CS226442B2 - Method of preparing 9-chloroprostaglandine derivatives - Google Patents

Description

The present invention relates to a process for the preparation of novel 9-chloroprostaglandin derivatives. The use of these compounds as medicaments is also discussed herein.

It is known from the very state of the art of prostaglandins and their analogs that this class of substances is suitable, in view of their biological and pharmacological properties, for the treatment of mammals, including humans. However, their use as medicines often encounters difficulties. Most natural prostaglandins have too short a duration of action for therapeutic purposes as they are metabolically degraded too quickly by various enzymatic processes. All structural changes aim to increase the duration of action as well as selectivity of efficacy.

It has now been found that the novel 9-chloroprostaglandin derivatives have excellent activity specificity, better efficacy and longer duration of action than natural prostaglandins and are particularly suitable for oral administration.

The invention relates to a process for the preparation of 9-chloroprostaglandin derivatives of the general formula I

(I) wherein the chlorine atom at the 9-position is in the α or β-position and where

R 1 is OR 2 with R 2 as hydrogen, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, phenyl, as well as a 5-membered or 6-membered heterocycle containing one atom. nitrogen, oxygen or sulfur, or an NHR3 radical having R3 as C1 -C10 acyl radical, C1 -C4 alkanesulfonic acid ester radical or hydrogen and

A is -CH 2 -CH 2 - or cis-CH = CH-

B is --CH2 --CH2 or --trans --CH.dbd.CH--,

W represents a free or functionally modified hydroxymethylene group, or a free or functionally modified group

CH3 —C— group,!

OH wherein the hydroxy group is in the α or β position,

D and E together represent a direct bond or

D represents a straight-chain or branched C1-C10 alkylene group optionally substituted by fluorine atoms; and

E represents an oxygen or sulfur atom or a direct bond,

R <i denotes a free or functionally modified hydroxy group,

R 5 represents an alkyl group having 1 to 6 carbon atoms which is optionally substituted by halogen, a cycloalkyl group having 5 or 6 carbon atoms, an optionally substituted halogen group or a 5- or 6-membered heterocycle containing one nitrogen, oxygen or sulfur atom and optionally wherein Rt it has the meaning of the hydroxy group, also its salts with physiologically compatible bases.

The alkyl groups R 2 are straight-chain or branched alkyl groups having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, butyl, isobutyl or tert-butyl. Preferred C 1 -C 4 alkyl groups are methyl, ethyl, propyl, isobutyl and butyl.

The cycloalkyl group R 2 contains 5 or 6 carbon atoms in the ring, for example, cyclopentyl, cyclohexyl.

Suitable heterocyclic groups for R2 are five- or six-membered heterocycles containing one heteroatom, nitrogen, oxygen or sulfur. For example, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, but also other groups may be mentioned.

Suitable acid residues are physiologically tolerated residues. Preferred acids are C 1 -C 10 organic carboxylic acids and C 1 -C 4 sulfonic acids which include the aliphatic, cycloaliphatic, aromatic, aromaticaliphatic and heterocyclic series. These acids may be saturated, unsaturated and / or polybasic and / or substituted in the usual manner. Examples of substituents include alkyl, hydroxy, alkoxy, oxo, amino 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, trimethylacetic acid, diethylacetic acid, tert-butyl acetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, ethoxyacetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, aminoacetic acid, , adipic acid, benzoic acid, benzoic acid substituted with halogen, trifluoromethyl, hydroxy, alkoxy or carboxylic acid, ni cotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. Suitable sulfonic acids are methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, [3-chloroethanesulfonic acid, butanesulfonic acid, N, N-dimethylaminosulfonic acid, N, N-diethylaminosulfonic acid, N, N-bis ([3-chloroethyl] aminosulfonic acid). , N, N-diisobutylaminosulfonic acid and N, N-dibutylaminosulfonic acid.

The hydroxy groups in W and R4 may be functionally modified, for example by etherification or esterification, wherein the free or modified hydroxy groups in W are in the α or β position.

Suitable ether and acyl radicals are those known to those skilled in the art. Preferably, ether residues such as tetrahydropyranyl silyl, tetrahydrofuranylsilyl, α-ethoxyethylsilyl, trimethylsilylsllyl, dimethylsilyl, tert-butylsilylsilyl, and tribenzylsilyl are readily cleavable. Acyl radicals which can be used are the same radicals as R3, in particular acetyl, propionyl, butyryl and benzoyl.

Suitable alkyl groups R 5 are straight and branched chain saturated and unsaturated radicals having from 1 to 6

With carbon atoms which may be optionally substituted with aryl or optionally substituted halogen. For example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, benzyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m-chlorobenzyl and p-chlorobenzyl groups may be mentioned.

The cycloalkyl group R 5 may contain 5 or 6 carbon atoms in the ring. For example, a cyclopentyl or cyclohexyl radical may be mentioned.

Possible heterocyclic groups R5 are five or six-membered heterocycles which contain 1 heteroatom, preferably nitrogen, oxygen or sulfur. For example, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and the like can be mentioned.

Suitable alkylene groups D are straight or branched chain saturated or unsaturated alkylene radicals having up to 10 carbon atoms, preferably saturated alkylene groups having up to 10 carbon atoms, in particular up to 5 carbon atoms, which may optionally be substituted by fluorine atoms. For example, methylene, fluoromethylene difluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene may be mentioned. group, 1,1-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyltrimethylene, 1-methyleneethylene, 1-methylenetetramethylene.

Inorganic and organic bases known to those skilled in the art for the formation of physiologically compatible salts are suitable for salt formation. For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-hydroxymethylmethylmethylamine and the like can be mentioned.

The invention therefore relates to a process for the preparation of 9-chloroprostaglandin derivatives of the formula I.

where the hydroxy group is in the α or β position,

B and where

R 1, B, D, E and R 5 are as defined above and the free hydroxy groups of R 4 and W are protected, reacted via the sulfonic acid intermediate ester with the chloride of formula III

RsCl (III), where

R6 is lithium, sodium, potassium or tetraalkylammonium having an alkyl of 1 to 6 carbon atoms, and optionally the liberated protected hydroxy groups are then liberated in any order in the obtained reaction products and / or the free hydroxy groups are esterified and / or hydrogenated, the free hydroxy groups are etherified and / or the esterified carboxyl group is saponified and / or the free carboxyl group is esterified and / or the free carboxyl group is converted into an amide.

The reaction of the compound of formula II to the 9-sulfonic acid ester is carried out in a manner known per se by treatment with alkylsulfonyl chloride or arylsulfonyl chlorides in the presence of an amine such as pyridine or triethylamine at temperatures of -60 to +100 ° C, preferably -20 to +50 ° C. Nucleophilic substitution of the 9-sulfonate with a chlorine atom is carried out with an alkali metal chloride, preferably lithium chloride or tetraalkylammonium chloride, preferably tetrabutylammonium chloride in an inert solvent such as dimethylformamide, dimethylsulfoxide, dimethoxyethane, tetrahydrofuran and the like, at temperatures of 0 to 100 ° C. 80 ^e C.

The release of functionally modified hydroxy groups is carried out by known methods. For example, the cleavage of hydroxyl protecting groups such as the tetrahydropyranyl moiety is carried out in an aqueous solution of an organic acid such as oxalic acid, acetic acid, propionic acid, and the like or in an aqueous solution of an inorganic acid such as hydrochloric acid. To improve the solubility, it is preferable to add an inert organic solvent miscible with water. Suitable organic solvents are, for example, alcohols such as methanol and ethanol and ethers such as dimethoxyethane, dioxane and tetrahydrofuran, preferably tetrahydrofuran. The cleavage is preferably carried out at temperatures of 20 to 80 ° C.

The saponification of acyl groups is carried out, for example, with alkali metal carbonates or alkaline earth metal carbonates or alkaline earth metal hydroxides in an alcohol or an aqueous alcohol solution. Suitable alcohols are aliphatic alcohols, for example methanol, ethanol, butanol and the like, preferably methanol. Alkali metal carbonates and alkali metal hydroxides include potassium and sodium salts. Potassium salts are preferred.

Examples of suitable alkali earth metal carbonates and hydroxides are calcium carbonate, calcium hydroxide and barium carbonate. The reaction is carried out at -10 to +70 degrees Celsius, preferably at + 25 ° C.

The introduction of the ester group —OR2 after R1 in which R2 represents a C1 -C10 alkyl group is carried out by methods known to those skilled in the art; The 1-carboxy compounds are reacted, for example, with diazo-hydrocarbons in a manner known per se. Esterification of the diazocarbon is accomplished, for example, by mixing a solution of the diazocarbon in an inert solvent, preferably diethyl ether, with a 1-carboxy compound in the same or another inert solvent, such as methylene chloride. After completion of the reaction, the solvent is removed after 1 to 30 minutes and the ester is purified in the usual manner. Diazoalkanes are either known or can be prepared by known methods (Org. Reactions, v. 8, pp. 389-394 (1954)).

The introduction of the ester group —OR2 after R1, in which R2 represents a substituted or unsubstituted aryl group, is carried out by methods known to those skilled in the art. For example, the 1-carboxy compound with the corresponding aryl hydroxy compounds can be reacted in an inert solvent with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine or triethylamine. ethylene chloride, ethylene chloride, ethylene chloride, and the like, may be used as solvents. chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures from -30 to + 50 ° C, preferably at 10 ° C. . ·. .

If —C — C—; the double bonds in the primary product are to be reduced by hydrogenation according to known methods.

The hydrogenation of the double bond at the 5, 6 position is carried out in a manner known per se at low temperatures, preferably at about -20 ° C, in a hydrogen atmosphere, in the presence of a noble metal catalyst. For example, 10% palladium on carbon is suitable as a catalyst.

If the double bond at both the 5, 6 and 13,14 positions is to be hydrogenated, then the reaction is carried out at higher temperatures, preferably at about 20 ° C.

The prostaglandin derivatives of the formula I with Rt in the meaning of the hydroxy group can be converted into the salt by suitable amounts of the corresponding inorganic bases under neutralization. For example, by dissolving the corresponding PG acids in water containing a stoichiometric amount of the base, a solid inorganic salt is obtained after evaporation of water or addition of a water-miscible solvent such as alcohol or acetone.

For the production of the amine salt, which is carried out in a conventional manner, PG acid is dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether, acetonitrine or benzene, and at least a stoichiometric amount of the amine is added to this solution. The salt usually precipitates out in solid form or is isolated in the usual manner after evaporation of the solvent.

The introduction of the NHR3 amide group is carried out by methods known to those skilled in the art. The carboxylic acids of the formula I (R 1 = OH) are first converted in the presence of a tertiary amine, for example triethylamine, with isobutyl chloroformate into a mixed anhydride. The reaction of the mixed anhydride with the alkali metal salt of the corresponding amide or ammonia (R 5 = H) is carried out in an inert solvent or solvent mixture, for example tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide, at temperatures from -30 to +60 ^° C. at 0 to 30 ° C.

A further possibility for introducing the NHR3 amide group after R1 is by reacting a 1-carboxylic acid of formula I (R1 = OH) in which free hydroxyl groups are optionally protected intermediate with compounds of formula IV

O - C = N - R ₃ where

R3 is as defined above.

The reaction of a compound of formula I (R 1 -OH) with an isocyanate of formula IV is carried out; optionally with the addition of a tertiary amine such as triethylamine or pyridine. The reaction may be carried out without solvent or in an inert solvent, for example preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene at temperatures of -80 to 100 ° C, preferably at 0 to 30 ° C.

If the starting product contains hydroxyl groups in the prostaglandin residue, these OH groups are also reacted. If end products containing free hydroxyl groups in the prostane radical are subsequently desired, it is preferable to start from the starting products in which they are protected, preferably by easily cleavable ether or acyl radicals.

Compared to PGE derivatives, the novel 9-chloroprostaglandins are more stable.

The novel 9-chloropostaglandin derivatives of the formula I are valuable medicaments because they have a substantially better (higher) specificity and, in particular, a considerably longer effect than the corresponding natural prostaglandins with a similar spectrum of action.

The new prostaglandin analogs have a strong luteolytic effect, i.e. substantially less dosages are required to induce luteolysis than the corresponding natural prostaglandins.

Even for induction of abortions, especially after oral administration, considerably smaller doses of new prostaglandin analogs are required compared to natural prostagiandin.

When registering isotonic uterine contractions in narcotized rats and isolated rat uterus, the substances produced by the method of the invention are shown to be substantially more effective and retain their effect longer than natural prostaglandins.

The novel prostaglandin derivatives are useful after a single enteral or parenteral administration to induce menstruation or to interrupt pregnancy. They are further suitable for synchronizing sexual cycles in female mammals such as rabbits, cattle, horses, pigs and the like. Further, the prostaglandin derivatives of the invention are useful for cervical dilation as a preparation for diagnostic and therapeutic interventions.

The good tissue specificity of the antifertile agents of the present invention is shown when tested in other smooth muscle organs, such as guinea pig ileum or isolated rabbit trachea, where substantially less stimulation is observed than with natural prostaglandins. The compounds of the invention also have bronchospasmolytic activity. In addition, they cause the nasal mucosa to collapse.

The active compounds according to the invention prevent gastric acid secretion, show a cytoprotective and ulcer healing effect and thus counteract the undesirable consequences of non-steroidal anti-inflammatory agents (prostaglandin-inhibitor synthesis).

Some compounds cause a decrease in blood pressure, regulating in cardiac arrhythmias and preventing platelet aggregation, resulting in additional applications.

For medical use, the active compounds can be converted in a suitable form for inhalation, oral or topical administration.

Aerosol solutions are preferably used for inhalation.

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

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

For vaginal administration, for example, suppositories are suitable and customary.

The invention also relates to medicaments based on the compounds of the formula I and the usual excipients and carriers.

The active compounds according to the invention are intended to serve in conjunction with excipients known and customary in pharmacy, for example for the production of preparations for inducing abortion, for controlling the cycle, for commencing labor or for treating hypertonia. For this purpose, but also for other uses, the preparations may contain from 0.01 to 50 mg of active compound.

The following examples are intended to illustrate the invention without limiting it.

Example 1

(5Z, 13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methyl ester

To a solution of 5.72 g of (5Z, 13Ej- (9S, 11R, 15R) -9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18,19,20-tetranor) methyl ester -5,13-Prostadienoic acid (made from the corresponding acid in methylene chloride by reaction with a 0.5 M ethereal solution of diazomethane at 0 ° C in 17 ml of pyridine, at 0 ° C, 3.8 g of p-toluenesulfonic acid chloride is added, stirred 16 After 15 hours at room temperature, 15 ml of water are added, stirred for 2.5 hours at room temperature, made up with 1 liter of ether and shaken in succession with water, 5% sulfuric acid, 5% sodium bicarbonate solution and water. The product was dried (MgSO 4) and evaporated in vacuo to give 6.56 g of 9-tosylate as a colorless oil.

Company ID:

2950, 2875, 1733, 1600, 1590, 1496, 1396,

13.65, 1240, 974 / cm.

A solution consisting of 3.6 g of 9-tosylate in 150 ml of dimethylformamide is stirred for 4 hours with 2.1 g of lithium chloride at 60 DEG C. under argon. It is then poured onto a 10% sodium chloride solution, extracted three times with a 1: 1 mixture of ether and hexane, the organic extract is shaken three times with water, dried over magnesium sulphate and evaporated in vacuo.

2.9 g of the 9/3-chloro compound are obtained as a colorless oil.

Company ID:

2955, 1734, 1603, 1591, 978 cm @ -1.

In order to cleave the tetrahydropyranyl ether, 2.9 g of the crude product obtained above are stirred for 16 hours at room temperature with 80 ml of a 65:35:10 mixture of acetic acid, water and tetrahydrofuran and then evaporated in vacuo. The residue was purified by silica gel chromatography eluting with ether. 1.1 g of the title compound is obtained as a colorless oil.

Company ID:

3600, 3400 (broad), 2940, 1730, 1603, 1591,

975 / cm.

Example 2 (5Z, 13E) - (9R, 11R, 15R) -9-chloro-11,15-dihyd226442 roxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid

450 g of the methyl ester produced according to Example 1 are stirred for 5 hours with 15 ml of a solution of potassium hydroxide in ethanol and water (a solution prepared by dissolving 2 g of potassium hydroxide in 75 ml of ethanol and 25 ml of water). It was then acidified to pH 4 with 10% citric acid solution and extracted with methylene chloride. The organic extract was washed once with brine, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel with methylene chloride / methanol as eluent gave 405 mg of the title compound as a colorless oil.

Company ID:

3600, 3400 (wide), 2930, 2855, 1710, 1600,

1590, 971 cm @ -1.

Example 1 and d 3

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid methyl ester

To a solution of 1.15 g of (13E) - (9S, 11R, 15R) -9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18,19,20-tetranor methyl ester -13-Prostenoic acid (made from the corresponding acid in methylene chloride by reaction with a 0.5 M ethereal solution of diazomethane at 0 ° C) in 3.5 ml pyridine was added at 0 ° C 720 mg of p-toluenesulfonic acid chloride, stirred for 16 hours at 0 ° C and 48 hours at 25 ° C. It is then made up with 0.3 ml of water, stirred for 2.5 hours at 25 [deg.] C., ether is added, shaken in succession with water, 5% sulfuric acid, 5% sodium bicarbonate solution and water. The product was dried over magnesium sulfate and evaporated in vacuo. 1.4 g of 9-tosylate are thus obtained as a colorless oil.

Company ID:

2950, 2873, 1732, 1600, 1591, 1495, 1365,

1240, 975 cm @ -1.

A solution consisting of 0.92 g of 9-tosylate in 60 ml of dimethylformamide was stirred for 4 hours with 550 mg of lithium chloride at 60 ° C under argon. It is then poured onto a 10% sodium chloride solution, extracted three times with a 1: 1 mixture of ether and hexane, the organic extract is shaken three times with water, dried over magnesium sulfate and evaporated in vacuo. 0.72 g of the 9/3-chloro compound is obtained as a colorless oil.

Company ID:

2955, 1733, 1602, 1590, 978 cm @ -1.

In order to cleave the tetrahydropyranyl ether, 0.72 g of the crude product obtained above is stirred for 16 hours at 25 DEG C. with 15 ml of a 65:35:10 mixture of acetic acid, water and tetrahydrofuran and then evaporated in vacuo. The residue was purified by silica gel chromatography. Elution with ether gave 0.29 g of the title compound as a colorless oil.

Company ID:

3600, 3400 (wide), 2945, 1731, 1602, 1590,

976 / cm.

Example 4 (13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid

Analogously to Example 2, 0.19 g of the title compound is obtained in the form of a colorless oil from 0.25 g of the methyl ester prepared according to Example 3.

Company ID:

3600, 3400 (wide), 2935, 2857, 1710, 1600,

1592, 972 cm @ -1.

Example 5

(5Z, 13E) - (9R, 11R, 15R) -9-Chloro, 15-dlhydroxy-16- (m-chlorophenoxy) -17,18,19.20-tetranor-5,13-prostadlenic acid methyl ester

To a solution of 2.95 g of (5Z, 13Ej- (9S, 11R, 15R) -9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -16- (m-chlorophenoxy) -17,18 methyl ester), 19.20-tetranor-5,13-prostadienoic acid (made from the corresponding acid in methylene chloride by reaction with a 0.5 M solution of diazomethane at 0 ° C) in 8 ml of pyridine is added at 0 ° C 1.9 g of p-toluenesulfonic acid chloride, Stir for 16 hours at an ice bath temperature and for 48 hours at room temperature, then make up to 5 ml with water and stir

2.5 hours at room temperature, make up to 0.4 liters of ether, shake in succession water, 5% sulfuric acid, 5% sodium bicarbonate solution and water. The product was dried over magnesium sulfate and evaporated in vacuo. 3.4 g of 9-tosylate are thus obtained as a colorless oil.

Company ID:

2955, 2873, 1733, 1600, 1588, 972 cm @ -1.

A solution consisting of 3.4 g of 9-tosylate in 150 ml of dimethylformamide was stirred for 4 hours with 2.0 g of lithium chloride at 60 ° C under argon. It is then poured onto a 10% sodium chloride solution, extracted three times with a mixture consisting of hexane in a ratio

220442: 1, the organic extract was shaken three times with water, dried over magnesium sulfate and evaporated in vacuo.

2.7 g of the 9β-chloro compound are obtained as a colorless oil as a crude product. Company ID:

2955, 1733, 1600, 1587, 975 cm @ -1.

In order to cleave the tetrahydropyranyl ether, 2.7 g of the crude product obtained above are stirred for 16 hours at room temperature with 70 ml of a 65:35:10 mixture of acetic acid, water and tetrahydrofuran and then evaporated in vacuo. After purification of the residue on silica gel, 0.95 g of the title compound is obtained in the form of a colorless oil.

Company ID:

3600, 3420 (wide), 2940, 1732, 1600, 1588,

976 / cm.

Example 6 (5Z, 13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-5,13-prostadienoic acid

Analogously to Example 2, 460 mg of the title compound prepared according to Example 5 gave 460 mg of the title compound as a colorless oil.

Company ID:

3600, 3400 (wide), 2940, 2860, 1710, 1600,

1588, 973 cm @ -1.

Example 7

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-prostenoic acid methyl ester

To a solution of 600 mg of (13E) - (9S, 11R, 15R) -9-hydroxy-l, 15-Bis- (tetrahydropyran-2-yloxy) -16- ^(m-1 CH orf phenoxy) -17.18. 19,20-tetranor-13-prostenoic acid (produced by hydrogenation from (5Z, 13E) - (9S, 11R, 15R) -9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -16-) - m-chlorophenoxy) -17,18,19,20-tetranor-5,13-prostadienoic acid in ethyl acetate at 20 degrees Celsius with 10% palladium on carbon and an equivalent amount of hydrogen in 2 ml pyridine is added at 0 ° C 390 mg of p-toluenesulfonic acid chloride, stirred at ice bath temperature for 16 hours and at room temperature for 48 hours.

Then, 0.5 ml of water is added, stirred for 3 hours at room temperature, diluted with ether, shaken with water, 5% sulfuric acid, 5% sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated in vacuo. 680 mg of 9-tosylate are thus obtained as a colorless oil.

Company ID:

2955, 2873, 1732, 1600, 1588, 974 cm @ -1.

A solution consisting of 680 mg of 9-tosylate in 15 ml of dimethylformamide was stirred for 4 hours with 220 mg of lithium chloride at 60 ° C under argon. It is then poured onto a 10% sodium bicarbonate solution, extracted three times with a 1: 1 mixture of ether and hexane, the organic extract is shaken three times with water, dried over magnesium sulfate in vacuo. In this process, 520 mg of the 9/3-chloro compound is obtained in the form of an oil,

IC:

2955, 1732, 1600, 1588, 975 cm @ -1.

In order to cleave the tetrahydropyranyl ether, 520 mg of the previously obtained crude product are stirred at room temperature for 16 hours with 10 ml of a 65:35:10 mixture of acetic acid, water and tetrahydrofuran and then evaporated in vacuo. Purification of the residue on silica gel afforded 225 mg of the title compound as an colorless oil with ether. Example 8 (13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-prostenoic acid

Analogously to Example 2, the title compound was obtained from 200 mg of the methyl ester prepared according to Example 7 in a yield of 165 mg as a colorless oil.

Company ID:

3600, 3420 (wide), 2944, 2860, 1710, 1600,

1588, 975 cm @ -1.

Example 9 'W' .. f

(5Z, 13E) - (9S, 11R, 13RS) -9-Chloro-11,15a-dihydroxy-16-methyl-5,13-prostadienoic acid methyl ester

To a solution of 1.1 g of (5Z, 13Ej- (9S, 11R, 16RS) -9-hydroxy-16-methyl-11,15a-bis- (tetrahydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester (produced by from the corresponding acid in methylene chloride by reaction with a 0.5 M solution of diazomethane at 0 ° C)

Pyridine (3.5 mL) was added, at 0 ° C, 760 mg of p-toluenesulfonic acid chloride, stirred at 0 ° C for 16 hours and at 25 ° C for 48 hours. After working up according to Example 1, it is obtained

1.4 g of 9-tosylate as a colorless oil.

............................. ......

Company ID:

2955, 2870, 1732, 975 cm @ -1.

A solution consisting of 1.4 g of 9-tosylate in 60 ml of dimethylformamide was stirred for 4 hours with 840 mg of lithium chloride at 60 ° C under argon. After the usual work-up, 1.1 g of the 9β-chloro compound are obtained in the form of an oil. Company ID:

2960, 1732, 975 cm @ -1.

In order to cleave the tetrahydropyranyl ether, 1.1 g of the crude product obtained above are stirred at room temperature for 16 hours with 35 ml of a 65:35:10 mixture of acetic acid, water and tetrahydrofuran and then evaporated in vacuo. Chromatography of the residue on silica gel afforded 0.6 g of the title compound as an oil with ether.

Company ID:

3600, 3420 (broad), 2960, 1733, 976 cm @ -1.

Example 10 (5Z, 13E) - (9R, 11R, 16RS) -9-Chloro-11,15'-dihydroxy-16-methyl-5,13-prostadienoic acid

Analogously to Example 2, 0.39 g of the title compound is obtained in the form of a colorless oil from 0.5 g of the methyl ester prepared according to Example 9.

Company ID:

3600, 3400 (wide), 2945, 1710, 976 cm @ -1.

Example 11

(5Z, 13H) - (9R, 11R, 15S) -9-Chloro-11,15-dihydroxy-15-methyl-5,13-prostadienoic acid methyl ester

To a solution of (5Z, 13E) - (9S, HR, 15S) -9-hydroxy-15-methyl-11,15-bis- (tetrahydropyran-2-yloxy) -5,13-prostadienoic acid methyl ester (prepared from from the corresponding acid in methylene chloride by reaction with a 0.5 M solution of diazomethane) in 3.5 ml of pyridine, 691 mg of p-toluenesulfonic acid chloride is added at 0 ° C, stirred at 0 ° C for 16 hours and then at 25 ° C for 48 hours After working up as in Example 1, 1.25 g of 9-tosylate is obtained as a colorless oil.

Company ID:

2950, 2870, 1735, 1601, 1365, 1175, 978,

905 / cm.

R, a solution consisting of 1.20 g of 9-tosylate in ml of DMF was stirred with 720 mg of lithium chloride at 60 ° C for 4.5 hours under argon. Work up as in Example 1 gave 900 mg of the 9/3-chloro compound as an oil.

Company ID:

2955, 2868, 1735, 978 cm @ -1.

To cleave the protecting groups, 800 mg of the 9-chloro compound thus obtained is stirred with 20 ml of a mixture consisting of acetic acid, water and tetrahydrofuran in a ratio of 65: 35: 10 for 20 hours at 25 ° C. Evaporation in vacuo and chromatography of the residue on silica gel with methylene chloride gave 400 mg of the title compound as an oil.

Company ID:

3600, 3420 (wide), 2955, 2870, 1735, 976 cm @ -1.

Example 12 (5Z, 13E) - (9R, 11R, 15S) -9-Chloro-11,15-dihydroxy-15-methyl-5,13-prostadienoic acid

In analogy to Example 2, 230 mg of the title compound are obtained in the form of an oil from 300 mg of the methyl ester produced according to Example 11.

Company ID:

3600, 3400, 2950, 1710, 978 cm @ -1.

Example 13

(5Z, 13E) - (9R, 11R, 15R, 16RS) -9-Chloro-11,15-dihydroxy-16-fluoro-5,13-prostadienoic acid methyl ester

Mixture consisting of 1,2 g of (5Z, 13E) - (9S, 11R, 15R, 16RS) -9-hydroxy-16-fluoro-11,15-bis- (tetrahydropyran-2-yloxy) -5,13- of prostadienoic acid (made from the corresponding acid in methylene chloride by reaction with a 0.5 M solution of diazomethane at 0 ° C), 800 mg of p-toluenesulfonic acid chloride and 4 ml of pyridine was stirred at 0 ° C for 16 hours and then at 25 ° C for 48 hours Working up as in Example 1 gave 1.45 g of 9-tosylate as an oil.

Company ID:

2952, 2870, 1732, 1601, 1360, 1170, 978, 906 cm @ -1.

1.25 g of the tosylate thus obtained are heated to 60 DEG C. with 725 mg of lithium chloride in 50 ml of dimethylformamide with stirring for 4 hours. After working up in accordance with Example 1, 925 mg of the 9H-chloro compound is obtained as an oil,

Company ID:

2950, 1735, 976 cm @ -1.

To remove the protecting groups, 900 mg of the 9 / 5'-chloro compound thus obtained are mixed with 25 ml of a mixture consisting of glacial acetic acid, water and tetrahydrofuran in a ratio of 65: 35: 10 for 20 hours at 25 ° C. Evaporation in vacuo and chromatography of the residue on silica gel with methylene chloride afforded 450 mg of the title compound as an oil.

Company ID:

3605, 3420, 2952, 2868, 1735, 978 cm @ -1.

Example 14 (5Z, 13E) - (9R, 11R, 15R, 16RS) -9-Chloro-11,15-dihydroxy-16-fluoro-5,13-prostadienoic acid

Analogously to Example 2, 310 mg of the methyl ester prepared according to Example 13 gave 310 mg of the title compound as an oil.

Company ID:

3600, 3400, 2952, 2860, 1712, 978 cm @ -1.

Example 15

(5Z, 13E) - (9R, 11R, 15R) -9-Chloro-11,15-0-hydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid methylsulfonamide

A solution of 200 mg of (5Z, 13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid in 5 ml of dimethylformamide 80 mg of butyl chloroformate and 60 mg of triethylamine are added at 0 [deg.] C. After 30 minutes, 234 mg of methylsulfonamide sodium (made from methylsulfonamide and sodium methoxide) and 2 ml of hexamethylphosphoric triamide are added and stirred at 20 [deg.]. The reaction mixture was then added to citrate buffer (pH 5), extracted several times with ethyl acetate, the organic phase was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 80 mg of the title compound as an oil after chromatography on silica gel with methylene chloride.

Company ID:

3600, 3400, 1718, 1600, 1590, 1125, 972 cm @ -1.

Example 16

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid methylsulfonamide

In analogy to Example 15, the title compound is obtained as an oil from the compound prepared according to Example 4.

Company ID:

3605, 3410, 1720, 1600, 1588, 1125, 970 cm @ -1.

Example 17

(5Z, 13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-5,13-prostadienoic acid methylsulfonamide

Analogously to Example 15, the title compound is obtained in the form of an oil from the compound prepared according to Example 6.

Company ID:

3602, 3400, 1720, 1602, 1590, 1130, 970 cm.

Example 18

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-prostenoic acid methylsulfonamide

Analogously to Example 15, the title compound is obtained in the form of an oil from the compound prepared according to Example 8.

Company ID:

3602, 3400, 2960, 2870, 1720, 1601, 1590,

1125, 970 cm @ -1.

Example 19

(5Z, 13Ej- (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16,16-dimethyl-5,13-prosphadienoic acid methylsulfonamide

To a solution of 585 mg of (5Z, 13E) - (9R, 11R, 15R) -9-chloro-16,16-dimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -5,13-prostadienoic acid (produced from (5Z, 13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16,16-dimethyl-5,13-prostadlenic acid methyl ester, the preparation of which is described in Czechoslovak Patent No. 226 419 (PV 8647-80] by saponification with 1M sodium hydroxide in methanol) in 25 ml of tetrahydrofuran, 0.75 mg of methanesulfonyl isocyanate in 10 ml of tetrahydrofuran is added and stirred at 20 ° C for 6 hours, then neutralized with acetic acid and evaporated in vacuo. Dissolve in 100 ml of methylene chloride, shake with saturated sodium bicarbonate solution and water, dry over magnesium sulphate and evaporate in vacuo.

To remove the protecting groups, the residue is stirred with 10 ml of a mixture of glacial acetic acid, water and tetrahydrofuran in a ratio of 65: 35: 10 for 4 hours at 40 ° C, evaporated in vacuo and the residue absorbed on 20 g of silica gel. Elution with hexane / ethyl acetate 1: 1 removes impurities. Elution with ethyl acetate gave 200 mg of the title compound as an oil.

IC:

3600, 3420, 2955, 2868, 1718, 1120, 972 cm @ -1. Example 20

(5Z, 13E) - (9R, 11R, 16RS) -9-Chloro-11,15a-dihydroxy-16-methyl-5,13-prostadienoic acid methylsulfonamide

Analogously to Example 15, the title compound is obtained in the form of an oil from the compound prepared in Example 10.

IC:

3602, 3400, 1718, 1120, 972 cm @ -1.

Example 21

(5Z, 13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid isopropylsulfonamide

200 mg of (5Z, 13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid (from Example 2) Dissolve 5 ml of dimethylformamide and add 0 mg of isobutyl chloroformate and 60 mg of triethylamine at 0 ° C. After 30 minutes, 290 mg of isopropylsulfonamide sodium (made from isopropylsulfonamide and sodium methoxide) and 2 mL of hexamethylphosphoric triamide were added and stirred at 25 ° C for 3 hours. For work-up, it is taken up in 100 ml of citrate buffer (pH 5j), extracted several times with ethyl acetate, the organic phase is washed with brine, dried over magnesium sulphate and evaporated in vacuo to give 91 mg of the title compound after chromatography on silica gel with methylene chloride. oil.

Company ID:

3600, 3410, 2960, 2870, 1722, 1601, 1588,

1120, 974 cm @ -1.

Example 22

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid isopropylsulfonamide

Analogously to Example 21, 200 mg of (13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid is obtained (For production see example

4) 85 mg of the title compound as an oil.

IC:

3605, 3410, 2955, 2865, 1722, 1600, 1588

1125, 974 cm @ -1.

Example 23

(5Z.13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid

To a solution of 575 mg of (5Z, 13E) - (9R, 11R, 15R) -9-chloro-11,15-bis (tetrahydropyran-2-yloxy) -16-phenoxy-17,18,19,20-tetranor-5, 13-Prostadienoic acid (made from the corresponding methyl ester - see Example 1 by saponification with 1 M sodium hydroxide in methanol) in 15 ml of acetonitrile is added at 25 ° C 150 mg of triethylamine, cooled to 0 ° C and a solution of 105 mg of acetylisocyanate in 10 ml of acetonitrile, stirred for 2 hours at 25 ° C, concentrated in vacuo, diluted with 100 ml of water, adjusted to pH 5 by addition of 1N sulfuric acid, extracted several times with ether, washed with brine, dried over magnesium sulfate and evaporated in vacuo To remove the protecting group, stir the residue with 15 ml of glacial acetic acid, water and tetrahydrofuran (65: 35: 10) for 5 hours at 40 ° C, then evaporate in vacuo to dryness. 200 mg of the title compound was obtained as oils.

IC:

3600, 3400, 2945, 2862, 1708, 1600, 1588,

976 / cm.

Example 24

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid acetylamide

Analogous to Example 23, 450 mg of (13E) - (9R, 11R, 15R1-9-chloro-11,15-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18,19) are obtained, 20-Tetranor-13-prostenoic acid (made from the corresponding methyl ester - see Example 3 - by saponification with 1 M sodium hydroxide in methanol) 200 mg of the title compound as an oil.

IC:

3600, 3410, 2950, 2860, 1706, 1600, 1590,

976 / cm.

Example 25

(13Ej- (9R, HR, 15R) -9-chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-prostenoic acid acetylamide

In analogy to Example 23, 485 mg of (13E) - (9R, 11R, 15R) -9-chloro-11,15-bis- (tetrahydropyran-2-yloxy) -16- (m-chlorophenoxy) -17 was obtained. 18,19,20-tetranor-13-prostenoic acid (prepared from the corresponding methyl ester - see Example 7 - by saponification with 1 M sodium hydroxide in methanol) 225 mg of the title compound as an oil.

Company ID:

3600, 3400, 2948, 2858, 1706, 1602, 1590,

976 / cm.

Example 26

(5Z, 13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,2,0-tetranor-5,13-prostadienoic acid amide

400 mg of (5Z, 13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoic acid (see Example for preparation) 2) is dissolved in 10 ml of terahydrofuran and at 0 ° C added 140 mg of triethylamine and 171 mg of isobutyl ester of formic acid. After 1 hour at 0 ° C ammonia gas was introduced for 10 minutes, then allowed to stand at 25 ° C for 1 hour, diluted with 50 ml of water, extracted three times with 50 ml of methylene chloride each time and the combined extracts were shaken once with 20 milliliters of brine. and evaporated in vacuo. For purification, the residue is chromatographed on silica gel with a mixture of chloroform and ethyl acetate. 310 mg of the title compound is obtained as a waxy mass.

Company ID:

3600, 3535, 3415, 2995, 2930, 2860, 1676,

1600, 1588, 972 cm @ -1.

Example 27

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-propenoic acid amide

Analogously to Example 26, the title compound is obtained as an oil from the acid produced according to Example 4.

Company ID:

Example 28

(5Z, 13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-5,13-prosadienoic acid amide

Analogously to Example 26, the title compound is obtained as an oil from the acid prepared according to Example 6.

Company ID:

3600, 3450, 2998, 2930, 2862, 1670, 1600,

1585, 974 cm @ -1.

Example 29

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dihydroxy-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-prostenoic acid amide

Analogously to Example 28, the title compound is obtained in the form of an oil from the acid prepared according to Example 8.

Company ID:

3600, 3420, 2998, 2935, 2860, 1672, 1600,

1588, 972 cm @ -1.

Example 30

(13E) - (9R, 11R, 15R) -9-Chloro-11,15-dlhydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid tris-hydroxymethylaminomethane salt

To a solution of 410 mg of (13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranorprostenoic acid (see Example 4) in 70 ml of acetonitrile a solution of 122 mg of tris- (hydroxymethyl) aminomethane in 0.4 ml of water was added at 65 ° C. It is allowed to cool with stirring, decanted after 16 hours from the solvent and the residue is dried under vacuum. 365 mg of the title compound is obtained in the form of a white waxy mass.

M.p. 112 DEG C. (acetonitrile). IR (KBr): 3350 (broad), 2940, 1600, 1560, 1498, 1052, 978, 757 cm @ -1.

3600, 2535, 3410, 2996, 2930, 2860, 1670, 1601, 1588, 972 cm @ -1.

Claims (3)

A process for the preparation of 9-chloroprostaglandin derivatives of the formula I Wherein the chlorine atom at the 9-position is at the α or β-position and where R @ 1 is OR @ 2 with R @ 2 in the meaning of a hydrogen atom; 4 carbon atoms; 5 or 6 carbon atoms, phenyl, as well as a 5- or 6-membered heterocycle containing one nitrogen, oxygen or sulfur atom, or an NHR3 radical with R5 as acyl radical having from 1 to 10 carbon atoms, a radical of alkanesulfonic acid ester having 1 to 4 atoms carbon or hydrogen; and A is -CH2-CH2- or cis-CH = CH- B is --CH2 --CH2 - or --trans --CH.dbd.CH--, W represents a free or functionally modified hydroxymethylene group or a free or functionally modified group CH3 i -C-, OH wherein the hydroxy group is in the α or β position, D and E together represent a direct bond or D represents an alkylene group of up to 10 straight or branched chain carbon atoms optionally substituted by fluorine atoms; and E represents an oxygen or sulfur atom or a direct bond, R a denotes a free or functionally modified hydroxy group, R 5 represents an alkyl group having 1 to 6 carbon atoms which is optionally substituted by halogen, a cycloalkyl group having 5 or 6 carbon atoms, an optionally substituted halogen group or a 5- or 6-membered heterocycle containing one nitrogen, oxygen or sulfur atom and R 1 has the meaning of a hydroxy group, also a salt thereof with a physiologically tolerated base, characterized in that the compound of formula II wherein the hydroxy group is in the α or β position and wherein R 1, B, D, E and R 5 are as defined above, and the free hydroxy groups R a and W are protected, reacted via the sulfonic acid intermediate ester with the chloride of formula III ReCl (ΠΙ) where R6 is lithium, sodium, potassium or tetraalkylammonium having an alkyl of 1 to 6 carbon atoms, and optionally the liberated protected hydroxy groups are then liberated in any order in the reaction products obtained and / or the free hydroxy groups are esterified and / or the double bonds are hydrogenated; etherify and / or the esterified carboxyl group is saponified and / or the free carboxyl group is esterified and / or the free carboxyl group is converted into an amide.