can each be substituted by 1-3 halogen atoms, 1 phenyl group, 1-3 alkyl groups each having 1-4 C atoms, 1 chloromethyl, fluoromethyl, trifluoromethyl, carboxyl or hydroxy group.

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Straight and branched chain, saturated and unsaturated alkoxy radicals, preferably saturated with 1-10, in particular 1-6 C atoms, are suitable as the alkoxy group R 1. Examples include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert. Butoxy, pentoxy, hexoxy, heptoxy, octoxy, butenyloxy, isobutenyloxy, propenyloxy, alkyl groups R2 are those with 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl -, isobutyl and pentyl groups.

All inorganic and organic

Bases are considered as they are known to the person skilled in the art for the formation of physiologically tolerable salts. Examples include alkali metal hydroxides, such as sodium or potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.

The process according to the invention for the preparation of the new compounds of the formula I is characterized in that a lactol of the formula

(II)

OR,

wherein R2, R3, R4 and A have the meaning given above, and Rs and R6 are intermediately protected hydroxyl groups, with a Wittig reagent of the formula

Ph3 P = CH— (CH2> 3 — CORi (III)

wherein Ph represents a phenyl group and Ri the above

3 «has meaning, and compounds of the formula I, in which R 1 represents a hydroxyl group, are optionally converted into salts with physiologically compatible bases.

If compounds of the formula I are obtained which are present as Race-mat, these can be separated into the antipodes.

Another method according to the invention relates to the preparation of compounds of the formula

(IA)

wherein

Ri is a hydroxyl group, a straight or branched alkoxy group with 1-10 C atoms, a methylsulfamide group, a substituted or unsubstituted aryloxy group, a 0-CH2-UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V is a through one or more phenyl groups, alkoxy groups with 1-2 carbon atoms or halogen atoms, preferably bromine atoms, substituted phenyl ring,

A represents a - CH2 — CH2— or a trans - CH = CH group,

B represents an ice — CH = CH group,

7J represents the carbonyl group

R2 represents a hydrogen atom or an alkyl group with 1-5 C atoms,

50 R3 and R4 are the same or different and stand for H, F, Cl, Br, J, CF3, CH3 or alkoxy groups with 1-2 C atoms and if Ri represents a hydroxyl group, the salts with physiologically compatible bases, characterized in that is that 55 compounds of the formula I are first prepared by the process described above, the 11- and 15-hydroxyl groups are intermediately protected and then the 9-hydroxyl group is oxidized to the 9-keto group, and compounds obtained in which Ri is a hydroxyl group , optionally converted into salts with physiologically compatible bases. 60 The inventive reaction of the lactols II with the Wittig reagent of the formula III, which can be obtained from the corresponding phosphonium bromide with methanesulfinylmethyl sodium or potassium tert-butoxide in a customary manner in dimethyl sulfoxide, is preferably carried out at temperatures of 65 ° C. -100 ° C, preferably at 20 ° C-80 ° C, usually in an aprotic solvent, preferably dimethyl sulfoxide or dimethylformamide. The Wittig reagent can also be made from 4-Ri - CO-triphenylbu-

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tylphosphonium bromide are released with potassium tert-butoxide.

The oxidation of the 9-hydroxy group to the ketone, which takes place before the hydroxyl protective groups are split off, is usually carried out using the customary oxidizing agents, for example using Jones reagent (J. Chem. Soc. 1953, 25555). One works for. B. with an excess of the oxidizing agent in a suitable diluent, such as acetone, at temperatures between 0 ° C and - 50 ° C, preferably at - 20 ° C. The reaction is generally complete after 5 to 30 minutes, OK

The 9-hydroxy group is oxidized according to the invention after intermediate protection of the 11- and 15-hydroxy groups, for example by silylation (Chem. Comm. (1972), 1120). Silver carbonate on “Celite” or mixtures of chromium trioxide and is pyridine are suitable as further preferred oxidizing agents (Tetrahedron Letters 1968, 3363).

The hydroxyl protective groups are generally the radicals known to those skilled in the art, preferably cyclic α, β-unsaturated ethers, such as, for example, dihydropyran, dihydrofuran and α-ethoxyethylene and acyl radicals, such as, for example, aromatic and aliphatic organic acid groups, but preferably the benzoyl and acetyl radical.

The hydroxyl protective groups such as THP, THF can be eliminated by known methods in an aqueous solution of an organic acid, such as, for example, acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid. To improve the solubility, a water-miscible inert organic solvent is expediently added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferred. The hydrolysis is preferably carried out at temperatures between 20 ° C and 80 ° C. In the case of prostaglandin E type compounds, the hydrolysis is preferably carried out below 45 ° C. in order to avoid the formation of prostaglandin A compounds as a by-product.

To prepare the esters of the general formula I in which R 1 represents an alkoxy group with 1-10 C atoms, the 1-carboxy compounds can be reacted with diazo hydrocarbons in a manner known per se. The esterification with diazo hydrocarbons takes place, for example, by mixing a solution of the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the 1-carboxy compound in the same or in another inert solvent, such as methylene chloride. When the reaction has ended, preferably in 1 to 30 minutes, the solvent can be removed and the ester can be purified in the customary manner.

The prostaglandin derivatives of the general formula I with R 1 meaning a hydroxyl group can be converted into salts with equivalent amounts of the corresponding inorganic bases with neutralization. For example, when the corresponding PG acids are dissolved in water which contains the stoichiometric amount of the base,

after evaporation of the water or after adding a water-miscible solvent, for example alcohol or acetone, the solid inorganic salt.

To produce an amine salt, the PG acid is usually dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to this solution. The salt is usually obtained in solid form.

The lactoleather formula II serving as starting compounds can be prepared by combining 2-hydroxymethylphenols (saligenins) with dihalocarboxylic acids to give 1,3-benzodioxane-2-carboxylic acids of the general formula IV

25th

Civ ^

45

wherein R2, R3 and R4 have the meaning given above. The 1,3-benzodioxane-2-carboxylic acid thus obtained is in the 2 position as a racemate because of the asymmetric carbon atom, which can be separated into the optical antipodes by salt formation with optically active bases. The subsequent esterification can be carried out with the racemate or with the enantiomer. The 1,3-benzodioxane-2-carboxylic acid ester obtained in this way is preferably reacted with triphenylphosphine methylene or a methylphosphonic acid redialkyl ester and can then be used in a manner known per se by means of a Wittig or Wittig-Horner reaction with an aldehyde (preferably in the form of corresponding antipodes) a ketone of the general formula V can be represented

V,

wherein R2, R3, R4 and Rs have the meaning given above. The Ci6-diastereomer mixture which may be formed can be separated by the customary methods.

In the presence of noble metal salt catalysts, the ketone of the general formula V can be hydrogenated in an inert solvent, if desired in the 13.14 position (PG numbering).

The subsequent reduction to the a- and ß-Ci5 alcohols is usually carried out with sodium borohydride or zinc borohydride. The epimer mixture can according to the

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usually known methods are separated. After the introduction of hydroxyl protective groups, such as dihydropyran, in position 15 and optionally in position 11 (PG numbering), the lactone with diisobutyl aluminum hydride or lithium tri-tert-butoxy aluminum hydride can be used to produce the desired lactol general formula II can be reduced.

The reduction to the lactol of the general formula II can also be carried out without protective groups according to a simplified Corey synthesis according to German Offenlegungsschrift P 2328 131 with diisobutylaluminium hydride or lithium tri-tert-butoxy-aluminum hydride.

To introduce the hydroxyl protecting groups, the 11,15-diol (PG numbering) is reacted with, for example, dihydropyran in methylene chloride or chloroform using an acidic condensing agent, such as, for example, p-toluenesulphonic acid. The dihydropyran is generally used in excess, preferably in 4 to 10 times the theoretical amount. The reaction is usually complete at 0 ° C-30 ° C after 15-30 minutes.

One way of representing the starting compounds acety-lated in the 11-position is by reacting the lactol etherified in the 15-position (PG numbering) with acetic hydride in pyridine. After the lactol hydroxyl group has been released, a lactol of the formula II can be obtained.

The new prostanoic acid derivatives of the general formulas I and IA are valuable pharmaceuticals because, with a similar spectrum of action, they have a much stronger and, above all, much longer action than the corresponding natural prostaglandins.

The new prostaglandin analogues of the E and F type have a very strong luteolytic effect, i.e. To trigger luteolysis, much lower dosages are required than with the corresponding natural prostaglandins.

To trigger abortions, significantly smaller amounts of the new prostaglandin analogues are required compared to the natural prostaglandins.

The registration of the isotonic uterine contraction on the anesthetized rat and on the isolated rat uterus shows that the substances obtained according to the invention are considerably more effective and their effects last longer than with natural prostaglandins as the table below using the example of the compounds 1-8 according to the invention compared to identifies natural PG F2a. The investigations were carried out on gravid rats according to the usual methods. So gravid rats from 4th to 7th Day of pregnancy treated subcutaneously with the compounds obtained according to the invention.

The animals were sacrificed on day 9 and the uteri were examined for implantation sites.

table

Investigated Compound Relative Effect

PG F2a = 1 on abortion in the rat

1 (5Z, 13E) - (8R, 9S, 1 IR, 12R, 15R) - 300 9.1 l, 15-trihydroxy-15 - ({2S} -l, 3-benzodioxan-2-yl) -16, 17,18,19,20-pentanor-prostadienoic acid methyl ester

2 (5Z, 13E) - (8R, 9S, HR, 12R, 15R) - 30 9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16.17, 18,19,20-pentanor prostadienoic acid methyl ester

3 (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) - 30 9.1 l, 15-trihydroxy-15 - ({2S} -l, 3-benzodioxan-2-yl) -16.17 , 18,19,20-pentanor-prostadienoic acid (4-phenyl) phenacyl ester

Table (continued)

Investigated Compound Relative Effect

PG F2a = 1 on abortion in the rat

4 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) - 3 9, ll, 15-trihydroxy-15 - ({2S} -l, 3-benzodioxan-2-yl) -16.17, 18,19,20-pentanor-prostadienoic acid (4-phenyl) phenacyl ester

5 (5Z, 13E) - (8R, 9S, 1 IR, 12R, 15R) - 3 9, 11, 15-trihydroxy-15 - ({2R} -l, 3-benzodioxan-2-yl) -16.17 , 18,19,20-pentanor prostadienoic acid

6 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) - 3 9, 11, 15-Trüiydroxy-15 - ({2R} -l, 3-benzodioxan-2-yl) -l 6.17 , 18,19,20-pentanor-prostadienoic acid methyl ester

7 (5Z, 13E) - (8R, 9S, HR, 12R, 15S) - 10 9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16.17, 18,19,20-pentanor prostadienoic acid methyl ester

8 (5Z, 13E) - (8R, 9S, 1 IR, 12R, 15S) - 10 9.1 l, 15-trihydroxy-15 - ({2R} -l, 3-benzodioxan-2-yl) -16, 17,18,19,20-pentanor-prostadienoic acid methyl ester

As the table shows, the compounds produced according to the invention are equally abortive in a dose which is 3-300 times lower than that of 1 mg PG F2a per animal.

The new prostanoic acid derivatives are suitable for inducing menstruation or for interrupting pregnancy after a single intrauterine application. They are also suitable for synchronizing the sexual cycle in female mammals such as cattle, monkeys, pigs, rabbits, etc.

The good dissociation of effects of the substances that can be produced according to the invention is evident when examined on other smooth muscular organs, such as, for example, on the guinea pig ileum or on the isolated rabbit trachea, where a significantly lower stimulation can be observed than by natural prostaglandins.

The active substances of the PG E series mentioned have bronchodilator effects on the isolated rabbit trachea in vitro and strongly inhibit gastric acid secretion and have a regulating effect on cardiac arrhythmias. The new PG A and PG E series compounds also lower blood pressure and are diuretic.

The active ingredients of the F series produced according to the invention have a less bronchoconstrictor effect than natural prostaglandin F2a, which is of great advantage for their therapeutic use.

For medical use, the active ingredients can be converted into a form suitable for inhalation, for oral or parenteral administration.

Aerosol or spray solutions are expediently prepared for inhalation.

Tablets, coated tablets or capsules, for example, are suitable for oral administration.

Sterile, injectable, aqueous or oily solutions are used for parenteral administration.

The above-mentioned active ingredients are primarily intended to be used in conjunction with the auxiliaries known and customary in galenics, for example for the production of preparations for inducing abortion, for cycle control or for initiating birth. For this purpose, sterile aqueous solutions containing 0.01-10 ng / ml of the active compound can be used as an intravenous infusion solution. For the preparation of aqueous isotonic solutions, the acids are s

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15

and salts of compounds of the general formulas I and IA are particularly suitable. Alcohols such as ethanol and propylene glycol can be added to increase solubility.

example 1

(5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH, B = ice CH - CH; 1 la hydroxy group;

9H

Z Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

20th

a) 1,3-benzodioxane-2-carboxylic acid methyl ester

A solution of 12.4 g of saligenin in 100 ml of dimethylformamide was added dropwise to a suspension of 9.6 g of 50% sodium hydride in 100 ml of dimethylformamide with ice-water cooling. The reaction mixture was stirred at room temperature overnight.

9 ml of dichloroacetic acid were added to 50 ml of dimethylformamide while cooling with ice. A suspension of 5.3 g of 50% sodium hydride in 150 ml of dimethylformamide was added with ice cooling. The sodium hydride can also be added without solvent.

This sodium dichloroacetate solution was dropped at room temperature into the saligenin disodium solution prepared first. The reaction mixture was stirred at 60 ° C. for a total of 5 hours with the addition of potassium iodide. The dimethylformamide was distilled off on the oil pump during 35 of the last 3 hours. The semi-solid, brown residue was acidified to pH with concentrated aqueous citric acid solution and extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated on a rotary evaporator and mixed with diazomethane solution at approx. 10 ° C. After stirring for 1 hour at room temperature, the excess diazomethane and the solvent were removed using a water jet pump. The residue was poured into saturated sodium chloride solution, extracted with methylene chloride, the organic phase dried with magnesium sulfate, concentrated and purified by column chromatography on silica gel with hexane / 5-10% ethyl acetate. 6 g of 1, 3-benzodioxane-2-carboxylic acid methyl ester, melting point 28-29 ° C., were obtained. 50

b) [2-Oxo-2- (1,3-benzodioxan-2-yl) ethylidene] triphenyl phosphorane

40 ml of a 2.52 m butyl-lithium solution in hexane were added dropwise to a suspension of 39 g of triphenylmethylphosphonium umbromide in 250 ml of absolute ether at room temperature under argon and the mixture was stirred for 15 hours, likewise under argon and at room temperature. A solution of 9.78 gl, 3-benzodioxan-2-car-bonic acid methyl ester in 100 ml of absolute ether was added dropwise to the yellow ylene solution, the mixture was stirred at room temperature for 60 hours, the white precipitate was filtered off, dissolved in water and extracted with Ether.

The organic phase was combined with the filtrate, washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel with hexane / 20-100% ethyl acetate and then recrystallized from ethyl acetate.

Yield: 12 g, melting point 95-98 ° C.

c) (IS, 5R, 6R, 7R) -6 - [(E) -3-oxo-3 - ({2RS} -l, 3-benzo-dioxan-2-yl) -1-propenyl] -7 - benzoyloxy-2-oxabicyclo- [3,3,0] -octan-3-one 7 g (IS, 5R, 6R, 7R) -6-formyl-7-benzoyloxy-2-oxabicy-s cIo [3,3, 0] -octan-3-one [EJ Corey et al. J. Amer. Chem. Soc. 91, 5675 (1969)] and 11.2 g of [2-oxo-2- (1,3-benzodioxan-2-yl) ethylidene] triphenylphosphorane were stirred for 16 hours in 300 ml of benzene under argon at room temperature. The mixture was then evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel with hexane / 20-60% ethyl acetate as the eluent. 5 g of oil were obtained.

d) (IS, 5R, 6R, 7R, 3 / R) -6 - [(E) -3-hydroxy-3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propenyl] - 7-benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one

A solution of 2 g of the ketone obtained in c) in 140 ml of absolute dimethoxyethane was mixed with 140 ml of ethereal zinc borohydride solution (preparation: newer methods of preparative organic chemistry, vol. 4, p. 241, Verlag Chemie) and added under argon for 2 hours Room temperature stirred. After dilution with 100 ml of ether, the reaction solution was carefully mixed with water, shaken with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness in vacuo. The reaction products were separated by column chromatography on silica gel with hexane / 30-60% ethyl acetate as the mobile phase. The a-alcohol was eluted as the first product.

Yield: 0.8 ge) (2RS, 3aR, 4R, 5R, 6aS, 3 / R) -4 - [(E) -3-Hydroxy-3 - ({2RS} -1,3 -benzodioxan-2-yl ) -1-propenyl] -5 -hydroxy-perhydrocyclopenta [b] -furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4, Rs, Rö = hydrogen atom; the OH group at C-3 'is a-permanent.

5.5 ml of a 20% solution of diisobutylaluminum hydride in toluene were added under argon to a solution of 550 mg of the lactone alcohol shown in d) in 20 ml of absolute toluene, cooled to -60 ° C., and the mixture was stirred for 30 minutes. 60 ° C and terminated the reaction by dropwise addition of 2 ml of isopropanol. After adding 20 ml of water, the mixture was stirred at 0 ° C. for 15 minutes, extracted with ethyl acetate and / or methylene chloride, shaken with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness in vacuo. 520 mg of crude product of the above lactol were obtained, which was used in the next step without further purification.

f) (5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16.17, 18,19,20-pentanorprostadienic acid

General formula I: A = trans CH = CH; B = ice CH = CH; IIIa hydroxy group;

_.OH

Z = H; Ri = OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

To a solution of 3.46 g of 4-carboxybutyltriphenylphosphonium bromide in 10 ml of absolute dimethyl sulfoxide (DMSO) was added 14.98 ml of a solution of methanesulfinyl-methyl sodium in absolute DMSO (preparation: 2 g of 50% sodium hydride suspension were dissolved in 40 ml of absolute DMSO at 70 ° C) and stirred at room temperature for 30 minutes. This red-brown colored solution was cooled with water to a solution of 520 mg of that obtained in e)

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Lactols dropped in 5 ml of absolute DMSO. The reaction mixture was then stirred for 2 hours at 50 ° C. under argon, then the main amount of DMSO was distilled off on an oil pump (bath temperature 40-50 ° C.), 50 ml of ice water were added to the residue and the mixture was extracted three times with ether. This ether extract was discarded. The aqueous phase was acidified to pH »with 10% citric acid solution, extracted four times with an ether / hexane mixture (1: 1) and three times with methylene chloride. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel with methyl chloride / 1-10% ethanol as the mobile phase.

Yield: 310 mg g) The prostaglandic acid obtained according to f) was dissolved in methylene chloride and esterified with ethereal diazomethane solution. The evaporation residue was chromatographed on silica gel with methylene chloride / 4% isopropanol as the eluent. The prostaglan-din-carboxylic acid methyl ester listed as Example 1 was obtained.

Yield: 288 mg (a] g = +0.8 "(c = 0.25; CHCb)

IR: 3400 (wide), 1730.1590, 1490.980, 750 cm \

Example 2

(5Z, 13E) - (8R, 9S, llR, 12R, 15S) -9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

.OH

Z = ^ C '^ rH; Ri = OCH3, OH; R2, Rj, R4 = hydrogen atom, the OH group at C-15 is ß-permanent.

In the reaction of (IS, 5R, 6R, 7R) -6 - [(E) -3-oxo-3 - ({2RS} -l, 3-benzodioxan-2-yI-l- propenyl] -7-benzoyloxy-2-oxabicyclo [3,3,0] -octan-3-one the ß-alcohol was eluted from the column as the 2nd product:

a) (IS, 5R, 6R, 7R, 3'S) -6 - [(E) -3-hydroxy-3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propenyl] -7- benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one

Yield: 0.5 g b) (2RS, 3aR, 4R, 5R, 6aS, 3'S) -4 - [(E) -3-hydroxy-3-

({2RS} -1,3-benzodioxan-2-yl) -1-propenyl] -5-hydroxy-perhydrocyclopenta [b] furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4, R5, R6 = H; the OH group at C 3 'is β-permanent.

410 mg of the β-alcohol obtained according to a) were reacted with diisobutylaluminium hydride analogously to the procedure in Example 1 e). 400 mg of crude product were obtained.

c) (5Z, 13E) - (8R, 9S, IIR, 12R, 15S) -9, II, 15-trihydroxy-15- ({2RS} -1,3-benzodioxan-2-yl) -16.17, 18,19,20-pentanor prostadienoic acid

General formula I: A = trans CH = CH; B = ice CH = CH; lla hydroxy group.

• DH

Z = ~ ^ c ^ H; Ri = OH; R2, R3, Rj = H; the OH group at C-15 is β-permanent.

The 400 mg of lactol obtained in b) were, without further purification, analogous to the procedure in Example 1 f) with 2.66 g of 4-

Carboxybutyltriphenylphosphoniumbromid and 11.52 ml of the methanesulfinylmethylsodium solution described there implemented.

Yield: 220 mg.

d) The prostaglandic acid obtained according to c) was dissolved in methylene chloride and esterified with ethereal diazomethane solution. The evaporation residue was chromatographed on silica gel with methylene chloride / 4% isopropanol as the eluent. The methyl prostaglandincarboxylate listed as Example 2 was obtained.

Yield: 198 mg [a] g = -0.8 ° (c = 0.25; CHCLs)

IR: 3400 (wide), 1730.1590, 1490.980, 750 cm

Example 3

(5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - [{2R} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor-prostadienoic acid and methyl esters

General formula I: A = trans CH = CH; B = ice CH = CH; 11 a-hydroxy group,

.OH

Z = H; Ri = OCH3, OH; R2, Ri, R4 = H;

the OH group at C-15 is a-permanent.

a) (IS, 5R, 6R, 7R) -6 - [(E) -3-oxo-3 - ({2R} -l, 3-benzo-dioxan-2-yl) -l-propenyl] -7- benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one

The substance was obtained in the form of colorless crystals by benzene / ether crystallization of the oil described in Example 1 c).

Melting point: 129-130 ° C; yes] "= —147.4 ° (CHCh)

b) (IS, 5R, 6R, 3'R) -6 - [(E) -3-hydroxy-3 - ({2R} * '- 1,3-benzo-dioxan-2-yI) -l-propenyl ] -7-benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one

From 1.5 g of the ketone obtained according to Example 3a), the α-alcohol was obtained as the first product of column chromatography according to Example 1d) by zinc borohydride reduction.

Yield: 0.61 g [a] 23 = _ioi, 3 ° (CHCb)

c) (2RS, 3aR, 4R, 5R, 6aS, 3'R) -4 - [(E) -3-Hydroxy-3 - ({2R} -1,3-benzodioxan-2-yl) -1-propenyl ] -5-hydroxy-perhydro-cyclopenta [b] furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4, Rs, R6 = hydrogen atom, the OH group at C — 3 'is a-constant.

600 mg of the a-alcohol obtained according to b) were reacted with diisobutylaluminum hydride analogously to the procedure in Example le). 450 mg of crude product were obtained.

d) (5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - ({2R} -l, 3-benzodioxan-2-yl) -16.17, 18,19,20-pentanorprostadienic acid

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group,

OH

Z => C- * H; Ri = OH, R2, R3, R4 = hydrogen atom, the OH group at C-15 is a-permanent.

The 450 mg of lactol obtained in c) were, without further purification, analogous to the procedure in Example 1 f) with 3.8 g of 4-

s

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Carboxybutyltriphenylphosphoniumbromid and 16.5 ml of the methanesulfinylmethylsodium solution described there implemented.

Yield: 315 mg e) The prostaglandic acid obtained according to d) was dissolved in methylene chloride and esterified with ethereal diazomethane solution. The evaporation residue was chromatographed on silica gel with methylene chloride / 1-6% isopropanol as eluent. The prostaglandin carboxylic acid methyl ester listed as Example 3 was obtained.

Yield: 299 mg; [tx] g? = -21.2 ° (c = 0.4; CHCb) IR: 3400 (broad), 1730.1590, 1490.980.750 cm "1.

Example 4

(5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -9,11,15-trihydroxy-15 - ({2R} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor-prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

OH

Z = ^ Xl- ^ H; Ri = OCH3, OH; R2, R.% R-t = hydrogen atom, the OH group at C-15 is ß-permanent.

In the zinc borohydride reduction of (IS, 5R, 6R, 7R) -6 - [(E) -3-oxo-3 - ({2R} -l, 3-benzodioxan-2-yl) - described under 3 b) l-propenyl] -7-benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one (Example 3a) the ß-alcohol was eluted from the column as the second product:

a) (IS, 5R, 6R, 7R, 3 / S) -6 - [(E) -3-hydroxy-3 - ({2R} -l, 3-benzodioxan-2-yl) -l-propenyl] - 7-benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one Yield: 0.41 g; [a] o3 = —128 ° (CHCb)

b) (2RS, 3aR, 4R, 5R, 6aS, 3 / S) -4 - [(E) -3-Hydroxy-3 - ({2R} -l, 3-benzodioxan-2-yl) -l-propenyl ] -5-hydroxy-perhydro-cyclopenta [b] furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4, Rs, Rè = hydrogen atom, the OH group at C-3 'is β-permanent.

410 mg of the β-alcohol obtained according to a) were reacted with diisobutylaluminium hydride analogously to the procedure in Example 1 e). 400 mg of crude product were obtained.

(c) (5Z, 13E) - (8R, 9S, llR, 12R, 15S) -9, ll, 15-trihydroxy-

15 - ({2R} -l, 3-benzodioxan-2-yl) -16.17, 18, 19.20 -

pentanor-prostadienoic acid

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

OH

Z = H; Ri = OH; R2, R3, R4 = hydrogen atom,

the OH group at C-15 is β-permanent.

The 400 mg lactol obtained in b) were reacted without further purification analogously to the instructions in Example 1 f) with 2.66 g 4-carboxy-butyltriphenylphosphonium bromide and 11.52 ml of the methanesulfinylmethyl sodium solution described there.

Yield: 230 mg d) The prostaglandic acid obtained according to c) was dissolved in methylene chloride and esterified with ethereal diazomethane solution. The evaporation residue was chromatographed on silica gel with methylene chloride / 1-6% isopropanol as eluent. The prostaglandin carboxylic acid methyl ester listed as Example 4 was obtained.

Yield: 212 mg; [a] g = -46.4 ° (c = 0.25; CHCb) IR: 3400 (broad), 1730.1590, 1490.980, 750 cm.

Example 5

(5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy ~ 15 - ({2S} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = cis CH = CH. lla-hydroxy group; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

a) (IS, 5R, 6R, 7R) -6 - [(E) -3-oxo-3 - ({2S} -l, 3-benzo-dioxan-2-yl) -l-propenyl] -7- benzoyloxy-2-oxabicyclo- [3,3,0] octan-3-one

The mother liquor obtained according to Example 3a) was chromatographed on silica gel using hexane / 20-50% ethyl acetate as the eluent.

[a] g = 18.8 ° (CHCb)

b) (IS, 5R, 6R, 7R, 3 / R) -6 - [(E) -3-hydroxy-3 - ({2S} -l, 3-benzodioxan-2-yl) -l-propenyl] - 7-benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one

From 3 g of the ketone obtained according to Example 5 a), according to Example 1 d), the α-alcohol was obtained as the first product of a repeated column chromatography by zinc borohydride reduction.

Yield: 1.1 g.

c) (2RS, 3aR, 4R, 5R, 6aS, 3'R) -4 - [(E) -3-Hydroxy-3 - ({2S}) - l, 3-benzodioxan-2-yl) -l- propenyl] -5-hydroxy-perhydro-cyclopenta [b] furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4, Rs, Ro-H; the OH group at C-3 'is a-permanent.

800 mg of the a-alcohol obtained according to 5 b) were reacted with diisobutylaluminum hydride analogously to the procedure in Example 1 e). 750 mg of crude product were obtained.

d) (5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - ({2S} -l, 3-benzodioxan-2-yl) -16.17, 18,19,20-pentanor prostadienoic acid

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

OH

Z = ^; C ^ ag | H; Ri = OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

The 750 mg of lactol obtained in c) were reacted without further purification analogously to the procedure in Example 1 f) with 5.1 g of 4-carboxybutyltriphenylphosphonium bromide and 22 ml of the methanesulfinylmethyl sodium solution described there.

Yield: 480 mg e) The prostaglandic acid obtained according to d) was dissolved in methylene chloride and esterified with ethereal diazomethane solution. The evaporation residue was chromatographed on silica gel with hexane / 50-95% ethyl acetate as the mobile phase. The prostaglandin carboxylic acid methyl ester listed as Example 5 was obtained.

Yield: 450 mg; [a] g = + 51.2 ° (c = 0.5; CHCb) IR: 3400 (broad), 1730.1590, 1490, 980, 750 cm \

5

10th

15

20th

25th

30th

35

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45

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55

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625 236

10th

Example 6

(5Z, 13E) - (8R, 9S, IIR, 12R, 15S) -9, II, 15-trihydroxy-15 - ({2S}) - 1,3-benzodioxan-2-yI) -16,17,18 , 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

OH

Z = ^> C "^ H; R i = OCH.% OH; R2, Rs, R4 = H; the OH group at C-15 is β-permanent.

In the zinc borohydride reduction of (IS, 5R, 6R, 7R) -6 - [(E) -3-oxo-3 - ({2S} -l, 3-benzodioxan-2-yl) described in Example 5b) -1-propenyl] -7 -benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one (Example 5a) the β-alcohol was eluted from the column as the 2nd product:

a) (IS, 5R, 6R, 7R, 3 / S) -6 - [(E) -3-hydroxy-3 - ({2S} -l, 3-benzodioxan-2-yl) -l-propenyl] - 7-benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one

Yield: 0.7 g b) (2RS, 3aR, 4R, 5R, 6aS, 3 / S) -4 - [(E) -3-hydroxy-3-

({2S} -1,3-benzodioxan-2-yl) -1-propenyl] -5-hydroxy-perhydro-cyclopenta [b] furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4, Rs, Rö = H; the OH group at C 3 'is β-permanent.

600 mg of the β-alcohol obtained according to 6 a) were reacted with diisobutylaluminum hydride analogously to the procedure in Example 1 e). 470 mg of crude product were obtained.

c) (5Z, 13E) - (8R, 9S, llR, 12R, 15S) -9, ll, 15-trihydroxy-15 - ({2S} -l, 3-benzodioxan-2-yl) -16.17, 18,19,20-pentanor prostadienoic acid

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

OH

Z = ^ Cl- ^ H; Ri = OH; R2, Rs, Ra = H;

the OH group at C-15 is β-permanent.

The 470 mg lactol obtained in b) were reacted without further purification analogously to the procedure in Example 1 f) with 3.8 g 4-carboxybutyltriphenylphosphonium bromide and 16.5 ml of the methanesulfinylmethyl sodium solution described there.

Yield: 330 mg d) The prostaglandic acid obtained according to c) was converted into the prostaglandin carboxylic acid methyl ester analogously to Example 5 e).

Yield: 290 mg; [a] g = + 50 ° (c = 0.5; CHCb.) IR: 3400 (broad), 1730.1590, 1490, 980, 750 cm

Example 7

(5Z, 13E) - (8R, llR, 12R, 15R) -ll, 15-dihydroxy-9-oxo-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = cis CH = CH; 1 la hydroxy residue; Z = C = O; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

a) (IS, 5R, 6R, 7R, 3'R) -6 - [(E) -3-hydroxy-3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propenyl] - 7-hydroxy-2-oxabicyclo [3,3,0] octan-3-one A mixture of 1.97 g (IS, 5R, 6R, 7R, 3'R) -6 - [(E) -3 -

Hydroxy - ({2RS} -l, 3-benzodioxan-2-yl) -l-propenyl] -7-ben-zoyloxy-2-oxa-bicyclo [3,3,0] octan-3-one (prepared according to example 1 d) and 622 mg of potassium carbonate (anhydrous) in 91 ml of methanol (absolute) were stirred for 2 hours at room temperature under argon. The mixture was then poured into 90 ml of 0.1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried with magnesium sulfate and evaporated in vacuo. Chromatography of the crude product on silica gel (ether / ethyl acetate = 7: 3) 1 »gave 1.20 g of colorless oil.

b) (IS, 5R, 6R, 7R, 3'R) -6 - [(E) -3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propenyl] -3 ', 7 -bis- (tetrahydropyranyIoxy) -2-oxabicyclo- [3,3,0] octan-3-one 15 6.1 ml was added to a solution of 1.85 g of the diol obtained in a) in 50 ml of methylene chloride at an ice bath temperature Dihydropyran (freshly distilled) and 15 mg p-toluenesulfonic acid, stirred 15 'at this temperature, diluted with methylene chloride and shaken with sodium carbonate solution. The organic phase was washed with water, dried with magnesium sulfate and evaporated in vacuo. Chromatography on silica gel (ether) gave 2.2 g of the bis-tetrahydropyranyl ether.

25 c) (2RS, 3aR, 4R, 5R, 6aS, 3'R) -4 - [(E) -3 - ({2RS} -l, 3-benzo-dioxan-2-yl) -l-propenyl] -3 ', 5-bis- (tetrahydropyranyl-oxy) perhydro-cyclopentental [b] furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4 = H; Rs, R6 = THP; the OTHP group at C-3 'is a-permanent. 30 22 ml of a 20% DIBAH solution in toluene were added dropwise under argon to a solution of 2.2 g of the lactone obtained in b), cooled to -70 ° C., in 85 ml of absolute toluene. After 30 ', the reaction was terminated by dropwise addition of isopropanol and the mixture was stirred at 0 ° C. with the addition of 30 ml of water 15' 35. The mixture was then extracted with ethyl acetate, washed with brine, dried with magnesium sulfate and evaporated in vacuo. 2.2 g of lactol were obtained as a colorless oil.

40 d) (5Z, 13E) - (8R, 9S, IIR, 12R, 15R) -9-hydroxy-ll, 15-bis- (tetrahydropyranyloxy) -15 - ({2RS} -l, 3-benzodioxan-2- yl) -16,17,18,19,20-pentanor-prostadienoic acid

34.7 ml of a solution of methanesulfinylmethyl sodium in absolute dimethyl sulfoxide (solution: 2.5 g of 50% sodium hydride suspension in 50 ml of absolute dimethyl sulfoxide for 1 hour) were added dropwise to a solution of 9.5 g of 4-carboxybutyltriphenylphosphonium bromide in 40 ml of absolute dimethyl sulfoxide stir at 70 ° C) and stirred 30 'at room temperature. This ylene solution was then added dropwise at 15 ° C. to a solution of 2.16 g of the lactol obtained in c) in 40 ml of absolute dimethyl sulfoxide within 15 ′ and the mixture was stirred at 50 ° C. for 2 hours. The solvent was then largely distilled off under an oil pump vacuum and 45 ° C., the residue was taken up in 80 ml of water and extracted three to 55 times with ether. The organic extract was discarded. The aqueous phase was acidified to pH 4-5 with 10% citric acid solution and extracted four times with a mixture of hexane / ether 1 + 1. The ether / hexane extract was washed with brine, dried with magnesium sulfate 60 and evaporated in vacuo. After chromatography of the evaporation residue on silica gel, 2.48 g of the acid was eluted with ether as a colorless oil.

e) (5Z, 13E) - (8R, 11, R, 12R, 15R) -9-oxo-11,15-bis- (tetra-65 hydro-pyranyloxy) -15 - ({2RS} -l, 3- benzodioxan-2-yl) -16,17,18,19,20-pentanor-prostadienoic acid

A solution of 2.35 g of the alcohol obtained in d) in 30 ml of acetone was added at - 20 <; with 2.46 ml Jones-

11

625 236

Reagent (J. Chem. Soc. 1953,2555) and stirred 30 'at -20 ° C. Then 3 ml of isopropyl alcohol was added dropwise, the mixture was stirred at 20 ° C. for 10 ', diluted with ether and shaken three times with water. The organic phase was dried with magnesium sulfate and evaporated in vacuo. This gave t2.1 g of the ketone as a colorless oil.

f) (5Z, 13E) - (8R, 11R, 12R, 15R) -11.15-dihydroxy-9-oxo-

15 - ({2RS} -l, 3-benzodioxan-2-yl) -16.17, 18, 19.20 -

pentanor-prostadienoic acid

General formula I: A = trans CH = CH; B = cis CH = CH; IIIa hydroxy group; Z = C = 0; Ri = OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

2.1 g of the bis-tetrahydropyranyl ether obtained according to e) were stirred for 5 hours at 40 ° C. in 42 ml of a mixture consisting of 65 parts of glacial acetic acid, 35 parts of water and 10 parts of tetra-hydrofuran. The mixture was then evaporated to dryness at 0.1 torr and the crude product was purified by column chromatography. With chloroform / ethanol 95 + 5, 450 mg of the E2 derivative was eluted as a colorless oil.

g) To a solution of 130 mg of the acid obtained in f) in 4 ml of methylene chloride, 7 ml of an ethereal diazomethane solution were added dropwise at an ice bath temperature, the mixture was stirred 2 'and then evaporated in vacuo. After chromatography of the crude product on silica gel (ether / dioxane 95: 5), in addition to mixed fractions, 56 mg of the prostaglandin carboxylic acid methyl ester listed as example 7 were obtained as a completely uniform oil by thin layer chromatography.

IR: 3400 (wide), 1740, 1730, 1590, 1490, 980, 750 cm.

Example 8

(5Z, 13E) - (8R, llR, 12R, 15S) -ll, 15-dihydroxy-9-oxo-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor prostadienoic acid and methyl ester General formula I: A = trans CH = CH; B = cis CH = CH; lla-hydroxy group; Z = C = 0; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is β-permanent.

a) (IS, 5R, 6R, 7R, 3'S) -6 - [(E) -3-hydroxy-3 - ({2RS} -l, 3-benzodioxan-2-yl-l-propenyl] -7-hydroxy -2-oxabicyclo [3,3,0] octan-3-one

2.16 g (IS, 5R, 6R, 7R, 3 / S) -6 - [(E) -3-hydroxy - ({2RS} -l, 3-benzodioxan-2-yl) - 1-propenyl] - 7-benzoyloxy-2-oxabicyclo [3,3,0] octan-3-one (prepared according to Example 2a) and 687 mg of anhydrous potassium carbonate were stirred in 99 ml of methanol at room temperature for 2.5 hours. 99 ml of 0.1N HCl were then added, the mixture was stirred with 15 'extracted with ethyl acetate, the organic phase was shaken with brine, dried and evaporated in vacuo. The crude product was chromatographed on silica gel. 1.38 g of the diol was obtained as a colorless oil.

b) (IS, 5R, 6R, 7R, 3'S) -6 - [(E) -3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propenyl] -3 /, 7-bis - (tetrahydropyranyloxy) -2-oxabicyclo- [3,3,0] octan-3-one

4.5 ml of dihydropyran (freshly distilled) and 10 mg of p-toluenesulfonic acid were added to a solution of 1.38 g of the diol obtained in a) in 30 ml of methylene chloride at an ice bath temperature, and the mixture was stirred at about 5 ° C. for 15 ' , diluted with methylene chloride, shook with sodium bicarbonate solution, with brine, dried with magnesium sulfate and evaporated in vacuo. After chromatography of the crude product on silica gel (ether / hexane 8: 2), 1.91 g of bistro-tetrahydropyranyl ether was obtained as a colorless oil.

c) (2RS, 3aR, 4R, 5R, 6aS, 3'S) -4 - [(E) -3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propenyl] -3 ', 5 -bis- (tetrahydro-pyranyloxy) -perhydro-cyclopenta [b] furan-2-ol

General formula II: A = trans CH = CH; R2, R3, R4 = H; Rs, R6 = THP; the OTHP group at C-3 'is β-permanent.

In analogy to the procedure in Example 7 c), 1.91 g of the lactone obtained in b) was reduced in 75 ml of absolute toluene with 19 ml of diisobutylaluminum hydride (DIBAH) solution. After the usual work-up, 1.93 g of lactol were obtained as a colorless oil.

d) (5Z, 13E) - (8R, 9S, IIR, 12R, 15S) -9-hydroxy-ll, 15-bis (tetra-hydropyranyloxy) -15 - ({2RS} -l, 3-benzo-dioxane -2-yl) -16,17,18,19,20-pentanor prostanic acid

In analogy to the procedure in Example 7 d), 1.93 g of the lactol obtained according to c) were prepared in 30 ml of absolute DMSO with a ylene solution which was prepared from 8.47 g of 4-carboxy-butyltriphenylphosphonium bromide and 31 ml of methanesulfinylmethyl sodium solution , implemented. After the usual work-up, the crude product was purified by column chromatography. With ether, 2.1 g of the acid was eluted as a colorless oil.

e) (5Z, 13E) - (8R, llR, 12R, 15S) -9-oxo-ll, 15-bis- (tetra-hydro-pyranyloxy) -15 - ({2RS} -l, 3-benzodioxan-2 -yl) -16,17,18,19,20-pentanor-prostadienoic acid

In analogy to the procedure in Example 7 e), 2.05 g of the alcohol obtained in d) was oxidized in 50 ml of acetone with 2.14 ml of Jones reagent at −20 ° C. After working up, 1.84 g of the ketone was obtained as a colorless oil.

f) (5Z, 13E) - (8R, IIR, 12R, 15S) -ll, 15-dihydroxy-9-oxo-15 - ({2RS} -l, 3-benzodioxan-2-y!) - 16.17 , 18,19,20-pentanor prostadienoic acid

General formula I: A = trans CH = CH; B = cis CH = CH; lla-hydroxy group; Z = C = 0; Ri-OH, R2, R3, R4 = H; the OH group at C-15 is β-permanent.

Analogously to the procedure in Example 7 f), 1.84 g of the bis-tetrahydropyranyl ether obtained according to e) was stirred with 18 ml of the acetic acid / THF mixture. After working up and chromatography on silica gel (chloroform / ethanol = 95/5), 528 mg of the E2 derivative were obtained as a colorless oil.

g) 98 mg of the prostaglandic acid obtained according to f) was converted into the prostaglandin carboxylic acid methyl ester analogously to Example 7 g).

Yield: 76 mg;

IR: 3400 (wide), 1740, 1730, 1590, 1490, 980, 750 cm.

Example 9

(5Z, 13E) - (8R, llR, 12R, 15R) -ll, 15-dihydroxy-9-oxo-15 - ({2R} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = cis CH = CH; lla-hydroxy group; Z = C = 0; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

The preparation is carried out analogously to Example 7 a) -g) from the starting compound prepared according to Example 3 b). Yield 400 mg of prostadienoic acid as a colorless oil, 60 mg of prostadienoic acid remethyl ester (made from 130 mg of acid)

IR: 3500-3400, 1740, 1730, 1590, 1490, 980, 750 cm.

Example 10

(5Z, 13E) - (8R, IIR, 12R, 15S) -ll, 15-dihydroxy-9-oxo-15 ({2R} -l, 3-benzodioxan-2-yl) -16.17, 18.19 , 20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = cis CH = CH; lla-hydroxy group; Z = C = 0; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is β-permanent.

s

10th

IS

2 #

25th

30th

35

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55

fiO

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12

The preparation is carried out analogously to Example 8 a) -g) from the starting compound prepared according to Example 4 a).

Yield: 510 mg of prostadienoic acid as a colorless oil; 70 mg methyl prostadate (from 100 mg acid) IR: 3500-3400, 1740, 1730, 1590, 1490, 980, 750 cm.

Example 11

(5Z, 13E) - (8R, 11R, 12R, 15R) -11.15 -Dihydroxy-9-oxo-15 - ({2S} -l, 3-benzodioxan-2-yl) -16.17.17, 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = cis CH = CH; lla-hydroxy group; Z = C = Ö; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

The preparation is carried out analogously to Example 7 a) -g) from the starting compound prepared according to Example 5 b).

Yield: 310 mg of prostadienoic acid as a colorless oil; 50 mg methyl prostate (from 120 mg acid) IR: 3500-3400, 1740, 1730, 1590, 1490, 980, 750 cm \

Example 12

(5Z, 13E) - (8R, 1 IR, 12R, 15S) -11.15-Dihydroxy-9-oxo-15 - ({2S} -l, 3-benzodioxan-2-yl) -16.17.17 , 19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = cis CH = CH; lla-hydroxy group; Z = C = 0; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is β-permanent.

The preparation is carried out analogously to Example 8 a) -g) from the starting compound prepared according to Example 6 a).

Yield: 410 mg of prostadienoic acid; 150 mg methyl prostadate (from 210 mg acid)

IR: 3500-3400, 1740, 1730, 1590, 1490, 980, 750 cm-1.

Example 13

(5Z) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor prostate acid and methyl ester

General formula I: A = CH2-CH2; B = ice CH = CH; 1 la hydroxy group;

.OH

Z = H; Ri = OCH1, OH; R2, R3, R4 = H;

the OH group at C-15 is a-permanent.

a) (IS, 5R, 6R, 7R, 3'R) -6- [3-hydroxy-3 - ({2RS} -1,3-benzodioxan-2-yl) -l-propyl] -7-benzoyloxy- 2-oxa-bicyclo [3,3,0] octan-3-one

2.3 g of the a-alcohol obtained according to Example 1 d) and 230 mg of palladium on carbon (10%) were shaken in 40 ml of ethyl acetate under a hydrogen atmosphere for 2 hours. After filtering and evaporating, 2.3 g of the above alcohol were obtained as a colorless oil.

IR: 3600, 1775, 1720, 1590, 1490, 770 cm No olefinic protons were visible in the NMR spectrum.

b) (IS, 5R, 6R, 7R, 3'R) -6- [3-hydroxy-3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propyl] -7-hydroxy- 2-oxa-bicyclo [3,3,0] octan-3-one

2.20 g of the saturated alcohol obtained in a) gave 1.34 g of the saturated diol as a fabeless oil by transesterification according to Example 7 a).

IR: 3600 strong, 1775.1590.1490.760 cm.

c) (IS, 5R, 6R, 7R, 3'R) -6- [3 - ({2RS} -l, 3-benzodioxane

2-yl) -l-propyl] -3 ', 7-bis (tetrahydropyranyloxy) -

2-oxabicyclo [3,3,0] octan-3-one

From 1.13 g of the diol obtained in b) was obtained

Dihydropyran analogous to Example 7 b) 1.08 g of the above bistrahydropyranyl ether as a colorless oil. IR: 1775, 1590, 1490, 1100, 760 cm \

d) (2RS, 3aR, 4R, 5R, 6aS, 3'R) -4- [3- {2RS} -l, 3-benzo-dioxan-2-yl) -l-propyl] -3,5-bis (tetrahydropyranyl-oxy) -perhydro-cyclopenta [b] furan-2-ol

General Formula II: A = CH2-CH2; R2, R3, R4 = H; Rs, R6 = THP; the OTHP group at C-3 'is a-permanent.

According to Example 7 c), 1.06 g of the above lactol was obtained as a colorless oil by reducing 1.08 g of the bis (tetrahydropyranyl) ether prepared according to c). IR: 3600.1590, 1490.1100, 760 cm.

e) (5Z) - (8R, 9S, 1 lR, 12R, 15R) -9-hydroxy-l 1,15-bis- (tetrahydro-pyranyloxy) -15- ({2RS} -1,3-benzodioxane 2- yl) -16,17,18,19,20-pentanor-prostic acid

1.06 g of the lactol obtained according to d) were converted into 866 mg of the above-mentioned prostatic acid according to Example 7 d).

IR: 3600-3400.1710.1590.1490, 1100.760 cm.

f) (5Z) - (8R, 9S, llR, 12R, 15R) -9-ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18, 19.20 pentanor prostate acid

310 mg of the compound obtained according to e) were stirred in 9 ml of a mixture of acetic acid / water / tetrahydrofuran = 65/35/10 for 3 hours at 50 ° C. The mixture was evaporated to dryness in vacuo and, after chromatography on 10 g of silica gel (chloroform / ethanol 4 +1), 211 mg of the above compound were obtained as a colorless oil. IR: 3600-3300, 1710, 1590, 1490, 760 cm.

g) 7 ml of an ethereal diazomethane solution were added dropwise to a solution of 130 mg of the acid obtained in f) in 4 ml of methylene chloride at an ice bath temperature, the mixture was stirred for 15 'and then evaporated in vacuo. After chromatography of the crude product on silica gel (methylene chloride / 3% isopropanol), 90 mg of the prostagla-dincarboxylic acid methyl ester listed as example 13 were obtained.

IR: 3600-3300, 1730, 1590, 1490, 760 cm.

Example 14

(5Z) - (8R, 9S, llR, 12R, 15S) -9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor-prostic acid and methyl ester

General Formula I: A = CH2-CH2; B = ice CH = CH; 1 la hydroxy group;

.OH

Z = Ri = OCH3, OH; R2, R3, Ra = H;

the OH group at C-15 is β-permanent.

a) (IS, 5R, 6R, 7R, 3 / S) -6- [3-hydroxy-3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propyl] -7-benzoyloxy- 2-oxa-bicyclo [3,3,0] octan-3-one

Analogously to Example 13 a), 2.4 g of the β-alcohol obtained according to Example 2a was hydrogenated to 2.4 g of the above-mentioned saturated alcohol. A colorless oil was obtained. Ir: 3600.1775.1720.1590.1490.770 cm \

b) (IS, 5R, 6R, 7R, 3'S) -6- [3-hydroxy-3 - ({2RS} -l) 3-

benzodioxan-2-yl) -l-propyî] -7-hydroxy-2-oxa-bicyclo [3,3,0] octan-3-one

From 2.3 g of the saturated alcohol obtained in a) was obtained by transesterification with potassium carbonate

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Example 7 a) 1.39 g of the saturated diol as a colorless oil. IR: 3600 strong, 1775.1590.1490.760 cm \

c) (IS, 5R, 6R, 7R, 3 / S) -6- [3 - ({2RS} -l, 3-benzodioxan-2-yl) -l-propyl] -3 /, 7-bis (tetrahydropyranyloxy ) -2-oxa-bicyclo- [3,3,0] octan-3-one

From 1.0 g of the diol prepared according to b), 0.93 g of the above bis (tetrahydropyranyl) ether was obtained as a colorless oil with dihydropropyran analogously to Example 7 b). IR: 1775.1590, 1490, 1100.760 cnT1

d) (2RS, 3aR, 4R, 5R, 6aS, 3'S) -4- [3- {2RS} -l, 3-benzo-dioxan-2-yl) -l-propyl] -3 ', 5-bis ( tetrahydropyranyl-oxy) -perhydro-cyclopenta [b] furan-2-ol

According to Example 7 c), 0.7 g of the above lactol was obtained as a colorless oil by reduction of 0.74 g of the bis (tetrahydropyranyl) ether prepared according to c). IR: 3600.1590, 1490.1100, 760 cm.

e) (5Z) - (8R, 9S, IIR, 12R, 15S) -9-hydroxy-II, 15-bis- (tetrahydropyranyloxy) -15 - ({2RS} -l, 3-benzodioxan-2-yl) - 16,17,18,19,20-pentanor-prostic acid

0.7 g of the lactol obtained according to d) were converted according to Example 7 d) into 0.51 g of the above-mentioned prostatic acid. IR: 3600-3400, 1710, 1590, 1490, 1100, 760 cm f) (5Z) - (8R, 9S, llR, 12R, 15S) -9, ll, 15-trihydroxy-15 - ({2RS} -l , 3-benzodioxan-2-yl) -16,17,18,19,20-pentanor-prostic acid

Analogously to the procedure in Example 13 f), from 345 mg of the triol obtained in e), 219 mg of the above compound were obtained as a colorless oil.

IR: 3600-3300, 1710, 1590, 1490, 760 cm \

g) Analogously to the esterification described in Example 13 g), 85 mg of the prostaglandin carboxylic acid methyl ester listed as Example 14 were obtained from 120 mg of the acid obtained according to f).

IR: 3600-3300, 1730, 1590, 1490, 755 cm-1

Example 15

(5Z) - (8R, 9S, 11R, 12R, 15R) -9,11,15-trihydroxy-15 - ({2R} -l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor-prostic acid and methyl ester General formula I: A = CH2-CH2; B = ice CH = CH; 11 a-hydroxy group;

.OH

Z = ^? G. ^ H; Ri = OCH3, OH; R2, Rs, R-t = H; the OH group at C-15 is a-permanent.

Starting from the a-alcohol obtained according to Example 3 b), the title compounds were obtained analogously to the reaction stages described for Example 13 a) -g). IR: 3500-3300, 1730, 1590, 1490, 760 cm "1

Example 16

(5Z) - (8R, 9S, llR, 12R, 15S) -9, ll, 15-trihydroxy-15 - ({2R} -l, 3-benzodioxan-2-yI) -16,17,18,19, 20-pentanor-prostic acid and methyl ester General formula I: A = CH2-CH2; B = ice CH = CH; 11 a-hydroxy group;

OH

Z = ^> C - ^ «H; Ri = OCH3, OH; R2, R3, R-t = H; the OH group at C-15 is β-permanent.

Starting from the β-alcohol obtained according to Example 4 a), the title compounds were obtained analogously to the reaction stages described for Example 14 a) -g).

IR: 3400 (broad), 1730.1590, 1490.760 cm-1

Example 17

(5Z) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - ({2S} - l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor prostate acid and methyl esters

General formula I: A = CH2-CH2; B = ice CH = CH;

I la-hydroxy group;

OH

Z = ^ pcl ^ É H; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is a-permanent.

Starting from the a-alcohol obtained according to Example 5 b), the title compounds were obtained analogously to the reaction stages described for Example 13 a) -g).

IR: 3400 (broad), 1735.1590, 1490.760 cm-1

Example 18

(5Z) - (8R, 9S, 1 IR, 12R, 15S) -9,11,15-trihydroxy-15 - ({2S) -l, 3-benzodioxan-2-yl) -16,17,18,19 , 20-pentanor-prostic acid and methyl esters

General formula I: A = CH2-CH2; B = ice CH = CH;

II a-hydroxy group;

OH

Z = ^> C '- «H; Ri = OCH3, OH; R2, R3, R4 = H;

the OH group at C-15 is β-permanent.

Starting from the β-alcohol obtained according to Example 6 a), the title compounds were obtained analogously to the reaction stages described for Example 14 a) -g).

IR: 3400 (broad), 1735.1590, 1490.760 cm-1

Example 19

(5Z) - (8R, IIR, 12R, 15R) -ll, 15-dihydroxy-9-oxo-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor prostate acid and methyl esters

General Formula I: A = CH2-CH2; B = ice CH = CH; 1 la hydroxy group;

Z = ^> C = O; Ri = OCH3, OH; R2, R3, R4 = H; the OH group at C-15 is β-permanent.

a) (5Z) - (8R, IIR, 12R, 15R) -ll, 15-bis (tetrahydro-pyranyloxy) -9-oxo-l 5 - ({2RS} -1,3 -benzodioxan-2-yl) - 16,17,18,19,20-pentanor-prostic acid

300 mg of the compounds obtained according to Example 13 e) are converted into the abovementioned compound by oxidation analogously to Example 7 e), and 210 mg are obtained as a colorless oil. IR: 3600-3300,1740,1710,1590,1490,760 cm b) (5Z) - (8R, llR, 12R, 15R) -ll, 15-dihydroxy-9-oxo-15 - ({2RS} -l , 3-benzodioxan-2-yl) -16,17,18,19,20-pentanor-prostic acid

According to Example 7 f), 90 mg of the above-mentioned compound were obtained as a colorless oil from 150 mg of the compound obtained in a).

IR: 3600-3400, 1740, 1710, 1590, 1490, 760 cm s

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c) Analogously to Example 7 g), 75 mg of the prostaglandin carboxylic acid methyl ester were obtained from 90 mg of the acid obtained in b).

IR: 3600-3400, 1740, 1730, 1590, 1490, 750 cm Example 20

(5Z) - (8R, IIR, 12R, 15S) -ll, 15-dihydroxy-9-oxo-15- ({2RS} -1,3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor prostate acid and methyl esters

General formula I: A = CH2-CH2; B = ice CH = CH; IIIa hydroxy group;

Z = = O; Ri = OCH3, OH; R2, Rs, R-t = H; the OH group at C-15 is β-permanent.

a) (5Z) - (8R, IIR, 12R, 15S) -ll, 15-bis (tetrahydro-pyranyloxy) -9-oxo-15 - ({2RS} - l, 3-benzodioxan-2-yl) -16 , 17,18,19,20-pentanor-prostic acid

280 mg of the compound obtained according to Example 14 e) were converted into the above-mentioned compound by oxidation analogously to Example 7 e). 180 mg were obtained as a colorless oil.

IR: 3600-3300, 1740, 1710, 1590, 1490, 760 cm b) (5Z) - (8R, llR, 12R, 15S) -ll, 15-dihydroxy-9-oxo-15 - ({2RS} -l , 3-benzodioxan-2-yl) -16,17,18,19,20-pentanor-prostic acid

According to Example 7 f), 145 mg of the compound obtained in a) were converted to 80 mg of the diol mentioned above. IR: 3600-3400.1740.1710.1590, 1490.755 cm-1

c) Analogously to Example 7 g), from 80 mg of the acid obtained in b), 56 mg of the prostaglandin carboxylic acid remethyl ester mentioned were obtained.

IR: 3600-3400.1740.1730.1590, 1490.755 cm

Example 21

(5Z) - (8R, IIR, 12R, 15R) -ll, 15-dihydroxy-9-oxo-15 - ({2R} -l, 3-benzodioxan-2-yl) -16.17, 18.19, 20-pentanor prostate acid and methyl esters

General formula I: A = CH2-CH2; B = ice CH = CH; 11 a-hydroxy group.

Z = ^> C = O; Ri = OCHs, OH; R2, Rs, R4 = H; the OH group at C-15 is a-permanent.

Starting from the derivative of Example 15 corresponding to 13 e), the title compounds were obtained analogously to the reaction stages described for Example 19 a) -c). IR: 3500-3400, 1740, 1730, 1590, 1490, 750 cm

Example 22

(5Z) - (8R, IIR, 12R, 15S) -ll, 15-dihydroxy-9-oxo-15 - ({2R} -l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor prostate acid and methyl esters

General formula I: A = CH2-CH2; B = ice CH = CH; 1 la hydroxy group;

Z = ^> C = O; Ri = OCHs, OH; R2, Rj, R4 = H; the OH group at C-15 is a-permanent.

Starting from the derivative of Example 16 corresponding to 14 e), the title compounds were obtained analogously to the reaction stages described for Example 19 a) -c). IR: 3600-3400.1740.1730.1590, 1490.755 cm 1

Example 23

(5Z) - (8R, IIR, 12R, 15R) -ll, 15-dihydroxy-9-oxo-15 - ({2S} -l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor prostate acid and methyl esters

General formula I: A = CH2-CH2; B = ice CH = CH; 1 la hydroxy group;

Z = ^> C = O; Ri = OCHs, OH; R2, R3, R4 = H;

the OH group at C-15 is a-permanent.

Starting from the derivative of Example 17 corresponding to 13 e), the title compounds were prepared analogously to the reaction stages described for Example 19 a) -c). IR: 3600-3400.1740.1730.1590, 1490.755 cm

Example 24

(5Z) - (8R, IIR, 12R, 15S) -ll, 15-dihydroxy-9-oxo-15 - ({2S} -l, 3-benzodioxan-2-yl) -16,17,18,19, 20-pentanor prostate acid and methyl esters

General formula I: A = CH2-CH2; B = ice CH = CH; 1 la hydroxy group;

Z = ^ = C = O; Ri = OCHs, OH; R2, Rs, R4 = H; the OH group at C-15 is β-permanent.

Starting from the derivative of Example 18 corresponding to 14 e), the title compounds were prepared analogously to the reaction stages described for Example 19 a) -c). IR: 3500-3400, 1740, 1730, 1590, 1490, 750 cm 1

*

Example 26

(5Z, 13E) - (8R, 9S, 1 lR, 12R, 15R) -9,11,15-trihydroxy-15- ({2RS} - l, 3-benzodioxan-6-brom-2-yl) -l 6,17,18,19,20-pentanor prostadienoic acid and methyl ester

General formula I: A = trans CH = CH; B = cis CH = CH; lla-hydroxy group; Ri = OCH3, OH; R2, R4 = H; R3 = Br (p-constant to phenolic oxygen); the OH group at C-15 is a-permanent.

a) 5-bromo-2-hydroxy-benzyl alcohol

11.5 ml of bromine in 100 ml of carbon tetrachloride were added dropwise at 0-5 ° C. to a suspension of 24.8 g of saligenin and 24 g of calcium carbonate in a solvent mixture of 200 ml of carbon tetrachloride and 220 ml of methylene chloride. The reaction mixture was stirred for 24 hours at room temperature, then filtered and the precipitate washed with carbon tetrachloride. The CCk / ŒftCk phase was discarded. The solid was taken up in ethyl acetate / water, the organic phase was separated off, dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from methylene chloride. Leaf-like, colorless crystals (24 g) were obtained.

Melting point: 107-109 ° C (methylene chloride)

b) l, 3-Benzodioxan-6-bromo-2-carboxylic acid methyl ester

A solution of 20.3 g of the 5-bromo-2-hydroxybenzyl alcohol obtained in a) in 110 ml of dimethylformamide was added dropwise to a suspension of 9.6 g of 50% sodium hydride in 100 ml of dimethylformamide with ice-water cooling. The reaction mixture was at room temperature overnight

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touched. 8.62 ml of dichloroacetic acid were then added dropwise to 100 ml of dimethylformamide while cooling with ice. 5.04 g of 50% sodium hydride were then added in portions with ice cooling. This sodium dichloroacetate solution was stirred for 30 minutes at room temperature and then the bromine saligenin disodium solution prepared first was dropped into s. After addition of 1.5 g of sodium iodide, the reaction mixture was stirred for 4.5 hours at 60 ° C., during the last 2.5 hours most of the dimethylformamide was distilled off in vacuo. After cooling, the residue was acidified to pH 3 with aqueous citric acid solution, saturated with sodium chloride and shaken out several times with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated on a rotary evaporator and mixed with ethereal diazomethane solution at 0 ° C. until gas evolution ceased and the reaction solution remained yellow. The solvent was removed together with excess diazomethane in vacuo after stirring for half an hour at room temperature. The remaining bright crystal slurry 20 was purified by column chromatography on silica gel with methylene chloride or hexane / 10% ethyl acetate as the mobile phase.

Yield: 12.6 g

Melting point: 120 ° C (matted small needles made of methylene chloride / hexane)

c) [2-Oxo-2- (1,3-benzodioxan-6-bromo-2-yl) ethylidene] -triphenylphosphorane

15.63 ml of a 2.15 m butyllithium solution in hexane were added dropwise to a suspension of 13 g of triphenylmethylphosphonium umbromide (dried for 4 hours at 40 ° C. on an oil pump) in 85 ml of absolute ether with ice cooling and in an argon atmosphere and then stirred for 15 hours at room temperature. 4.59 g of the methyl 1,3-benzodioxane-6-bromo-2-carbonate obtained in b) was added dropwise to the yellow ylene solution in 75 ml of absolute benzene, the mixture was stirred at room temperature for 1 hour, the white precipitate was filtered off and dissolved Water and extracted with ether. The organic phase was combined with the filtrate, washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel with hexane / 20-100% ethyl acetate.

Yield: 5.6 g

Melting point: 172 ° -174 ° C (ethyl acetate)

The further reaction steps were carried out analogously to the instructions in 1 c) -g).

In an analogous manner, all other prostaglandic acids and esters described in the present examples can also be converted into the derivatives corresponding to Example 26.

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Example 27

(5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18, 19,20-pentanor-prostadienoic acid (4-phenyl) phenacyl ester. 55

General formula I: A = trans CH = CH; B = ice CH = CH; 11 a-hydroxy group;

Z =

OH

H; Ri -

O-CH2-CO - <0

R2, R3, R4 = H; the OH group at C-15 is a-permanent.

75 mg of the prostadienoic acid obtained according to Example 1 f) were stirred with 21 mg of triethylamine and 53 mg of p-phenylphe-

nacyl bromide in 4 ml acetone for 12 hours at room temperature under argon. After dilution with water, the mixture was extracted with ether, the ether extract was shaken with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was filtered through 5 g of silica gel with an ether / dioxane mixture. After recrystallization from methylene chloride / hexane, 55 mg of the title compound were obtained as colorless crystals.

Melting point: 118 ° C

IR: 3600, 1740, 1695, 1590, 1490, 980, 750 cm. Analogously to Example 27, all other prostaglandic acids described in the preceding examples can also be converted into the corresponding phenacyl esters.

Example 28

Tris (hydroxymethyl) aminomethane salt of

(5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-

15 - ({2RS} -l, 3-benzodioxan-2-yl) -

16,17,18,19,20-pentanor-prostadienoic acid

A solution of 32.9 mg of tris (hydroxymethyl) aminomethane in 0.1 ml of water was added to a solution of 103 mg of the prostadienoic acid prepared according to Example 1 f) in 14 ml of acetonitrile at 60 ° C., and the mixture was left at room temperature for 14 hours stand. 76 mg of the above salt were obtained as colorless crystals.

Analogously to Example 28, all other prostaglandic acids described in the preceding examples can also be converted into the corresponding tris (hydroxymethyl) amino methane salts.

Example 29

(5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, ll, 15-trihydroxy-

15 - ({2S} -l, 3-benzodioxan-2-yl) -16,17,18,19,20-

pentanor-prostadienoic acid (4-phenyl) phenacyl ester

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

OH

Z = ^> C- ^ H; Ri = O-CH2-CO— (CT) <g>

R2, R3, R4 = H; the OH group at C-15 is a-permanent.

130 mg of the prostadienoic acid obtained according to Example 5 d) are reacted analogously to Example 39 and 85 mg of the title compound are obtained as colorless crystals.

Melting point: 79 ° C-80 ° C IR: 3430.1745.1695.1585,1225.1030, 760, 750,

720 cm

Example 30

(5Z, 13E) - (8R, 9S, llR, 12R, 15S) -9, ll, 15-trihydroxy-

15 - ({2S} -l, 3-benzodioxan-2-yI) -16,17,18,19,20-

pentanor-prostadienoic acid (4phenyl) phenacyl ester

General formula I: A = trans CH = CH; B = ice CH = CH; lla-hydroxy group;

.OH

m H; Ri = O-CH2-CO

60

R2, R3, R4 = H; the OH group at C-15 is β-permanent.

100 mg of the prostadienoic acid prepared according to Example 6 c) are reacted analogously to Example 39 and 115 mg of the title compound are obtained as colorless crystals.

«S melting point: 60 ° C

IR: 3440, 1740, 1700, 1590, 1240, 1030, 760, 725 cm 1

B

Claims (10)

625 236 2 PATENT CLAIMS 1. Process for the preparation of new 1,3-benzodioxane prostanoic acid derivatives of the formula I and their antipodes and racemates (I.) wherein R1 is a hydroxyl group, a straight or branched alkoxy group with 1-10 C atoms, a methylsulfamide group, a substituted or unsubstituted aryloxy group, an O-CHî UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V represents a phenyl ring substituted by one or more phenyl groups, alkoxy groups having 1-2 C atoms or halogen atoms, A represents a —CH2 — CH2— or a trans-CH = CH group, B represents a cis-CH = CH group, 20 Z represents the hydroxymethylene group, R2 represents a hydrogen atom or an alkyl group with 1-5 C atoms, 25 R3 and R4 are the same or different and represent H, F, Cl, Br, J, CF3 CH3 or alkoxy groups with 1-2 C atoms and if Ri represents a hydroxyl group, the salts with physiologically compatible bases, characterized in that a lactol of the formula 30th (II) OR, wherein R2, R3, R4 and A have the meaning given above, and Rs and R6 are intermediately protected hydroxy groups, with a Wittig reagent of the formula Phs P = CH- (CH2) 3-CORi (III) 55 wherein Ph represents a phenyl group and Ri has the meaning given above, and compounds of the formula I obtained, in which Ri represents a hydroxyl group, optionally converted into salts with physiologically compatible bases. 2. The method according to claim 1, characterized in that compounds which are present as racemates are separated into the antipodes. 3. The method according to claim 1, characterized in that (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -9,11,15-trihydroxy-15 - ({2S} -l, 3-benzodioxan-2-yl) -16, 17,18,19,20-penta-nor-prostadienoic acid methyl ester. 4. The method according to claim 1, characterized in that one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -9,11,15-trihy- 60 65 droxy-15 - ({2RS} -l, 3-benzodioxan-2-yl) -16,17,18,19,20-pen-tanor-prostadienoic acid methyl ester. 5. The method according to claim 1, characterized in that (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -9, 11, 15-trihydroxy-15 ({2S} -l, 3- benzodioxan-2-yl) -16,17,18,19,20-penta-nor-prostadienoic acid methyl ester. 6. The method according to claim 1, characterized in that (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -9, 11, 15-trihydroxy-15 ({2RS} -l, 3- benzodioxan-2-yl) -16,17,18,19,20-pen-tanor-prostadienic acid methyl ester. 7. The method according to claim 1, characterized in that (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -9, 11, 15-trihydroxy-15 - ({2RS} -l, 3rd -benzodioxan-6-brom-2-yl) -16,17,118, -19,20-pentanor-prostadienic acid methyl ester. 8. The method according to claim 1, characterized in that obtained compounds in which Ri is a hydroxyl group are converted into the corresponding esters. 9. Process for the preparation of new 1,3-benzodioxane-prostanoic acid derivatives of the formula IA and their antipodes and racemates 3rd 625236 (IA) wherein Ri is a hydroxyl group, a straight or branched alkoxy group with 1-10 C atoms, a methylsulfamide group, a substituted or unsubstituted aryloxy group, a 0-CH2-UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V represents a phenyl ring substituted by one or more phenyl groups, alkoxy groups having 1-2 C atoms or halogen atoms, A represents a —CH2 — CH2 or a trans — CH = CH group, B represents a cis-CH = CH group, Z 'represents the carbonyl group, 15 20th 25th R2 represents a hydrogen atom or an alkyl group with 1-5 C atoms, R3 and R4 are the same or different and stand for H, F, Cl, Br, J, CF3, CHs or alkoxy groups with 1-2 C atoms and if Ri represents a hydroxyl group, the salts with physiologically compatible bases, characterized in that a compound of the formula I is prepared by the process according to claim 1, the 11- and 15-hydroxy groups are intermediately protected and then the 9-hydroxy group is oxidized to the 9-keto group, and compounds obtained in which Ri is a hydroxyl group, if appropriate converted into salts with physiologically compatible bases. It is generally known that the diverse effects of prostaglandins, both in the mammalian organism and in vitro, are short-lived, since they are rapidly converted into pharmacologically inactive metabolites. For example, a largely inactive metabolite is formed by oxidation of the allylic hydroxy function on carbon atom 15 by 15-hydroxy-prostaglandin dehydrogenases. It was therefore desirable to develop prostaglandin analogs with a spectrum of activity comparable to that of natural prostaglandins and to change the structure 35 to increase the duration and selectivity of effectiveness. It has now been found that the new 1,3-benzodioxane prostaglandins surprisingly have a longer duration of action, greater selectivity and better activity than the natural prostaglandins.