CH641447A5 - Process for preparing prostanoic acid derivatives - Google Patents

Abstract

Novel prostanoic acid derivatives of the general formula <IMAGE> in which the substituents are defined in claim 1, are prepared. These compounds are obtained by reacting an aldehyde of the formula <IMAGE> with a compound of the formula Vb, which compound releases the side chain located in the 12 position. In the compound of the formula IV, the two hydroxyl groups which are eliminated after the reaction is complete are protected. The prostanoic acid derivatives which are obtained may be used for the same pharmacological purposes as the natural prostaglandins. <IMAGE>

Description

** WARNING ** Beginning of DESC field could overlap end of CLMS **.

represent, where Rlo has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH group, B denotes a trans-CH = CH group, W is a free, etherified or esterified hydroxymethylene group, a free or ketalized carbonyl or a

-Group, where R11 is an alkyl group with 1-5 C atoms and the OH group a- or ss-position and can be etherified or esterified, R2 represents a hydrogen atom or an alkyl group, R2 represents a hydrogen atom or an alkyl group, R4 = R5 represents a methyl group or R4 represents a chlorine atom if R3 represents a methyl group or R5 represents a chlorine atom if! R4 denotes a methyl group and, if Re represents a hydroxyl group, its physiologically tolerable salts with bases, characterized in that a compound of the formula I is prepared by the process according to claim 1 and in this the 9-hydroxyl group is oxidized to the 9-keto group and compounds obtained, which are present as the free acid, optionally converted into the corresponding salts.

8. Process for the preparation of new prostanoic acid derivatives of the formula

where Rl is a

-Group, in which R6 represents a hydroxyl group, a straight or branched, saturated or unsaturated alkoxy group, a substituted or unsubstituted aryloxy group, an O-CH2-UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V is a through denotes one or more phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms substituted phenyl ring, or in which R6 is an -NHR, 0 group, in which Rlo is an optionally substituted alkyl, C3 C8 cycloalkyl, a heteroaryl or Aryl group or an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms, R7 and R8 represent hydrogen atoms or alkyl groups with 1-4 C atoms and R9 either an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms or an inorganic acid or a

Represent a group, where Rlo has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH group, B means a trtns-CH = CH group, W is a free, etherified or esterified hydroxymethylene group, a free or ketalized carbonyl or a

-Group, where Rli is an alkyl group with 1-5 C atoms and the OH group - or, 3-position and etherified or esterified, means, R2 stands for a hydrogen atom or an alkyl group, R3 denotes a hydrogen atom or an alkyl group, R4 = R5 denotes a methyl group or R4 represents a chlorine atom if R5 represents a methyl group or R3 represents a chlorine atom if R4 represents a methyl group, and, if Re represents a hydroxyl group, their physiologically acceptable salts with bases, characterized in that the process according to claim 7 a compound of the formula IA prepares and this dehydrated with elimination of the 11-hydroxy group and compounds obtained, which are present as free acid, optionally converted into the corresponding salts.

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

wherein R, a

-Group, in which Re represents a hydroxyl group, a straight or branched, saturated or unsaturated alkory group, a substituted or unsubstituted aryloxy group, an O-CH2 UV group, where IJ is a direct bond, a carbonyl or carbonyloxy group and V is one through one or more Phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms, preferably bromine atoms, a substituted phenyl ring or an -NHR, 0 group, in which Rlo is an optionally substituted alkyl, C3-C8-cycloalkyl, a heteroaryl or Represents an aryl group or an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms, R7 and R6 hydrogen atoms or alkyl groups with 1-4 carbon atoms and Re either an acid residue of an organic carboxylic or sulfonic acid with 1-15 carbon atoms or an inorganic acid or a

Represent a group, where Rlo has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH group,

B denotes a trans-CH = CH group, W is a free, etherified or esterified hydroxymethylene group, a free or ketalized carbonyl or a

-Group, where R1l is an alkyl group with 1-5 C atoms and the OH group - or 3-position and can be etherified or esterified, R2 represents a hydrogen atom or an alkyl group, R2 represents a hydrogen atom or an alkyl group, R4 = R5 represents a methyl group or R4 represents a chlorine atom when Rs represents a methyl group or R5 represents a chlorine atom when R4 represents a methyl group, and, if R6 represents a hydroxyl group, its physiologically acceptable salts with bases.

As alkyl groups R2 and R3, straight-chain and branched-chain alkyl radicals with 1-5 carbon atoms are preferred, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl groups. The methyl and ethyl groups are preferred.

Examples of substituted or unsubstituted aryloxy groups R6 are: phenoxy "1-naphthoxy and 2-naphthoxy, each of which can be substituted by 1-3 halogen atoms, 1 phenyl group, 1-3 alkyl groups each with 1-4 carbon atoms, 1 Chloromethyl, fluoromethyl, trifluoromethyl, carboxyl or hydroxyl group.

Possible alkoxy groups R6 are straight-chain and branched, saturated and unsaturated alkoxy radicals, preferably saturated ones having 1-10, in particular 1-6, carbon atoms.

Examples include methoxy, ethoxy, propoy, butoxy, isobutoxy, tert. Butoxy, pentoxy, hexoxy, heptoxy, octoxy, butenyloxy, isobutenyloxy, propenyloxy.

All inorganic and organic bases such as are known to the person skilled in the art for the formation of physiologically compatible salts are suitable for salt formation. 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 alkyl groups Rlo are straight or branched alkyl groups, preferably with 1-10 carbon atoms, such as methyl, ethyl, propyl, isobutyl, butyl, pentyl, heptyl and decyl groups.

The alkyl groups Rlo can optionally be substituted one or more times, preferably by halogen atoms, alkoxy groups, optionally substituted aryl groups, dialkylamines and tralkylammonium.

Examples of substituents that may be mentioned are fluorine, chlorine or bromine atoms, phenyl, dimethylamine, diethylamine, methoxy, ethoxy.

Preferred alkyl groups Rlo are methyl, ethyl, propyl, isobutyl, butyl, trichloromethyl and trifluoromethyl.

Cycloalkyl groups Rlo are as those with 3-8 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl.

Both substituted and unsubstituted aryl groups and heteroaryl groups, such as, for example, phenyl, are suitable as aryl groups Rlo. 1-naphthyl and 2-naphthyl, each of which can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl or alkoxy group and thienyl, furyl , Pyridyl. Substitution in the 3- and 4-positions on the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl, is preferred.

Physiologically acceptable acid residues are particularly suitable as acid residues R6 and Rlo. Organic carboxylic acids and sulfonic acids have 1-15 carbon atoms and can belong to the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. Examples of the substituents are alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms.

For example, the following carboxylic acids may be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, tert-butyl acetic acid, trimethyl acetic acid, acetic acid, tri-acetic acid , Cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, acetic acid, acetic acid, acetic acid, ethyl acetic acid, acetic acid, acetic acid, acetic acid, benzoic acid, hydrochloric acid, hydrochloric acid, troxy acid, and benzoic acid Benzoic acids substituted by carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. Particularly preferred acyl radicals are those with up to 10 carbon atoms.

Examples of sulfonic acids are methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, isopropylsulfonic acid, β-chloroethanesulfonic acid, butanesulfonic acid, cyclopropanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, nosulfonic acid, n-benzenesulfonic acid, n-benzenesulfonic acid, methylsulfonic acid, methylsulfonic acid, diethyl-chloroethyl acid, N, N-bis (, 8-chloroethyl) -aminosulfonic acid, N, N-diisobutylaminosulfonic acid, N, N-dibutylaminosulfonic acid, pyrrolidono-, piperidino-, piperazino-, N-methylpiperazino-, thiopheno- and morpholinosulfonic acid in question.

The usual inorganic acids, such as sulfuric and phosphoric acid, can also be used for R9.

The alkyl groups R7 and R3 are straight and branched chain alkyl radicals with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert. Butyl radical. The methyl and ethyl groups are preferred.

The radicals known to the person skilled in the art are usually suitable as ether and acyl radicals. Easily split off ether residues such as tetrahydropyranyl, tetrahydrofuranyl, z-ethoxyethyl, trimethylsilyl, dimethyl tert are preferred. called butyl-silyl and tri-p-benzyl-silyl radical.

Possible acyl radicals are the same as those mentioned for R6; Examples include ethyl. Propionyl. Butyryl and benzoyl.

Alkyl radicals R ″ are straight- and branched-chain alkyl radicals with 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl radicals. The methyl and pentyl radicals are preferred Ethyl group.

Further new compounds which can be prepared according to the invention have the following formulas

wherein the substituents have the meaning given above.

The process according to the invention for the preparation of new compounds of the formula 1 is characterized in that an aldehyde of the formula

in which A and R have the meaning given above and the hydroxyl groups in the 9- and 11-position are protected by ether or ester groups. with a compound of the general formula

where R 'is a lower alkyl radical and Ph, W. R2, K ,. R4 and R, which have the meaning given above, are set, then the protective groups are split off and a carboxy compound obtained is converted into a physiologically acceptable salt, optionally with a base.

The reaction of the aldehydes IV with the phosphonates of the general formula Vb can be carried out in a manner known per se at temperatures from 0.degree. C. to 1000.degree. C., preferably at () "C to 80" C. be carried out in an aprotic solvent, such as, for example, dimethyl sulfoxide, dimethylol amide, benzene, toluene, xylene, diethyl ether, tetrahydrofuran. Dioxyn, chloroform, methylene chloride, etc.

The optional introduction of the ester group into Rl, in which R6 represents a saturated or unsaturated alkoxy group, preferably with 1-1 () carbon atoms, can be carried out by methods known to the person skilled in the art. The l-carboxy compounds are reacted, for example, with diazo hydrocarbons in a manner known per se. The esterification with diazo hydrocarbons is carried out, for example, by a solution of the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the l-carboxy compound in the same or in a different inert solvent, e.g. Methylene chloride, mixed. After the reaction has ended, preferably in 1 to 30 minutes, the solvent can be removed and the ester purified in the usual way.

Diazoalkanes are either known or can be prepared by known methods [Org. Reactions Vol. 8, pp. 389-394 (1954)].

To introduce the ester group in Rl, in which Re represents a substituted or unsubstituted aryloxy group, the 1-carboxy compounds can be reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is usually carried out at temperatures between -30 ° C. and + 50 ° C., preferably at 10 ° C.

For the preferred introduction of the ester group in R1, in which R6 denotes an O-CH2-U-V group, the l-carboxy compound of the general formula 1 can be mixed with a halogen compound of the general formula Hal-CH2-U-V, where Hal is a halogen atom, preferably bromine. U represents 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, preferably bromine atoms, in the presence of a hydrogen halide-releasing agent.

Agents which split off hydrogen halide are, for example, silver oxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or amines, such as trimethylamine, trilithylamine. Tributylamine, trioctylamine and pyridine are used. The reaction with the halogen compound is carried out in an inert solvent, preferably in acetone, acetonitrile, dimethylacetamide, dimethylformamide or dimethyl sulfoxide at temperatures from -80 ° C. to + 110 ° C., preferably at room temperature.

The preferred introduction of a

-Group can also take place according to methods known per se, such as, for example - if R7 and R8 are hydrogen atoms - by reducing the prostanoic acid ester with lithium aluminum hydride. Should R5 mean a hydrogen atom and R3 an alkyl group. for example, the prostane acid derivative can be reduced to the aldehyde with diisobutylaluminum hydride, and this can then be reacted with alkyllithium. If R7 and R are alkyl groups, the reduction to the alcohol is usually carried out by reacting a prostanoic acid ester with alkyl lithium.

The subsequent esterification of the alcohols usually takes place in a manner known per se, for example by mixing an alcohol with an acid derivative such as e.g.

Acid halide in the presence of a base such as e.g. Tri, ithylamine is implemented or - if R9 is a

-Group means - preferably by reacting a 1-alcohol with an isocyanate by the customary methods. R1 meaning a

-Group can be prepared by known methods, such as by reacting a prostaglandic acid with an isocyanate.

The new compounds of the formula IA presented above are prepared according to the invention by first preparing a compound of the formula I, as described above, and in this oxidizing the 9-hydroxyl group to the 9-keto group and obtaining compounds which are present as the free acid, optionally converted into the corresponding salts.

The 9-hydroxyl groups present can be oxidized by methods known per se using the customary oxidizing agents. For example, the 9-hydroxyl group can be oxidized with intermediate protection of any 15-hydroxyl groups present by silylation (Chem. Comm. 1972, 1120) using Jones reagent.

According to the invention, the new compounds of the formula IB are obtained by dehydrating new compounds of the formula IA.

The dehydration of the 9-oxo compound, in which the 11-hydroxyl group and a hydrogen atom are split off from the 10-position to form a prostaglandin A derivative, can be carried out under conditions that are generally known to the person skilled in the art. In general, the dehydration takes place in a solution of an organic acid, such as acetic acid, or an inorganic acid, such as hydrochloric acid, or in an acetic anhydride-pyridine mixture at temperatures between 20 ° C. and 80 ° C.

The 9- or 15-carbonyl groups can be ketalized in a manner known per se. For example, ethylene glycol is used for heating in the presence of an acidic catalyst with separation of water. Particularly suitable acidic catalysts are p-toluenesulfonic acid and perchloric acid.

The release of the functionally modified hydroxyl groups described above can take place by known methods. For example, the elimination of hydroxyl protective groups, such as the tetrahydropyranyl radical, is carried out in an aqueous solution of an organic acid, such as, for example, oxalic acid, acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid.

A water-miscible inert organic solvent is expediently added to improve the solubility. Suitable organic solvents are, for example, alcohols such as methanol and ethanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran and acetone. Tetrahydrofuran is preferred.

The cleavage is preferably carried out at temperatures between 20 "C. and 80" C.

The acyl groups are saponified, for example, with alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or in an aqueous solution of an alcohol.

Aliphatic alcohols, such as, for example, methanol, ethanol, butanol, etc., preferably methanol, are suitable as alcohols. Potassium and sodium salts may be mentioned as alkali metal carbonates and hydroxides, the potassium salts being preferred. Calcium carbonate, calcium hydroxide and barium carbonate, for example, are suitable as alkaline earth carbonates and hydroxides.

The reaction takes place in particular at -100.degree. C. to +70.degree. C., preferably at +25.degree.

The prostaglandin derivatives of the general formula I with R1 meaning a carboxy group can be converted into salts with suitable 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, the solid inorganic salt is obtained after the water has been evaporated or a water-miscible solvent, for example alcohol or acetone, has been added.

For the preparation of an amine salt, which can be done in the usual way, e.g. the PG acid, for example, dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine was added to this solution. The salt is usually obtained in solid form or is isolated in the usual way after evaporation of the solvent.

The racemates can be separated by methods known per se, such as by salt formation with an optionally active base, for example dehydroabiatylamine, amphetamine, quinine, etc.

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

The new prostaglandin analogs obtained according to the invention have a very strong uterine contracting and luteolytic effect, i.e. to trigger an abortion, lower doses are required than with the corresponding natural prostaglandins.

When the isotonic uterine contraction is recorded in the anesthetized rat and in the isolated rat uterus, it is found that the substances according to the invention are significantly more effective and their effects last longer than with the natural prostaglandins.

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

The good dissociation of the effects of the substances that can be prepared according to the invention is shown in the examination of other smooth muscle organs, such as the guinea pig ileum or the isolated rabbit trachea, where significantly less stimulation can be observed than with the natural prostaglandins.

The active ingredients of the PG E series obtainable according to the invention show bronchodilatory action in vitro on the isolated rabbit trachea and strongly inhibit gastric acid secretion and have a regulating effect on cardiac arrhythmias. The new compounds of the PG A and PG E series also lower blood pressure and have a diuretic effect.

The active compounds of the F series obtained 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.

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

In particular, sterile, injectable, aqueous or oily solutions are used for parenteral administration.

The active ingredients obtained according to the invention can be used in conjunction with the customary auxiliaries known in galenics, for example for the production of preparations for triggering an abortion, for controlling the cycle or for initiating a birth. For this purpose, sterile aqueous solutions containing 0.01-10 µg / ml of the active compound can be used as an intravenous solution for infusion. The acids and salts of general formula I are particularly suitable for preparing aqueous isotonic solutions. Alcohols such as ethanol and propylene glycol can be added to increase solubility. Furthermore, suppositories for intravaginal application can easily be produced.

Example 1 (SZ, 13E) - (8R, 9S, llR, 12R, 15s) -9, II, Ig-trihydroxy-19-methyl-5, 13,18-methyl prostatrienoate General formula I: A = cis CH = CH; B = trans CH = CH;

R1 = COOCH3; R2, R3 = R4, R5 = CH3.

(5Z, 13E) - (8R, 9S, 1 1R, 12R, 15S) -9.1 1,15-trihydroxy-19- -methyl-5, 13.1 8-prostatrienoic acid was dissolved in a little methylene chloride and washed with ethereal diazomethane Solution added. The mixture was stirred for a short time and then excess diazomethane and the solvent were removed in vacuo. The evaporation residue was purified by column chromatography on silica gel with methylene chloride / 1-8% ethanol as the mobile phase. 180 mg of the title methyl prostatrienoate were obtained.

IR: 3390, 3000-2860, 1735, 1670, 1650, 1440, 1170, 1055, 1020 cm-l.

Example 2 (5Z, 13E) - (8R, 9S, llR, 12R, 15R) -9, 1 1,15-trihydroxy-19- -methyl-5,13,18-prostatrienoic acid, methyl ester General formula I: A = cis CH = CH; B = trans CH = CH;

R2, R3 = H; R4, Rs = CH3.

The (5Z, 13E) - (8R, 9S, 1 1R, 12R, 15R) -9,1 1,15-trihydroxy- -19-methyl-3,13,18-prostatrienoic acid was according to the procedure given in Example 1 with ethereal diazomethane solution implemented. After purification by chromatography on silica gel using methylene chloride / 1-6% ethanol as the mobile phase, 110 mg of the title methyl prostatrienoate were obtained.

IR: 3400, 3000-2860, 1737, 1670, 1650, 1440, 1170, 1055, 1025 cm-l.

Example 3 (5Z, 13E) - (8R 1 iR, 12R, 15S) -9-Oxo-11, 15-dll? Ydrnxy-19- -methyl-5,13,18-prostatrienoic acid and methyl ester General formula I: A = cis CH = CH; B = trans CH = CH;

R1 = COOCH3; R2, R3 = H; R4, R6 = CH3.

a) (5Z, 13E) - (8R, llR, 12R, 15RS) -19-methyl-9-oxo-11 15- -bis (tetrahydropyran-2-yloxy) -5.13. 18- prostatrienoic acid At -20 "C a solution of 2.6 g (5Z, 13E) - (8R, 9S, 11 R, 12R, lsRS) -9-hydroxy-19-methyl-l 1,15-bis- (tetrahydropyran-2-yloxy) -5,13,18-prostatrienoic acid in 33 ml acetone was mixed with 3.72 ml Jones reagent and stirred at this temperature for 30 min. 3.3 ml isopropanol were then added dropwise and more was stirred 10 min at -200 ° C., diluted with ether and washed three times with water. The organic phase was dried over magnesium sulphate and concentrated in vacuo. 2 g of the title compound were obtained.

b> 2 g of the bispyranyl ether obtained in the previous reaction stage were stirred in 44 ml of a mixture which consisted of 65 parts of glacial acetic acid, 35 parts of water and 10 parts of tetrahydrofuran for 3.5 hours at 30 ° C. The mixture was then concentrated several times with benzene in an oil pump vacuum at room temperature. 1.7 g remained. Chromatography on silica gel (ethyl acetate / methanol) enabled the title prostrienoic acid to be separated off as the more polar product.

c) Analogously to the procedure described in Example 1, the title methyl prostatrienate was obtained by esterification of the acid obtained in the previous reaction stage with diazomethane or, better, the 15z, j3-OH acid mixture and subsequent chromatographic separation of the more polar, desired 15x alcohol -Methyl ester obtained with methylene chloride / 1-4% ethanol as a mobile phase.

IR: 3400, 3000-2860, 1740, 1670, 1650, 1440, 1160, 1075 cm-l.

Example 4 (5Z, 13E) - (8R, 1 1R, 12R, 15R) -9-Oxo-l 1,15-dihydroxy-19- -methyl-5,13,18mprostatrienoic acid methyl ester General formula I: A = cis CH = CH ; B = trans CH = CH:

R2, R, = H; R4, R5 = CH3 a) The title prostrienoic acid was obtained by chromatographic separation as a more non-polar product from the product mixture obtained in Example 3b).

b) The title methyl prostatricate was obtained either analogously to the esterification with diazomethane described in Example 1 from the title prostatrienic acid a) or better by chromatographic separation as a more non-polar product from the 15x obtained by diazomethane esterification (according to the procedure in Example 3b), ss-OH-acid mixture) obtained 15-isomer mixture with methylene chloride / 1-4% ethanol as a flow agent Example 5 (5Z, 10Z, 13E) - (8R, 12R, 15S) -15-Hydroxy-% oxo-19-methyl--5,10,15,18-prostatetraenoic acid methyl ester General formula I: A = cis CH = CH; B = trans CH = CH;

R1 = COOCH3; R2, R3 = H; R4, R5 = CH3.

A solution of 77 mg (5Z, 13E) - (8R, 11R, 12R, 15S) -9- -oxo- 11,1 5-dihydroxy- 1 9-methyl-5 13,1 8-prostatrienoic acid (see Example 3) in 6 ml of 90% acetic acid, the mixture was stirred for 19 hours at 60 ° C. and then evaporated in vacuo. After chromatography on silica gel (ether / 5% dioxane), the prostatetraenoic acid was esterified with ethereal diazomethane solution. 40 mg of the title compound were obtained as weak yellow-colored oil 1.

IR: 3400, 3000-2860, 1730, 1700, 1670, 1650, 1590, 1440, 1170, 1040 cm- '.

Example 6 (5Z. 1 OZ. 13E) - (8R, 12R,, so, 12R .15R) -15-Hydroxy-9-oso-19-methyl--5.10.13,18-prostate tetraic acid and methyl ester General formula I: A = cis CH = CH; B = trans CH-CH;

R1 = COOCH3; R2, R3 = H; R4, R5 = CH The title compounds were prepared from the compound described in Example 4) according to the procedure described in Example 5).

IR: 3400, 3000-2860, 1730, 1705, 1675, 1650, 1590, 1440, 1165, 1045 cm-l.

Example 7 {5Z. I 3E) - {8R, 9S, 1 JR, 12R, 15S) -9, 11, 15-Trihydrnxy-19-rne-th ', l-5, 13, 18-pi'ostatnei'säi're- (4 -phe'iyl) -phen acyl ester General formula 1: A = cis CH = CH; B = trans

R2 R3 = H; R4. Rs = CH3.

66 mg of (SZ, 13E) - (8R, 9S, 11 R, 1 2R, 1 5S) -9.1 1,1 5-trihydroxy-1 9-methyl-5, 131 8-prostatrienoic acid were added with 21 mg Triethylamine and 53 mg of p-phenylphenacyl bromide in 4 ml of acetone were stirred for 14 hours at room temperature under argon. After dilution with water it was extracted with ether. the ether extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride / 1-5% isopropanol). 52 mg of the title compound were obtained.

IR: 35 (10-3400, 3000-2860, 1735, 1670, 1650, 1440, 1175. 1 (150, 980 cm In analogy to Example 7, all of the other prostaglandic acids described in the preceding examples can also be converted into the corresponding phenacyl esters.

Example 8 Tris- (hydroxyethyl) -ani'z onietha'is salt of (5Z. 1 3E) - (8R 9S, 11 R, 12R. 15S) -9. 11. 15-Tiihyd> vxy- 19-nzeth) 'l-5, 13,18 -prosta trirnsiiu r'e General Formula 1: A t cis CH = CH; B = trans CH = CH:

R, = COONH3C (CH2OH) 3; R2, R5 = H; R4, R5 = CH3.

To a solution of (5Z, 13IE) - (8R, 9S, 1 IR, 12R, 15S) - 9,11,1 5-trishydroxy- l 9-methyl-5,13.1 prostatrienic acid in 14 ml acetonitrile was added 60 C a solution of 32.9 mg tris (hydroxymethyl) aminomethane in 0.1 ml water and left to stand for 14 hours at room temperature. 65 mg of the title compound were obtained.

In analogy to Example 8), all other prostaglandic acids described in the preceding examples can also be converted into the corresponding tris (hydroxymethyl) aminomethane salts.

Example 9 (13E) - (8R, 11R, 12R, 15S) -9-Oxo-1 1,15-dihydroxy-19-methyl- -13,18-prostadienoic acid a) 2- (4-methyl-3-pentenyl ) -2-oxoethane phosphonic acid dimethyl ester To a solution of 94 g of dimethyl methanephosphonate in 1100 ml of abs. Tetrahydrofuran was added dropwise under argon at -60 C within one hour 454 ml of a 1.68 m butyllithium solution in hexane. After stirring for a further 15 minutes, a solution of 33.2 g of 5-methyl-4-hexenoic acid methyl ester in 100 ml of abs. Tetrahydrofuran was added dropwise within 30 minutes at -650C. The mixture was stirred for two hours at this temperature and then 40 ml of glacial acetic acid were added dropwise at room temperature.

It was then concentrated at 40 C in vacuo and the Subsequently residue in 100 ml of water and 1.5 Ltr.

Ether added. It was shaken with saturated sodium chloride solution, the organic phase was dried over magnesium sulfate and concentrated to dryness on a rotary evaporator. The residue was purified by column chromatography on silica gel using ethyl acetate / 0-10% methanol as the eluent. 50 g of the desired compound were obtained.

IR: 1715, 1260, 1032, 815 / cm.

b) (13E) - (8R, 9S, 1 JR. 12R) -9-Benzoyloxy-1 9-methyl- 15-oxo- - I 1- (ie: rahydropyran-2-yloxy) - 13, 18-prostadietic acid- methyl ester To a suspension of 76 mg of 50% sodium hydride (suspended in oil) in 10 ml of dimethoxyethane freshly distilled over lithium aluminum hydride, 370 mg of the phosphonate obtained according to example a) were added under argon at room temperature. dissolved in 5 ml of abs. Dimethoxy ethane. dripped. After the addition of 68 mg (previously dried in a vacuum oven for 2 hours at 50 ° C.), the reaction mixture was stirred for two hours at room temperature. The suspension was then cooled to -200 ° C. and added dropwise with 930 mg (8R.9S, 11 R, 1 2S) - 9-Benzoyloxy-1 3-oxo-1 1 - (tetrahydropyran-2-yloxy) - - 14,15,16,17,1 8,1 9.20-heptanor-prostanoic acid methyl ester, dissolved in 14 ml abs. Dimethoxylithane, added. The temperature was then allowed to rise from 200 at room temperature over the course of 2 hours in order to then stir the reaction solution for a further three hours at room temperature. At -100C, 0.16 ml of glacial acetic acid and approx.

100 ml of water were added. The phases were separated, the aqueous extracted five times with ether, the organic phases were combined and washed with 4% sodium bicarbonate and saturated sodium chloride solution. After drying over magnesium sulfate, the mixture was concentrated to dryness on a rotary evaporator. The residue was purified by column chromatography on silica gel using ethyl acetate / hexane = 1/3 as the flow agent. One received 710 mg of the title compound.

IR (film): 1740, 1720, 1670, 1630, 1590, 1580, 1275, 1113,1070,1025,715 / cm.

c) (13E) - <8R .9S. I IR. 2R J5S) -9-Benzvloxy-19-methyl-15- -iiydroxy-11 - (tetrahydropyra'z-2-yk> xy) - 13,18-prostadienoic acid methyl ester To a solution, cooled to -450C, of 0.71 g of the ketone obtained in the previous reaction stage in 15 ml of abs. Methanol was added in portions (), 3 g of sodium borohydride. After stirring for a further 15 minutes at -45 ° C., 0.64 ml of glacial acetic acid were also added dropwise to the reaction solution at this temperature. After the solution had been stripped off using a rotary evaporator, methylene chloride / water was added to the residue, solid sodium chloride was added to the separated water phase and the mixture was extracted twice with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The isomers were separated by repeated column chromatography on silica gel with hexane / 33-100% ethyl acetate as the eluent. 320 mg of the title compound were isolated as the most polar product.

The diastereomeric 15,3-hydroxyl compound resulting from the reaction as a less polar component was through Jones oxidation to the ketone b) and then renewed Sodium borohydride reduction largely to the desired Title compound transferred.

IR (film): 3400 (broad), 1740, 1720, 1600, 1580, 1275, 1120, 1070, 1020, 710 / cm.

d) (13E) -68R, 9S, I I R, 12R, ISS) -9-benzoyloxy-19-methyl-I 1, - 15-bis (tetrahydropyran-2-yloxy) -13, methyl prostadienoate To a solution of 320 mg of that obtained according to c) Alcohol in 9 ml abs. Methylene chloride was added to 0.08 ml of dihydropyran (freshly distilled over potassium hydroxide) and 15 mg of p-toluenesulfonic acid at ice bath temperature, the mixture was stirred at 0 C for one hour and then extracted with it beforehand Methylene chloride dilute reaction solution with saturated Sodium hydrogen carbonate solution and water. The organic phase was dried over magnesium sulfate and im Reduced vacuum. The residue was chromatography by Säulenchro on silica gel with ethyl acetate / hexane = 1 / as Purified solvent. One received 360 mg of the desired Connection.

IR (film): 1740, 1720, 1605, 1580, 1275, 1115, 1080, 1025, 715 / cm.

e) (13E) - (8R, 9S, 1 lR, 12R, ISS) -9-hydroxy-1 9-methyl-11,15- -bis- (tetrahydrnpyrw-2-y1oxy) -13,18-prnestage acid of 360 mg of the benzoate obtained according to d) in 12 ml of methanol, 3.3 ml of 2N potassium hydroxide solution were added and the mixture was stirred at room temperature for 23 hours. The reaction mixture was then on Rotary evaporator concentrated, the residue with 10 ml Added water, acidified with citric acid to pH = 5 and extracted three times with 150 ml of ethyl acetate each time. The combined organic phases were washed neutral with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with hexane / 33-100% ethyl acetate and ethyl acetate! 5% methanol as the eluent. 222 mg of the title compound were obtained.

IR (film): 3460, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1020, 810 / cm.

t (13E) - (8R, 11R, 12R, 15S) -9-Oxy-19-methyl-1 1, 15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid To one at -20pC A cooled solution of 232 mg of the alcohol obtained according to e) in 38 ml of acetone was added to 0.29 ml of Jones reagent and the mixture was stirred at this temperature for 35 minutes. Then 0.38 ml of isopropanol was added, the mixture was stirred for a further 10 minutes, diluted with cold ether, washed three times with cold, saturated sodium chloride solution, the organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue (256 mg) was used in the next reaction stage without further purification.

IR (film): 2730, 2660, 1740, 1710, 1110, 1075, 1025, 810 / cm.

g) (13E) - (8R, l l, 11R I5S) -9-0xo-11,1 5-dihyrlroxy-l 9-nthyf-13,18-prostadiens ure The obtained according to the above-mentioned procedure 256 mg were made in 4.9 ml of a mixture for 18 hours Glacial acetic acid / water / tetrahydrofuran (65/35/10) stirred at room temperature. It was then concentrated several times with benzene in an oil pump vacuum at room temperature.

The residue was obtained by column chromatography Silica gel cleaned with ethyl acetate as a flow agent. He kept 88 mg of the title compound.

IR (film): 3500, ca.2700, 1735, 1715, 1080 / cm.

Claims (8)

PATENT CLAIMS 1. Process for the preparation of new prostanoic acid derivatives of the formula where R1 is a - represents a group in which R6 represents a hydroxyl group, a straight or branched, saturated or unsaturated alkoxy group, a substituted or unsubstituted aryloxy group, an O-CH2-UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V is a through denotes one or more phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms substituted phenyl ring, or in which R6 is an -NHR10 group, in which Rlo is an optionally substituted alkyl, C38-cycloalkyl, a heteroaryl or aryl group or an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms, R5 and R8 are hydrogen atoms or alkyl groups with 1-4 C atoms and R9 is either an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms or an inorganic acid or a Represent a group, where Rlo has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH- group, B denotes a trans-CH = CH group, W is a free, etherified or esterified hydroxymethylene group, a free or ketalized carbonyl or a -Group, where R11 is an alkyl group with 1-5 C atoms and the OH group x- or, ± can be continuously and etherified or esterified, R2 stands for a hydrogen atom or an alkyl group, R3 denotes a hydrogen atom or an alkyl group, R4 = R5 represents a methyl group or R4 represents a chlorine atom when RB represents a methyl group or R5 represents a chlorine atom if R4 represents a methyl group, and, if R6 represents a hydroxyl group, its physiologically acceptable salts with bases, characterized in that an aldehyde of the general formula (IV) in which A and R1 have the meaning given above and the hydroxyl groups in the 9- and 11-position are protected by ether or ester groups, with a compound of the general formula where R 'denotes a lower alkyl group and Ph, W, R2, R3, R4 and R5 have the meaning given above, reacted, then splitting off the protective groups and converting a 1-carboxy compound obtained, optionally with a base, into a physiologically acceptable salt. 2. The method according to claim 1, characterized in that compounds obtained, which are present as a racemate, are separated. 3. The method according to claim 1, characterized in that compounds obtained, which are present as the free acid of the group Rl, converted into the corresponding saturated or unsaturated alkyl, optionally substituted aryl or phenacyloxy esters. 4. The method according to claim 1, characterized in that etherified hydroxymethylene groups of group W present in the compounds obtained are cleaved. 5. The method according to claim 1, characterized in that esterified hydroxymethylene groups of group W are saponified in the compounds obtained. 6. The method according to claim 1, characterized in that (5Z, 13E) - (8R, 9S, llR, 12R, 15S) -9,11,15-tri-hydroxy-l9-methyl-5,13,18- produces methyl prostatric acid. 7. Process for the preparation of new prostanoic acid derivatives of the formula where R1 is a -Group, in which R6 represents a hydroxyl group, a straight or branched, saturated or unsaturated alkoxy group, a substituted or unsubstituted aryloxy group, an O-CHfU-V group, where U is a direct bond through a carbonyl or carbonyloxy group and V one through a or more phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms substituted phenyl ring, or in which R6 is an -NHR, 0 group, in which Rlo is an optionally substituted alkyl, C2-C8 cycloalkyl, a heteroaryl or Aryl group or an acid residue of an organic carboxylic or sulfonic acid with Represents 1-15 carbon atoms, R, and Ra are hydrogen atoms or alkyl groups with 1-4 C atoms and R9 either an acid radical of an organic carboxylic or sulfonic acid with 1-15 C atoms or an inorganic acid or a Represent a group, where Rlo has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH group, B denotes a trans-CH = CH group, W is a free, etherified or esterified hydroxymethylene group, a free or ketalized carbonyl or a -Group, where R11 is an alkyl group with 1-5 C atoms and the OH group a- or ss-position and can be etherified or esterified, R2 represents a hydrogen atom or an alkyl group, R2 represents a hydrogen atom or an alkyl group, R4 = R5 represents a methyl group or R4 represents a chlorine atom if R3 represents a methyl group or R5 represents a chlorine atom if! R4 denotes a methyl group and, if Re represents a hydroxyl group, its physiologically tolerable salts with bases, characterized in that a compound of the formula I is prepared by the process according to claim 1 and in this the 9-hydroxyl group is oxidized to the 9-keto group and compounds obtained, which are present as the free acid, optionally converted into the corresponding salts. 8. Process for the preparation of new prostanoic acid derivatives of the formula where Rl is a -Group, in which R6 represents a hydroxyl group, a straight or branched, saturated or unsaturated alkoxy group, a substituted or unsubstituted aryloxy group, an O-CH2-UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V is a through denotes one or more phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms substituted phenyl ring, or in which R6 is an -NHR, 0 group, in which Rlo is an optionally substituted alkyl, C3 C8 cycloalkyl, a heteroaryl or Aryl group or an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms, R7 and R8 represent hydrogen atoms or alkyl groups with 1-4 C atoms and R9 either an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms or an inorganic acid or a Represent a group, where Rlo has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH group, B means a trtns-CH = CH group, W is a free, etherified or esterified hydroxymethylene group, a free or ketalized carbonyl or a -Group, where Rli is an alkyl group with 1-5 C atoms and the OH group - or, 3-position and etherified or esterified, means, R2 stands for a hydrogen atom or an alkyl group, R3 denotes a hydrogen atom or an alkyl group, R4 = R5 denotes a methyl group or R4 represents a chlorine atom if R5 represents a methyl group or R3 represents a chlorine atom if R4 represents a methyl group, and, if Re represents a hydroxyl group, their physiologically acceptable salts with bases, characterized in that the process according to claim 7 a compound of the formula IA prepares and this dehydrated with elimination of the 11-hydroxy group and compounds obtained, which are present as free acid, optionally converted into the corresponding salts. The invention relates to a process for the preparation of new prostanoic acid derivatives of the general formula I. wherein R, a -Group, in which Re represents a hydroxyl group, a straight or branched, saturated or unsaturated alkory group, a substituted or unsubstituted aryloxy group, an O-CH2 UV group, where IJ is a direct bond, a carbonyl or carbonyloxy group and V is one through one or more Phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms, preferably bromine atoms, a substituted phenyl ring or an -NHR, 0 group, in which Rlo is an optionally substituted alkyl, C3-C8-cycloalkyl, a heteroaryl or Represents an aryl group or an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms, R7 and R6 hydrogen atoms or alkyl groups with 1-4 carbon atoms and Re either an acid residue of an organic carboxylic or sulfonic acid with 1-15 carbon atoms or an inorganic acid or a Represent a group, where Rlo has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH group, ** WARNING ** End of CLMS field could overlap beginning of DESC **.