IE891626L - New leukotriene B4 derivatives, a process for their¹production and their use as pharmaceutical agents - Google Patents

Abstract

Leukotriene-B4 derivates are disclosed having the formula (I), in which R1 is the residue CH2OH, the residue COOR5 or the residue CONHR6, A is a transmethylene group, a trans-CH=CH-CH=CH-methylene group or a tetramethylene group, B is a straight or branched chain, saturated or insaturated alkylene group with up to 10 C-atoms, D is a direct link, oxygen, sulfur, a -C=C- group or a -CH=CR7- group, B and D form together a direct link, R2 and R3 can be identical or different, and represent a hydrogen atom or an acid residue of an organic acid with 1 to 15 C-atoms and R4 is a hydrogen atom, an alkyl residue, a cycloalkyl residue, an aryl residue or a heterocyclic residue with 5 to 6 members and, when R5 is a hydrogen atom, their salts with physiologically compatible bases and their cyclodextrinclathrates. A process for producing these derivates and their use as medicaments are also disclosed.

Description

"la" - i"7 O c o O / U The invention relates to novel leukotriene B4 derivatives s to processes for the preparation thereof, and to their use as medicaments.

Leukotriene B4 (LT34) was discovered in 1979 by B. S&smelssson to be a metabolite of arachidonic acid, During biosynthesis, the enzyme 5~lipoxygena.se first forms leukotriene as key intermediate which is then converted by a specific hydrolase into LTB4.

COOH arechidonic ecicl lipoxygenase H. ,00 H V COOK coon leukotriene A& (LTA4) leukotriene 34 (LTB$) g 1 u t a th i o ne - S-transferase leukotriene C4 (LTC4) The nomenclature of leukotrienes can be found in the following works: a) B. Sarauelssor. at aj..,, Prostaglandins 12, 645 (1930); 17, 785 (1979). b) C.N. Serhan g£ aJL. , Prostaglandins 3Jh 201 (1987).

The physiological and, especially,, the pathophysiological importance of leukotriene B4 is summarised in some more recent works: a) The Leukotrienes, Chemistry and Biology eds. L.W. Chakrin, D.M. Bailey, Academic Press 1984. b) J.w. Gillard &1-, Drugs of the Future X2, ^53 (1987). c) B. Samuelsson al., Science 237 f 1171 (1987). d) C.W. Parker, Drug Development Research lft, 277 (1987) .

It is known that LTB& causes leukocytes to adhere to the blood vessel wall. LTB4 has chemotactic effects, that is to say, it attracts leukocytes up a gradient of increasing concentration - Owing to its cheaotactic activity, it also changes vascular permeability indirectly, synergism with prostaglandin E2 being observed. LT34 apparently plays ar decisive role in inflammatory, allergic and iatatunological processes. Antagonists of LTB^ itself or inhibitors of enzymes that are involved in the synthesis of LT84 should, as specific drugs, be effective in particular against disorders that involve inflammation and allergic reactions™ In addition to therapeutic possibilities that are the result of the antagonising of LTB4 with LTB4 analogues, it has recently been demonstrated that leukotriene S4 agonists are useful in and could potentially be applied in the treatment of fungal diseases of the skin (H. Kayama, Prostaglandins M, 797 (1988)).

Leukotrienes are especially involved in skis diseases that involve inflammatory processes (increased vascular permeability and oedema formation, cell infiltration), increased proliferation of the skin cells and itching, such as, for example, in the case of eczemas, erythemas, psoriasis, pruritus and acne. Pathologically increased leukotriene levels are involved in the occurrence of many dermatitid.es , either as a cause thereof or there is a connection between the persistence of the dermatitides and the leukotrienes. Markedly increased leukotriene levels ware measured, for example, in the case of psoriasis and atopical dermatitis.

It has now been found that the incorporation of the chemically and metabolically labile cis-AP»7-double bond of LT84 into a 1,2-substituted phenyl ring results in the stabilisation of LTB4, there also being obtained, especially by further derivatisation of the functional groups, LTB^ derivatives that strongly antagonise the action of natural LTB4. That is to say, the invention includes LTB4 analogues which, depending on the structural characteristics and tissue type, can act as antagonists, agonists and partial antagonists.

The invention relates to leukotriene B4 derivatives of formula I wherein I?^ represents the radical CH20H; the radical COOH5 in which R5 represents a hydrogen atom, an alky! radical having from 1 to 10 carbon atoms, a cyclo- (I) - <1 - alkvl radical having from 3 to 10 carbon atoms, an aryi radical having from 6 to 10 carbon atoms that is optionally mono™ to tr*i-substituted by chlorine, bromine, phenyl, alkyl having from 1 to 4 carbon atoms, chloroiaathyl, f luoromethyl, trifluoromethyl, carboxy, Ci-C^-alkoxv or by hydroxy, a -CH2™CO-aryl radical having from 6 to 10 carbon atoms for arvl, or a 5- or 6-meinbered heterocyclic radical having at least one hetero atom; or R^ represents the radical COMHRg, in which R6 represents an alkanoyl or aikanesulphonyl radical having froia 1 to 10 carbon atoms or the radical R5, A represents a trans. trans-CH=CH~CH=CH- or tetra- methylene group, B represents a straight-chain or branched-chain saturated or unsaturated alkylene group having up to 10 carbon atoms that may optionally be substituted by fluorine, or represents the grouj 2~ group or a ~CH=CR7~ group in which Ry represents hydrogen, C^-Cg-alkvl, chlorine or bromine, B and D together represent a direct bond, R2 and R3 may be identical or different and represent a hydrogen atom or an acid radical of an organic acid having from 1 to 15 carbon atoms and.

R4 represents a hydrogen atom,, an alkyl radical having from 1 to 10 carbon atoms, an alkyl radical having from 1 to 10 carbon atoms that is substituted by chlorine or by bromine, a cycloalkyl radical having from 3 to 10 carbon atoms, an aryl radical having from 6 to 10 carbon atoms that is optionally mono- s or di-substituted by chlorine, bromine, phenyl, alkyl having front l to 4 carbon atoms, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, Cj_-c4-alkoxy in which n = 1, 2 or 3, D represents a direct bond, oxygen, sulphur, a -C=C- or by hydroxy, or represents a 5- or 6-memberad. heterocyclic radical having at least one hete.ro atom, and, if R5 represents a hydrogen atom, the salts thereof with physiologically tolerable bases and the cyclodextrin clathrates thereof,, with the proviso that R2 and R3 do not each represent hydrogen when A represents tcana,£Ean&-CH=CH-CH=CH~ and Rj_ represents the radical -COOR5 or -COMHRs„ Compounds of the formula I wherein each of R2 and R3 represents hydrogen and A represents -CH=CH-CH=CK~ and Ri represents the radical -COOR5 or -CONHRg have been previously described in EP-A 0 319 900 which, however, had not been published at the priority date of the present application.

Suitable alkyl groups R5 are straight-chain or branched-chain alkyl groups having fross 1 to 10 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert.-Butyl, pentyl, neopentyl, hexyl, heptyl and. decyl. The alkyl groups R5 may optionally be mono- to poly-substituted by halogen atoms, alkoxy groups, optionally substituted aryl and aroyl groups, by dialkylamino and trialkylaamoniuia each having from 1 to 4 carbon atoiss in the alkyl moiety; mono-substitution is to be preferred. There nay be mentioned as substituents, for example,, fluorine, chlorine or bromine, phenyl, dinethylamino, diethylamino, methoxy and ethoxy. There nay be mentioned as preferred alkyl groups R5 those having from 1 to 4 carbon atoms.

Suitable aryl and aroyl groups are the aryi radicals mentioned hereinafter. suitable aryl groups R5 are both substituted and unsub- - 6 - stituted aryl groups, such as, for example, phenyl, 1-naphtftvl and 2-naphthyl, each of which may be substituted by from 1 to 3 halogen atoms (fluorine, chlorine, bromine), a phenyl group, from 1 to 3 alkyl groups each 5 having fro® 1 to 4 carbon atoms, a chlorosiethyl f fluoro methyl , trifluoromethyl, carboxy8 hydroxy or alkoxy group having from 1 to 4 cartoon atoms. Preferred substit-uents in the 3- and 4-positions on the phenyl ring are, for example, fluorine, chlorine, alkoxy or trifluoro-10 methyl,,, and in the 4-position, on the other hand, hydroxy.

The cycloalkyl group may contain fro® 3 to 10, preferably 5 or 6, carbon atoms in the ring. The rings may be substituted by alkyl groups having from l to 4 carbon 1 5 atoms. Cyclopentyl, cyclohexyl and aethylcyclohexyl ma.y be mentioned by «ay of example.

Suitable heterocyclic groups R5 are 5- and 6-membered aromatic heterocycles containing at least l hetero atom, preferably nitrogen, oxygen or sulphur. There may be 20 mentioned by way of example 2~furyl, 2-thienyl, 2~ pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrinidinyl, pyridasinyl, pyrasinyl, 3-furyl, 3-thienyl, 2-tetrazolyl, inter Suitable as acid radical R6 are physiologically tolerable 2 5 acid radicals. Preferred acids are organic carboxylic acids and sulphonic acids having from 1 to 15 carbon atoras that belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series.

Those acids may be saturated, unsaturated and/or poly-30 basic and/or substituted in the customary wanner. Alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms may be mentioned as examples of the substi tuents. The following carboxylic acids may be mentioned by way of _ 7 - 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 5 acid, tridecylic acid, mvristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert„-butyl-acetic acid, cyclopropylacetic acidf cvclopentylacetic acid, cyclohexylacetic acid, cvclopropanecarboxylic acid, cyclohexanecarboxylic acid,, phenylacetic acid, phenoxy-10 acetic acid, methoxyacetic acid, ethoxyacetic acid,, mono-, di- and tri-chloroacetic acid, asninoacetic acid, diethylarainoacetic acid,, piperidinoacetic acid, xaorpho-linoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted by halogen, tri™ 15 fluoromethyl, hydroxy, alkoxy or carboxy groups, nicoti nic acid,, isonicotinic acid, furan-2-carboxylic acid and cyclopentylpropionic acid. Especially preferred acvl radicals and alkanesulphonyl radicals are those having up to 10 carbon atoms» Suitable sulphonic acids are, for 20 example, methanesulphonic acid, athanesu1phonic acid, isopropanesulphonic acid,, B-chloroethanesulphonic acid, but an e s u 1 phon i c acid,, cyclopentanasul phonic acid, cyclohexanesulphonic acid, bsnzenesulphonic acid, o~ toluenesulphonic acid, g-chlorobenzenesulphonic acid, 25 N,M-d.iaiet.hylaiainosulphonic acid, N,K-diethvlaminosul- phonic acid, N,N-bis-(B-chloroethy1)-arainosulphonic acid, N,N~diisobut:ylaminosulplioriic acid, N,N-dibutylamino-sulphonic acid, and pyrrolidine-, piperidino-, piper-azino-, N-xnethy Ipiperazino- and morpholino-sulphonic 30 acid.

Su.itable alkyl groups R4 are straight-chain and branched-ehain, saturated and unsaturated alkyl radicals, preferably saturated alkyl radicals,, having frosi 1 to 10, especially from 1 to S, carbon atoms, which may option-35 ally be substituted by optionally substituted aryl.

There nay be mentioned toy way of example: methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, property 1, pentenyl, benzyl, b- and p-chlorobenzyl groups. If the alkyl groups R4 are halo-substituted, fluorine, chlorine and bromine are suitable as halogen., The cycloalkyl group nay contain from 3 to 10,, preferably frost 3 to 6, cartoon atoms in the ring* The rings may toe substituted by alkyl groups, having from 1 to 4 carbon atoms. There raay be Mentioned toy way of example: cyclopropyl, cyclobutyl, cyelopentyl, cyclohexyl and methy1eyelohexy1.

Suitable substituted and unsubstituted aryl groups R4 are, for example: phenyl, l-naphthvl and 2-naphthyl, each of which way be substituted by fro® 1 to 3 halogen atoas, a phenyl group, from 1 to 3 alkyl groups each, having from 1 to 4 carbon atoms, by a chloromethyl, fluoromethyl, trifluoromethyl„ carboxy, <^-04-alkoxy or hydroxy group. Preferably, the substitution is in the 3- and 4-positions on the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl or, in the 4-position, by hydroxy.

Suitable heterocyclic groups R^ are 5- and 6-membered aromatic heterocycles that contain at least 1 hetero atom, preferably nitrogen,, oxygen or sulphur. There aay be mentioned by way of example: 2-furvl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidiwyl, pyridazinyl, pvrazinyl, 3-furyl, 3-thienyl, inter alia- Suitable as the alkylene group B are straight-chain or branched-chain, saturated or unsaturated alkylene radicals, preferably saturated alkylene radicals having from I to .10, especially from 1 to 5, carbon atoms, whicr may optionally be substituted by fluorine atoms. There may be mentioned by way of example: methylene, fluoro-methylene, difluoromethylene, ethylene, 1,2-propylene, ethylethylene, trmethylene, tetramethylene, penta-Methylene, 1,1-difluoroethylene, l-fluoroethylene, 1-methyltetramethylene, 1-methyltrimethylene„ 1-methylene-ethylene and 1-methylenetetramethylene.

Suitable acid radicals R2 and R3 are physiologically tolerable acid radicals. Preferred acids are organic carboxylic acids and sulphonic acids having from 1 to 15 carbon atoros that belong to the aliphatic, cvcloaliph-atic, aromatic, aromatic-aliphatic or heterocyclic series. Those acids nay foe saturated, unsaturated and/or polybasic and/or may be substituted in customary manner. Alkyl,, hydroxy, alkoxy, oxo or amino groups or halogen atoms may be mentioned as examples of the 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.-butyl-acetic 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 atoms or by trifluoromethyl, hydroxy, alkoxy or carboxv groups, nicotinic acid, isonicotinic acid,, furan-2-carboxylic acid and cyclopentylpropionic acid. Especially - 10 - 10 1 5 20 preferred acid radicals and are acvl radicals having up to 10 carbon atoms.

Inorganic and organic bases, such as are known to the person skilled in the art for the formation of physiologically tolerable salts, are suitable for salt formation. There may be mentioned by way of examples alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides„ such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanol-amine, triethanolamine, N-snethylglucamine, inorpholine, tris-(hydroxymethyl)-methylamine, etc..

In order to prepare the ciathrates according to the invention, the compounds of the general formula I are dissolved in a pharmacologically harmless solvent, for example an alcohol, preferably etfienolf a ketone, for example acetone, or an ether, for example diethyl ether, and mixed with aqueous solutions of a-, B- orT-cvclo-dextrin, preferably B-cvclodextrin, at from 20 to 80"c, or the "eye1odexfcrin is added to the acids in the form of the aqueous solutions of their salts, for example the sodium or potassium salts, and, after dissolution, the equivalent amount of an acid, for example hydrochloric acid or sulphuric acid, is added.

The invention relates also to a process for the preparation of the leukotri ena-B4 derivatives of the formula I according to the invention, which is characterised in that a benzaldehyde of the formula II cho (II) or 3 - 11 - wherein a, b, d, r3 and R4 ars as defined above, is reacted, optionally after protecting free hydroxy groups, with an organomagnesium compound of the formula III X--Mg-CH2-CH2-CH2~CH2-CHRa (III) , 5 wherein X is chlorine, broiaine or iodine and Rs is a 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 ester-ified and/or the 1-hydroxy group is oxidised to the 10 carboxylic acid and/or double bonds are hydrogenated and/or an esterified carboxy group (R1=COOH5) is hydro-lysed and/or reduced and/or a carboxy group (R5=K) is esterifled and/or a free carboxy group (R5=H) is converted into an amide (Ri=C0NHRs) or a carboxy group is 15 converted with a physiologically tolerable base into a salt.

Suitable ether radicals Rg in the compound of formula iii are those radicals familiar to the person skilled in the art. Readily removable ether radicals, such as, for 20 example, diraethyl»tert.-butylsily 1, trimethylsilyl, tribenzylsilyl, diphenyl-tert.-butvlsilyl„ tetrahydro-pvranyl, tetrahydrofuranyl and e-ethoxyethvl, to narae but a few, are preferred.

The reaction of the compound of the formula ii with an 25 organometa11ic compound of the formula iii is effected in a manner known oer in an inert solvent or solvent mixture, such as, for example, diethyl ether, tetrahydro-furan, dioxane, toluene or diraethoxyethane, preferably diethyl ether or tetrahydrofuran. The reaction is 30 carried out at temperatures of from -100"C to 60'C, preferably at from -78~C to 0"C.

The preparation of the compound of the formula III required for this reaction is effected by reacting the corresponding hydroxy halide by ether if ication %?ith dihydropyran and jp-toluanesulphonic acid and subsequent reaction with magnesium* The reduction to the compounds of the formula I in which represents a -CHjOH- group is carried out with a reducing agent suitable for the reduction of esters or carboxylic acids, such as, for example, lithiu/m aluminium hydride, diisobutylaluminium hydride, etc.. Suitable solvents are diethyl ether, tetrahydrofuran, disaethoxy-ethane, toluene, etc.. The reduction is carried out at temperatures of from -30"C up to the boiling temperature of the solvent used, preferably from o"c to 30*C.

The esterification of the alcohols of the formula I (R2 = H and/or R3 = H) is effected in a manner known oar se. For example, the esterification is carried out by reacting an acid derivative, preferably an acid halide or acid anhydride, in the presence of a base, such as, for example, sodium hydride, pyridine, triethylamine, tributylasine or 4~dimethylaminopyridine, with an alcohol of the formal a X. The reaction can be carried out without a solvent or in an inert solvent, preferably acetone, acetonitrile, dimethyl&cetamide or DKSO, at temperatures above or below room temperature, for example from -80"C to 100C, preferably at room temperature.

The oxidation of the 1-hydroxv group is carried out in accordance with methods known to the person skilled in the art. There may £hs used as oxidising agent„ for example: pyridinium dichrornate (Tetrahedron Letters, 1979, 399), Janes reagent (J„ Chera. Soc. 1953, 2555) or platinuxa/oxygen (Adv. in Carbohydrate Chen. 12, 169 (1962) or Collins oxidation and subsequent Jones oxid ation. The oxidation with pyridinium chromate is carried out at temperatures of from 0"c to 100*C„ preferably at frosTi 20"c to 40 *C, in a solvent that is inert towards the oxidising 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 3 0" C £, in acetone as solvent.

The oxidation with platinum/oxygen is carried out at temperatures of from O'C to 60"C, preferably at from 20"C to 4Q*C, in a solvent that is inert towards the oxidising agent, such as(, for example, ethyl acetate.

The hydrolysis of the esters of the formula I is carried out in accordance with methods known to the person skilled in the artp such as, for example, with basic catalysts. The compounds of the formula I can be separated into the optical isomers by customary separation methods.

The freeing of the functionally modified hydroxy groups is carried out in accordance with known methods. For example, the removal of hydroxy-protecting 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, inter alia, or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid. A water-miscible inert organic solvent is advantageously added in order to improve the solubility. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxy-efchane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The removal is preferably carried out at temperatures of frosa 20"C to 80*C. The removal of the silyl ether protecting groups is carried out, for example, with tstrabutylaramonium 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 preferably carried out 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™ Suitable alcohols are aliphatic alcohols, such as, for example, methanol, ethanol, butanol, etc., preferably methanol- Potassium and sodium salts nay be mentioned as alkali metal carbonates and hydroxides. 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 , in which Rg represents an alkyl group having from 1 to 10 carbon atoms is carried out in accordance with methods known to the person skilled in the art. The 1-carboxy compounds are reacted, for example, with diasohydro-carbons in a manner known i®. 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 30 minutes, the solvent is removed and the ester in purified in customary manner. Diaso- - 15 - alkanes are either Known or can be prepared in accordance with known methods. [Org. Reactions vol. 8, pages 389 - 394 (1954)].

The introduction of the ester group -C for Ri , in \ or5 5 which R2 represents a substituted or unsubstituted aryl group, is carried out in accordance with methods known to the parson skilled in the art. For example, the l-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiinide in the presence 10 of a suitable base, for example pyridine, DMA? or triethylamine, i.n an inert solvent. Suitable solvents are methylene chloridef ethylene chloride,, chloroform, ethyl acetate and tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures of fross -30"C to 15 +50"C, preferably at 10*C.

If C=C double bonds contained in the primary product are to be reduced, the hydrogenation is carried out in accordance with methods known oer se.

The hydrogenation of the & 8>10~diene system is carried 20 out in a manner known per se at low temperatures, preferably at approximately fro® ~20"C to +30*C, in a hydrogen atmosphere in the presence of a noble metal catalyst, h suitable catalyst is, for example, 10 % palladium-on-carbon. 2 5 The leukotriene-B4 derivatives of the formula I in which R5 represents a hydrogen atom can be converted into a salt with suitable amounts of the corresponding inorganic bases with neutralisation. For example., the solid inorganic salt is obtained by dissolving the correspond-30 ing acids in water containing the stoichiometric amount of the base, and then evaporating the water or adding a - 16 - water-miscibla solvent, for example an alcohol or acetone.

In order to prepare an amine salt, the LT-B^ acid is dissolved, for example, in a suitable solvent, for 5 example ethanol„ acetone, diethyl ether, acstonitrile or benzene, and at least the stoichiometric amount of the amine is added to the solution„ The salt is usually obtained in solid forra or is isolated in customary manner after evaporating the solvent. o // 1 o The introduction of the amide group -C-HKR^ for R^ is carried out in accordance with methods known to the person skilled in the art. The carboxylic acids of the formula I (Rg^H) are first converted with chloroformic acid isobutyl ester into the nixed anhydride in the j 5 presence of a tertiary amine, such as,, for example, triethylaraine. The reaction of the mixed anhydride with an alkali metal salt of the corresponding aside or with ammonia (RQ=H) is carried out in an inert solvent or solvent mixture, such as, for example, tetrafcydrofuran, 20 dimethoxyethane, dimethylf oriaaruide, hexamethy1phosphoric acid triamide, at temperatures of from -3C' c to -60"c, preferably at from 0"c to 30"c.

A further method of introducing the amide group —C—NHRg for consists in reacting a l-carcoxylic acid 25 of the formula I (R5=H), in which free hydroxy groups are optionally intermediately protected, with compounds of the formula iv, O = C = N - R6 (IV) wherein R6 is as defined above. - 17 - The reaction of the compound of the formula I (R5=H) with an isocyanate of the formula IV is carried out optionally with the addition of a tertiary amine, such as, for example, triethylamine or pyridine. The reaction can be 5 carried out without a solvent 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 at from 0™C to 30*c„ 10 If the starting material contains OH groups in the leukotriene-B^ radical t then those OH groups are also caused to react. If it is ultimately desired to obtain end products that contain free hydroxy groups, it is advantageous to use starting materials in which those 15 hydroxy groups are intermediately protected by preferably readily removable ether or acyl radicals.

The compounds of the formula II used as starting material can be prepared, for example, by converting in a manner known per se, 2-(hydroxymethyl)-benzyl alcohol into the 2o monosilyl ether of the formula V Oxidation, for example with pyrolusite, yields the aldehyde of the formula VI (vi) - 18 - which is converted in a wittig-Horner olefination with the phosphonate of the formula VII and a base and optionally by subsequent hydrogenation into the ester of the formula VIII in which A is as defined above. Suitable bases are, for example, potassium tert.-butoxide, diazabicyclononane or sodiu«i hydride. Reduction of the .aster group, for example with DIBAH, and subsequent oxidation of the resulting primary alcohol, for exasaple -*?ith pyrolusite or Collins reagent, yields the aldehyde of the formula IX (IX).

The organometal reaction of the aldehyde of the formula TK with a Grignard reagent of the formula X 15 X-Mg-B-D-R4 (X) wherein B, D and R4 ©re as defined above and X represents chlorine, bromine or iodine, yields, after protection of the hydroxy group (for example by acylation) the compounds of the formula XI - 19 - The preparation of the compound of the formula X required for the organometallie reaction is effected by reacting the corresponding terminal halide with magnesium. 5 Reaction of the silyl ether XI with tetrabutylammonium fluoride yields the alcohol of the formula XII B - D - R, (XII) OR, 10 The oxidation of the primary alcohol group in XII, for example with pyrolusite or Collins reagent or pyridinium dichromate„ yields the aldehyde of the formula II, The compounds of the formula I have anti-inflammatory and anti-allergic action« They also exhibit antimycotic properties. Consequently, the novel leukotriene 84 derivatives of the formula I are valuable pharmaceutical 15 active ingredients. The compounds of the formula I are especially suitable for topical administration since they exhibit a dissociation between desired topical activity and undesired systemic side effects.

The novel leukotriene B4 derivatives of the formula I 20 are suitable in combination with the excipients and carriers customary in galenical pharmacy for the local - 10 - treatment of contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, burns, tinea, pruritus vulvae et ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruber planus et verrucosus 5 and similar skin diseases.

The medicament specialities are prepared in custoraary manner by converting the active ingredients with suitable additives into the desired forms of administration, such as, for example: solutions, lotions, ointments, creams or 10 plasters. In the medicaments so formulated, the active ingredient concentration 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. 15 m addition, the novel compounds are also very suitable, optionally in combination with the customary carriers and excipients, for the preparation of inhalation agents which, can be used for the treatment of allergic disorders of the'respiratory system, such as, for example, bron-20 chial asthma or rhinitis.

The novel leukotriene-B4 derivatives are also suitable in the form of capsules, tablets or dragees that preferably contain from 0.1 to 100 mg of active ingredient or are administered orally, or in the form of suspensions that 25 contain preferably from 1 to 200 mg of active ingredient per unit dose and are administered rectally, for the treatment of allergic disorders of the intestinal tract, such as colitis ulcerosa or colitis granulomatosa.

The novel leukotriene-B^ derivatives can also be used in 30 combination, such as, for example, with lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonists, leukotriene-D^, antag- - 21 - onists, leukotriene-E4 antagonists, leukotriene-F4 antagonists, phosphodiesterase inhibitors or PAF antagonists .

The compounds of this invention can be administered, for 5 example, analogously to the known anti-inflammatory and anti-allergic active ingredient dexamethasone, a glucocorticoid. A typical dose used systemically for the mentioned indications would be from 0.1 to 50 mg/kg/day or, in the case of topical administration, from 1 to 10 10 times per day in conventional formulations already mentioned above. A particular dosage for a specific indication, patient and cosapound can be determined as a matter of routine, for example by using the standard pharmaceutical instructions in conjunction with the 15 standard protocol described in "Models in Dermatology, 1987, ed. A.J. Haibach, N.J. Lowe, Karger, Basis™- The dosage range for inhalation agents is from 0.01 to 5 mg/kg/dav.

Whether a compound acts as an antagonist, as an agonist 2 0 or as a partial antagonist can be determined in each case as a matter of routine by using a conventional pharmacological protocol which measures 1. the ability of a compound to act reciprocally with LTB4-receptors (Methods in Ensymology 163. 1988, 25 pages 340-344) or 2. the ability of the compound to increase or inhibit the LTB^-induced chemotaxis of white blood cells in vitro (Methods in Ensymologv 162, 1988, pages 38-50). 30 Thus,, all compounds of this invention bind to the ltb4 receptor and exhibit in vitro in a functional test, such as chemotaxis, antagonistic, agonistic or partially - 22 - antagonistic functions.

Antagonists are useful in skin diseases that involve inflammatory processes (increased vascular permeability and oedema formation, call infiltration) , increased 5 proliferation of the skin cells and itching, such as, for example, in the case of eczemas, erythemas, psoriasis, pruritus, acne and ulcerative colitis and asthmatic pulmonary diseases. Agonistic compounds are potentially useful in the treatment of diseases in which the support 10 of the physiological defence mechanism is helpful, for example in the case of fungal diseases of the skin. Partial antagonists can be defined in accordance with Terence P. Kenakin: Pharmacologic Analysis of Drug-Receptor Interactions, 1987, Raven Press.

I 5 An example of an agonist is, for example: OH Examples of antagonists are, for example: OAC OH CK Example 1 (1RS1—l-f 2-((15,3E)-(5RS)-5-acetoxv-l,3-tridecadianvl)-ohanvl l-l-acetoxv~5-Dentanol A solution of 4 g of 4~chloro-l-tetrahydropyranyloxy-butane in 4 nsl of tatrahydrofuran and 0.125 of dibromo-mathane is added dropwise at 25*C under argon to SSO mg of magnesium- The who la is heated for 5 minutes at 70 "c, stirred for 30 xainutes at 25"c and. diluted with 12-5 ml of tatrahydrofuran.

A solution of 1.5 g of 2~((IE,3E)~(5RS) -5-acatoxy-i , 3~ tridecadieny 1) -benzaldehyde in 15 sal of tetrahy rof uran is added dropwise at -70"c under argon to 10 ml of that organomagnssium solution and the whole is stirred for 2 hours at -70 *C. 50 ml of saturated ammonium chloride solution are added and the ■whole is extracted three times with ether. The organic phase is shaken with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residua is chromatographed on silica gel. Using hexane/ethyl acetate (6+4), 2.9 g of (1RS)-1~(2-((IE, 3E)-(5RS)-5-acetoxy-l,3-tridecadienyl)-phenyl]~l-hydroxy-5-tetrahydropyranyloxypentane are obtained in the form of a colourless oil.

IR (CHC13): 3600, 3450, 2930, 2860, 1727, 1245, 988 cm"1.

For the purpose of acetylation, 5 ml of acetic anhydride are added to a solution of 2.7 g of the alcohol described above in 10 sal of pyridine and the whole is stirred for 16 hours at 24"C. It is than concentrated ifl vacuo with the addition of toluene and the residua is chrowsato-graphed on silica gel. Using hexane/ethyl acetate (44-1), 2.4 q of the acetate are obtained in the form of a colourless oil.

IR; 2930, 2860 „ 1729, 1245, 989 cm"1. - 2\ - In order to remove the protecting groups, 2»3 g of the acetate prepared above are stirred with 50 ral of a mixture of acetic acid/wEter/tetrahydrofuran (65+35+10) for 20 hours at 25"C«, The whole is then concentrated with the addition of toluene and the residue is chromato-graphed on silica gel- Using hexane/ethyl acetate (44-6), 1.1 g of the title compound are obtained in the form of a colourless oil. 0.5 g of (lRS)-l-(2-((lE,3E)~(5RS)-5-hvdroxy-1,3-tridecadienyl) -phenyl ]~l-acetoxy-5™pantanol is also eluted as the more polar secondary component. IR of the title compound: 3610, 3450, 2930, 2859, 1730, 1245, 988 CM™1.

The starting material for the above title compound is prepared as followss la) 5~f 2-tert.-butvldimethvlsilvloxvmethvl)-ohenvl 1-f2E.4E^-oentadienoic acid ethvl ester 22.16 g of tert.-butyldisnethylsilvl chloride are added at 0" C under argon to a solution of 20 g of 2-hydroxymethyl~ benzyl alcohol and 20 g of imidazole in 170 ml of dimethyl formamide and the whole is stirred for 16 hours at 2 5" C. It is diluted with 1.6 litres of ether, shaken twice with 100 ml of 10 % sulphuric acid each time, washed neutral with brine, dried over magnesium sulphate and concentrated by evaporation vacuo. The residue is chromatographed on silica gel. Using hexane/ether (6+4), 17 g of 2-fcert.-butyldim IR: 3600, 3450 f 2953, 2930t, 2860, 835 cm"1. 45 g of pyrolusite are added to a solution of 16.3 g of the silyl ether prepared above in 250 nl of methylene chloride and the whole is stirred for 5 hours at 25"c. It - 25 - is then filtered, concentrated by evaporation and chroraatographed on silica gel. Using hexane/ether (6 + 4), 15 g of 2-tert.-butyldimethyIsilyloxymethylbensaldehyde are obtained in the form of a colourless oil.

IR: 2958, 2930, 2859, 1692, 1600, 1572, 836 cm"1.

For the purpose of Wittig-Horner olefination, 6.4 g of potassium tert.-butoxide ara added at -20°C to a solution of 15 g of phosphonocrotonic acid triethvl ester and the whole is stirred for 30 minutes at -20"C„ A solution of 15 g of 2-tert--butyldimethylsilyloxvmethylbenzaldehyde is then added dropwise to the resulting solution and the whole is stirred for 1 hour at -20™C„ It is then poured onto 200 nil of ice-water and extracted three times with 200 ml of ether each time, and the organic phase is washed neutral with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ether (6+4), 15.4 g of the title compound are obtained in the form of a colourless oil.

IR: 2958, 2930, 2858, 1700, 1627, 1255, 998, 838 cm"1. lb) l~f 2-i'tert.-butvldimethvlsilvloxvrasthvl)-ahenvl }-(IS.3E1-aantadien-5-al 84 ml of an approximately 1.2 molar solution of diiso-butylaluninium hydride in toluene are added dropwise at -70°C under argon to a solution of 17.5 g of the ester prepared in accordance with Example la in 4 00 ml of toluene and the whole is stirred for 3 0 minutes at -70"C„ 30 ml of isopropanol and than 40 ml of water are then added dropwise. 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 hexane/- - 26 - ethyl acetate (4-5-6), 11.9 g of 1- [ 2 - ('cert - -butyIdimethy1-silyloxymethyl)-phenyl]-(IE,3E)-pentadien-5-ol are obtained in the form of a colourless oil.

IR: 3610, 3450, 2958, 2930, 1255, 990, 838 cm"1. 40 g of pyrolusite are added to a solution of 8.5 g of the alcohol prepared above in 250 ml of methylene chloride and the whole is stirred for 4 hours at 25°C. It is then filtered, concentrated by evaporation and chromatographed on silica gel. Using hexane/ethvl acetate (8+2), 7 g of the title compound are eluted in the form of a colourless oil.

IR: 2958, 2930, 28S0, 2741, 1675, 1620, 1600, 985, 838 cm*"1. lc) 5~acetoxv-l-f 2-f tert. -butvldirriethvlsilvloxvmethvl )-phenvl1-CIE,35 ^ ~tridecadiene A solution of 7.95 ml of octvl bromide in 12 ml of ether is added dropwise, with heating, to 1.12 g of magnesium in 5 ml* of ether. A solution of 6.2 (= 20.5 mM) of the aldehyde prepared in accordance with Example lb in 100 ml of ether is added dropwise at -20 *C under argon to 12 ml (= 22.8 mM) of this Grignard solution and the whole is stirred for 2 hours at -20°c. 60 ml of saturated ammonium chloride solution are added, the whole is extracted three times with ether, 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 hexane/ethvl acetate (6+4), 6.5 g of 5-hydroxy-l~[2-(tert.-butyIdiraethyIsilyloxymethvl)-phenyl)-(IE,3E) ™cridecadiene are eluted in the form of a colourless oil, IR: 3610, 3450, 2930, 2860, 989, 839 cm"1.

For the purpose of acetylation, 12 ml of acetic anhydride - 27 - are added to a solution of 6=4 g of the alcohol prepared above in 25 ml of pyridine and the whole is stirred for 16 hours at 24"C. It is then concentrated in vacuo with the addition of toluene and the residue is chromato-5 graphed on silica gel. Using hexane/ether (8+2), 6.2 g of the title compound are aluted in the form of a colourless oil.

IR: 2930, 2858, 1726, 1250, 887, 838 CTa"1.

Id) 2~((IE-3ET-f 5RS>-5-acetoxv~l.3-tridecadienvl)- 10 bensaldehvde 12.3 g of tetrabutylammonium fluoride are added at 0"C to a solution of 6.1 g of the acetate prepared in accordance with Example 1c in 400 ml of tetrahydrofuran. The whole is stirred for 0.5 hour at 0"'C and. for 3 hours '5 at 24"c. It is then diluted with 400 ml of ether and shaken three times with 200 sal of brine each time, and. the organic phase is dried aver magnesium sulphate and concentrated by evaporation in vacuo - The residue is chromatographed on silica gel. Using hexane/ethyl acetate 2o (6+4), 4.5 g of the benzyl alcohol are eluted in the form of a colourless oil.

IR: 3600, 2925, 2855, 1725, 1255, 988 cm"1. 8 g of pyrolusite are added to a solution of 2.3 g of the benzyl alcohol prepared above in 60 ml of methylene 25 chloride and the whole is stirred for 4 hours at 24"c. It is then filtered, washed with methylene chloride and concentrated by evaporation is vacuo. The residue is chromatographed with hexane/ethyl acetate (4+1) on silica gel. 2.2 g of the title compound are obtained in 30 the for® of a colourless oil.

IR: 2925, 2855, 2740, 1728, 1695, 1598, 1255, 988 cm"1.

Example 2 (5RS)-5-acetoxy-5~f2~fIE.3E W5RS)-5-acetoxy-l,3-trideca-ciienvl) -phenyl 1-pentanoic acid A solution of 0.85 g of (IRS)—1—[2—((lE,3E)-(5RS)-5~ acetoxv-1,3-tridecadienyl)-phenyl]-l-acetoxy-5-pentanol (prepared in accordance with Example 1) in 25 ml of methylene chloride is added dropwise at o'c, with stirring, to a mixture of 3.3 g of Collins reagent (chromic acid-pvridine complex) in 25 ml of methylene chloride and the whole is stirred for 30 minutes at o'c. It is then diluted with a mixture of hexane/ether (2*1), filtered over Celite and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel.

Using hexane/ethyl acetate (4H-1), 650 rag of (IRS)~1™[ 2™ ((IE,3E)-(5RS)-5-acetoxy~l,3-tridecadienyl)-phenyl]-l~ acetoxy-5-pentanal are obtained in the form of a colourless oil.

IR: 2930, 2860, 2730, 1727, 1245, 988 cm"1. 1 ml of Jones reagent (J. Chem. Soc. 1953. 2555) is added dropwise, with stirring, at -20°C to a solution of 600 mg of the aldehyde prepared above in 20 ml of acetone and the whole is stirred for 10 minutes at -20*C. 5 ml of isopropanol are then added, the whole is stirred for 10 minutes, diluted with 50 ml of ether, filtered and washed with ether, and the ether phase is shaken twice with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using hexane/ethyl acetate (54-4), 545 mg of the title compound are obtained in the forru of a colourless oil.

IE: 3520 (broad), 1728, 1245, 988 cm"1. - 29 - Example. 3 (IRSLtirJ,2-( (IE, 3E) -f 5RS ) -5-hvdroKy-i . 3-tridecadienvl) -ohenvl l-»l5-oentanadiol 4,6 ml of a 0.5M sodium hydroxide solution are added at 24"C to a solution of 190 mg of (IRS)-l-[2-((IE,3E)- (5RS)-5-hydroxy-1,3-tridecadienyl)-phenyl]-l-acetoxy-5-pentanol (prepared in Example l) in 4.5 il of methanol and the whole is stirred for 30 minutes at 24"C under argon. It is than diluted with 10 ml of water, acidified to pH 5-6 with 10 % citric acid solution and extracted four times with 30 ml of ethyl acetate each time. The organic phase is shaken with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed or silica gel. Using ethyl acetate/hexane (4+1), 113 mg of the title compound are obtained in the form of a colourless oil.

IR" 3610, 3450, 2930, 2860, 988 cm"1.

Example 4 (5RS)-5^acetoxv-5"r2-f5RS)-5-acetoxvtridecanvl)-ohenvl 1-pentanoic acid 15 mg of 10 % palladium-on-carbon are added to a solution of 150 mg of (5RS)-5-acefcoxy-5~[2-(lE,3E)-(5RS) -S'-acetoxy-l, 3-tridecadienyl)-phenyl ]-pentanoic acid in 5 ml of ethyl acetate and the suspension is shaken for 3 hours at 24"C under a hydrogen atmosphere.. The whole is then filtered and concentrated by evaporation ia vacuo. The residue is chromatographed on silica gel to yield, in addition to non-polar, secondary products, 91 mg of the title compound in the form of a colourless oil.

IR: 3510 (broad), ,2930, 2860, 1727, 1250 cm"1. - 30 - Example _5 r 5RS)-5-hydroxv-5-f2 — ( f5RS)~5-hvdroxvtridecanyl)-phenyl]-pentanoic acid t 0.27 ml of a 0.5N sodium hydroxide solution is added at 5 24*C to a solution of 13 mg of the hydrogenation product prepared in accordance with Example 5 in 0.27 ml of methanol and the whole is stirred for 16 hours at 24 °C under argon. It is then diluted with 2 ml of water, acidified to pH 4 at O'c with 10 % citric acid solution, 10 and extracted three times with methylene chloride™ The organic extract is shaken with brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel. Using ethyl acetate/hexane (4+1), g mg of the title compound 15 are eluted in the form of a colourless oil.

IR: 3500 (broad), 2928, 2559, 1710 cm"1.

Example 6 ( 5RS ) -5~acetoxy~5--r 2~( IE. 3E1 -( 5RS) ~5~acetoxy~l, 3-trideca-dienvlV-ahenvl1-oentanoic acid methvl ester 20 An ethereal diasomethane solution is added dropwise at O'C to a solution of 120 mg of the acid prepared in accordance with Example 2 in 6 ml of methylene chloride until the colour remains yellow and the whole is stirred for 15 minutes at O'C. It is then concentrated by 25 evaporation in vacuo and the residue is chromatographed on silica gel. Using hexane/ethyl acetate (9*1), 103 mg of the title compound are obtained in the form of a colourless oil. f IR : 2930, 2858, 1735, 1245, 988 cm"1. - 31 - Example 7 £5RS)~5-acetoxv-5-f 2-(5RS)-5-acetoxvtridecanvl)-pheny1 pantanoic acid methyl ester An ethereal diazomethane solution is added dropwise at 5 O^C to a solution of 43 jaq of the acid prepared in accordance with Example 5 in 3 ral of methylene chloride until the colour remains yellow and the whole is stirred for 15 minutes at q"c, It is then concentrated by evaporation in vacuo and the residue is chromatographed 10 on silica gel. Using hexane/ethyl acetate (9+1), 33 mg of the title compound are obtained in the form of a colourless oil.

IR- 2929, 2858, 1736, 1250 cm"1.

Example 8 15 (5RS)-5-hvdroxv~5-f2-f(5RS T-5-hvdroxvtridecanvl)-ohenvl1- pentanoic acid methvl ester An ethereal diazomethane solution is added dropwise at 0*C to -a solution of 19 mg of the acid prepared in accordance with Example 6 in 2 ml of methylene chloride 20 until the colour remains yellow and the whole is stirred for 15 minutes at 0"C. It is then concentrated by evaporation in vacuo and the residue is chromatographed on silica gel. Using hexane/ethyl acetate (3+2), 16 lag of the title compound ara obtained in th© form of a colour-25 less oil.

IR: 3590 f 2928, 2560, 1735 cm"1.

Example 9 (5RS)-5-benzovloxv-5-f2-f fIE,3E)-(5RS^-S-benzovIoxv-l„3-tridecadienvl)-phenvl1-pentanoic acid methvl ester 30 170 Big off bensoyl chloride are added at 24 "C to a solution of 190 lag of the methyl ester prepared in accordance with Example 8 in 3 ml of pyridine and the whole is stirred for 16 hours at 2 4 ° C« 0.3 mi of water is then added and the whole is stirred for 2 hours, diluted with ether and shaken in succession with water, 5 % sulphuric acid, water, 4 % sodium hydrogen carbonate solution and water. The whole is dried over magnesium sulphate and concentrated by evaporation in vacuo and the residue is chromatographed on silica gel. Using hexane/-ethyl acetate (9+1), 185 mg of the title compound are obtained in the form of a colourless oil.

IR: 2930. 2860, 1733. 1250. 988 cm"1.

Claims (6)

- 33 - Patent Claims

1. Leucotriene-B^ derivatives of the formula I OR I (I) 'U OR therein 5 RL 10 15

2. 0 A B represents the radical CH2OH; the radical coor5 in which R5 represents a hydrogen atom, an alkyl radical having from 1 to 10 carbon atoms, a cvclo-alkyl radical having from 3 to 10 carbon atoms, an aryl radical having from 6 to 10 carbon atoms that is optionally mono- to tri-substituted by chlorine, bromine, phenyl, alkyl having from 1 to 4 carbon atoms, chloromethyl, fluoromethyl, trifluoromethyl, carboxy, Ci~C4-alkoxy or by hydroxy, a -ch2~-CO~aryl radical having from 6 to 10 carbon atoms for aryl, or a 5™ or 6~membered heterocyclic radical having at least one hetero atom; or Ri represents the radical COHHR5, in °#mich R6 represents an alkanoyl or alkanesulphonyl radical having from l to 10 carbon atoms or the radical R5, represents a trans. trans~CH=Cl-I-CH=CH~ or tetra-methylene group, represents a straight-chain or branched-chain saturated or unsaturated alkylene group having up to 10 carbon atoms that may optionally be substituted by fluorine, or represents the group -C-CH2- - 34 - in which n = 1, 2 or 3, D represents a direct bond, oxygen, sulphur, a -C=C-group or a -CH=CR7- group in which R7 represents hydrogen, C^-Cs-alkyl, chlorine or bromine, 5 B and D together represent a direct bond, R2 and R3 may be identical or different and represent a hydrogen atom or an acid radical of an organic acid having from 1 to 15 carbon atoms and r4 represents a hydrogen atom, an alkyl radical having 10 from 1 to 10 carbon atoms, a cycloalkvl radical having fro® 3 to 10 carbon atoms, an aryl radical having from 5 to 10 carbon atoms that is optionally ro.ono- or di-substituted by chlorine, bromine,, phenyl, alkyl having from 1 to 4 carbon atoms, 15 chloromethyl, fluoromethyl, trifluoromethyl„ carboxy, C^-C^-alkoxy or by hydroxy, or represents a 5- or 6-membered heterocyclic radical having at least one hetero atom, and, if R5 represents a hydrogen atom, the salts thereof 20 «ith physiologically tolerable bases and the cyclodextrin clathrates thereof, with the proviso that R2 and R3 do not each represent hydrogen when A represents trans. trans-CH=CH~CH=CH- and represents the radical -coor5 or -CONHR6 „ 25 2. Process for the preparation of leucotriene-B^ derivatives of the formula i, characterised in that a benzaldehyde of the formula II, - 35 - wherein k, 8, D„ R3 and R4 are as defined above, is reacted, optionally after protecting free hydroxy groups, with an organoraagnesium compound of the formula III X-Hg-CH2-CH2-CH2-CH2-0-R8 (III), 5 wherein X is chlorine,, bromine or iodine and Rg is a 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 esterif ied and/or the 1-hydroxy group is oxidised to the 10 carboxylic acid and/or double bonds are ftydrogenated and/or an esterified carboxy group (Rj^CGORg) is hydro-lysed and/or reduced and/or a carboxy group (R5-H) is esterified and/or a free carboxy group (R5=H) is converted into an asside (Ri=CQKHRg) or a carboxy group is 15 converted with a physiologically tolerable base into a salt.

3. Medicament comprising one or more compounds according to'claim 1 and customary excipients and carriers,

4. A compound substantially as hereinbefore described with 20 reference co the Examples.

5. A process substantially as hereinbefore described with reference to the Examples.

6. A medicament substantially as hereinbefore described with reference to the Examples. 35a - Dated this 19th day of May 1989 CRUICKSHANK & CO. Agents for the Applicant 1 Holies Street Dublin 2