DD234668A5 - PROCESS FOR THE PREPARATION OF NEW 9-HALOGEN PROSTAGLANDINES - Google Patents

Abstract

9-halogen-prostane having the formula (I) wherein Hal represents a chlorine or fluorine atom in position $g(a) or $g(b); R1? represents the rest CH2?OH or the formula (A) with R2? representing a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic rest or R1? represents the rest of formula (B) with R3? representing an acid rest or the rest R2?; A is a group -CH2?-CH2?-, -CH=CH- trans or -C=C-; W is free or functionally transformed hydroxy methylene group or a free or functionally transformed group having the formula (C), the group OH susceptible of being in position $g(a) or $g(b); D and E represent together a direct bound or D represents a straight branched or cyclic chain alkylene group with 1 to 10 atoms of carbon, substituted optionally by fluorine atoms, and E represents oxygen or sulfur, a direction bound, a bound -C=C- or a group -CR6?=CR7?, R6? and R7? being different and representing hydrogen, chlorine or alkyl with 1 to 4 atoms of carbon; R4? is a free or functionally modified hydroxy group; R5? is a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl, an optionally substituted aryl or a heterocyclic group; as well as, if R2? represents a hydrogen atom, the salts thereof with physiologically acceptable bases, the preparation process thereof and the pharmaceutical utilization thereof.

Description

-C group, where the OH group may be a- or / 3-membered,

OH

D and E together are a direct bond or D is a straight-chain, branched-chain or cyclic alkylene group having 1-10 C atoms, optionally substituted by

Fluorine atoms is substituted, and E represents an oxygen or sulfur atom, a direct bond, a -C ^ == C bond or a -CR ₆ == CR ₇ group,

wherein R ₆ and R ₇ are different and represent a hydrogen atom, a Cloratom or a Ci-Cr-alkyl group, R _{4 is a} free or functionally modified hydroxy group, R5 is a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl, a optionally substituted

Aryl or a heterocyclic group,

and if R _{2 has} the meaning of a hydrogen atom, their salts with physiologically acceptable bases, characterized in that, in a manner known per se, a compound of the formula II

¹ AWDER ₅

wherein the 9-OH group can be a-or 3-substituent and R _{1 is} the radical _c ^ OR ₂ with R ₂ in the meaning of alkyl, cycloalkyl, aryl or heterocyclic radical or the radical

-C ^ with R ₃ in the meaning of an acid radical, an alkyl, cycloalkyl, aryl or a heterocyclic radical

NH R ₃

represents and

A, D, E and R _{5 have} the meanings already given above, after previous protection of free OH groups in R ₄ and W with carbon tetrachloride / Triphenylphosphi ^ hexachloroethane / Tnphenylphosphin or Diethylaminoschwefeltrifluorid or after conversion of the 9-hydroxy group in a 9-sulfonic acid ester Reacting tetra-n-butylammonium fluoride and subsequently releasing protected hydroxy groups in any order and / or esterifying, etherifying and / or hydrogenating double bonds hydrogenated and / or an esterified carboxyl group) = C-OB ₂ ) and / or a free carboxyl group (R ₂ = H ) converted into an amide (R ₁ = -C-NHR ₃ ) and / or a free or esterified

Carboxyl group (Ri = -C-OR ₂ ) reduced. '

Field of application of the invention ~~

The invention relates to a process for the preparation of novel 9-haiogen prostaglandin derivatives of the following formula I.

Characteristic of the known technical solutions

From the very extensive state of the art of prostaglandins and their analogs, it is known that this class of substances, because of their biological and pharmacological properties, is suitable for the treatment of mammals, including humans. Their use as a medicine, however, often encounters difficulties. Most natural prostaglandins have too short a duration of action for therapeutic purposes because they are metabolically degraded too rapidly by various enzymatic processes. All structural changes aim to increase the duration of action as well as the selectivity of the efficacy.

Object of the invention

The new 9-halogen prostaglandin derivatives have excellent specificity, better activity, longer duration of action than natural prostaglandins and their derivatives and are particularly suitable for oral administration.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of new 9-halo-prostaglandin derivatives available, which are superior in their duration of action and selectivity of the effectiveness of the natural prostaglandin derivatives

 The invention is now a process for the preparation of novel θ-halogen-prostaglandin derivatives of the formula I.

4 -

wherein Hal is an α or / 3-position chlorine or fluorine atom,

R _{1 is} the radical CH ₂ OH or -C-OR ₂ with R ₂ meaning a hydrogen atom, an alkyl-cycioalkyl, aryl or heterocyclic radical or

R _{1 is} the radical -C-NHR ₃ with R ₃ in the meaning of an acid radical or the radical R ₂ and A is a -CH ₂ -CH ₂ -, a trans-CH == CH- or a -C == C group .

W is a free or functionally modified hydroxymethylene group or a free or functionally modified

CH ₃ -C group,

OH '

where the OH group may be <* - or ß-permanently

D and E share a direct bond or

D is a straight-chain, branched-chain or cyclic alkylene group having 1-10 C atoms, optionally substituted by

Fluorine atoms is substituted, and ·

E represents an oxygen or sulfur atom, a direct bond, a-Cs = C bond or a -CR ₆ == CR ₇ group, where R ₇ R ₇ and R ₇ are different and represent a hydrogen atom, a chlorine atom or a C 1 -C ₄ - Alkyl group mean.

R _{4 is} a free or functionally modified hydroxy group,

R _{5 represents} a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl, an optionally substituted aryl or a heterocyclic group,

and if R _{2 has} the meaning of a hydrogen atom, their salts with physiologically acceptable bases.

As alkyl groups R ₂ are to be considered straight or branched alkyl groups having 1-10 C atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, decyl. The alkyl groups R ₂ may optionally be mono- to polysubstituted by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups, dialkylamino and Trialkyiamrrionium, wherein the simple substitution should be preferred. Examples of suitable substituents are fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. Preferred alkyl groups R ₂ are those having 1-4 C atoms, such as. For example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl

call.

Suitable aryl groups R ₂ are both substituted and unsubstituted aryl groups, for example phenyl, 1-naphthyl and 2-naphthyl, each of which may be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each having 1-4C Atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group having 1-4 C atoms. Preferably, the substituents in the 3- and 4-position on the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.

The cycloalkyl group R ₂ may contain in the ring 3-10, preferably 5 and 6 carbon atoms. The rings may be substituted by alkyl groups of 1-4 carbon atoms. Examples which may be mentioned are cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.

Suitable heterocyclic groups R ₂ are 5- and S-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples which may be mentioned are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl and others

As acid radical R * are physiologically acceptable acid residues in question. As acids are organic carboxylic acids and

Suitable sulfonic acids having 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic ^ aromatic, aromatic-aliphatic and heterocyclic series. These acids may be saturated, unsaturated and / or polybasic and / or substituted in the usual way. As examples of the substituents, mention may be made of alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms. The following carboxylic acids may be mentioned as examples: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecynic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid , Cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic 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, succinic acid, adipic acid, benzoic acid, with halogen, trifluoromethyl, hydroxy , Alkoxy or carboxy groups, substituted benzoic acids, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. Preferred acyl radicals are considered to be those having up to 10 carbon atoms. As sulfonic acids are, for example, alkanesulfonic acids having 1-10 C atoms such. B. methanesulfonic acid, Äthansulfonsäure, isopropanesulfonic acid and butanesulfonic acid and ß-chloroethanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, NN-dimethylaminosulfonic acid, NN-Diäthylaminosulfonsäure, NN-bis - (/ 3-chloroethyl) -aminosulfonic acid, NN Diisobutylaminosulfonic, NN-Dibutylaminosulfonsäure, pyrrolidino, piperidino, piperazino, N-methylpiperazino and Morpholinosulfonsäure in question. Particular preference is given to acyl radicals or alkanesulfonic acid radicals having 1-4 C atoms. The hydroxy groups in W and R ₄ may be functionally modified, for example by etherification or esterification, wherein the modified hydroxy group in W a- or / may be constant, with free hydroxy groups are preferred.

Suitable ether and acyl radicals are the radicals known to the person skilled in the art. Preference is given to readily eliminable ether radicals, for example the tetrahydropyranyl, tetrahydrofuranyl, a-ethoxyethyl, trimethylsilyl, dimethyl-tert-butyl-silyl and tribenzylsilyl radical. Suitable acyl radicals are the same as those mentioned for R ₃ with organic carboxylic acids, namely, for example, acetyl, propionyl, butyryl and benzoyl. Suitable alkyl and alkenyl groups R ₅ are straight-chain and branched-chain alkyls having 1-10 and alkenyl radicals having 2-10, in particular 1-6 or 2-6 C atoms, which are optionally substituted by optionally substituted phenyl, alkyl 1-4 C atoms or halogen may be substituted. Examples which may be mentioned are methyl, ethyl, propyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl and benzyl, and in the event that D and E together are a direct compound , optionally substituted in the 1-position by fluorine or Ci-C ₄ -alkyl-substituted alkynyl having 2-6 C-atoms. Suitable alkynyl radicals are: ethynyl, propyn-1-yl, propyn-2-yl, 1-methylpropin-2-yl, 1-fluoropropyne-2-yl, 1-ethylprop-2-yl, 1-fluorobutin-2 yl, butyn-2-yl, butyn-3-yl, 1-methylbutyn-3-yl, 1-methylpentin- 3-yl, 1-fluoropentin- 3-yl, 1-methylpentin- 2-yl, 1-fluoropentin-2-yl, 1-methylpentino-4-yl, 1-fluoropentino-4-yl, hexyn-1-yl, 1-methylhexyn-2-yl, 1-fluorohexyn-2-yl, 1-methylhexyne 3-yl, 1-methylhexyn-4-yl, hexyn-3-yl, 1,1-dimethylpropyn-2-yl, 1,1-dimethylbutyn-3-yl, 1,1-dimethylpentin-3-yl, 1, 1-Dimethylpentin-4-yl, 1,1-dimethylhexin-3-yl, 1,1-dimethylhexin-4-yl, etc. For halogen as a substituent of the alkyl and alkenyl groups R ₅ , bromine, chlorine and fluorine are suitable. Preference is given to chlorine and fluorine. The cycloalkyl group R ₅ may contain in the ring 3-10, preferably 3-6 carbon atoms. The rings may be substituted by alkyl groups of 1-4 carbon atoms. Examples which may be mentioned are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl. Suitable substituted or unsubstituted aryl groups Rg are, for example: phenyl, 1-naphthyl and 2-naphthyl, each of which may be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each having 1-4 C atoms, one Chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, alkoxy or hydroxy group. Preferably, the substitution in 3- and 4-position on the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy. Suitable heterocyclic groups R ₅ are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples which may be mentioned are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, inter alia, as alkylene group D are straight-chain or branched-chain, ring-shaped, saturated and unsaturated alkylene radicals, preferably saturated with 1-10, in particular 1-5 C atoms, in question, which may optionally be substituted by fluorine atoms. Examples which may be mentioned are: methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1,1-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyl-trimethylene, 1-methylene-ethylene, 1-methylene-tetramethylene, 2-methyl-trimethylene, 2-methyl-tetramethylene, 1,1-trimethylene-ethylene, 1,2-methylethylene. If a double bond is present, it is in the alkylene radicals in the 2-, 3- or 4-position.

For salt formation, inorganic and organic bases are suitable, as are known to those skilled in the formation of physiologically acceptable salts. Examples which may be mentioned are alkali metal hydroxides such as sodium and potassium hydroxide, Erdaikalihydroxide such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglycine, morpholine, tris (hydroxymethyl) -methyiamin etc.

The process for the preparation of the 9-Halogenprostaglandinderivate of formula I according to the invention is characterized in that in a conventional manner, a compound of formula II

CH

(II)

A-W-D-E-R -

^R 4

wherein the 9-OH group can be a- or / 3-constantly and

Ri is the radical -C-OR2 with R2 in the meaning of alkyl, cycloalkyl, aryl or heterocyclic radical or the

Rest -C with R ₃ in the meaning of an acid radical, an alkyl, cycloalkyl, aryl or heterocyclic

·· -,. ^ NHR ₃ "_

Represents restes and

A, D, E and R5 have the meanings already given above, after prior protection of free OH groups in R ₄ and W with carbon tetrachloride / triphenylphosphine, hexachloroethane / triphenylphosphine or diethylaminosulfur trifluoride or after conversion of the 9-hydroxy group into a 9-suifonic acid ester with tetra-trifluoride. reacting n-butylammonium fluoride and subsequently releasing protected hydroxy groups in any order and / or esterifying free hydroxy groups,

etherified and / or double bonds hydrogenated and / or saponified an esterified carboxyl group (Ri = -C-OR ₂ ) and / or

ζ, ⁰  : "" "

a free carboxyl group (R ₂ = H) converted into an amide (Ri = -C-NHR3) and / or a free or esterified

Carboxyl group (Ri_ = -C-OR ^ reduced.

The reaction of the compounds of formula II to give the compounds of formula I with carbon tetrachloride and triphenylphosphine or hexachloroethane / triphenylphosphine in an inert solvent such as dimethylformamide, dimethylacetamide, acetonitrile, methylene chloride at temperatures between ^{0 0} C and 8O ⁰ C, preferably 2O ⁰ C. to 45 ⁰ C in the presence of a base such as pyridine, triethylamine, etc.

The reaction of the compounds of the formula II to give the compounds of the formula I with shark meaning a fluorine atom is carried out with diethylaminosulfur trifluoride in a solvent such as dichloromethane at temperatures between -12O ⁰ C and 0 ⁰ C, preferably at -70 ⁰ C, optionally in Presence of a base such as pyridine. Substituting an alcohol of formula II with a / 3-standing 9-hydroxy group, we obtain compounds of formula I with 9-α-halogen atom, if one uses an alcohol with an α-hydroxy group, one obtains with compounds 9/3 halogen atom.

The reduction to the compounds of formula I with Ri in the meaning of a -CH ₂ OH group is carried out with a suitable reducing agent for the reduction of esters or carboxylic acids reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, etc. Suitable solvents are diethyl ether, tetrahydrofuran, dimethoxyethane, toluene, etc. in question. The reduction is carried out at temperatures of -3O ⁰ C to the boiling point of the solvent used, preferably 0 ⁰ C to 3O ⁰ C.

The release of the functionally modified hydroxyl groups is carried out by known methods. For example, the removal of hydroxy protecting groups, such as the Tetrahydropyranylrestes, in an aqueous solution of an organic acid, such as. As oxalic acid, acetic acid, propionic acid, inter alia, or in an aqueous solution of an inorganic acid, such as. Hydrochloric acid. To improve the solubility, a water-miscible inert organic solvent is conveniently added. Suitable organic solvents are, for. As alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The cleavage is preferably carried out at temperatures between 2O ⁰ C and 8O ⁰ C. The saponification of the acyl groups is carried out, for example, with alkali or alkaline earth carbonates or hydroxyden in an alcohol or in the aqueous solution of an alcohol. Suitable alcohols are aliphatic alcohols, such as methanol, ethanol, butanol, etc., preferably methanol. Alkaline carbonates and hydroxides may be mentioned as potassium and sodium salts. Preference is given to the potassium salts.

Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction takes place at -1O ⁰ C to + 7O ⁰ C, preferably at +25 ⁰ C.

The introduction of the ester group -C ^ for R ₁ , in which R _{2 represents} an alkyl group having 1-10 C atoms, takes place after

OR 2

the methods known in the art. The 1-carboxy compounds are reacted, for example, with diazohydrocarbons in a conventional manner. The esterification with diazohydrocarbons z. B, characterized in that a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, with the 1-carboxy compound in the same or in another inert solvent, such as. As methylene chloride, mixed. After completion of the reaction in 1 to 30 minutes, the solvent is removed and the ester purified in a conventional manner. Diazoalkanes are either known or can be prepared by known methods [Org. Reactions Vol.8, pages 389-394 (1954)].

The introduction of the ester group -C ^ for R ₁ in which R _{2 represents} a substituted or unsubstituted aryl group,

OR 2

takes place according to the methods known to those skilled in the art. For example, the 1-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine, DMAP, triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures between -30 ° C and + 50 ° C, preferably at 10 ° C.

The prostaglandin derivatives of formula I with R ₂ meaning a hydrogen atom can be converted into a salt with suitable amounts of the corresponding inorganic base with neutralization. For example, in dissolving the corresponding PG acids in water containing the stoichiometric amount of the base, after evaporation of the water or after addition of a water-miscible solvent, eg. As alcohol or acetone, the solid inorganic salt.

For the preparation of an amine salt, which takes place in the usual way, the PG acid z. B. in a suitable solvent, for example ethanol, acetone, diethyl ether, acetonitrile or benzene and added at least the stoichiometric amount of the amine of this solution. The salt usually accumulates in solid form or is isolated by evaporation of the solvent in a conventional manner.

The introduction of the amide group -C-NHR3 for R ₁ is carried out by the methods known to those skilled in the art. The carboxylic acids of the formula I (R ₂ = H) are first converted into the mixed anhydride in the presence of a tertiary amine, such as, for example, triethylamine, with isobutyl chloroformate. The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R ₃ = H) or the corresponding amine is carried out in an inert solvent or solvent mixture, such as tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide, at temperatures between -30 ° C and + 60 ° C, preferably at 0 ° C to 30 ° C.

A further possibility for the introduction of the amide group -C-NHR3 for R ₁ with R ₃ The meaning of an acid radical consists in the reaction of a 1-carboxylic acid of the formula I (R ₂ = H), in which the free hydroxy groups are optionally intermediately protected , with compounds of the formula III

O = C = NR ₃ (III),

wherein R _{3 has} the meaning given above

The reaction of the compound of the formula I (R ₂ = H) with an isocyanate of the formula III

optionally followed by the addition of a tertiary amine, such as. For example, triethylamine or pyridine. The reaction can be carried out without solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80 ° C to 100 ° C, preferably at 0 to 30 ° C.

If the starting product contains OH groups in the prostane radical, these OH groups are also reacted. If final products are ultimately desired which contain free hydroxyl groups in the prostane radical, it is expedient to start from starting materials in which they are intermediately protected by ether or acyl radicals which are preferably readily cleavable.

The compounds of the formula II having a 9a-hydroxy group and serving as starting material are either known or can be prepared by the process given in DE-OS 2627910.

The compounds of formula II with a 9/3-hydroxy group are obtained from the 9a-hydroxy compounds by an inversion reaction, as z. In Synthesis, 292-294 (1980).

Compared to PGE derivatives, the new prostaglandin analogues are characterized by greater stability. The new prostaglandin analogues of the formula I are valuable drugs, since they have a similar spectrum of activity a significantly improved (higher specificity) and above all much longer effect than the corresponding natural prostaglandins.

The new prostaglandin analogs are strongly luteolytic, d. H. To induce luteolysis, much lower doses are required than with the corresponding natural prostaglandins.

Also, to induce abortions, especially after oral or intravaginal administration, significantly lower levels of the new prostaglandin analogs compared to the natural prostaglandins are required.

Upon registration of the isotonic contraction of the anus on the anesthetized rat and on the isolated rat uterus, it appears that the substances according to the invention are much more effective and their effects last longer than with the natural prostaglandins.

The new prostaglandin derivatives are suitable for inducing menstruation or interrupting pregnancy after single enteral or parenteral administration. They are also suitable for synchronizing the sexual cycle in female mammals such as rabbits, cattle, horses, pigs, etc. Furthermore, the prostaglandin derivatives according to the invention are suitable for cervical dilation in preparation for diagnostic or therapeutic procedures. The good tissue specificity of the antifertil effect substances 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 a much lower stimulation is observed than by the natural prostaglandins. The substances according to the invention also act bronchospasmolytically. In addition, they cause a swelling of the nasal mucosa. The active compounds according to the invention inhibit gastric acid secretion, have a cytoprotective and ulcer-healing effect and thus counteract the undesired consequences of non-steroidal anti-inflammatory agents (prostaglandin synthesis inhibitors). They also have a cytoprotective effect on the liver, kidneys and also on the pancreas. Some of the compounds have antihypertensive effects, regulate cardiac arrhythmias, and inhibit platelet aggregation with the resulting potential uses. The new prostaglandins can also be used in combination, for. With / 3-blockers, diuretics, phosphodiesterase inhibitors, calcium antagonists and antigestagens.

The dose of the compounds is 1-1 500 / ig / kg / day when administered to the human patient. For medical use, the active ingredients may be converted to a form suitable for inhalation, oral, parenteral or local (e.g., vaginal) administration.

For inhalation Arosollösungen be prepared suitably.

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

For parenteral administration, sterile, injectable, aqueous or oily solutions are used.

For vaginal administration z. As suppositories suitable and common.

The invention thus also relates to pharmaceutical compositions based on the compounds of the formula I and customary excipients and carriers, including cyclodextrin clathrates.

The active compounds according to the invention are intended to be used in conjunction with the excipients known and customary in galenics, for example. As for the preparation of preparations for inducing a Abortes, for cycle control, to initiate a birth, for the treatment of hypertension or for the treatment of gastrointestinal disorders such. B. for the healing of gastric and duodenal ulcers serve. For this purpose but also for other applications the preparations can contain 0,01-100 mg of the active compound.

embodiments

The following examples are intended to explain the invention in more detail, without any limitation being imposed thereon.

example 1

(9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trienoic acid methyl ester. To a solution of 1.80 g of OSJIR.IBRJ Dimethyl-S-hydroxy-H 1 -B-bis-tetrahydropyrane trans-trienoic acid methyl ester and 3.37 g of triphenylphosphine in 60 ml of 1,2-dichloroethane are added dropwise at ⁰ ° C. a solution of 3.20 g of hexachloroethane and 3.80 ml of triethylamine in 60 ml of 1, 2-dichloroethane. The mixture is stirred for 1 hour at 20 ⁰ C, then diluted with 20QmI Diehlormethan, shaken successively with sodium bicarbonate solution and brine, dried over MgSO ₄ and evaporated in vacuo. The residue is chromatographed on silica gel with toluene / ethyl acetate (95: 5). This gives 1.05 g of oily ORJIR ^ SRl-g-chloro-ie ^ e-dimethyl-njB-bis-tetrahydropyran ^ -xylxyl-prosta - ^ -s-transtriensauremethyiester. To cleave the protecting groups, the resulting ester is stirred with 15 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) for 24 hours at 20 ° C. It is then diluted with ice-water, mixed to neutral point with dilute sodium hydroxide solution and extracted several times with Diehlormethan. The combined extracts are shaken with brine, dried over magnesium sulfate and evaporated in vacuo. For purification, chromatograph on silica gel with hexane / 10-40% ethyl acetate to give 580 mg of the title compound as an oil

 IR: 3600, 3410, 2958.1 958, 1732.1135.1 020, 976 / cm

 The 9a alcohol used as starting material is obtained as follows:

(6RS, 9S, 11R, 15R) -6,9-dihydroxy-16,16-dimethyl-11,15-bis (tetrahydropyran-2-yloxy) -prost-4-yne-13-transenoic acid methyl ester

Dissolve 7.29 g of diisopropylamine in 100 ml of ether with 12.90 g Hexamethyiphosphorsäuretriamid, cooled to -20 ° C and added dropwise under argon 48ml of a 1.5M ethereal solution of methyllithium. It is then cooled to -70 ° C and added dropwise 3.53g 4-pentynoic acid dissolved in 70 ml of ether. The mixture is stirred for a further 2 hours at 20 ° C. and then a solution of 2.80 g (2RS, 3aR, 4R, 5R, 6aS) -4 - [(E) - (3R) -4,4-dimethyl-3- (2-one) is added dropwise. tetrahydropyran-2-yloxy) -1-octenyl] -5- (tetrahydropyran-2-yloxy) -perhydrocyclopenta [b] furan-2-ol in 60 ml of ether. The mixture is stirred for 48 hours at 2O ⁰ C, diluted with water and acidified to pH4 with citric acid. It is extracted several times with dichloromethane, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is treated with excess ethereal diazomethane for 15 minutes and the solution is evaporated to dryness. The oily residue is chromatographed on silica gel with hexane / ethyl acetate (1: 1) chromatographies. 2.15 g of the title compound are obtained as an oil. IR: 3600.2955,2130,1735,1153,1 020,980 / cm.

enoate

To a solution of 2.10 g (6RS, 9S, 11R, 15R) -6,9-dihydroxy-16,16-dimethyl-11,15-bis (tetrahydropyran-2-yloxy) -prost-4-in-13- trans-enoic acid methyl ester in 15 ml of pyridine is added 4 ml of acetic anhydride and allowed to stand at 20 ⁰ C for 16 hours. It is then concentrated in vacuo, diluted with ether, washed with water, dried over magnesium sulfate and evaporated in vacuo. For purification, the mixture is filtered through silica gel with hexane / ethyl acetate (7: 3) to give 2.19 g of the title compound as an oil. IR: 2958.2125, 1738.1, 252.1, 023, 976 / cm.

(9S, 11R, 15R) -9-acetoxy-16,1 & dimethyl-11,15-bis (tetrahydropyran-2-yloxy) -prosta-4,5,13-transtriensäuremethylester

To a cooled to -10 ° C suspension of 3.02 g of copper) I) iodide in 50 ml of ether is added dropwise with stirring 23.2 ml of a 1.5M solution of methyl lithium in ether. It is then cooled to -75 ⁰ C and dripping 50ml of an ethereal solution of 2.10g (6RS, 9S, 11R, 15R) -6,9-diacetoxy-16,16-dimethyl-11,15-bis- (tetrahydropyran- 2-yloxy) -prost-4-in-13-transenoic acid methyl ester within 15 minutes. The mixture is stirred for 5 hours at -75 ° C, then diluted with ammonium chloride solution, stirred for 1 hour at 20 ⁰ C and extracted with ether. The extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with hexane / 20-70% ethyl acetate to give 1.1 g of the title compound as an oil

 IR: 2951.1977, 1738.1248, 1021, 978 / cm.

(^ S, 11R, 15R) -16.1 & -Dimethy ^ -9-hydroxγ-11,15-bis <tetrahydropγran-2-yloxy) -prosta-4,5,13-traπstriensäuremethylester

To a solution of 1.05 g of (9S, 11R, 15R) -9-acetoxy-16,16-dimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -prosta-4,5,13-trans-trienoic acid methyl ester in 20 ml of methanol is added 300 mg of anhydrous potassium carbonate and stirred for 3 hours at room temperature. Concentrate at 30 ⁰ C in vacuo, diluted with water and extracted several times with dichloromethane. The combined extracts are shaken with brine, dried over magnesium sulfate and added in vacuo. This gives 920 mg of the title compound as an oil

 IR: 3600, 2945.1, 980.1, 736.1, 021, 976 / cm.

Example 2

Analogously to Example 1, from 500 mg (9R, 11R, 15R:) - 16,16-dimethyl-9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -prosta-4,5,13- Trans-trienoic acid methyl ester 145 mg of the title compound as an oil.

IR: 3600.3405.2956.1 977.1735,1135.1 021.976 / cm.

The 9/3 alcohol used as starting material is prepared as follows:

(9R, 11R, 15R) -16,16-dimethyl-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) -prosta-4,5,13-transtriensäuremethylester

To a solution of 1.69 g (gSJIR.ISRI.ie.-dimethyl-1-yl-hydroxy-IIJS-bis-tetrahydropyran ^ -syloxyl-prosta-SJS-trans-trienoic acid in 25 mL pyridine is added 1,15 gp-toluenesulfonyl chloride in O ^c and allowed to stand for 48 hours at 20 ° C. It is then cooled again to 0 °, treated with 0.1 ml of water and stirred for 1 hour For workup, diluted with einskaltem ether, shaken successively with ice-cold 10% sulfuric acid, sodium bicarbonate solution and brine , dried over magnesium sulfate and evaporated in vacuo to give 2.30 g of oily 9-tosylate, which is dissolved in 80ml Dimethylsuifoxid, treated with 6g Kaliumnitrit and heated for 3 hours at 80 ° C. It is then diluted with water, extracted with ether , Wash the extract with brine, dry over magnesium sulfate and evaporate in vacuo, purify the residue by chromatography on silica gel with hexane / ethyl acetate (20-50%) to give 1.01 g of the title compound as an oil

 IR: 3600, 3410.1 978.1 735.1 181.1 025, 972 / cm.

Example 3

To a solution of 100mg O

Trienoic acid methyl ester in 10 ml of methanol is added 150 mg of potassium hydroxide dissolved in 1 ml of water and allowed to stand for 5 hours at 2O ⁰ C. After concentration in vacuo, it is diluted with water, acidified to pH 4 with citric acid and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. This gives 85 mg of the title compound as an oil.

IR: 3600, 3420, 2955.1 976.1 712.1178.1 022, 976 / cm.

Example 4

(9RJIRRISSJeRS) -S-chloro-II, 15-dihydroxy-1 & -methyl-prosta-4,5,13-trans-trienoic acid methyl ester In analogy to Example 1, from 1.25 g (9S, 11R, 15S, 16RS) - 9-Hydroxy-16-methyl-11,15-bis- (tetrahydropyran-2-yloxy) -prosta-4,5,13-trans-trienoic acid methyl ester 410 g of the title compound as an oil.

IR: 3600, 3405, 2958, 2885.1, 976.1, 732.1, 021, 976 / cm.

The starting material for the preparation of the title compound is obtained according to Example 1a from (2RS, 3aR, 4R, 5R, 6aS) -4 - [(E) - (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-one yloxy) -1-octenyl] -5- (tetrahydropyran-2-yloxy) perhydrocyclopenta [b] furan-2-

Example 5

(9R, 11R, 15S, 16RS) -9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trienoic acid. In analogy to Example 3, ORJIR ^ SSjeRSJ-g- Methyl chloro-HJS-dihydroxy-ε-methyl-prosta ^ SJS-transstrienoate the title compound as an oil

 IR: 3600, 3420, 2948, 1 978.1 710, 1021, 978 / cm.

Example 6

(9R, 11R ₁ ISR) -S-chloro-II, IB-dihydroxy -phenophenoxy- ITJS.IS ^ O-tetranor-prosta - ^. IS-trans-trienoic acid methyl ester In analogy to Example 1 is obtained from 950 mg (9S, 11R, 15R) -9-hydroxy-16-phenoxy-11,15-bis (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-prosta-4,5,13-trans-triensäuremethylester 310 mg of the title compound as a colorless oil.

IR: 3600, 3402.2954, 2888.1 978.1732.1 600.1 585.1 021, 978 / cm.

The starting material for the preparation of the title compound is obtained from (2RS, 3aR, 4R, 5R, 6aS) -4 - [(E) - (3R) -4-phenoxy-3- (tetrahydropyran-2-yloxy) -1-butenyl ] -5- (tetrahydropyran-2-yloxy) -perphydrocyclopenta [b] furan-2-ol according to Example 1 a.

Example 7

In analogy to Example 3 is obtained from ORJI

4,5,13-Trans-trienoic acid methyl ester the title compound as an oil.

IR: 3600.3420, 2960.2885.1 976.1711.1 600.1 588.1 022, 977 / cm.

Example 8 OR.IIR.IBRJ-S-chloro-H.IB-dihydroxY-ie-e-trimethylene-prosta-methyl-IS-trans-trienoic acid In analogy to Example 1, 1.20 g of OS.IIR.ISRMJ -Hydroxy-H.IS-bis-ftetrahydropyran ^ -yloxyMejetrimethylen-prosta-4,5,13-trans-trienoic acid methyl ester 390 mg of the title compound as an oil.

IR: 3600, 34040, 2948, 2882, 975, 1735, 1021, 976 / cm.

The starting material for the preparation of the title compound is obtained from (2RS, 3aR, 4R, 5R, 6aS) -4 - [(E) - (3R) -3- (tetrahydropyran ^ -yloxyM ^ trimethylene-i-octenyl-S-tetrahydropyran ^ -yloxyl-perhydrocyclopentatblfuran ^ ol.

Example 9 (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16,16-trimethylene-prosta-4,5,13-trans-trienoic acid. In analogy to Example 3, (9R, 11R , 15R) -9-chloro-11,15-dihydroxy-16,1-trienoic acid methyl ester the title compound as an oil. IR: 3600, 3420, 292, 2884, 1976, 1712, 1022, 976 / cm.

Example 10 (9R, 11R, 15S, 16RS) -9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien-1 »-insäuremethylester In analogy to Example 1 is obtained from 985 mg (9R, 11R, 15S, 16RS) -9-hydroxy-16-methyl-11,15-bis (tetrahydropyran-2-yloxy) -prosta-4,5,13-trans-triene-18-methyl-acidate 320 mg of the compound as an oil.

IR: 3600.3405.2050.1 978.1734.1021,974 / cm.

The starting material for the preparation of the title compound is obtained according to Example 1 a from (2RS, 3aR, 4R, 5R, 6aS) -4 - [(E) -OS ^ RSI-methyl-S-itetrahydropyran ^ -yloxyl-i-octene - ^ - inylj-S-detrahydropyran ^ -yloxy) - perhydrocyclopenta [b] furan-2-ol.

Example 11

(9R, 11R, 15S, 16RS) -9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5- _r 13-trans-triene-18-acetic acid. Analogously to Example 3, (9R , 11R, 15S, 16RS) -9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trantrien-18-insacid, the title compound as an oil. IR: 3600, 3415, 2955, 2884, 1978, 1710, 1022, 974 / cm.

Example 12

Analogously to Example 1, 1.20 g (9S, 11R, 15S, 16RS) -16,20-dimethyl-9-hydroxy-11,15-bis- (tetrahydropyran-2-yloxy) -prosta-4,5 are obtained , 13-trans-trien-18-insäuremethylester380mg derTiteiverbindung as an oil.

IR: 3600, 3400.2955, 1978.1, 732, 1022, 976 / cm.

The starting material for the preparation of the titanium compound is obtained according to Example 1a from (2RS, 3aR, 4R, 5R, 6aS) -4 - [{E) - (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy ) -1-nonene-6-ynyl] -5- (tetrahydropyran-2-yloxy) -perhydrocyclopenta [b] furan-2-ol.

Example 13

(9R, 11R, 15S, 16RS) -9-chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,13-trans-tria-18-acetic acid. The procedure is analogous to that of Example 3 OR.IIR ^ SSjeRSl-g-chloro-II.is-dihydroxy-IE ^ O-dimethyl-prosta ^ SJS-transstrien-18-insäuremethylester the title compound as an oil. IR: 3600.3409.2952.2880.1 978.1711.1 023.976 / cm.

EXAMPLE 14 (9R, 11R, 15R) -11,15-dihydroxy-16 _r 16-dimethyl-9-fluoro-prosta-4,5,13-trans-trienoic acid To a solution of 1.25 g of (9S, 11R, 15R ) -16,16-dimethyl-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) -prosta-4,5,13- trans-triensäuremethylesterin20mi dichloromethane and 0.5 ml of pyridine are added at -70 ⁰ C 0.3 ml diethylaminosulfur trifluoride (DAST) and after 15 minutes another 0.1 ml DAST. After a further 15 minutes, 50 ml of 5% sodium bicarbonate solution, the cooling bath is removed, stirred vigorously for 10 minutes at 20 °, then extracted with dichloromethane, the extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is stirred for 24 hours with 20 ml of a mixture of acetic acid-water-tetrahydrofuran (65/35/10), evaporated in vacuo and the crude product is purified by chromatography on silica gel with hexane / diethyl ether (1: 1). 410 mg of (9R, 11R, 15R) -HJS-dihydroxy-ethylene-S-fluoro-prosta ^ SJS-trans-trienoic acid methyl ester are obtained as oil.

To saponify the ester is dissolved in 20 ml of methanol, treated with 500 mg of potassium hydroxide dissolved in 2 ml of water and allowed to stand for 4 hours at 20 °. Then concentrated in vacuo, diluted with water, acidified with citric acid to pH4 and extracted with dichloromethane. The extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. This gives 370 mg of the Ti compound as an oil.

IR: 3600, 3420, 2948, 2878.1, 976, 1710, 1022, 978 / cm.

Example 15

(9R, 11R, 15R) -11,15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trienoic acid. Analogously to Example 14 is obtained from 1.15 g of (9S, 11R, 15R) -9-hydroxy-16-phenoxy-11,15-bis- (tetrahydropyran-2-yloxy) 17,18,1S ^ O-tetranor-prosta ^ S.IS- trans-trienoic acid methyl ester 335 mg of the titanium compound as an oil. IR: 3600.3420.2955.2889.1 978.1708.1 601.1 588.1 023.976 / cm.

Example 16

In analogy to Example 14, 235 mg of the titanium compound are obtained from 810 mg of OSJI 2-yloxy) -prosta-4,5,13-trans-trien-18-n-methylic acid as an oil. IR-SFIFIN. 341S 7949? S ??. 1 97fi. 1 710. 1 023. 978 / cm.

Example 17 (9R, 11R, 15R) -11,15-dihydroxy-9-fluoro-1 & -phenoxv-17,18,19,20-tetranor-prosta-4,5,13-trans-trienoic acid phenacyl ester

210 mg of (9R _r 11R, 15R) -11,15-dihydroxy-9-fluoro-16-phenoxy-17J 8,19,2-tetrahydorodiester, 5,13-trans-trienoic acid are dissolved in 10 ml of acetone, It is mixed with 139 mg of ω-bromoacetophenone and 1.5 ml of triethylamine and stirred overnight at 20 ⁰ C. It is diluted with ether, shaken successively with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel with dichloromethane / 10% acetone to give 195 mg of the title compound as an oil

 IR: 3600, 3010, 2948.1 978 (wide), 1 600.1 588.1139.1 022, 974 / cm.

Claims (1)

Invention claim: 1. Process for the preparation of new 9-halo-prostaglandin derivatives of the forms! I shark (D ^% 4 Hal is an a- or / 3-position chlorine or fluorine atom, R _{1 is} the radical CH ₂ OH or -C-OR ₂ with R ₂ in the meaning of a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R _{1 is} the radical -C-NHR _{3 m} jt R ₃ meaning an acid residue or the radical R ₂ and A is a-CH ₂ -CH ₂ -, a trans-CH == CH-or-C ^ = C-group,
W is a free or functionally modified hydroxymethylene group or a free or functionally modified