CH625211A5 - Process for the preparation of thiaprostaglandins - Google Patents

Description

The invention relates to a process for the preparation of new 13-thiaprostenoic acid derivatives of the general formula I.

10th

(ch2) 3-coor

1

ch = ch-

ch2 "c (or"

c k_ -r j n 2n

\

C P m 2m + 1

wherein

R1 H or alkyl with 1 to 4 carbon atoms,

m 0 or an integer from 1 to 5,

n is 0 or an integer from 1 to 9,

R2 is hydrogen, alkoxy with 1 to 4 carbon atoms, phenyl, phenoxy, pyridyl, thienyl, naphthyl, phenyl substituted by F, Cl, Br, OH, OCH3, CH3 or CF3 or by F, Cl, Br, OH, OCH3, CH3 or CF3 substituted phenoxy, and

R3 is H, methyl or ethyl,

and a wavy line () indicates that these bonds can be er / / 3-permanent,

and their physiologically acceptable salts.

It is known that prostaglandin-analogous compounds in which the side chains have been varied or one or more carbon atoms have been replaced by heteroatoms can have a better pharmacological activity than the natural prostaglandins. Structurally similar 13-thiaprostanoic acid derivatives with a saturated upper side chain and an optionally substituted alkyl radical in the lower side chain are known from Swiss Patent 590 220.

The object of the present invention is to create new pharmaceuticals. This object has been achieved by finding the new compounds of the formula I which, owing to their properties, can be used to produce new medicaments.

It has been found that the 13-thiaprostenoic acid derivatives of the formula I have valuable pharmacological properties. The prostatic acid derivatives of the formula I can influence the function of the corpus luteum, the egg transport through the fallopian tube, the nidation and fertility. Thus, the compounds of the formula I in particular have an oestrus-synchronizing effect, for example in cattle. Furthermore, there are, for example, hypotensive effects, which e.g. on the barbiturate anesthetized cat with continuous infusion. In this test, arterial blood pressure is recorded kymographically. The test substances are infused over a period of 10 minutes in aqueous propylene glycol solution.

In addition, vasodilatory, antiinflammatory, diuretic, anticonvulsant, gastric juice secretion, platelet aggregation, lipid breakdown and noradrenaline release inhibiting, as well as nasal decongestant decongestant properties occur with the 13-thiaprostenoic acid derivatives of the formula I, which also use this method according to common methods can be determined.

The compounds of the formula I and / or their physiologically acceptable salts can therefore be used as medicaments and also as intermediates for the preparation of other medicaments.

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625 211

The compounds of the formula I contain at least 4 asymmetric carbon atoms on the five-membered ring. Further asymmetry centers can occur in the thioether side chain. The compounds of formula I can therefore occur in a variety of stereoisomeric forms; they are usually in the form of racemic mixtures.

The invention relates to a process for the preparation of a 13-thiaprostenoic acid derivative of the general formula I and its physiologically acceptable salts, which is characterized in that a compound of the general formula II

wherein

R2, R3, m and n have the meanings given above, with a compound of the general formula III

[(R4) 3P- (CH2) 4-COOR '] (+ 1 X <-> III

wherein

R4 alkyl having 1 to 6 carbon atoms, phenyl, naphthyl or phenyl or naphthyl substituted by alkyl having 1 to 4 carbon atoms, and

X means Cl, Br or J, and

R1 has the meaning given above,

implements.

An acid of the formula I obtained can then be converted into an ester of the formula I with R1 = alkyl having 1 to 4 carbon atoms by reaction with a corresponding esterifying agent, and an obtained ester of the formula I with R1 = alkyl with 1 to 4 carbon atoms -Atoms can be converted into an acid of the formula I by reaction with a hydrolyzing agent and a compound of the formula I obtained can be cleaved into its racemates and / or enantiomers. Furthermore, an acid of the formula I obtained (R1 = H) can be converted into one of its physiologically acceptable salts by treatment with a base or can be liberated from one of its salts by treatment with an acid.

In the above formulas, R1 is in particular hydrogen, but also an alkyl radical, preferably an unbranched one having up to 4 carbon atoms, such as methyl, ethyl, propyl or n-butyl, but also a branched one, such as isopropyl or tert-butyl .

m is preferably 0, 1 or 2, but preferably also 5 if n is also 5 and R2 is H.

CmH2m + l is therefore, in addition to hydrogen (m = 0), alkyl having 1 to 5 carbon atoms, preferably unbranched, such as methyl, ethyl, propyl, butyl or pentyl; but also branched like isopropyl or isobutyl.

When R2 is H, n is preferably 5, 6 or 7. If R2 is not H, n is preferably 0 or 1.

In those compounds of the formula I in which CnH2n is a branched alkylene radical, the radical CmH2m + 1 is generally an unbranched alkyl radical, preferably methyl or ethyl, because of the possible steric hindrance, in particular if the branching in CnH2n is in the 1st Position. If C "H2n is a branched alkylene radical, any branching that may still occur in CmH2m + 1 is generally as far as possible from the 1 position.

In addition to a C-C or C-O single bond (n = O, R2 not equal to H), CnH2n means alkylene with 1 to 3 C atoms, preferably methylene, ethylidene or isopropylidene.

In addition, CnH2n can also alkylene with 4 to 9 C atoms, preferably unbranched alkylene with 4 to 9 C atoms, such as tetramethylene, pentamethylene, hexamethylene or heptamethylene, but also branched alkylene with 4 to 9 C atoms, such as

-CH (CH3) CH2CH2-, -CH2CH (CH3) CH2-,

-C (CH3) 2CH2-, -CH (CH3) CH (CH3> -,

-CH (C2Hs) CH2 -, - CH (CH3) CH2CH2CH2-,

-CH2CH (CH3) CH2CH2 -, - C (CH3) 2CH2CH2-,

-CH (CH3) CH (CH3) CH2 -, - CH (C2H5) CH2CH2-,

-CH (CH3) CH2CH2CH2CH2 -, - C (CH3) 2CH2CH2CH2-,

-CH (CH3) CH (CH3) CH2CH2-,

-CH (CH3) CH2CH2CH2CH2CH2-,

-CH (CH3) CH (CH3) CH2CH2CH2-,

-CH2CH2CH2CH2C (CH3) 2-,

-CH (CH3) - (CH2) 6- or -C (CH3) 2- (CH2) 6- mean.

The grouping CnH2n-R2 with R2 = H is therefore, in addition to hydrogen, preferably alkyl having 1 to 9 carbon atoms, preferably unbranched alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or nonyl but also all about an alkyl radical with 3 to 9 carbon atoms, in particular branched in the 1-position, such as isopropyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-methylpentyl, 1,1-dimethylbutyl, 1-ethylbutyl , 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, l-ethyl-2-methylpropyl, 1-ethyl-l-methylpropyl, 1-methylhexyl, 1,1-dimethylpentyl, 1-ethylpentyl, 1 , 1-dimethylhexyl, 1,1-dimethylheptyl, 1,3,3-trimethylbutyl or 1,1,2,2-tetramethylpropyl; but e.g. also 3,3-dimethylbutyl or 4,4-dimethylpentyl.

R2 denotes hydrogen, methoxy, ethoxy, phenyl, phenoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-naphthyl, one, two or three times by F, Q, Br, OH, OCH3, CH3 or CF3 substituted phenyl or phenoxy substituted once, twice or three times by F, Cl, Br, OH, OCH3, CH3 or CF3. If R2 is a substituted phenyl or a substituted phenoxy radical, it is preferably monosubstituted, the substituent being found in the o-position, but in particular in the m- or p-position.

R2 is therefore preferably m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, p-bromophenyl, p-hydroxyphenyl, p-methoxyphenyl, m-trifluoromethylphenyl, p-tri-fluoromethylphenyl, phenoxy, m-fluorophenoxy, p-fluorophenoxy, m-chlorophenoxy, p-chlorophenoxy, p-bromophenoxy, p-hydroxyphenoxy, p-methoxyphenoxy, p-methylphenoxy, m-trifluoromethylphenoxy or p-trifluoromethylphenoxy, but also for example 2,4-dichloro, 3, 4-dichloro, 2,4-dibromo, 2,4-dimethyl, 3,4-dimethyl, 2,4-dimethoxy, 2,3-dimethoxy, 2,4,6-trimethyl or 3,4,5-trimethoxyphenyl or phenoxy.

In addition to methyl or ethyl, R3 preferably denotes hydrogen.

Those compounds of the formula I in which at least one of the symbols R1, R2, R3, m and n has one of the meanings given above are particularly preferred.

Some of these preferred groups of compounds can be characterized by the sub-formulas Ia to Ig below, which otherwise correspond to the formula I and in which the symbols not specified have the meaning given for the formula I, but in which R1 = H,

in Ib R1 = methyl or ethyl,

in le n = 0 or 1,

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625 211

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in Id m = 1,

in le R2 = m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenoxy, p-fluorophenoxy, m-chlorophenoxy or p-chlorophenoxy,

in If R1 = H, methyl or ethyl, R3 = H, CnH2n-R2 = pentyl, hexyl, heptyl, 1-methylpentyl or 1,1-dimethylpentyl and CmH2m + i = H or methyl,

in Ig R1 = R3 = H, CnH2 "-R2 = pentyl, phenoxymethyl or m-chlorophenoxymethyl, and Cm ^ m-n = H or methyl.

The compounds of formula I are structurally related to the prostaglandins, which are derived from 7- (2-octylcyclopentyl) heptanoic acid (prostanoic acid). The compounds of formula I are derived from 13-thiaprostanoic acid.

The R4 radicals can be the same or different and in particular are phenyl. Preferred radicals R4 are also the methyl and the ethyl group. In addition, R4 can assume all other meanings given above, for example propyl, butyl, isobutyl, pentyl, isopentyl, hexyl, naphthyl, o-, m- or p-tolyl.

X is in particular Br, but also Cl and optionally J.

The reactions described below for the preparation of the starting compounds, but also of the compounds of the formula I, are analogous processes. Their reaction conditions can be found in the standard works of preparative organic chemistry, e.g. Hou-ben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart or Organic Syntheses, J. Wiley, New York - London - Sydney.

The compounds of the formula II and III are known or can be prepared from known compounds in analogy to known processes.

The compounds of the formula II are obtainable from the compounds of the formula IV

iv with a compound of formula VI

S-CH, -C (OR

^ CnH2n-R

CmH2m + 1

wherein

T is -CO- or -CHOR5-, and R5 is methyl or ethyl, and R2, R3, m and n have the meanings given above,

by reduction (when T is -CO-) with diisobutylaluminum hydride in toluene at about -90 to about -70 ° C, or by acidic hydrolysis (when T is -CHOR5-) e.g. with 0.03 normal hydrochloric acid in acetonitrile / water mixtures at room temperature.

The compounds of formula IV are in turn obtainable by reacting the known compounds Va and Vb

0

0- \

? ™ 3

V—

V

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, C H0 -R n 2n ms-ch2-c (or ~

VI

CmH2m + 1

wherein

M represents H, an equivalent of an alkali or alkaline earth metal atom or ammonium, and

R2, R3, m and n have the meanings given above,

M is preferably H, Na, K, '/ 2 Ca, or NH4 +.

In addition, M can also be an equivalent of another alkali metal or alkaline earth metal atom or one with 1 to 4 alkyl radicals with preferably 1 to 6 C atoms, with cycloalkyl radicals with preferably 5 to 7 C atoms or with aralkyl radicals with preferably 7 to 11 C atoms Substituted ammonium ion mean.

These compounds of formula VI are only partially known. You can by known methods, for example from the corresponding

2- (CnH2n — R2) -2-CmH2m + i-oxiranes can be prepared by reaction with H2S and, if appropriate, subsequent conversion into their alkali metal, alkaline earth metal or ammonium salts. Likewise, the 2- (CnH2n-R2) -2-CraH2m + i-oxiranes can be reacted directly with alkali metal, alkaline earth metal or ammonium hydrogen sulfides, in which case the compounds of the formula III with M not equal to H are obtained directly.

The phosphonium salts of the formula III are known, for example from DOS 2 431 930 and from Tetrahedron Letters 1970, Issue 4, pages 311 to 313.

Particularly important intermediates of the formula VI are those of the formula Via, which otherwise correspond to the formula VI and in which M, m and n have the meanings given there, but in which R2 is phenoxy, pyridyl, thienyl, naphthyl, by F, Q, Br , OH, OCH3 or CF3 substituted phenyl or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3 and R3 is hydrogen. Of particular importance are the intermediates of the formula VIb, which otherwise correspond to the formula Via, but in which n = 1. Above all, however, the intermediates of the formula Vie are valuable, which otherwise correspond to the formula VIb, but in which m = 0 or 1. The compounds of the formula VI and in particular those of the preferred formulas Via to VIc can be obtained by reacting the carbonyl compounds of the formula VII

CmH2m + 1-CO-CnH2n-R2 VII

wherein m, n and R2 have the meaning given above with an agent forming methylene radicals, for example di-azomethane or trimethylsulfoxonium iodide, to give the epoxides of the formula VIII

CH.

55

60 where m 2m + 1

CH - C-C H0 -R <^ 2y n 2n

'0

viii m, n and R2 have the meaning given above, and reaction of these epoxides with H2S, preferably in the presence of a suitable inert solvent, for example a lower alkanol such as methanol or ethanol and in particular in the presence of a basic catalyst, for example an alkali metal hydroxide such as NaOH or KOH , or an amine such as diethylamine, triethylamine, piperidine or morpholine.

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625 211

Of the starting products of the formula Va or Vb, those are of particular importance in which all of the drawn bonds connected with the five-membered ring are a-permanent:

0

RA 11

? \ he \

'*

The reaction of a compound of formula II with a compound of formula III is carried out according to methods known per se, for example by Wittig reaction (whereby one works in the presence of a strong base, for example an alkali metal hydride such as NaH or a lithium alkyl compound such as butyllithium), preferably in Dimethyl sulfoxide (DMSO) as a solvent at temperatures between about 15 ° and about 80 ° C. It is particularly expedient to work under an inert gas atmosphere, for example under nitrogen.

An ester of the formula I (R1 = alkyl having 1 to 4 carbon atoms) can be prepared from an acid of the formula I (R1 = H) by reaction with an esterifying agent. Esterifying agents are, for example, alcohols with up to 4 carbon atoms, preferably in the presence of an inorganic or organic acid, such as HCl, HBr, HJ, H2S04, H3P04, trifluoroacetic acid, a sulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid, or one acidic ion exchanger; Diazoalkanes with up to 4 carbon atoms, preferably diazomethane; Olefins (e.g. isobutylene), preferably in the presence of acidic catalysts (e.g. ZnCl2, BF3, H2S04, arylsulfonic acid, pyrophosphoric acid, boric acid, oxalic acid); Alkyl halides with up to 4 carbon atoms, preferably bromides, such as ethyl, propyl, isopropyl or butyl bromide, but also the corresponding chlorides or iodides; Carboxylic acid or sulfonic acid alkyl esters, where the acid residue can be any and the alkyl residue contains up to 4 carbon atoms, preferably methyl, ethyl, propyl, isopropyl or butyl acetate, formate, methyl sulfonate, ethyl sulfonate or p -toluenesulfonate; and in particular also dialkylsulfuric acid esters with up to 4 carbon atoms, such as dimethyl sulfate or diethyl sulfate.

The esterification is advantageously carried out in an inert, preferably anhydrous solvent, for example an ether such as diethyl ether or THF, an alcohol, preferably one of the alcohols mentioned having up to 4 carbon atoms, or else in a hydrocarbon such as petroleum ether, hexane, benzene or toluene, or in mixtures of these solvents at temperatures between -10 and 40 °, preferably at room temperature. The response times are usually between 30 minutes and 20 hours.

Esters of the formula I (R1 = alkyl having 1 to 4 carbon atoms) can be converted into compounds of the formula I with R1 = H by hydrolysis. Basic hydrolysis to the acids of the formula I (or their salts) is preferred. The process is preferably carried out in aqueous media, for example in mixtures of water with alcohols, preferably lower alkanols, such as methanol or ethanol, or with ethers, such as ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, THF or dioxane at temperatures between 0 and 40 °, preferably at room temperature. The response times are approximately 1 to 12 hours.

The free carboxylic acids of the formula I (R1 = H) can be converted into one of their physiologically acceptable metal or ammonium salts by reaction with a base. As

Salts are in particular the sodium, potassium, magnesium, calcium and ammonium salts, furthermore substituted ammonium salts, such as. B. the dimethyl and diethylammonium, monoethanol, diethanoi and triethanolammonium, cyclohexylammonium, dicyclohexylammonium and dibenzylethylenediammonium salts. Conversely, acids of the formula I can be liberated from their metal and ammonium salts by treatment with acids, especially mineral acids, such as hydrochloric or sulfuric acid.

The compounds of formula I are mostly obtained as mixtures of different stereoisomeric forms, i.e. usually as mixtures of racemates. Racemates can be isolated from the racemate mixtures and obtained in pure form, for example by recrystallization of the compounds themselves or of readily crystallizing derivatives, by distillation, but in particular with the aid of chromatographic methods, both adsorption-chromatographic or distribution-chromatographic methods and mixed forms being suitable.

The racemates can be separated into their optical antipodes by known methods, as given in the literature. The chemical separation method is preferred. So you can react an optically active base with the carb-oxyl group of a compound of formula I. For example, one can use diastereomeric salts with optically active amines, such as quinine, cinchonidine, brucine, cinchonine, hydroxy-xyrindamine, morphine, 1-phenylethylamine, 1-naphthylethylamine, phenyloxynaphthylmethylamine, quinidine, strychnine, basic amino acids, such as lysine Form amino acid esters. In a similar manner, ester diastereomers can be prepared by esterifying carboxylic acids of the formula I (R1 = H) with optically active alcohols, such as borneol, menthol, octa-nol-2. The resulting diastereomeric salts or esters are separated by crystallization and the optically active compounds are released from the mixture.

However, the other functional groups present in the compounds of the formula I can also be used to form diastereomers. So you can e.g. Esterify OH groups with optically active acids such as (+) - and (-) - tartaric acid or camphoric acid and obtain the pure enantiomers from these derivatives.

Furthermore, it is of course possible to obtain optically active compounds using the methods described, by using starting materials which are already optically active.

The new compounds of formula I and their physiologically acceptable acid addition salts can be used for the production of pharmaceutical preparations by bringing them into a suitable dosage form together with at least one carrier or auxiliary and optionally together with one or more further active ingredient (s). The preparations thus obtained can be used as pharmaceuticals in human or veterinary medicine. Suitable carrier substances are organic or inorganic substances which are suitable for enteral, parenteral or topical application and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate , Talk, petroleum jelly. Tablets, dragees, capsules, syrups, juices, drops or suppositories are used in particular for enteral application, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for parenteral application, and ointments, creams or powder for topical application. The new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or auxiliary substances such as lubricants,

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Preservatives, stabilizers and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, coloring, flavoring and / or flavoring substances. If desired, they can also contain one or more other active ingredients.

The substances are preferably administered in a dosage of 0.01 to 200 mg per dosage unit; the dosage depends on the species treated, the form of application and the purpose of treatment, it can therefore also fall below or exceed the values given above.

For example, if one wishes to utilize the oestrus-synchronizing action of the compounds of the formula I, in particular of the formula Ig, it is particularly advantageous, e.g. Injecting cattle (cows or heifers) from about 0.1 mg to about 20 mg, preferably from about 0.5 mg to about 15 mg, in particular from about 1.5 mg to about 10 mg, of the active ingredient. It is favorable to administer the effective dose by a single injection between about the 7th day and about the 12th day of the cycle, but it is also possible to inject partial doses several times and, if appropriate, over several days. In other farm animals too, for example dogs, horses, sheep and pigs, the estrus can be synchronized by administering a compound of the formula I, in particular the formula Ig. The effective dose varies depending on the average body weight of the treated species and can easily be determined by a person skilled in the art using the guide values given above for cattle.

IR spectra (IR) were characterized by indicating the main bands (as a film).

The NMR spectra (NMR) were measured in CDC13 against t-tramethylsilane and characterized by indicating the signals in ppm; where m = multiplet, q = quartet, t = triplet, d = doublet and s = singlet.

Each of the compounds of the formula I mentioned in the following examples is particularly suitable for the preparation of medicaments.

example 1

A solution of 2.1 g of 5-tri-phenylphosphoniovaleric acid, dissolved in 10 ml of dry DMSO, is added dropwise to a stirred solution, which is added to 10 ml of dry by adding 0.27 g of NaH (as a 50% suspension in mineral oil) DMSO was obtained and holds the mixture at 70 ° for 1 hour. After cooling to room temperature, 0.3 g of 2-oxa-3,7-dihydroxy-6- (2-hydroxy-2-methyl-heptylmercapto) -bicyclo [3,3,0] octane is added dropwise with nitrogen and stirring,

dissolved in 5 ml of dry DMSO to dissolve the phosphorylide and stirred for a further 2 hours at 50 °. After cooling, the reaction mixture is poured into a mixture consisting of 10 ml of ethyl acetate, 40 g of dry ice and 50 ml of water, the organic phase is separated off, the aqueous phase is washed three times with 50 ml of ethyl acetate each containing 20 g of dry ice, and the combined organic phases are washed with water, dries over MgS04, the solvent is distilled off and, after chromatographic purification of the residue (silica gel / chloroform), 9.1 l, 15-trihydroxy-15-methyl-13-thia-5-prostenic acid are obtained,

IR: 1710, 2200 and 3700 cm "1;

NMR: 0.85 (t), 1.2 (s), 1.0-2.6 (m), 2.6-3.05 (m + s), 4.15 (m), 5.1 - 5.4 (m).

The following can be obtained analogously by reacting the corresponding starting compounds of the formula II with the ylide of 5-triphenylphosphoniovaleric acid:

9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-

17,18,19,20-tetranor-5-prostatic acid,

IR: 1210, 1505, 1710, 2700, 2940, 3700 cm "1;

NMR: 1.1-2.6 (m), 2.7-3, l (m), 4.05 (m), 4.2 (m), 5.30 (m),

5.45 (m), 6.85 (s), 6.95 (d)

(using 2-oxa-3,7-dihydroxy-6- (2-hydroxy-

3-p-fluorophenoxypropylmercapto) bicyclo [3,3,0] octane as starting compound II);

9, 11, 15-trihydroxy-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-prostic acid,

IR: 1710, 2400, 3650 cm "1;

NMR: l, l-2.6 (m), 2.6-3, l (m), 4.05 (m), 4.2 (m), 5.3 (m), 5.4 (m ), 6.6—7.4 (m)

(using 2-oxa-3,7-dihydroxy-6- (2-hydroxy-3-m-chlorophenoxypropylmercapto) bicyclo [3,3,0] octane as starting compound II); 9,11 -dihydroxy-15-methoxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostic acid,

IR: 1210, 1505, 1710, 2700, 2940, 3700 cnT1; NMR: l, l-2.6 (m), 2.95 (m), 3.50 (s), 3.75 (m), 4.0 (m), 4.10 (m), 5, 40 (m), 5.60 (m), 6.85 (d), 6.95 (d)

(using 2-oxa-3,7-dihydroxy-6- (2-methoxy-3-p-fluorophenoxypropylmercapto) bicyclo [3,3, o] octane as starting compound II); 9,11,15-trihydroxy-16,16-dimethyl-13-thia-5-prostatic acid,

IR: 1195, 1205, 1705, 3600 cm "1;

(using 2-oxa-3,7-dihydroxy-6- (2-hydroxy-3,3-dimethyl-heptylmercapto) bicyclo [3,3,0] octane as starting compound II); 9, 11, 15-trihydroxy-15-methyl-17-phenyl-13-thia-18,19,20-trinor-5-prostatic acid IR: 1600, 1700, 2950, 3400 cm "';

NMR: 1.35; 4.18; 5.42; 7.22;

(using 2-oxa-3,7-dihydroxy-6- (2-hydroxy-2-methyl-4-phenylbutylmercapto) bicyclo [3,3,0] octane as starting compound II); 9, 11, 15-trihydroxy-15-methyl-17-m-chlorophenyl-13-thia-18,19,20-trinor-5-prostatic acid IR: 1050, 1240, 1600, 1710, 2900, 3400 cm "1;

NMR: 1.32; 4.0-4.3; 5.35; 7.0-7.2;

(using 2-oxa-3,7-dihydroxy-6-

(2-hydroxy-2-methyl-4-m-chlorophenyl-butylmercapto) bicyclo [3,3,0] octane as starting compound II); 9,11,15-trihydroxy-15-methyl-17-m-trifluoromethylphenyl-13-thia-18,19,20-trinor-5-prostatic acid IR: 1720, 3450 cm "1;

NMR: 1.35; 5.25; 5.48; 7.45;

(using 2-oxa-3,7-dihydroxy-6- (2-hydroxy-2-methyl-4-m-trifluoromethylphenyl-butylmercapto) bicyclo [3,3,0] octane as starting compound II); 9,11,15-trihydroxy-15-methyl-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-prostatic acid IR: 1600, 1710, 2900, 3400 cm "1;

NMR: 1.40; 4.20; 4.95; 5.45; 6.7-7.3;

(using 2-oxa-3,7-dihydroxy-6-

(2-hydroxy-2-methyl-3-m-chlorophenoxypropylmercapto) bicyclo [3,3,0] octane as starting compound II); 9,11,15 -Trihydroxy-15-methyl-16-p-fluorophenyl-13-thia-17,18,19,20-tetranor-5-prostatic acid as an oil

IR: 1210, 1510, 1705, 2700, 2940 and 3650 cm "1;

(using 2-oxa-3,7-dihydroxy-6- (2-hydroxy-2-methyl-3-p-fluorophenyl-propyl-mercapto) bicyclo [3,3,0] octane as starting compound II) .

Example 2

100 mg of 9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostic acid are added.

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dissolved in 10 ml of diethyl ether with excess ethereal diazomethane solution until no more nitrogen development can be determined. The solvent is distilled off and after chromatographic purification (silica gel / benzene: chloroform = 1: 1) of the residue, 9,11,15-trihydro-xy-16-p-fluorophenoxy-13-thia-17,18,19,20 is obtained -tetra-nor-5-pro-strong acid methyl ester.

IR: 1210, 1505, 1735 and 3650 cnr1.

Example 3

a) 0.1 g

9,11,15 -Trihydroxy- 16-p-fluorophenoxy-13-thia-

Methyl 17,18,19,20-tetranor-5-prostenate are stirred for 90 hours in a mixture of 2 ml of an aqueous saturated NaCN solution and 6 ml of methanol. It is saturated with NaCl, extracted with chloroform, the organic phase is washed with water, dried over MgSO4, the solvent is distilled off and, after chromatographic purification of the residue (silica gel / CHC13: CH3OH = 9: 1), 9,11,15-trihydroxy- 16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostic acid.

b) Dropwise to an ethanolic sodium ethanolate solution, made from 0.12 g of sodium and 10 ml of dry ethanol, 2.2 g

9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia

17,18,19,20-tetranor-5-prostic acid,

dissolved in 10 ml of dry diethyl ether, the solvent is distilled off and the sodium salt of 9,11,15 -trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostensic acid is obtained as residue.

c) A mixture of 1.54 g of the silver salt of 9, 11, 15-trihydroxy-16-p-fluorophenoxy-13-thia is stirred

17,18,19,20-tetranor-5-prostic acid,

0.52 g of ethyl iodide and 10 ml of dry ethanol for 4 hours at room temperature, add 20 ml of dry diethyl ether, filter, distill off the solvent and obtain the residue 9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia 17,18,19,20-tetranor-5-prostonic acid ethyl ester.

Example 4

A solution of 4.2 g of 5-tri-phenylphosphoniovaleric acid, dissolved in 20 ml of dry DMSO, is added dropwise to a stirred solution, which is added to 20 ml of dry by adding 0.54 g of NaH (as a 50% suspension in mineral oil) DMSO was obtained and the mixture was kept at 65 ° for 1 hour. After cooling to room temperature, 0.6 g of 2-oxa-3,7-syn-dihydroxy-6-anti- (2-hydroxy-2-methyl-

heptylmercapto) cis bicyclo [3,3,0] octane,

dissolved in 10 ml of dry DMSO to dissolve the phosphoryid and stir for a further 2 hours at 50 °. The procedure is as described in Example 1 and 9a, 11a, 15-trihydroxy-15-methyl-13-thia-5-cis-prostic acid are obtained.

IR: 1710, 2200, 3700 cm-1;

NMR: 0.85 (t), 1.2 (s), 1.0-2.6 (m), 2.6-3.05 (m + s), 4.15 (m), 5.1 -5.4 (m).

625 211

The same is true by reacting 5-triphenylphosphoniova-leric acid

2-oxa-3,7-syn-dihydroxy-6-anti- (2-hydroxy-3-m-chloropheno-

xy-propylmercapto) -cis-bicyclo [3,3,0] octane in the presence of NaH

9a, llla, 15-trihydroxy-16-m-chlorophenoxy-13-thia-

17,18,19,20-tetranor-5-cis-prostic acid available,

IR: 1710, 2400, 3650 cm "1;

NMR: 1.1-2.6 (m), 2.6-3, l (m), 4.05 (m), 4.2 (m), 5.3 (m), 5.4 (m ), 6.6-7.4 (m).

The compounds 2-oxa-3,7-syn-dihydroxy-6-anti- (2-hydroxy-2-methyl-

heptylmercapto) cis bicyclo [3,3,0] octane and

For example, 2-oxa-3,7-syn-dihydroxy-6-anti- (2-hydroxy-3-m-chlorophenoxy-xy-propylmercapto) -cis-bicyclo [3,3,0] octane can be prepared by reacting the Connection Va ',

2-oxa-6,7-cis-epoxy-3-oxo-cis-bicyclo [3,3,0] octane, (= compound I from J. Amer. Chem. Soc. 94, 4344 [1972] with 2nd -Hydroxy-2-methyl-heptanethiol or with 2-hydroxy-3-chloro-phenoxypropanethiol and subsequent reduction of the reaction products with diisobutylaluminum hydride in toluene at -78 ° C.

The following example 5 describes the preparation of a compound of the formula VI:

Example 5

a) Wash 20 g of a 20% sodium hydride dispersion in paraffin oil three times with 30 ml of dry n-pentane, remove the solvent, add 33 g of trimethylsulfoxonium iodide, then add 100 ml of dimethyl sulfoxide, stir for 20 minutes at room temperature until the evolution of gas is complete, a solution of 14.2 g of 2-heptanone in 15 ml of dimethyl sulfoxide is added dropwise, the mixture is stirred for a further 2 hours, 500 ml of water are added with ice-cooling, the mixture is extracted three times with 250 ml of ether, the combined ether extracts are washed with water and dried with sodium sulfate, the solvent is distilled off and, after fractionation of the residue, 2-methyl-2-pentyloxirane is obtained as a colorless liquid; Kp = 55 ° (20 mm Hg).

b) Hydrogen sulfide is introduced into 150 ml of methanol while cooling with ice until the weight gain is 3.2 g, a solution of 370 mg of diethylamine in 11 ml of methanol and then 4.8 g of 2-methyl-2-pentyloxirane in 18 ml of methanol are added , leads another 15 minutes of hydrogen sulfide gas into the solution, leaves to stand for 12 hours at room temperature, the solvent is distilled off, the residue is dissolved in 50 ml of petroleum ether (bp = 50-70 °), washed with water, dried with sodium sulfate, distilled Solvent and receives as residue 2-hydroxy-2-methyl-heptanethiol as a colorless liquid;

IR: 920, 1140, 1380, 1465, 2570 and 3450 cm "1;

NMR: signals at 0.96 ppm, 1.26

NMR: signals at 0.96 ppm, 1.26 ppm, 2.27 ppm and 2.67 ppm.

7

5

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15

20th

25th

30th

35

40

45

50

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Claims (5)

625 211 2nd PATENT CLAIMS 1. Process for the preparation of a 13-thiaprostenoic acid derivative of the general formula I (ch 2 3 -coor ch = ch- c h- -r ^ ^ n 2n s-ch - c (or) v 2 \ 1 C H0 1 where m 2m + 1 R1 H or alkyl with 1 to 4 carbon atoms, m 0 or an integer from 1 to 5, n is 0 or an integer from 1 to 9, R2 is hydrogen, alkoxy with 1 to 4 carbon atoms, phenyl, phenoxy, pyridyl, thienyl, naphthyl, phenyl substituted by F, CI, Br, OH, OCH3, CH3 or CF3 or by F, Cl, Br, OH, OCH3, CH3 or CF3 substituted phenoxy, and R3 is H, methyl or ethyl, and a wavy line () indicates that these bonds are a- or can be ß-constant, and their physiologically acceptable salts, characterized in that a compound of general formula II ii S-CH2-C (OR- C H., -R 'n 2n C H, TT »/ i wonn R2, R3, m and n have the meanings given above, with a compound of the general formula III (+> 5. The method according to claim 1, characterized in that a compound of the formula I obtained is split into its en-antiomers. 20th 25th 30th 35 40 [(R4) 3P- (CH2) 4-COOR1] (+, X (-1 III wherein R4 alkyl having 1 to 6 carbon atoms, phenyl, naphthyl or phenyl or naphthyl substituted by alkyl having 1 to 4 carbon atoms, and X means Cl, Br or J, and R1 has the meaning given above, implements and that one optionally converts an acid of the formula I obtained by treatment with a base into one of its physiologically acceptable salts or liberates it from one of its salts by treatment with an acid. 2. The method according to claim 1, characterized in that one converts an acid of the formula I obtained by reaction with a corresponding esterifying agent into an ester of the formula I with R1 = alkyl having 1 to 4 carbon atoms. 3. The method according to claim 1, characterized in that converting an obtained ester of formula I with R1 = alkyl having 1 to 4 carbon atoms by reaction with a hydrolyzing agent in an acid of formula I with R1 = H. 4. The method according to claim 1, characterized in that one splits a compound of formula I obtained in its Ra-cemate. 50 60 65