IE920792A1 - Novel leukotriene-B4 derivatives, processes for the¹preparation thereof and their use as medicaments - Google Patents

Abstract

The invention discloses new leukotriene B4 derivatives of formula (I), wherein R?1 stands for CH2?OH, CH3?, CF3?, COOR?5, CONR?6R?7, or R?1 together with R?2 stands for a carbonyl group, R?2 and R?3 are the same or different and stand for H or an organic acid residue containing 1 to 15 carbon atoms, R?4 stands for H, C1?-C10? alkyl, possibly substituted one or more times by chlorine or bromine, C3?-C10? cycloalkyl, a C6?-C10? aryl residue possibly substituted one or more times by chlorine, bromine or phenyl, C1?-C4? alkyl, C1?-C4? alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5- or 6-membered aromatic heterocyclic ring with at least one heteroatom, R?5 stands for hydrogen, C1?-C10? alkyl, C3?-C10? cycloalkyl, a C6?-C10? aryl residue possibly substituted one to three times by chlorine, bromine or phenyl, C1?-C4? alkyl, C1?-C4? alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2?-CO-(C6?-C10?) aryl or a 5- or 6-membered ring with at least one heteroatom, A stands for a trans,trans-CH=CH-CH=CH, a -CH2?CH2?-CH=CH- or a tetramethylene group, B stands for a C1?-C10? straight-chain or branched-chain alkylene group, possibly substituted by fluorine, or the group of formula (a), D stands for a direct bond, oxygen, sulphur, -C=C-, -CH=CR8? or, together with B, for a direct bond, R6? and R7? are the same or different and stand for H or C1?-C4? alkyl or R7? stands for H and R6? stands for C1?-C10? alkanoyl or C1?-C10? alkanesulphonyl, R8? stands for H, C1?-C5? alkyl, chlorine or bromine, n is equal to 3 to 5 and, when R5? stands for hydrogen, their salts with physiologically tolerable bases and their cyclodextrin clathrates.

Description

COMPLETE SPECIFICATION Novel leukotriene-BA derivatives, processes for the preparation thereof and their use as medicaments Patent Application by SCHERING AKTIENGESELLSCHAFT, a German Company of Berlin and Bergkamen, Federal Republic of Germany. as the te ~ A?, LTB4 antagonists that contain a six-membered ring basic structural element are already known from German Offenlegungsschrift DE 39 17 597.

The invention relates to novel leukotriene B4 deriva5 tives, to processes for their preparation and to their use as medicaments.

Leukotriene B4 (LTB4) was discovered in 1979 by B. Samuelsson et al as a metabolite of arachidonic acid. During biosynthesis, as a result of the enzyme 5-lipoxy10 genase leukotriene A4 is first of all formed as the key intermediate, which is then converted by a specific hydrolase into LTB4 H OOH :e ► arachidonic acid l-UDCTC leukotriene C4 (LTC4) tfl2 0 70f2 The nomenclature of the leukotrienes can be found in the following works: a) B. Samuelsson et al. . Prostaglandins 19 , 645 (1980); 17, 785 (1979). b) C.N. Serhan et al. , Prostaglandins 34., 201 (1987) .

The physiological and especially the pathophysiological significance of leukotriene B4 is summarised in a few more recent works: a) The Leukotrienes, Chemistry and Biology, eds. L.W. Chakrin, D.M. Bailey, Academic Press 1984. b) J.W. Gillard et al., Drugs of the Future 12 , 453 (1987). c) B. Samuelsson et al.. Science 237, 1171 (1987) . d) C.W. Parker, Drug Development Research 3.0., 277 (1987). LTB4 is revealed in those works as being an important inflammation mediator for inflammatory disorders in which leucocytes migrate into the diseased tissue .

LTB4 is known to cause the adhesion of leucocytes to the blood vessel wall. LTB4 is chemotactically active, that is to say it triggers a directed migration of leucocytes towards a gradient of increasing concentration. Furthermore, on account of its chemotactic activity it indirectly changes vascular permeability, a synergism with prostaglandin E2 being observed. LTB4 clearly plays a decisive role in inflammatory, allergic and immunological processes .

Leukotrienes, and especially LTB4, are involved in skin disorders that involve inflammatory processes (increased vessel permeability and oedema formation, cellular infiltration), increased proliferation of skin cells and itching, such as, for example, in the case of eczema, erythema, psoriasis, pruritus and acne. Pathologically increased leukotriene concentrations are either causatively involved in the development of many dermatites, or there is a connection between the persistence of the Ll <4 ·', A If dermatites and the leukotrienes. Distinctly increased leukotriene concentrations have been measured, for example, in the skin of patients suffering from psoriasis or atopic dermatitis.

Furthermore, leukotrienes and LTB4 are involved especially in arthritis, chronic lung disorders (for example asthma), rhinitis and inflammatory skin disorders.

LTB4 receptor antagonists, or inhibitors of those enzymes involved in the synthesis of LTB4, should be effective as specific medicines, especially against disorders involving inflammation and allergic reactions.

In addition to the possible therapeutic uses that may be derived from antagonization of the L>TB4 effect with LTB4 analogues, it has also been possible to demonstrate the usefulness of leukotriene B4 agonists and their potential application to the treatment of fungal diseases of the skin. (H. Katayama, Prostaglandins 34, 797 (1988)).

The invention relates to leukotriene B4 derivatives of formula I wherein R1 represents CH2OH, CH3, CF3, COOR5, CONR6R7 or R1 together with R2 represents a carbonyl group, R2 and R3 , which are the same or different, each represents H or an organic acid radical having from 1 to 15 carbon atoms, R4 represents H, (C^ _cio) alkyl optionally mono- or poly-substituted by chlorine or by bromine, C3-C1Qcycloalkyl, Cg-C^aryl optionally mono- or poly-substituted independently from one another by chlorine, bromine, phenyl, C1-C4alkyl, C3-C4alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5- or 6-membered aromatic heterocyclic ring having at least 1 hetero atom, R5 represents hydrogen, Cj-C^galkyl, C3-C10cycloalkyl, C6-C10aryl optionally substituted by from 1 to 3 substituents chlorine, bromine, phenyl, C^-C4alkyl, C1-C4alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(Cg-C10)aryl or a 5- or 6-membered ring having at least 1 hetero atom, A represents a trans. trans-CH=CH-CH=CH. a -CH2CH2-CH=CH- or a tetramethylene group, B represents a straight-chain or branched C3-C10alkylene group that may optionally be substituted by fluorine, or represents the group -C-ch?-, (εις; n D represents a direct bond, oxygen, sulphur, -C=C-, -CH=CR8 or, together with B may also represent a direct bond, R8 and R7 are the same or different and each represents H or C1-C4alkyl or R7 represents H and R6 represents C^-C^Qalkanoyl or C-L-C10alkanesulphonyl, R8 represents H, C1-C5alkyl, chlorine or bromine, n is 3 to 5 and, when R5 represents hydrogen, the salts thereof with physiologically tolerable bases and the cyclodextrin clathrates thereof.

The groups OR2 and OR3 may be in the a- or β-configuration. Formula I includes both racemates and the possible pure diastereoisomers and enantiomers. 3.^ ·Ζ' - 5 The alkyl groups R5 may be straight-chained or branched alkyl groups having from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl. The alkyl groups R5 may optionally be mono- to poly-substituted by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups having from 6 to 10 carbon atoms (for substitution see under aryl R5) , dialkylamino and trialkylammonium having from 1 to 4 carbon atoms in the alkyl moiety, wherein single substitution shall be preferred. As substituents there may be mentioned by way of example fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, and ethoxy. There may be mentioned as preferred alkyl groups R5 those having from 1 to 4 carbon atoms.

The cycloalkyl group R5 may contain from 3 to 10, preferably 5 or 6, carbon atoms in the ring. The rings may be substituted by alkyl groups having from 1 to 4 carbon atoms. Cyclopentyl, cyclohexyl and methylcyclohexyl may be mentioned by way of example.

There come into consideration as aryl groups both substituted and unsubstituted aryl groups having from 6 to 10 carbon atoms, such as, for example, phenyl, 1naphthyl and 2-naphthyl, each of which may be substituted by from 1 to 3 halogen atoms (F, Cl, Br) , a phenyl group, from 1 to 3 alkyl groups each having from 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy group or an alkoxy group having from 1 to 4 carbon atoms. Preferred substituents in the 3- and 4-position on the phenyl ring are, for example, fluorine, chlorine, alkoxy or trifluoromethyl, but in the 4-position hydroxy is preferred. gi '' There come into consideration as heterocyclic groups R5 5- and 6-membered aromatic heterocycles that contain at least 1 hetero atom, preferably nitrogen, oxygen or sulphur. 2-Furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl etc. may be mentioned by way of example.

There come into consideration as the acid radical R6 physiologically tolerable acid radicals. Preferred acids are organic carboxylic acids and sulphonic acids having from 1 to 15 carbon atoms that belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. Those acids may be saturated, unsaturated and/or polyhydric and/or may be substituted in customary manner. C14alkyl, hydroxy, C14alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br) may be mentioned as examples of substituents. The following carboxylic acids may be mentioned by way of example: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic 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 tri-chloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morphoiinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted by halogen (F, Cl, Br) or trifluoromethyl, hydroxy, C14alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid and cyclopentylpropionic acid. There come into consideration as especially preferred acyl radicals and alkanesulphonyl radicals, those having up to 10 carbon atoms. There come into consideration as sulphonic acids, for example, methanesulphonic acid, ethanesulphonic acid, isopropanesulphonic acid, β-chloroethanesulphonic acid, butanesulphonic acid, cyclopentanesulphonic acid, cyclohexanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, p-chlorobenzenesulphonic acid, N, N-dimethylaminosulphonic acid, N,N-diethylaminosulphonic acid, N,N-bis(β-chloroethyl)-aminosulphonic acid, N, N-diisobutylaminosulphonic acid, N,N-dibutylaminosulphonic acid, pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- and morpholino-sulphonic acid.

There come into consideration as alkyl groups R4 straight-chained and branched, saturated and unsaturated alkyl radicals, preferably saturated alkyl radicals, having from 1 to 14, especially from 1 to 10, carbon atoms, that may optionally be substituted by optionally substituted phenyl (for substitution see under aryl R5) . Methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m- and p-chlorobenzyl groups may be mentioned by way of example. If the alkyl groups R4 are halo-substituted, there come into consideration as halogens fluorine, chlorine and bromine.

There come into consideration as an example of halosubstituted alkyl groups R4 alkyls having terminal trifluoromethyl groups.

The cycloalkyl group R4 may contain from 3 to 10, preferably from 3 to 6, carbon atoms in the ring. The rings may be substituted by alkyl groups having from 1 to 4 carbon atoms. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and methylcyclohexyl may be mentioned by way a 2 of example.

There come into consideration as substituted and unsubstituted aryl groups R4 , for example: phenyl, 1-naphthyl and 2-naphthyl, each of which may be substituted by from 1 to 3 halogen atoms, a phenyl group, from 1 to 3 alkyl groups each having from 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, CjC4alkoxy or hydroxy group. Substitution in the 3- and 4positions on the phenyl ring for example by fluorine, chlorine, alkoxy or trif luoromethyl, or in the 4-position by hydroxy, is preferred.

There come into consideration as heterocyclic aromatic groups R4 5- and 6-membered heterocycles that contain at least 1 hetero atom, preferably nitrogen, oxygen or sulphur. There may be mentioned by way of example 2furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl etc..

There come into consideration as alkylene group B straight-chained or branched, saturated or unsaturated alkylene radicals, preferably saturated having from 1 to 10, especially from 1 to 5, carbon atoms, which may optionally be substituted by fluorine atoms. The following may be mentioned by way of example: methylene, fluoromethylene, difluoromethylene, ethylene, 1,2propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1,2-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyl-tri-methylene, 1-methylene-ethylene, 1-methylene-tetramethylene.

The alkylene group B may furthermore represent the group -C-CH wherein n=3-5, preferably 4-5.

X © There come into consideration as acid radicals R2 and R3 physiologically tolerable acid radicals. Preferred acids are organic carboxylic acids and sulphonic acids having from 1 to 15 carbon atoms that belong to the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocyclic series. Those acids may be saturated, unsaturated and/or polyhydric and/or may be substituted in customary manner. There may be mentioned as examples of the substituents C1 ^alkyl, hydroxy, ^alkoxy, oxo and amino groups and halogen atoms (F, Cl, Br).

The following carboxylic acids may be mentioned by way of example: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and tri-chloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted by halogen (F, Cl, Br), trifluoromethyl, hydroxy, 4alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid and cyclopentylpropionic acid. There come into consideration as especially preferred acid radicals R2 and R3 acyl radicals having up to 10 carbon atoms .

The alkyl radicals R^ and R7 are straight-chained or branched alkyl radicals, especially straight-chained, such as, for example, methyl, ethyl, propyl, butyl, R8 as C s-alkyl represents straight-chained or branched alkyl radicals as already mentioned for R^ and R5 .

Preferred alkyl radicals R8 are methyl, ethyl, propyl and isopropyl.

There are suitable for salt formation inorganic and organic bases as known to the person skilled in the art for the formation of physiologically tolerable salts. There may be mentioned by way of example alkali metal 10 hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)-methylamine etc..

Preferred compounds of the present invention are compounds of formula I wherein the radicals have the following meanings: R1 represents CH2OH, COOR5 wherein R5 represents a hydrogen atom, an alkyl radical having from 1 to 10 carbon atoms, a cycloalkyl radical having 5 or 6 carbon atoms, or a phenyl radical optionally substituted by 1 or 2 substituents chlorine, bromine, phenyl, C^alkyl, C1 4alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or 25 hydroxy; A represents a trans, trans-CH=CH-CH=CH- or tetramethylene group; B represents a straight-chained or branched, saturated or unsaturated alkylene group having up to 10 carbon atoms that may optionally be substituted by fluorine, or represents the group -C-ch wherein n=3-5; D represents a direct bond, oxygen, sulphur, a -C=Cgroup or a -CH=CR8 group wherein R8 represents hydrogen, C1_5alkyl, chlorine or bromine; B and D together represent a direct bond; R2 and R3 are identical or different and each represents hydrogen or an organic acid radical having from 1 to 15 carbon atoms; R1 and R2 together represent a carbonyl group; R4 represents a hydrogen atom, C^-C^galkyl, cycloalkyl having 5 or 6 carbon atoms, or a phenyl radical optionally substituted by 1 or 2 substituents chlorine, bromine, phenyl, C14alkyl, C14alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy and, when R5 represents a hydrogen atom, the salts thereof with physiologically tolerable bases and the cyclodextrin clathrates thereof.

Especially preferred compounds of the present invention are compounds of formula I wherein the radicals have the following meaning: R1 represents CH2OH, or COOR^ wherein R5 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms; A represents a trans. trans-CH=CH-CH=CH- or tetramethylene group; B represents a straight-chained or branched alkylene group having up to 5 carbon atoms; D represents a direct bond or a -OC- group or a -CH=CR8 group wherein R8 represents hydrogen or C15alkyl; B and D together represent a direct bond; R2 and R3 are identical or different and each represents hydrogen or an organic acid radical having from 1 to 6 carbon atoms; V R1 and R2 together represent a carbonyl group; R4 represents a hydrogen atom or Cj-C-^Qalkyl and when r5 represents a hydrogen atom, the salts thereof with physiologically tolerable bases and the cyclodextrin clathrates thereof.

The invention furthermore relates to a process for the preparation of compounds of formula I that ic- characterised in that an aldehyde of formula II CHO (II) , or3 wherein A, B, D, R3 and R4 are as defined above, is reacted, optionally after the protection of free hydroxy groups, with an organomagnesium compound of formula III X-Mg-CH2-CH2-CH2-CH2-R9 (III), wherein X represents chlorine, bromine or iodine and R9 represents -CH3, CF3 or -OR10 in which R1() represents a readily removable ether radical and, optionally then, in any sequence, isomers are separated, protected hydroxy groups are freed and/or a free hydroxy group is esterified and/or a 1-hydroxy group is oxidized to carboxylic acid and/or double bonds are hydrogenated and/or an esterified carboxy group (R1=COOR5) is hydrolysed and/or reduced and/or a carboxy group (R9=H) is esterified and/or a free carboxy group (R5=H) is converted into an amide (R1=CONHR®R7) or a carboxy group is converted into a salt with a physiologically tolerable base.

There come into consideration as ether radicals R9 in the compound of formula III radicals familiar to the person skilled in the art. Preferred are readily removable ether radicals, such as, for example, dimethyl-tertbutylsilyl, trimethylsilyl, tribenzylsilyl, diphenyltert-butylsilyl, tetrahydropyranyl, tetrahydrofuranyl and α-ethoxyethyl, to name only a few.

The reaction of the compound of formula II with an organometallic compound of formula III is carried out in a manner known per se in an inert solvent or solvent mixture, such as, for example, diethyl ether, tetrahydrofuran, dioxane, toluene or dimethoxyethane, preferably diethyl ether or tetrahydrofuran. The reaction is carried out at temperatures of from -100°C to 60°C, preferably at -78°C to 0°C.

The preparation of the compound of formula III required for that reaction is carried out by reaction of the corresponding hydroxy halide by etherification with dihydropyran and p-toluenesulphonic acid and subsequent reaction with magnesium.

The reduction to compounds of formula I wherein R1 represents a CH2OH group is carried out with a reducing agent suitable for the reduction of esters or carboxylic acids, such as, for example, lithium aluminium hydride, diisobutylaluminium hydride etc. There come into consideration as solvents diethyl ether, tetrahydrofuran, dimethoxyethane, toluene etc. The reduction is carried out at temperatures of from -30°C to the boiling temperature of the solvent used, preferably at from 0°C to 30°C.

The esterification of the alcohols of formula I (R2 = H and/or R2 = H) is carried out in a manner known per se. For example, the esterification is carried out by reacting an acid derivative, preferably an acid halide or acid anhydride, with an alcohol of formula I in the presence of a base, such as, for example, NaH, pyridine, triethylamine, tributylamine or 4-dimethylaminopyridine. The reaction can be carried out without solvents or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide or DMSO at temperatures above or below room temperature, for example from -80°C to 100°C, preferably at room temperature.

The oxidation of the 1-hydroxy group is carried out according to methods known to the person skilled in the art. There may be used as oxidizing agents, for example, pyridinium dichromate (Tetrahedron Letters. 1979, 399), Jones reagent (J. Chem. Soc. 1953. 2555) or platinum/oxygen (Adv. in Carbohydrate Chem. 17., 169 (1962) or Collins oxidation and subsequent Jones oxidation. The oxidation with pyridinium dichromate is carried out at temperatures of from 0°C to 100°C, preferably from 20°C to 40°C in a solvent inert towards the oxidizing agent, for example dimethylformamide.

The oxidation with Jones reagent is carried out at temperatures of from -40°C to +40°C, preferably from 0°C to 30°C, in acetone as solvent.

The oxidation with platinum/oxygen is carried out at temperatures of from 0°C to 60°C, preferably from 20°C to 40°C, in a solvent inert towards the oxidizing agent, such as, for example, ethyl acetate.

The hydrolysis of the ester of formula I is carried out according to methods known to the person killed in the art, such as, for example, with basic catalysts. The compounds of formula I may be separated into the optical isomers by conventional methods of separation. to Functionally modified hydroxy groups are freed according to known methods. For example the removal of hydroxyprotecting groups, such as, for example, 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. In order to improve solubility, a water-miscible inert organic solvent is advantageously added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The removal is carried out preferably at temperatures of from 20°C to 80°C. The removal of the silyl ether protecting groups is carried out, for example, with tetrabutylammonium fluoride or with potassium fluoride in the presence of a Crown ether. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxane, methylene chloride etc.. The removal is carried out preferably at temperatures of from 0°C to 80°C.

The hydrolysis of the acyl groups is carried out, for example, with alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or in an aqueous solution of an alcohol. There come into consideration as alcohol aliphatic alcohols, such as, for example, methanol, ethanol, butanol etc., preferably methanol. As alkali metal carbonates and hydroxides potassium and sodium salts may be mentioned. The potassium salts are preferred.

Suitable alkaline earth metal carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is carried out at from -10°C to +70°C, preferably at +25°C.

The introduction of the ester group - C for R1, in which represents an alkyl group having from 1 to 10 carbon atoms, is carried out according to methods known to the person skilled in the art. The 1-carboxy compounds are reacted in a manner known per se. for example, with diazohydrocarbons. The esterification with diazohydrocarbons is carried out, for example, by mixing a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, with the 1-carboxy compound in the same or in a different inert solvent, such as, for example, methylene chloride. When the reaction is complete in from 1 to 3 0 minutes, the solvent is removed and the ester is purified in customary manner. Diazoalkanes are either known or can be prepared according to known methods [Org. Reactions Vol. 8, pages 389-394 (1954)] . .0 The introduction of the ester group \OR5 in which R5 represents a substituted or unsubstituted aryl group, is carried out according to methods known to the person skilled in the art. For example, the 1carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine, DMAP or triethylamine, in an inert solvent. There come into consideration as solvents methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures of from -30°C to +50°C, preferably at 10°C. u-\> r 2 If C=C double bonds contained in the primary product are to be reduced, the hydrogenation is carried out according to methods known per se.

The hydrogenation of the Δ.8'10-diene system is carried out in a manner known per se at low temperatures, preferably at approximately from -20°C to +30°C, in a hydrogen atmosphere in the presence of a noble metal catalyst. 10 % palladium-on-carbon, for example, is suitable as catalyst.

The leukotriene B4 derivatives of formula I wherein R5 represents hydrogen can be converted with suitable amounts of the corresponding inorganic bases into salts by neutralisation. For example, by dissolving the corresponding acids in water that contains the stoichiometric amount of the base, the solid inorganic salt is obtained after evaporating off the water or after the addition of a water-miscible solvent, for example alcohol or acetone.

To produce an amine salt, the LTB4 acid is, for example, dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether, acetonitrile or benzene, and at least the stoichiometric amount of the amine is added to that solution. The salt precipitates usually in solid form, or is isolated in customary manner after evaporating the solvent.

II The introduction of the amide group - C - NHRg in which Rg represents alkanoyl is carried out according to methods known to the person skilled in the art. The carboxylic acids of formula I (R5=H) are first of all converted with chloroformic acid isobutyl ester in the q . presence of a tertiary amine, such as, for example, triethylamine, into the mixed anhydride. The reaction of the mixed anhydride with the alkali metal salt of the corresponding amide or with ammonia (Rg=H) is carried out in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide or hexamethylphosphoric acid triamide, at temperatures of from -30°C to +60°C, preferably from 0°C to 30°C.

A further possible method of introducing the amide II group - C-NHR6 comprises reacting a 1-carboxylic acid of formula I (Rg=H) , in which the free hydroxy groups are optionally intermediately protected, with compounds of formula IV O = C = N - Rg (IV) wherein Rg has the meaning given above.

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

In order to produce the other amides, for example the desired acid anhydrides may be reacted with ammonia or the corresponding amines.

If the starting product contains OH groups in the leukotriene B4 radical, those OH groups are also reacted. If, ultimately, end products are desired that contain free hydroxy groups, then advantageously starting materials are used in which the hydroxy groups are inter5 mediately protected by preferably readily removable ether or acyl radicals.

The separation of the enantiomers and/or diastereoisomers is carried out according to methods known to the person skilled in the art, for example high-pressure liquid chromatography on optically active carriers.

The compounds of formula II used as starting material may be prepared, for example, by converting cis- or transbis-1,2-hydroxymethyl-cyclopentane (obtainable from cisor trans-cyclopentane-1.2-dicarboxylic acid by reduction, see, for example, A. Padwa et al. , J. Org. Chem. 54., 817 (1989); O. Caamaus et al. . Euro J. Med. Chem. 22 . 311 (1987)) in a manner known per se into the monosilyl ether of formula V wherein R11, R12 and R15 are identical or different and each represents C1-C4alkyl or phenyl.

By oxidation, for example, with Collins reagent, or by the Swern process, the aldehyde of formula VI is obtained /*" z^w^OSi'R12 CT CHO τ>< & * ' II iitOJ^PCH^CO^Et ί VIIJ or I! fEtO)2P-CH2CH=CH-COOEt which by a Wittig-Horner olefination with the phosphonate of formula VII and a base and optionally subsequent hydrogenation as well as subsequent reduction of the ester group, oxidation of the primary alcohol, WittigHorner olefination once again with the phosphonate of formula VII and optionally subsequent hydrogenation, or a Wittig-Horner reaction of the aldehyde of formula VI with a phosphate of formula VIII, is converted into the ester of formula IX , COOEt (IX) wherein A has the meaning given above. There come into consideration as bases, for example, potassium tert15 butanolate, diazabicyclononane and sodium hydride.

Reduction of the ester group, for example with DIBAH, and subsequent oxidation of the resulting primary alcohol, for example with manganese dioxide or Collins reagent, results in the aldehyde of formula X CHO (X) , ^820/ The organometal reaction of the aldehyde of formula X with a Grignard reagent of formula XI X-Mg-B-D-R4 (XI) , wherein B, D and R4 are as defined above and X represents 5 chlorine, bromine or iodine, results, after protection of the hydroxy group and optional separation of the diastereoisomers (for example by acylation) , in compounds of formula XII The preparation of the compound of formula XI required for the organometal reaction is carried out by reacting the corresponding terminal halide with magnesium. By reacting the silyl ether XII with tetrabutylammonium fluoride, the alcohol of formula XIII is obtained (XIII).

The oxidation of the primary alcohol group in XIII, for example with Collins reagent or pyridinium dichromate, results in the aldehyde of formula II.

The compounds of formula XII wherein B represents a CH2 20 group and D represents a -ClC- or CH-CR® group can be obtained, for example, by an organometal reaction of a propargyl halide and subsequent alkylation with a corresponding alkyl halide and optionally. subsequent Lindlar hydrogenation.

An alternative construction of the lower chain starts from the aldehyde of formula XIV which resulted from the Witting-Horner reaction of the aldehyde VI and subsequent reduction and oxidation (XIV) .

Wittig-Horner olefination of the aldehyde XIII with a phosphonate of formula XV o o II II (CH3O)2PCH2-C-8-0-R4 (XV) and reduction of the resulting ketone then resulted in the alcohol of formula XIII.

The insertion of the chemically and metabolically labile cis- 6'7-double bond of LTB4 into a cis- or trans-1.2substituted cyclopentyl ring results in stabilisation, and especially by further derivatisation of the functional groups LTB4 derivatives are obtained that can act as LTB4 antagonists.

The compounds of formula I have an anti-inflammatory and anti-allergic activity. In addition they exhibit anti20 mycotic properties. As a result, the novel leukotriene B4 derivatives of formula I are valuable pharmaceutical active ingredients. The compounds of formula I are suitable especially for topical administration, since they exhibit a dissociation between desired topical activity and undesired systemic side effects.

The novel leukotriene B4 derivatives of formula I are suitable, in combination with the excipients and carriers customary in galenical pharmacy, for the local treatment of contact dermatitis, a wide variety of eczemas, neurodermatoses, erythroderma, Pruritus vulvae et ani. Rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and similar skin disorders.

The preparation of the medicament specialities is carried out in customary manner by converting the active ingredient together with suitable additives into the desired form of administration, such as, for example: solutions, lotions, ointments, creams or plasters.

The concentration of active ingredient in the so-formulated medicaments depends on the form of administration. In the case of lotions and ointments an active ingredient concentration of from 0.0001 % to 1 % is preferably used.

Furthermore, the novel compounds, optionally in combination with customary carriers and excipients, are also suitable for the preparation of inhalants, which can be used for the treatment of allergic disorders of the respiratory tract, such as, for example, bronchial asthma or rhinitis.

Furthermore, the novel leukotriene B4 derivatives are suitable also in the form of capsules, tablets or dragees that preferably contain from 0.1 to 100 mg of active ingredient and are administered orally, or in the form of suspensions that preferably contain from 1 to 200 mg of active ingredient per unit dose and are administered rectally, also for the treatment of allergic disorders of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa. •fc The novel leukotriene B4 derivatives may also be used in combination, such as, for example, with lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonists, leukotriene D4antagonists, leukotriene E4-antagonists, leukotriene F4antagonists, phosphodiesterase inhibitors, calcium antagonists or PAF antagonists.

The following embodiment Examples serve to explain the process of the invention in more detail. In the Examples, diastereoisomers not characterised in detail have been characterised in the 12-position as polar or non-polar (for example diastereoisomer non-polar (12)) .

Examples Example 1 (+/-)-(5RS)-5-Acetoxy-5-icis-(2RS) - 2-((IE,3E)-(5RS)-5acetoxy-l,3-tridecadienvl) (IRS) -cvclopentyl] -pentanoic acid diastereoisomer non-polar (12) A solution of 11.1 g of 4-chloro-l-(tert-butyldimethylsilyloxy) -butane in 10 ml of tetrahydrofuran is added dropwise at 25eC, under argon, to 2.44 g of magnesium, a crystal of iodine is added, and the whole is heated for 10 minutes at 70°C, stirred for 30 minutes at 25°C and diluted with 31 ml of tetrahydrofuran.

A solution of 495 mg of cis-(IRS) -1-formvl-(2RS)-2[ (IE, 3E) - (5RS) -5-acetoxy-l, 3-tridecadienyl] -cyclopentane (diastereoisomer non-polar (12)) in 1.7 ml of tetrahydrofuran is added dropwise at -70°C, under argon, to 2.96 ml of the above organomagnesium solution, and the whole is stirred at -70°C for 1.5 hours. 8 ml of saturated ammonium chloride solution are added, the whole is extracted three times with ether, and the organic phase is shaken with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ether (8+2), 480 mg of the alcohol are obtained in the form of a colourless oil.

IR(CHC13) : 3600, 2930, 2860, 1725, 1373, 1450, 993, 836 cm'1.

For the acetylation, 2.0 ml of acetic anhydride are added to a solution of 1.8 g of the above-described alcohol in 5 ml of pyridine and the whole is stirred at room temperature for 23 hours. The whole is then concentrated in vacuo with the addition of toluene and the residue is chromatographed on silica gel. Using hexane/ether (8+2), 1.88 g of the acetate are obtained in the form of a colourless oil.

IR: 2930, 2862, 1730, 1610, 1375, 1255, 993, 840 cm'1.

For the silyl ether cleavage, 1.35 g of the aboveprepared acetate in 80 ml of tetrahydrofuran are stirred with 2.26 g of tetrabutylammonium fluoride for 20 minutes at 0°C and for 4 hours at 24°C under argon. The whole is then diluted with ether, washed three times with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with ether, yielding 960 mg of the 1-alcohol in the form of a colourless oil.

IR: 3600 (broad), 2930, 2860, 1736, 1610, 1373, 1250, 990 cm'1.

For the oxidation of the 1-hydroxy group, 5.4 g of Collins reagent are added to 940 mg of the above-prepared alcohol in 54 ml of methylene chloride at 0°C, and the whole is stirred for 20 minutes at 0°C and subsequently diluted with a mixture of hexane/ether (1+1). Celite is added and the whole is filtered, washed with hexane/ether Ο 2 0 7^2 (1+1) and concentrated by evaporation in vacuo. The 1aldehyde so obtained is used immediately without being further purified. 1.67 ml of Jones reagent (J. Chem. Soc. 1953, 2555) are added dropwise with stirring, at -25°C, to a solution of 800 mg of the above-prepared aldehyde in 29 ml of acetone, and the whole is stirred for 15 minutes at -25°C under argon. 5.8 ml of isopropanol are then added, and the whole is stirred for 5 minutes, diluted with 200 ml of ether, shaken twice with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ether (1+1) 570 ml of the title compound are obtained in the form of a colourless oil.

IR: 3520(broad), 2930, 2860, 1726, 1373, 1255, 990, 948 cnfl.

The starting material for the above title compound is prepared as follows: la) 3-fCis-1-(tert-butyl-dimethylsilvloxvmethvl) cyclopent-2-νΠ-(2E)-propenoic acid ethyl ester 127 ml of a 1.2 molar solution of diisobutylaluminium hydride in toluene are added dropwise at 0°C, under argon, to a solution of 8.7 g of 2hydroxymethyl-cyclopentanecarboxylie acid lactone (O. Caamano et al.. Euro. J. Med. Chem. 22, 311 (1987)) in 127 ml of toluene, and the whole is stirred for 50 minutes at 0°C. 25 ml of isopropanol and 63 ml of water are then added dropwise, and the whole is stirred for 2 hours at 22°C, filtered, washed with methylene chloride and concentrated by evaporation in vacuo. The residue is purified by chromatography on silica gel. Using ethyl acetate/hexane (4+1), 7 g of cis-1.2-dihydroxymethylOs cyclopentane is obtained in the form of a colourless liquid. IR: 3600, 3400, 2960, 1060 cm’1.

A solution of 13 g of the above-prepared diol in 5 ml of tetrahydrofuran is added dropwise at 22°C to a suspension of 4.36 g of sodium hydride (in the form of a 55 % suspension in mineral oil) in 200 ml of tetrahydrofuran, and the whole is stirred for 45 minutes at 22°C. 15 g of tert-butyldimethylsilyl chloride are then added, and the whole is stirred for 45 minutes at 22°C and then diluted with approximately 1.5 1 of ether. The ether extract is washed with 10 % potassium carbonate solution, shaken three times with water, dried with sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ether (95+5), 20,9 cis-1-(tert-butyl-dimethylsilyloxymethyl)-2-hydroxymethylcyclopentane is obtained in the form of a colourless liquid.

IR: 3420 (broad), 2960, 2863, 1260, 840 cm'1. g of Collins reagent (chromic acid/pyridine complex) are added at 0°C to a solution of 16.9 g of the above-described monosilyl ether in 835 ml of methylene chloride and the whole is stirred for 30 minutes at 0°C. Dilution is then carried out with a mixture of hexane/ether (3+2), Celite is added, and the whole is filtered and concentrated by evaporation in vacuo. 16.2 g of the aldehyde, which is used without being further purified, is obtained.

IR: 2958, 2930, 2860, 2740, 1713, 840 cm'1.

For the Wittig olefination, 20.7 g of phosphonoacetic acid triethyl ester and 12.6 g of diazobicycloundecene (DBU) are added at 24°C to a stirred suspension of 3.9 g of lithium chloride in 277 ml of ar ο ώ .- i Cf ί, acetonitrile and the whole is stirred for 15 minutes. A solution of 16 g of the above-described aldehyde in 43 ml of acetonitrile is then added dropwise, and the whole is stirred for 2.5 hours at 24°C and subsequently diluted with ether. The whole is shaken in succession with water, 10 % sulphuric acid and water, dried with sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with hexane/ether (95+5), yielding 22.5 g of the title compound in the form of a colourless oil.

IR: 2960, 2860, 1710, 1650, 1260, 985, 840 cm1.

-[Cis-1-(tert-butyl-dimethylsilvloxvmethyl)cyclopent-2-yl]-(2E,4E)-pentadienoic acid ethyl ester 120 ml of a 1.2 molar solution of diisobutylaluminium hydride in toluene are added dropwise at -70°C, under argon, to a solution of 22.5 g of the α,βunsaturated ester prepared in accordance with Example la in 500 ml of toluene, and the whole is stirred for 30 minutes at -70°C. 30 ml of isopropanol, followed by 60 ml of water, are subsequently added dropwise and the whole is stirred for 2 hours at 22°C, filtered, washed with methylene chloride and concentrated by evaporation in vacuo. 22.5 g of the allyl alcohol, which is used without being further purified, are obtained.

IR: 3600, 3400, 2958, 840 cm1. g of manganese dioxide are added to a solution of 20.35 g of the above-prepared alcohol in 645 ml of toluene, and the whole is stirred for 5 hours at 24°C, filtered, concentrated by evaporation, and chromatographed on silica gel. Using hexane/ether (92+8), 17.6 g of the aldehyde are eluted in the 820 Ί form of a colourless oil.

IR: 2960, 2860, 2745, 1730, 1633, 1470, 975, 840 cm-2.

For the Wittig olefination, 20.5 g of phosphonoacetic acid triethyl ester and 12.4 g of diazabicycloundecene are added at 24°C to a stirred suspension of 3.88 g of lithium chloride in 274 ml of acetonitrile and the whole is stirred for 15 minutes. A solution of 17.5 g of the above-described a,β-unsaturated aldehyde in 43 ml of acetonitrile is then added dropwise, and the whole is stirred for 4 hours at 24°C and then diluted with ether. The whole is shaken in succession with water, 10 % citric acid solution and water, dried with sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed with hexane/ether (9+1) on silica gel, yielding 15.7 g of the title compound in the form of a colourless oil.

IR: 2958, 2860, 1705, 1640, 1616, 1255, 1003, 970, 838 cm~l. -fCis-1-(tert-butvl-dimethvlsilyloxymethvl-cyclopent-2-vll -pentadien-l-ol ml of a 1.2 molar solution of diisobutylaluminium hydride in toluene are added dropwise at -70°C, under argon, to a solution of 15 g of the ester prepared in accordance with Example lb in 416 ml of toluene, and the whole is stirred for 30 minutes at -70°C. 15 ml of isopropanol followed by 40 ml of water are then added dropwise, and the whole is stirred for 3 hours at 23°C, filtered, washed with methylene chloride and concentrated by evaporation in vacuo. The residue is purified by chromatography on silica gel. Using hexane/ether (8+2), 9.3 g of the alcohol are obtained in the form of a colourless oil.

IR: 3620, 3460, 838 cm1. 27.3 g of manganese dioxide are added to a solution of 9.3 g of the above-prepared alcohol in 273 ml of toluene and the whole is stirred for 6 hours at 24°C, subsequently filtered, concentrated by evaporation and chromatographed on silica gel.

Using hexane/ether (9 + 1), 6.9 g of the title compound are obtained in the form of a colourless oil.

IR: 2955, 2858, 2740, 1678, 1632, 986, 838 cm-1.

Id) (5RS) -5-Acetoxv-1- [cis-1- (tert-butyl-dimethylsilyloxymethyl) -cyclopent-2-yl] - (IE, 3E) -tridecadiene A solution of 17.8 g of octyl bromide in 24 ml of ether is added dropwise to 2.24 g of magnesium in 12 ml of ether with the application of heat, and the whole is stirred for 30 minutes at 25°C. A solution of 6.7 g of the aldehyde prepared in accordance with Example lc in 100 ml of ether is added dropwise at -20°C, under argon, to 17.2 ml (31.7 mmol) of the prepared Grignard solution, and the whole is stirred for 45 minutes at -20°C. Saturated ammonium chloride solution is added, and the whole is extracted three times with ether; the organic phase is shaken with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ethyl acetate mixtures, 3.35 g of the non-polar diastereoisomeric alcohol and 3.6 g of the polar diastereoisomeric alcohol are obtained in the form of colourless oils.

For the acetylation, 3.1 ml of acetic anhydride are added to a solution of 3.35 g of the above-prepared •Sfc O' ! non-polar diastereoisomeric alcohol in 8 ml of pyridine and the whole is stirred for 24 hours at room temperature and subsequently concentrated in vacuo with the addition of toluene. The residue is chromatographed on silica gel. Using hexane/ether (95+5), 3.5 g of the title compound (non-polar diastereoisomer) are obtained in the form of a colourless oil.

IR: 2938, 2860, 1725, 1655, 1252, 990, 838 cm'1.

In an analogous manner, 3.7 g of the title compound (in the form of the polar diastereoisomer) are prepared from 3.6 g of the above-prepared polar diastereoisomeric alcohol with 3.3 ml of acetic anhydride and 8.6 ml of pyridine.

IR: 2915, 2860, 1725, 1655, 1252, 990, 838 cm-1.

Cis-(IRS)-1-formyl-(2RS)-2-[(1E.3E)-(5RS) -5-acetoxv1,3-tridecadienvll-cvclopentane diastereoisomer non-polar (12) 7.35 g of tetrabutylammonium fluoride are added at 0°C to a solution of 3.5 g of the acetate prepared in accordance with Example ld (non-polar diastereoisomer) in 350 ml of tetrahydrofuran and the whole is stirred for 15 minutes at 0°C and for 5.5 hours at 24°C. Dilution is then carried out with 1 1 of ether, and the whole is washed three times with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ether (7+3), 2.45 g of the alcohol are eluted in the form of a colourless oil.

IR: 3620, 3450, 2930, 2860, 1725, 1260, 992 cm'1. 18.4 g of Collins reagent (chromic acid/pyridine complex) are added at 0°C to a solution of 2.4 g of the above-prepared alcohol in 75 ml of methylene chloride, and the whole is stirred for 20 minutes at 0°C. Dilution is then carried out with a mixture of hexane/ether (1+1), Celite is added, and the whole is filtered and concentrated by evaporation in vacuo. The aldehyde so obtained was used without being further purified.

IR: 2930, 2860, 2730, 1721, 1250, 990 cm'1.

Example 2 ( + /-) -(5RS)-5-Hvdroxv-5-icis-(2RS)-2- ( (1E,3E)-(5RS)-5hydroxv-1,3-tridecadienvl)-(IRS)-cvclopentyl] -pentanoic acid diastereoisomer non-polar (12) 7.7 ml of a 0.5 normal aqueous lithium hydroxide solution are added to a solution of 360 mg of the diacetate prepared in accordance with Example 1 in 7.7 ml of methanol, and the whole is stirred for 25 hours at 50°C, then acidified to pH 5 with 10 V sulphuric acid, diluted with ethyl acetate, shaken three times with brine, dried with sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed with ether/ethanol (99+1) on silica gel. 197 mg of the title compound are obtained in the form of colourless crystals (m.p. 71°C). IR: 3400, 2928, 2850, 1725, 1360, 1230, 995, 930 cm'1.

Example 3 (+/-)-(5RS)-5-Acetoxv-5-[cis-(2RS)-2-((IE,3E)-(5RS)-5hydroxy-i,3-tridecadienvl)-(IRS)-cvclopentyl]-pentanoic acid diastereoisomer non-polar (12) .5 ml of a 0.5 normal sodium hydroxide solution are added at 23°C to a solution of 255 mg of the non-polar diastereoisomeric diacetate prepared in accordance with Example I in 5.5 ml of methanol and stirring is carried out for 1.5 hours at 23°C under argon. The whole is then diluted with water and acidified to pH 5 with 10 V sulphuric acid at ice bath temperature. The whole is extracted with ethyl acetate, washed twice with brine, dried with sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using ether/hexane (8+2), 202 mg of the title compound are obtained in the form of a colourless oil.

IR: 3420, 2922, 2850, 1727, 1710, 1700, 1272, 990, 960 cm-1.

Example 4 ( + /-)-(5RS)-5-Hvdroxy-5- [cis-(2RS)-2-((1E,3E)-(5RS)-5hydroxy-1,3-tridecadienvl) - (IRS) -cyclopentyl) -pentan-l-ol diastereoisomer non-polar (12) 180 mg of the non-polar diastereoisomeric diacetate described in Example 1 are stirred for 60 hours at 24°C with 5.5 ml of a solution of potassium hydroxide in water and ethanol (preparation: 5 g of potassium hydroxide are dissolved in 67.5 ml of water and 182.5 ml of ethanol) . The whole is then acidified to pH 6 with 10 % citric acid solution and extracted four times with 20 ml of methylene chloride each time, and the organic phase is shaken with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel using ethyl acetate, yielding 103 mg of the title compound in the form of a colourless oil.

IR: 3610, 3370 (broad), 2930, 2860, 993 cm'1.

Example 5 ( + /-)-(5RS)-5-Acetoxy-5- [cis-(2RS)-2-((IE,3E)-(5RS)-5acetoxv-1,3-tridecadienvl) - (IRS) -cyclopentyl) -pentanoic acid diastereoisomer non-polar (12) A solution of 11.1 g of 4-chloro-l-(tert-butyldimethylsilyloxy)-butane in 10 ml of tetrahydrofuran is added dropwise at 25°C, under argon, to 2.44 g of magnesium, a crystal of iodine is added, and the whole is heated for 10 minutes at 75°C, stirred for 40 minutes at 25°C and diluted with 31 ml of tetrahydrofuran. q.~ A solution of 1.6 g of cis-(IRS)-l-formvl-(2RS) -2[ (IE, 3E) - (5RS) -5-acetoxy-l, 3-tridecadienyl) -cyclopentane (diastereoisomer polar (12)) in 5.5 ml of tetrahydrofuran is added dropwise at -70°C, under argon, to 9.6 ml of that organomagnesium solution, and the whole is stirred for 1 hour at -70°C. ml of saturated ammonium chloride solution are added, the whole is extracted three times with ether, and the organic phase is shaken with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ether (8+2), 1.3 g of the alcohol are obtained in the form of a colourless oil.

IR: 3610, 2930, 2860, 1725, 1374, 1451, 993, 836 cm-1.

For the acetylation, 2.1 g of acetic anhydride are added to a solution of 1.82 g of the above-described alcohol in 5.1 ml of pyridine and the whole is stirred for 22 hours at room temperature. The whole is then concentrated in vacuo with the addition of toluene, and the residue is chromatographed on silica gel. Using hexane/ether (9+1), 1.83 g of the acetate are obtained in the form of a colourless oil.

IR: 2930, 2860, 1728, 1608, 1375, 1255, 993, 840 cm-1.

For the silyl ether cleavage, 1.85 g of the aboveprepared acetate in 113 ml of tetrahydrofuran are stirred with 3.1 g of tetrabutylammonium fluoride for 20 minutes at 0°C and for 4 hours at 24°C under argon. The whole is then diluted with ether, washed three times with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with ether/hexane (8+2), yielding 1.3 g of the 1-alcohol in the form of a colourless oil.

IR: 3620, 3500, 2930, 2860, 1725, 1608, 1375, 1250, It fl 2 0 7 6j £ · 990 cm-1.

For the oxidation of the 1-hydroxy group, 7.2 g of Collins reagent are added to 1.25 g of the above-prepared alcohol in 71 ml of methylene chloride, and the whole is stirred for 20 minutes at 0°C and subsequently diluted with a mixture of hexane/ether (1+1) . Celite is added and the whole is filtered, washed with hexane/ether (1 + 1) and concentrated by evaporation in vacuo. The 1aldehyde so obtained is used immediately without being further purified. 2.3 ml of Jones reagent (J. Chem. Soc. 1953, 2555) are added dropwise with stirring, at -25°C, to a solution of 1.1 g of the above-prepared aldehyde in 40 ml of acetone, and the whole is stirred for 15 minutes at -25°C under argon. 8 ml of isopropanol are then added, and the whole is stirred for 5 minutes, diluted with 300 ml of ether, shaken twice with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using ether/hexane (7+3), 681 mg of the title compound are obtained in the form of a colourless oil.

IR: 3520(broad), 2930, 2859, 1725, 1373, 1250, 990, 948 cm’1.

The starting material for the above title compound is prepared as follows: 5a) Cis-(IRS)-1-formyl- (2RS)-2-f(IE,3E)-(5RS)-5-acetoxv1.3 -tridecadienvll-cvclopentane diastereoisomer polar (12) 7.73 g of tetrabutylammonium fluoride are added at 0°C to a solution of 3.68 g of (5RS)-5-acetoxy-lfcis-1-(tert-butyl-dimethylsilyloxymethyl)-cyclopent-2-yl)-(IE,3E)-tridecadiene (polar diastereo36 isomer), prepared in accordance with Example Id, in 360 ml of tetrahydrofuran, and the whole is stirred for 30 minutes at 0°C and for 5 hours at 24°C. Dilution is then carried out with 1 1 of ether, the whole is washed three times with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo, and the residue is chromatographed on silica gel. Using hexane/ether (7+3), 2.3 g of the alcohol are eluted in the form of a colourless oil. IR: 3620, 3450, 2930, 2860, 1725, 1250, 991 cm-1. g of Collins reagent (chromic acid/pyridine complex) are added at 0°C to a solution of 1.8 g of the above-prepared alcohol in 56 ml of methylene chloride, and the whole is stirred for 20 minutes at 0°C. Dilution is then carried out with a mixture of hexane/ether (1+1), Celite is added, and the whole is filtered and concentrated by evaporation in vacuo. The aldehyde so obtained was used without being further purified.

IR: 2930, 2860, 1720, 1250, 991 cm-1.

Example 6 ( + /-) -(5RS)-5-Hvdroxv-5-fcis- (2RS)-2-((IE,3E) -(5RS) -5hydroxy-1,3-tridecadienvl) - (IRS) -cvclopentvl] -pentanoic acid diastereoisomer polar (12) Analogously to Example 2, 174 mg of the title compound are obtained in the form of a colourless oil from 3 60 mg of the diacetate prepared in accordance with Example 5. IR: 3400, 2930, 2855, 1723, 1360, 1230, 995, 930 cm'1.

Example 7 ( + /-)-(5RS)-5-AcetOXV-5-fcis- (2RS)-2-((1E.3E)-(5RS)-5hydroxv-l,3-tridecadienvl) - (IRS)-cvclopentvl]-pentanoic acid diastereoisomer polar (12) Analogously to Example 3, 238 mg of the title compound <3 are obtained in the form of a colourless oil from 305 mg of the diacetate prepared in accordance with Example 5. IR: 3520, 2930, 2860, 1723, 1250, 990, 962 cm-1.

Example 8 ( + /-) -(5RS)-5-Hydroxy-5-Icis-(2RS)-2- ( (IE,3E)-(5RS)-5hydroxy-1,3-tridecadienyl)-(IRS)-cyclopentyll -pentan-Ιοί diastereoisomer polar (12) Analogously to Example 4, 115 mg of the title compound are obtained in the form of a colourless oil from 190 mg of the diacetate prepared in accordance with Example 5 (intermediate with the hydroxy group in the 1-position). IR: 3600, 3380 (broad), 2930, 2860, 992 cm1.

Example 9 (+/-)-(5RS)-5-Acetoxy-5-(trans-(2RS)-2-((IE,3E)-(5RS)-5acetoxy-1,3-tridecadienyl)-(IRS)-cyclopentyll -pentanoic acid diastereoisomer A A solution of 22.3 g of 4-chloro-1- (tert-butyldimethylsilyloxy)-butane in 20 ml of tetrahydrofuran is added dropwise at 25°C, under argon, to 4.87 g of magnesium, a crystal of iodine is added, and the whole is heated for 10 minutes at 70°C, stirred for 30 minutes at 25°C and diluted with 62.5 ml of tetrahydrofuran.

A solution of 8.1 g of trans-(IRS)-1-formyl-(2RS)-2[(IE,3E)-(5RS)-5-acetoxy-l,3-tridecadienyl]-cyclopentane in 27 ml of tetrahydrofuran is added dropwise at -70°C, under argon, to 48.3 ml of the above organomagnesium solution, and the whole is stirred for 1.5 hours at -70°C. 200 ml of saturated ammonium chloride solution are added, the whole is extracted with ether, and the organic phase is shaken with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with hexane/ethyl acetate (85+15), yielding 8.2 g of the alcohol in the form of a colourless oil.

IR: 3450, 2930, 2860, 1725, 1374, 1255, 993, 840 cm’1.

For the acetylation, 8.6 ml of acetic anhydride are added to a solution of 7.85 g of the above-prepared alcohol in 50 ml of pyridine and the whole is stirred for 21 hours at room temperature. The whole is then concentrated in vacuo with the addition of toluene, and the residue is chromatographed on silica gel. Using hexane/ethyl acetate (85+15), 7.6 g of the acetate are obtained in the form of a colourless oil.

IR: 2940, 2862, 1728, 1375, 1257, 992, 840 cm-1.

For the silyl ether cleavage, 7.55 g of the aboveprepared acetate in 500 ml of tetrahydrofuran are stirred with 12.7 g of tetrabutylammonium fluoride for 1 hour at 0°C and for 4 hours at 24°C under argon. The whole is then diluted with ether, washed three times with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ethyl acetate mixtures there are obtained by repeated chromatography 1.7 g of the nonpolar diastereoisomeric alcohol (diastereoisomer A) and 2.3 g of the polar diastereoisomeric alcohol (diastereoisomer B) in the form of a colourless oil.

IR (non-polar alcohol) : 3630, 3500, 2938, 2862, 1727, 1660, 1378, 1255, 992, 950 cm-1.

IR (polar alcohol): 3620, 3480, 2938, 2862, 1726, 1660, 1378, 1255, 992, 950 cm-1.

For the oxidation of the 1-hydroxy group, 10.7 g of Collins reagent are added to 1.55 g of the above-prepared non-polar alcohol (diastereoisomer A) in 122 ml of methylene chloride at 0°C, and the whole is stirred for 20 minutes at 0°C and subsequently diluted with a mixture of hexane/ether (1+1). Celite is added and the whole is ±920? filtered, washed with hexane/ether (1+1) and concentrated by evaporation in vacuo. The 1-aldehyde so obtained is used immediately without being further purified. 3.3 ml of Jones reagent (J. Chem. Soc. 1953. 2555) are added dropwise with stirring, at -25°C, to a solution of 1.57 g of the above-prepared aldehyde in 58 ml of acetone, and the whole is stirred for 15 minutes at -25°C under argon. 11.5 ml of isopropanol are then added, and the whole is stirred for 5 minutes, diluted with 400 ml of ether, shaken twice with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ethyl acetate (6+4) 1.2 g of the title compound are obtained in the form of a colourless oil.

IR: 3520, 2930, 2860, 1725, 1658, 1360, 1250, 990, 946 cm'1.

The starting material for the above title compound is prepared as follows : 9a) - [Trans-1- (tert-butyl-dimethylsilvloxvmethyl) -cyclopent2-yl]-(2E,4E)-pentadienoic acid ethyl ester 3.4 ml of concentrated sulphuric acid are added to a solution of 25 g of trans-cyclopentane-1.2-dicarboxylic acid in 64 ml of methanol and the whole is boiled at reflux for 14 hours. The excess alcohol is then distilled off, the residue is poured onto ice-water and extracted four times with ether and the organic phase is washed with sodium hydrogen carbonate solution and water, dried with sodium sulphate and concentrated in vacuo. The residue is distilled in vacuo at 25 ratorr. At 56°C, 27 g of trans-cyclopentane-1.2-dicarboxylic acid dimethyl ester are obtained in the form of a colourless liquid. ·*·" 3 ί /j Q IR: 2955, 2873, 1725, 1435 cm-1. 230 ml of a 1.2 molar solution of diisobutylaluminium hydride in toluene are added dropwise at 0°C, under argon, to a solution of 13 g of trans-cvclopentane-1.2dicarboxylic acid dimethyl ester in 300 ml of toluene and the whole is stirred for 2 hours at 0°C. 20 ml of isopropanol are then added dropwise, the whole is stirred for 5 minutes, 116 ml of water are added dropwise and the whole is stirred for 2 hours at 22°C, filtered, washed with methylene chloride and concentrated by evaporation in vacuo. The residue is purified by chromatography on silica gel. Using ethyl acetate, 8 g of trans-1,2dihydroxy-cyclopentane are obtained in the form of a colourless liquid.

IR: 3610, 3400, 2960, 1062 cm'1. 17.1 g of imidazole and 18.9 g of tert-butyldimethylsilyl chloride are added at 0°C to a solution of 16 g of trans1,2-dihydroxymethylcyclopentane in 146 ml of dimethylformamide and the whole is stirred for 22 hours at 24°C. Dilution is carried out with 1.6 1 of ether and the whole is shaken twice with 80 ml of 10 % sulphuric acid each time, washed with water until neutral, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel.

Using hexane/ethyl acetate (9+1), 12 g of trans-1- (tertbutyl - dimethyl s i 1 y 1 oxyme t hyl )-2- hy droxyme thyl- eye 1 o pentane are obtained in the form of a colourless liquid. IR: 3400, 2960, 2860, 1260, 840 cm'1. g of Collins reagent (chromic acid/pyridine complex) are added to a solution of 14.4 g of the above-described monosilyl ether in 750 ml of methylene chloride and the whole is stirred for 30 minutes at 0°C. Dilution is then carried out with a mixture of hexane/ether (3+2), Celite is added, and the whole is filtered and concentrated by evaporation in vacuo. 14 g of the aldehyde, which can be used without being further purified, are obtained.

IR 2958, 2860, 2720, 1719, 840 cm-1.

For the Wittig-Horner olefination, 16.1 g of phosphonocrotonic acid triethyl ester and 9.8 g of diazabicycloundecene (DBU) are added at 24°C to a stirred suspension of 2.7 g of lithium chloride in 536 ml of acetonitrile and the whole is stirred for 10 minutes. A solution of 13 g of the above-described aldehyde in 107 ml of acetonitrile is then added dropwise, and the whole is stirred for 3.5 hours at 24°C and then diluted with ether. The whole is shaken in succession with water, 10 % citric acid solution and water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed with hexane/ethyl acetate on silica gel, yielding 11 g of the title compound in the form of a colourless oil.

IR: 2958, 2860, 1705, 1640, 1620, 1470, 1255, 1000, 838 cm'1. 9b) - iTrans-1- (tert-butvl-dimethvlsilvloxvmethvl) -cvclopent2-vl]-(2E.4E)-pentadien-l-al ml of a 1.2 molar solution of diisobutylaluminium hydride in toluene are added dropwise at -70°C, under argon, to a solution of 9.8 g of the ester prepared in accordance with Example 9a in 250 ml of toluene and the whole is stirred for 30 minutes at -70°C. 10 ml of isopropanol are then added dropwise and, after 5 minutes, 30 ml of water are added dropwise, and the whole is stirred for 2.5 hours at 23°C, filtered, washed with methylene chloride and concentrated by evaporation in vacuo. The residue is purified by chromatography on silica gel. Using hexane/ether (7+3), 7.6 g of the k920 7 alcohol are obtained in the form of a colourless oil.

IR: 3610, 3450, 990, 940, 840 cm1.

For the aldehyde preparation, 22 g of manganese dioxide are added to a solution of 7.5 g of the above-prepared alcohol in 250 ml of toluene and the whole is stirred for 4 hours at 24°C, subsequently filtered, concentrated by evaporation and chromatographed on silica gel. Using hexane/ethyl acetate (6+2), 7.4 g of the title compound are obtained in the form of a colourless oil.

IR: 2960, 2860, 2740, 1682, 1638, 988, 940, 840 cm-1. 9c) (5RS) -5-Acetoxv-l- ftrans-l- (tert-butvl-dimethylsilvloxymethvl) -cyclopent-2-νΠ -1- (IE, 3E) -tridecadiene A solution of 17.8 g of octyl bromide in 24 ml of ether is added dropwise, with the application of heat, to 2.24 g of magnesium in 12 ml of ether and the whole is stirred for 30 minutes at 25°C. To 16.4 ml (=30.1 mmol) of that Grignard solution there is added dropwise at -20°C, under argon, a solution of 7.4 g of the aldehyde prepared in accordance with Example 9b in 130 ml of ether, and the whole is stirred for 45 minutes at -20°C. Saturated ammonium chloride solution is added, the whole is extracted three times with ether, and the organic phase is shaken with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ethyl acetate (7+3), 8.6 g of the alcohol (diastereoisomeric mixture) are obtained in the form of a colourless oil.

For the acetylation, 12.5 ml of acetic anhydride are added to a solution of 8.5 g of the above-prepared alcohol in 85 ml of pyridine and the whole is stirred at room temperature for 23 hours. The whole is then concentrated in vacuo with the addition of toluene and the residue is chromatographed on silica gel. Using hexane/ethyl acetate (97+3), 8.6 g of the title compound are obtained in the form of a colourless oil.

IR: 2938, 2860, 1725, 1657, 1255, 993, 945, 840 cm'1.

J 9d) Trans - (IRS)-1-formyl-(2RS)-2-ί(IE,3E)-(5RS)-5-acetoxy1,3-tridecadienyll-cvclopentane 19.9 g of tetrabutylammonium fluoride are added at O’C to a solution of 9.1 g of the acetate prepared in accordance with Example 9c in 900 ml of tetrahydrofuran and the whole is stirred for 15 minutes at 0°C and for 4 hours at 24°C. The whole is then diluted with 2 1 of ether, washed three times with brine, dried with sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ethyl acetate (7+3), 7.18 g of the alcohol are eluted in the form of a colourless oil.

IR: 3620, 3450, 2938, 2862, 1730, 1255, 995 cm'1. g of Collins reagent (chromic acid/pyridine complex) 20 are added at O’C to a solution of 8.1 g of the aboveprepared alcohol in 250 ml of methylene chloride and the whole is stirred for 20 minutes at O’C. Dilution is then carried out with a mixture of hexane/ether (1+1), Celite is added, and the whole is filtered and con25 centrated by evaporation in vacuo. The aldehyde so obtained was used without being further purified.

IR: 2930, 2860, 2731, 1721, 1250, 990 cm'1.

Example 10 ( + /-)- (5RS)-5-Hydroxy-5-Ttrans-(2RS)-2-((IE,3E) -(5RS)-520 hydroxy-1,3-tridecadienvl) - (IRS) -cyclopentyl] -pentanoic acid diastereoisomer A 168 mg of the title compound in the form of a colourless oil are obtained analogously to Example 2 from 250 mg of the diacetate prepared in accordance with Example 9. IR (film): 3400, 2930, 2858, 1715, 1660, 1250, 989, 930 cm-1.

Example 11 ( + /-) -(5RS)-5-Acetoxv-5-ftrans-(2RS)-2-((1E,3E) -(5RS)-5hvdroxy-1,3-tridecadienvl)-(IRS)-cvclopentyll -pentanoic acid diastereoisomer A 04 mg of the title compound in the form of a colourless oil are obtained analogously to Example 3 from 250 mg of the diacetate prepared in accordance with Example 9.

IR (film): 3450, 2930, 2860, 1736, 1713, 1660, 1245, 990 cm-1.

Example 12 ( + /-) -(5RS)-5-Acetoxy-5-itrans-(2RS)-2-((1E.3E)-(5RS)-5acetoxv-1,3-tridecadienvl) - (IRS) -cvclopentyll -pentanoic acid diastereoisomer B g of Collins reagent are added at 0°C to a solution of 2.2 g of the polar alcohol (diastereoisomer B) prepared in Example 9 in 173 ml of methylene chloride and the whole is stirred for 20 minutes at 0°C. Dilution is then carried out with a mixture of hexane/ether (1+1) , Celite is added and the whole is filtered, washed with hexane/ether (1+1) and concentrated by evaporation in vacuo. The 1-aldehyde so obtained is used immediately without being further purified. 4.7 ml of Jones reagent are added dropwise with stirring, at -25°C, to a solution of 2.25 g of the above-prepared aldehyde in 83 ml of acetone and the whole is stirred for 12 minutes at -25°C under argon. 16.5 ml of isopropanol are then added, and the whole is stirred for 5 minutes, diluted with ether, shaken with brine, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/4 ethyl acetate (6+4) 1.6 g of the title compound are obtained in the form of a colourless oil.

IR: 3620, 2930, 2860, 1721, 1658, 1370, 1250, 989, 946 cm-1.

Example 13 (+/-) -(5RS)-5-Hydroxv-5-[trans-(2RS)-2-((IE, 3E)-(5S)-5hydroxy-l,3-tridecadienyl)- (IRS)-cyclopentyl]-pentanoic acid diastereoisomer B 178 mg of the title compound in the form of a colourless oil are obtained analogously to Example 2 from 250 mg of the diacetate prepared in accordance with Example 12.

IR: 3600, 3420, 2930, 2859, 1730, 1660, 1250, 990 cm-1.

Example 14 ( + /-) -(5RS)-5-Acetoxv-5-[trans-(2RS)-2-((1E,3E)-(5S)-5hydroxy-l,3-tridecadienyl)-(IRS)-cyclopentyl]-pentanoic acid diastereoisomer B 187 mg of the title compound in the form of a colourless oil are obtained analogously to Example 3 from 250 mg of the diacetate prepared in accordance with Example 12.

IR (film): 3450, 2925, 2850, 1730, 1708, 1660, 1245 985 cm-1.

Example 15 (+/-) -(5RS)-5-Hydroxy-5-fcis-(2RS)-2-((1E.3E)-(5S)-5hydroxy-l,3-tridecadienyl)-(IRS)-cyclopentyl)-pentanoic acid methyl ester diastereoisomer non-polar (12) An ethereal diazomethane solution is added dropwise at 0°C to a solution of 85 mg of the acid prepared in accordance with Example 2 in 8 ml of methylene chloride until a yellow colour persists, and the whole is stirred for 15 minutes at 0°C. The whole is then concentrated by evaporation in vacuo, and the residue is chromatographed on silica gel. Using hexane/ethyl acetate (2+8), 69 mg of the title compound are obtained in the form of a Example 19 (+/-)-(5RS)-5-Hvdroxv-5-(cis-(2RS)-2-((IE,3E)-(5S)-5hydroxy-1,3-tridecadienvl)-(IRS)-cyclopentyll-pentanoic acid 1,5-lactone diastereoisomer polar (12) 0.5 g of anhydrous magnesium sulphate is added in portions at 24°C, over a period of 24 hours, to a solution of 27 mg of the carboxylic acid prepared in accordance with Example 6 in 5 ml of toluene and the whole is stirred for a further 24 hours at 24°C.

Filtration is then carried out and the residue obtained by concentration by evaporation is chromatographed on silica gel. Using toluene/ethyl acetate (7+3), 14 mg of the 1,5 lactone are eluted in the form of a colourless oil.

IR: 3600, 2930, 2860, 1728, 1250, 990 cm-1.

Claims (5)

CLAIMS:

1.) Leukotriene Β 4 derivatives of formula I wherein R 1 represents CH 2 OH, CH 3 , CF 3 , COOR 5 , CONR 6 R 7 or R 1 together with R 2 represents a carbonyl group, R 2 and R 3 , which are the same or different, each represents H or an organic acid radical having from 1 to 15 carbon atoms, R 4 represents H, (C^-Cjg)alkyl optionally mono- or poly-substituted by chlorine or by bromine, C 3 -C^gcycloalkyl, Cg-C 10 aryl optionally mono- or poly-substituted independently from one another by chlorine, bromine, phenyl, C 3 -C 4 alkyl, Cj-C 4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5- or 6-membered aromatic heterocyclic ring having at least 1 hetero atom, R 5 represents hydrogen, C^^-CiLgalkyl, C 3 -C 10 cycloalkyl, C 6 -Ci O aryl optionally substituted by from 1 to 3 substituents chlorine, bromine, phenyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH 2 -CO-(Cg-C^g)aryl or a 5- or 6-membered ring having at least 1 hetero atom, A represents a trans. trans-CH=CH-CH=CH. a -CH 2 CH 2 -CH=CH- or a tetramethylene group, B represents a straight-chain or branched Cj-Cjgalkylene group that may optionally be substituted by hydroxy, or represents a 5- or 6-membered aromatic heterocyclic ring having at least 1 hetero atom, represents hydrogen, C^-C^alky!, C3-C 10 cycloalkyl, Cg-CiQaryl optionally substituted by from 1 to 3 substituents chlorine, bromine, phenyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH 2 -CO-(Cg-C 10 )aryl or a 5- or 6- membered ring having at least 1 hetero atom, A represents a trans, trans-CH=CH-CH=CH, a -CH 2 CH 2 -CH=CH- or a tetramethylene group, B represents a straight-chain or branched C-^-C^alkylene group that may optionally be substituted by fluorine, or represents the group -C-CH?-. D represents a direct bond, oxygen, sulphur, -CsC-, -CH=CR® or, together with B may also represent a direct bond, R 6 and R 7 are the same or different and each represents H or Cj-C 4 alkyl or R 7 represents H and R 6 represents Ci-C^alkanoyl or C^-C^^Qalkanesulphonyl, R® represents H, C^-Cgalkyl, chlorine or bromine, n is 3 to 5 and, when R 5 represents hydrogen, the salts thereof with physiologically tolerable bases and the cyclodextrin clathrates thereof, characterised in that an aldehyde of formula II CHO or 3 wherein A, B, D, R 3 and R 4 are as defined above, is reacted, optionally after the protection of free hydroxy (II) , III groups, with an organomagnesium compound of formula X-Mg-CH 2 -CH 2 -CH 2 -CH 2 -R 9 (III), wherein X represents chlorine, bromine or iodine and R 9 represents -CH3, CF3 or -OR 10 in which R10 represents a

2. 5 readily removable ether radical and then optionally, in any sequence, isomers are separated, protected hydroxy groups are freed and/or a free hydroxy group is esterified and/or a 1-hydroxy group is oxidized to carboxylic acid and/or double bonds are hydrogenated and/or an 10 esterified carboxy group (R 1 =COOR 5 ) is hydrolysed and/or reduced and/or a carboxy group (R 5 =H) is esterified and/or a free carboxy group (R 8 =H) is converted into an amide (R 1 =CONHR 8 R 7 ) or a carboxy group is converted into a salt with a physiologically tolerable base. 15

3.) Pharmaceutical compositions that comprise one or more compounds according to claim 1. IS-920 7 f}2* - 52

4. Leukotriene B 4 derivatives substantially as hereinbefore described with reference to the examples.

5. A process for the preparation of leukotriene B 4 derivatives substantially as hereinbefore described with 5 reference to the examples . 3. 6· A pharmaceutical composition substantially as hereinbefore described with reference to the examples.