WO1998052912A2 - Leukotriene b4 antagonists, in particular 3-carba-tetrahydronaphthalene-ltb4 antagonists - Google Patents

Abstract

The invention relates to leukotriene B4 antagonists of formula (I), a method for the production and the pharmaceutical use thereof.

Description

 Leukotriene B4 antagonists, especially 3-carba-

Tetrahydronaphthalene LTB4 antagonists

The invention relates to new leukotriene B4 antagonists, processes for their

Manufacture and its use as a medicine. The new compounds are structural analogs of previously known leukotriene B4 antagonists, the one

Six-ring included as a basic structural element (DE-A 39 17 597, DE-A 42 27 790, DE 42 42 390).

Lipoxygenase

Arachidonic acid 5-HPETE

Leukotπen A ₄ (LTA ₄ )

Glutathione

Hydrolase S-transferase

Leukotπen B ₄ (LTB ₄ ) Leukotπen C ₄ (LTC ₄ )

Leukotriene B4 (LTB4) was discovered by B. Samuelsson and co-workers as a metabolite of arachidonic acid. In biosynthesis, the enzyme 5-lipoxygenase initially turns the leukotriene A4 as the central intermediate formed, which is then converted into the LTB4 by a specific hydrolase

The nomenclature of the leukotene can be found in the following work 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 summarized in some recent work

Leukotnenes, Chemistry and Biology eds LW Chaknn, DM Bailey, Academic Press 1984 b) JW Gillard et al, Drugs of the Future _ \ 2, 453 (1987) c) B Samuelsson et al, Science 237, 1171 .1987) d) CW Parker, Drug Development Research 1_0, 277 (1987), e) WR Henderscn Annais of Interna 'Medicine _ ^ 21_, 684 (1994) It follows that LTB4 is an important one

Inflammation mediator for inflammatory diseases is in which leukocytes migrate into the diseased tissue

The effects of LTB4 are triggered at the cellular level by binding LTB4 to a specific receptor

LTB4 is known to adhere leukocytes to the

Blood vessel wall causes LTB4 is chemotactically effective, ie it triggers a directed migration of leukocytes towards a gradient of increasing concentration.In addition, due to its chemotactic activity, it indirectly changes vascular permeability, whereby synergism with prostaglandin E2 is observed. LTB4 obviously plays in inflammatory, allergic and immunological processes play a crucial role

Leukotnene and especially LTB4 are involved in skin diseases that are associated with inflammatory processes (increased vascular permeability and edema, cell infiltration), increased propheration of skin cells and itching, such as eczema, erythema, psonasis, pruπtis and acne the formation of many dermatids is either causally involved, or there is a connection between the persistence of the dermatids and the leukotnenes clearly Increased leukote concentrations were measured, for example, in the skin of patients with psoasis or atopic dermatitis, allergic contact dermatitis, bullous pemphigoids, delayed pressure urticana and allergic vasculitis. Leukotenes and in particular LTB4 are also involved in diseases of internal organs for which an acute or chronic inflammatory component has been described. e.g. joint diseases (rheumatoid arthritis), diseases of the respiratory tract (asthma and chronic obstructive pulmonary diseases (OPD)), inflammatory bowel diseases (ulcerative colitis and Crohn's disease), as well as reperfusion damage (to cardiac, intestinal or kidney tissues), which can be caused by intermittent pathological occlusion of blood vessels such as glomerulonephπtis NSAID, gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases. Leukotnenes and especially LTB4 are also involved in the disease in multiple sclerosis and in the clinical appearance of the shock (triggered by infections, burns or complications in kidney dialysis or other perfusion techniques discussed separately) leukotne and especially LTB4 continue to have an impact on the

Formation of white blood cells in the bone marrow, on the growth of smooth muscle cells, keratinocytes and B-lymphocytes LTB4 is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells. Diseases with this appearance represent, for example, leukemia or Atherosclerosis, especially leukotne, and in particular LTB4 and derivatives, are suitable for lowering high levels of Tπglyceride and are therefore antiartherosclerotic and against obesity

By antagonizing the effects of LTB4 in particular, the

Active substances and their forms of administration of this invention are specific remedies for the disease of humans and animals, in which leukotnene in particular play a pathological role In addition to therapeutic options that can be derived from an antagonization of the LTB4 effect with LTB4 analogues, the usefulness and potential use of leukotriene B4 agonists for the treatment of

Fungal diseases of the skin are shown (H. Katayama, Prostaglandins 34, 797 (1988)).

The invention relates to leukothen B4 antagonists of the formula I

wherein

Rl CH ₂ OH, COOR ₄ or CONR ₅ R ₆ ,

R2 represents H or an organic acid residue with 1-15 C atoms,

R3 H, optionally mono- or polysubstituted C 1 -C 14 -alkyl, C 3 -C 12 -cycloalkyl, optionally independently of one another singly or multiply by halogen, phenyl, C 1 -C 4 -alkyl, C 1 -C 4 4-alkoxy, fluoromethyl,

Chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy substituted CQ-

Cι o ~ A.rylrest or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom symbolize, R4 H, C- | -C-ιo-alkyl, C3-C-ιo-cycloalkyl, optionally by 1-3 halogen,

Phenyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl,

Carboxyl or hydroxy substituted C -C -oo-aryl radical, CH2-CO- (C6-C-jo) aryl or a 5-6-membered aromatic heterocyclic ring with at least 1 hetero atom, B is a C- | -C- | og ^er ad - or branched chain alkylene group which may optionally be substituted by fluorine or the group

symbolizes

D can mean a direct bond, oxygen, sulfur, -CüC-, -CH = CRy, or together with B also a direct bond,

Y is an optionally mono- or polysubstituted C-i-Cg-alkyl, C3-

Ci Q-cycloalkyl, optionally substituted by aryl,

R5 and Rg are the same or different and H or optionally by

C 1 -C 4 -alkyl or R H and R 5 are C 1 -C 15 -alkanoyl or R8SO2- which are optionally substituted with OH,

R7 H, C ^< | Is -C5-alkyl, chlorine or bromine,

Rß has the same meaning as R3, m is 1-3, n is 2-5 and, if R4 is hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.

The group OR ₂ can be α or β. Formula I includes both racemates and the possible pure diastereomers and enantiomers.

Suitable alkyl groups R4 are straight-chain or branched-chain alkyl groups having 1 to 10 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl. The alkyl groups R4 can optionally be mono- to polysubstituted by halogen atoms, alkoxy groups, optionally substituted aryl or

Aroyl groups with 6-10 C atoms (for possible substituents see under Aryl R4), dialkylamino and trialkylammonium with 1-4 C atoms in the alkyl

Part, the simple substitution should be preferred. Examples of substituents are fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. Preferred alkyl groups R4 are those with

To call 1-4 carbon atoms. The cycloalkyl group R4 can be in the ring 3-10, preferably 5 and 6

Contain carbon atoms. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl and methylcyclohexyl.

Aryl groups R4 include both substituted and unsubstituted ones

Aryl groups with 6-10 C atoms, such as phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups each 1-4 C atoms, a chloromethyl, a fluoromethyl, trifluoromethyl, carboxyl, hydroxyl or alkoxy group with 1-4 C atoms. Preferred substituents in the 3- and 4-positions on the phenyl ring are, for example, fluorine, chlorine, alkoxy or trifluoromethyl, while in the 4-position hydroxyl.

The heterocyclic groups R4 are 5- and 6-membered aromatic

Heterocycles in question, which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyhdyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl and the like. a.

R5 acid residues are those of physiologically tolerated acids

Question. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. Examples of the substituents are C1-.4-

Alkyl, hydroxy, Cι_4 alkoxy, oxo or amino groups or halogen atoms (F,

Cl, Br) mentioned. Examples include the following carboxylic acids: 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, pentadecyl acid tπmethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid,

Cyclohexylessigsaure, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid phenylacetic acid, phenoxyacetic acid, Methoxyessigsaure, Ethoxyessigsaure, mono-, di- and Tπchloressigsaure, Aminoessigsaure, Diethylaminoessigsaure Pipendinoessigsaure, Morpholinoessigsaure, lactic acid, succinic acid, adipic acid, benzoic acid with halogen (F, Cl, Br) or trifluoromethyl, hydroxy , -C-4-alkoxy or carboxy groups substituted benzoic acids,

Nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. Preferred arylsulfonyl radicals and alkanesulfonyl radicals RgSθ2- are those which are derived from a sulfonic acid with up to 10 carbon atoms

Benzenesulfonic acid, p-toloisoisonic acid, p-chlorobenzenesulfonic acid, N, N-dimethylaminosulfonic acid, N, N-Dιιsobutylamιnosufonsaure, N, N-Dι-butylaminosulfonic acid, pyrrolidomo- pipendino-, piperazino-, M- and methyl-piperino-inp and M- methylpiperino

Suitable alkyl groups R3 are straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-14, in particular 1-10 C atoms, which may be substituted by optionally substituted phenyl (substitution s under aryl R5), for example May be mentioned methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl,

Hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyi, m and p-chlorobenzyl groups. If the alkyl groups R3 are halogen-substituted, halogen, fluorine, chlorine and bromine are suitable

Examples of halogen-substituted alkyl groups R3 are alkyls with terminal tπfluoromethyl groups

The cycloalkyl group R3 can contain 3-10, preferably 3-6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 Carbon atoms may be substituted by halogens. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, fluorocyclohexyl.

5 Examples of substituted or unsubstituted aryl groups R3 include

Consideration: phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1 -3 alkyl groups, each with 1-4 C atoms, a chloromethyl, fluoromethyl -, trifluoromethyl, carboxyl, C1 -C4 alkoxy or hydroxy group. The is preferred

10 Substitution in the 3- and 4-position on the phenyl ng, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.

The heterocyclic aromatic groups R3 are 5- and 6-glιedrιge

Heterocycles in question, which contain at least 1 heteroatom, preferably nitrogen, 15 oxygen or sulfur. Examples include 2-furyl, 1-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, and the like. a.

Suitable alkylene groups B are straight-chain or branched, saturated or unsaturated alkylene radicals, preferably saturated ones with 1-10, in particular with 1-5, carbon atoms, which can optionally be substituted by fluorine atoms. Examples include: methylene, fluoromethylene, difluoromethylene, ethylene, 1, 2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1, 2-difluoroethylene, 1-fluoroethylene, 1-25 methyltetramethylene, 1-methyl-tri-methylene, 1 -Methylene-ethylene, 1 -Methylene tetramethylene. The alkylene group B can also be the group

- C— CH, - or -CH— C / \ / \ (CH ₂ ) _n (CH ₂ )

represent, where n = 2-5, preferably 3-5. Possible acid residues R2 are those of physiologically acceptable acid residues. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the ahphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and / or to be polybasic and / or to be substituted in the usual way. Examples of the substituents are C 4 alkyl, hydroxy, C 4 alkoxy, oxo or amino groups or

Halogen atoms (F, Cl, Br) are mentioned, for example, the following carboxylic acids are formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid,

Valenanoic acid, isovaleπansaure, capronic acid, onanthic acid, caprylic acid,

Pelargonic acid, capric acid, undecyl acid, lauπnsaure tridecyl acid

Myπstinsaure, Pentadecylsaure, Tπmethylessigsaure, Diethylessigsaure, tert -

Butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid.Cyclohexane carboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and

Trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid,

Pipe dinoacetic acid, morpholmoacetic acid, lactic acid, succinic acid,

Adipic acid, benzoic acid with halogen (F, Cl, Br) or trifluoromethyl, hydroxy, C _j _4-alkoxy or carboxy-group-substituted benzoic acids,

Nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid As preferred acid residues R2 and R3 such acyl residues with up to 10

Considered carbon atoms

The alkyl radicals R5 and Rß, which optionally contain hydroxyl groups, are straight-chain or branched alkyl radicals, in particular straight-chain, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, particularly preferably methyl

R7 as C- | _5-alkyl means straight-chain or branched-chain alkyl radicals as have already been mentioned for R3 or R4. Preferred alkyl radicals R7 are methyl, ethyl, propyl and isopropyl Inorganic and organic bases are suitable for salt formation, as are known to the person skilled in the art for the formation of physiologically contractual salts. Examples include alkali hydroxides such as sodium and potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, wet nurse such as ethanolamine, diethanolamine, ethanolamine, N-methylglucamine, morpho n, Tπs- (hydroxymethyl) -methylamine, etc

In order to obtain the cyclodextrin clathrates, the compounds of the formula I are reacted with α-, β- or γ-cyclodextrin. Β-Cyclodextine derivatives are preferred

Preferred compounds of the present invention are compounds of the general formula I, the radicals having the following meaning

5 R- | is CH2OH, CONRsRß, COOR4 with R4 in the meaning of a

Hydrogen atom, an alkyl radical with 1-10 C atoms, a cycloalkyl radical with 5-6 C atoms, one optionally with 1-2 chlorine, bromine, phenyl, C-1.4-

Alkyl, C- | _4-alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or

Hydroxy substituted phenyl radical 0 Y is a methyl group m is 1-3

B is a straight-chain or branched-chain saturated or unsaturated alkylene group with up to 10 C atoms, which can optionally be substituted by fluorine, or the group -1

D is a direct compound, oxygen, sulfur, a -C≡C group or a - CH = CR7 group with R7 as hydrogen, Cj.ß-alkyl, chlorine or bromine, 0 B and D together are a direct bond, R2 means hydrogen or an organic acid residue with 1-15 C-

Atoms,

R5 and Rß have the meanings given above,

R3 is a hydrogen atom, C- _| _ιn-alkyl, cycloalkyl with 5-6 C-atoms, optionally by 1-2 chlorine, bromine, phenyl, C- | _4-alkyl, C-ι_4-alkoxy,

Chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy substituted

Phenyl radical and if

R4 means hydrogen, the salts of which are physiologically compatible with

Bases and cyclodextrin clathrates

Particularly preferred compounds of the present invention are compounds of the general formula I, where the radicals have the following meaning

R- | is CH2OH, CONRsRß, COOR4 with R4 in the meaning of a hydrogen atom, an alkyl radical with 1-4 carbon atoms

R2 means hydrogen or an organic acid residue with 1-6 C atoms, R3 is a hydrogen atom or Cι_- | n-alkyl, R5 and Rß have the meanings given above,

B is a straight-chain or branched-chain alkyl group with up to 5 carbon atoms or the group

D is a direct compound or a -C≡C group or a -CH = CR7 group with R7 as hydrogen or C- | _5-alkyl,

Y is a methyl group

B and D are a direct link together, and if R4 represents a hydrogen atom, its salts with physiologically compatible bases and its cyclodextrin clathrates

The invention also relates to a process for the preparation of the compounds of the general formula I according to the invention, which is characterized in that an aldehyde of the formula II,

wherein Y and m have the meaning given above, if appropriate after protecting free hydroxyl groups with an olefin reagent of the general formula III,

in which B, D and R3 have the meanings given above and Rg preferably denotes an alkyl group having 1-5 C atoms, methyl and ethyl are preferably reacted in the presence of a base and the resulting keto function is reduced and, if appropriate, subsequently separating isomers in any order, protects free hydroxyl groups and / or releases protected hydroxyl groups and / or oxidizes the 1-hydroxy group to carboxylic acid and / or esterifies a carboxyl group and / or converts a free carboxyl group into an amide or converts a carboxyl group with a physiologically acceptable base into a salt

The reaction of the compound of the general formula II with an olefining reagent of the general formula III is carried out at from -80 ° C. to 100 ° C., preferably from -20 ° C. to 80 ° C. in an aprotic Solvent or solvent mixture, for example tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethyl sulfoxide in the presence of a base. The bases used are, for example, sodium hydride, methensulfinylmethylnatnum, potassium tert-butoxide, lithium diisopropylamide, 1,5-diazabyclo [4 3 0] non-5-ene and DB-en in question

The subsequent reduction is carried out using a reducing agent suitable for the reduction of ketones, such as, for example, diisobutylaluminium hydride, zinc borohydride or sodium borohydride, preferably in the presence of cerium trichloride, etc. Diethyl ether, tetrahydrofuran or methanol or mixtures of these solvents are suitable as solvents. The reduction is carried out at temperatures of -50 ° C to 30 ° C, preferably -30 ° C to 0 ° C.

The oxidation of the 1-hydroxy group is carried out by the methods known to the person skilled in the art. The oxidizing agents which can be used are, for example, pyπdinium dichromate (Tetrahedron Letters, 1979, 399), Jones reagent (J Chem Soc 1953, 2555) or platinum / oxygen (Adv in Carbohydrate Chem T7 169 (1962) or Collins oxidation (Tetrahedron Letters 1968, 3363) and subsequent Jones oxidation. Oxidation with pyπdinium dichromate is inert to the oxidizing agent at temperatures from 0 ° C. to 100 ° C., preferably at 20 ° C. to 40 ° C. Solvents, for example dimethylformamide, carried out

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

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

The introduction of the ester group -COOR4 for R- | , in which R4 a

Represents alkyl group with 1-10 C atoms, is carried out according to the methods known to those skilled in the art. The 1-carboxy compounds are used, for example, with Diazohydrocarbons implemented in a manner known per se The esterification with diazohydrocarbons is carried out, for example, by dissolving the diazohydrocarbon in an inert solvent, preferably in diethyl ether, with the 1-carboxy compound in the same or in another inert solvent, such as methylene chloride, for example. mixed After the reaction has ended in 1 to 30 minutes, the solvent is removed and the ester is purified in the customary manner. Diazoalkanes are either known or can be prepared by known methods (Org Reactions Vol 8, pages 389-394 (1954))

The introduction of the ester group -COOR4 for R- | , in which R4 represents a substituted or unsubstituted aryl group, is carried out according to the methods known to the person skilled in the art. For example, the 1-carboxy compounds with the corresponding arylhydroxy compounds are reacted with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine, dimethylaminopyπdine, triethylamine, in an inert solvent as solvent come methylene chloride, ethylene chloride chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures between -30X and + 50 ° C, preferably at 10 ° C

The Leukotrιen-B4-Derιvate of formula I with R4 in the meaning of a

Hydrogen can be converted into a salt with suitable amounts of the corresponding inorganic bases with neutralization. For example, when the corresponding acids are dissolved in water which contains the stochiometric amount of the base, the water is evaporated off or a water-miscible solvent, for example alcohol, is added or acetone, the solid inorganic salt

To produce an amino salt, LTB4 acid is used, for example, in a suitable

Solvents, for example ethanol, acetone, diethyl ether, Acetonitπl or benzene dissolved and at least the stochiometric amount of the amine Solution added The salt is usually obtained in solid form or is isolated in the usual way after the solvent has evaporated

The amide group-CONHRs with R5 in the meaning of alkanoyl are introduced by the methods known to the person skilled in the art. The carboxylic acids of the formula I (R4 = H) are first converted into the mixed anhydride in the presence of a tertiary amine, such as, for example, methylamine, with isobutyl chloroformate The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (Rs = H) takes place in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide

Hexamethylphosphorsauretπamid, at temperatures between -30 ° C and + 60 ° C, preferably at 0 ° C to 30 ° C. Another way of producing the amides consists in the amidolysis of the 1-ester (R- | = COOR4) with the corresponding amine

Another possibility for the introduction of the amide group -CONHR5 is to convert a 1-carboxylic acid of the formula I (R4 = H) into the free one

Hydroxy groups are optionally protected as intermediates, with compounds of the formula IV,

0 = C = N - R ₅ (IV)

where R5 has the meaning given above

The reaction of the compound of formula I (R4 = H) with an isocyanate

Formula IV is optionally carried out with the addition of a tertiary amine, such as Tπethylamin or Pyridm. The reaction can be carried out without a solvent or in an inert solvent, preferably Acetonitπl, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80 ° C to 100 ° C, preferably at 0 ° C to 30 ° C. To produce the other amides, for example, the desired acid anhydrides can be reacted with ammonia or the corresponding amines.

If the starting product contains OH groups in the leukotriene B4 residue, these OH groups are also reacted. If end products which contain free hydroxyl groups are ultimately desired, it is expedient to start with starting products in which they are or are temporarily protected by ether or acyl radicals, which can be easily removed.

The separation of diastereomers and enantiomers is carried out by the methods known to the person skilled in the art, for example by column chromatography and / or HPLC.

The compounds of the general formula II which serve as starting material can be prepared, for example, by using a nitrile of the general formula V, in a manner known per se,

wherein m has the meanings given above, with a halide of the general formula (VI)

Y-Hal (VI)

in which Y has the meaning given above and Hai is a halogen atom, such as chlorine, bromine or iodine, alkylated in the presence of lithium diisopropylamide, the Nitrile saponified to acid with sodium hydroxide in ethylene glycol, cleaves the methyl ether with HBr and then converts the acid with methyl iodide in the presence of potassium carbonate into the ester of the general formula (VII).

Intermediate protection of the phenolic hydroxyl group with benzyl bromide, subsequent reduction of the ester group with diisobuytylaluminium hydride, silylation of the resulting alcohol with tert-butyl-dimethylsilylchloride and cleavage of the first benzyl ether produced by hydrogenation provides the phenol of the general formula (VIII)

The phenol thus obtained is converted into the triflate by means of trifluoromethanesulfonic anhydride and obtained by a palladium-catalyzed reaction in methanol and a carbon monoxide atmosphere of the esters of the general formula (IX).

Reduction of the ester of the general formula (IX) with diisobutylaluminum hydride, oxidation of the primary alcohol by manganese dioxide, Wittig-Homer olefination with the phosphonoacetic acid ethyl or trimethyl ester, subsequent hydrogenation and silyl ether cleavage gives the alcohol of the general formula (X)

Oxidation of the primary alcohol obtained e.g. with the Collins reagent or the Swern method lead to an aldehyde which, by means of Wittig-Homer olefination with the phosphonoacetic acid ethyl or trimethyl ester, gives the diester of the general formula (XI)

The diester (XI) is reduced to the corresponding diol with diisobutylaluminum hydride and the allyl alcohol with manganese dioxide is oxidized to the a, b-unsaturated aldehyde of the general formula (II)

The incorporation of the chemically and metabolically labile cis-Δ6> ⁷ double bond of the LTB4 into a cis-1, 2-substituted cycloalkyl ring leads to stabilization, in particular by further dehvating the functional groups and / or structural changes in the lower side chain, LTB4- Derivatives were obtained which can act as LTB4 antagonists (DE-A 3917597 and

DE-A 42 27 790.6 and DE-A 41 08 351 and DE-A 41 39 886.8 and DE-A 42 42 390).

It has now been found that by introducing an alkyl group into the 7-position and introducing a benzo-fused ring system for the 4,5,6,7-position (LTB4 nomenclature, counting starting with carboxyl-C-

Atom with 1) in such leukotriene B4 derivatives a longer duration of action, greater selectivity and better effectiveness can be achieved.

The compounds of formula I have anti-inflammatory, anti-allergic and anti-proliferative effects. The connections are also increased to lower

Triglyceride levels suitable. They also have antifungal properties. Consequently, the new leukotriene B4 derivatives of the formula I are valuable active pharmaceutical ingredients. The compounds of the formula I are suitable for topical and oral administration.

The new leukotriene B4 derivatives of the formula I are suitable in combination with the auxiliaries and excipients customary in galenical pharmacy for the local treatment of skin diseases in which leukotrienes play an important role, eg. For example: contact dermatitis, various types of eczema, neurodermatoses, erythroderma, pruritis vulvae et ani, rosacea, Erythermatodes cutaneus, psoriasis, lying ruber planus et verrueosus and similar skin diseases.

The new leukotriene B4 antagonists are also suitable for the treatment of multiple sclerosis and the symptoms of shock.

The pharmaceutical specialties are produced in the usual way by converting the active ingredients into the desired application form, for example: solutions, ointments, creams or plasters, with suitable additives.

In the pharmaceuticals formulated in this way, the active substance concentration depends on the form of administration. For lotions and ointments, an active ingredient concentration of 0.0001% to 3% is preferably used.

In addition, the new compounds, if appropriate in combination with the customary carriers and auxiliaries, are also well suited for the production of inhalants which can be used for the therapy of allergic diseases of the respiratory tract such as bronchial asthma or rhinitis.

The new leukotriene B4 derivatives are also suitable in the form of

Capsules, tablets or dragees, which preferably contain 0.1 to 100 mg of active ingredient and are administered orally or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dose unit and are applied rectally, also for the treatment of diseases of internal organs in which Leukotrienes play an important role, such as For example: allergic diseases of the intestinal tract, such as ulcerative colitis and granulomatous colitis.

In these new forms of application, the new LTB4 derivatives are not only suitable for treating diseases of internal organs with inflammatory processes, but also for diseases in which, depending on the leukotriene, the focus is on increased growth and the formation of new cells. Examples are leukemia (increased growth white blood cells) or atherosclerosis (increased smooth muscle cell growth from blood vessels).

The new leukotriene B4 dehvates can also be used in combination, such as. B. with lipoxygenase inhibitors, cyclooxygenase inhibitors, glucocorticoids,

Prostacyclin agonists, thromboxane antagonists, leukotriene D4 antagonists,

Leukotriene E4 antagonists, leukotriene F4 antagonists,

Phosphodiesterase inhibitors, calcium antagonists, PAF antagonists or other known forms of therapy of the respective diseases can be used.

The following exemplary embodiments serve to explain the method according to the invention in more detail.

example 1

3 - {(8RS) -8-methyl-8 - [(1 E, 3E) - (5RS) -5-hydroxy-6,6-trιmethylen-9-phenyl-1, 3-nonadιen-8-ιnyl] - 5,6,7,8-tetrahydronaphth-2-yl} propan-1-ol

A solution of 5.85 g of 2-oxo-3, 3-tri-methylene-6-phenyl-hex-5 is added dropwise to a suspension of 660 mg of sodium hydride (65% in mineral oil) in 34 ml of ethylene glycol dimethyl ether at 0 ° C. under nitrogen -ιn-phosphonsauredιmethylester in 34 ml of ethylene glycol dimethyl ether and stirred for 30 minutes at 0 ° C. Then a solution of 4.1 g of the aldehyde prepared in Example 1q) in 34 ml of ethylene glycol dimethyl ether is added and the mixture is stirred for 4 hours at 50 ° C. It is then saturated Ammonium chloride solution poured extracted with ether and the combined organic phases washed with semi-concentrated sodium chloride solution. Dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel with hexane / 0-30% ethyl acetate 4.51 g of 3 - {(8RS) -8-methyl-8 - [(1 E, 3E) -5-oxo-6,6-tπmethylen-9-phenyl-1, 3-nonadιen-8- ιnyl] -5,6,7,8-tetrahydronaphth-2-yl} -propan-1-ol as colorless oil IR (film) 3440 (bre it), 2932, 2841, 2709, 1694, 1682 1626, 1501, 1454, 1105

1058, 980, 819, 758 cm- ¹

For reduction, 579 mg of certrichloride heptahydrate are added to a solution of 4.69 g of the above-described ketone in 83 ml of methylene chloride and 8.3 ml of tetrahydrofuran at -60 ° C. and the mixture is stirred at this temperature for 20 minutes. 588 mg of sodium borohydride are added to this solution and stirred for 1.5 hours at -60 ° C. Then 6.5 ml of acetone are added dropwise, the mixture is stirred for 15 minutes, the pH is adjusted to pH7 with glacial acetic acid and the mixture is concentrated in vacuo. The residue is diluted with 1 liter of water / ether , extracted with ether and the combined organic phases washed with semi-concentrated sodium chloride solution, dried over sodium sulfate and after filtration, concentrated in vacuo. 4.46 g of the title compound is obtained as a colorless oil IR (film) 3370 (broad) without further purification. , 3005, 2923, 2840, 1652, 1598, 1571, 1490, 1442, 1280,

1157, 1094, 1050, 990, 911, 861, 815 cm ^"1 The starting material for the above title compound is prepared as follows:

1 a) 7-methoxy-1-methyl-1, 2,3,4-tetrahydronaphth-1 -yl-carbonitrile

25.3 g of diisopropylamine in 121 ml of tetrahydrofuran are added to 154.6 ml of butyllithium at 0 ° C. under nitrogen and stirring is continued for 30 minutes. Then 40.7 g of 7-methoxy-1, 2,3,4-tetrahydronaphth-1-yl carbonitrile in 138 ml of tetrahydrofuran are added to the reaction mixture and the mixture is stirred for 1 hour. Now add 107.9 g of methyl iodide in 374 ml of N, N-

Dimethylpropylene urea to the solution, stirred for 1 hour at -30 ° C and 1 hour at 0 ° C. The reaction mixture is poured onto saturated ammonium chloride solution, extracted with ether, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo.

The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-10% ethyl acetate, 33.69 g of the title compound is obtained as a colorless oil. IR (film): 3020, 2940, 2820, 2231, 1614, 1504, 1322, 1286, 1241, 1041, 867, 81 1, 735 cm- ¹ .

1 b) 7-methoxy-1-methyl-1, 2,3,4-tetrahydronaphth-1-yl-carboxylic acid 280 g are added to a solution of 45.7 g of the nitrile prepared in Example 1 a) in 1000 ml of ethylene glycol Sodium hydroxide and stirred at 160 ° C for 16 hours. It is then cooled, poured into water and adjusted to pH 1.5 with concentrated hydrochloric acid. Now it is cooled to 0 ° C., stirred for 2 hours, the precipitate is filtered off with suction and dried in vacuo. 46 g of the title compound are obtained as white crystals. IR (CHCI3): 3037 (broad), 2940, 1699, 161 1, 1505, 1464, 1284, 1 184, 1043, 884 cm ^'1 . 1 c) 7-hydroxy-1-methyl-1, 2,3,4-tetrahydronaphth-1-yl-carboxylic acid, methyl ester

20 g of the acid produced in Example 1 b) are mixed with 100 ml

Hydrogen bromide (47%) is added and the mixture is stirred at 140-150 ° C. for 18 hours, then poured onto ice water, saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and after filtration in vacuo concentrated The residue is dissolved in 128 ml of acetone and 57 ml of dimethyl sulfoxide, 13.9 g of carbonate followed by 14.3 g of methyl iodide and added for 18 hours

Room temperature stirred Then the precipitate is suction filtered, washed with ethyl acetate and the filtrate is concentrated in vacuo. The residue is diluted with ether, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. The residue thus obtained is purified by chromatography on silica gel With hexane / 0-50% ether, 12.4 g of the title compound are obtained as a colorless oil IR (CHCI3) 3595, 3402 (broad), 2950, 1720, 1612, 1505, 1435 1287, 1259,

1 184, 1 109, 981, 922, 868 cm- ¹

1 d) 7-Benzyloxy-1-methyl-1, 2,3,4-tetrahydronaphth-1 -yl-carboxylic acid, methyl ester

36.6 g of casium carbonate followed by 19.2 g of benzyl bromide are added to a solution of 12.4 g of the ester prepared in Example 1 c) in 150 ml of dimethylformamide and the mixture is stirred under nitrogen at room temperature for 20 hours

The mixture is then filtered off, washed with ethyl acetate and the filtrate is diluted with ether. The organic phase is washed with water and half-concentrated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. The residue thus obtained is purified by chromatography on silica gel with hexane / 0 -

10% ether gives 18.2 g of the title compound as a colorless oil IR (film) 3036, 2946, 2880, 1728, 1610, 1503, 1454, 1377, 1283, 1237,

1194, 1108, 1026, 809, 738 cm " ¹ 1e) 7-benzyloxy-1-methyl-1, 2, 3,4-tetrahydronaphth-1-yl-methanol

To a solution of 18.2 g of the ester prepared in Example 1d) in

290 ml of Toluoi are added at -70 ° C under nitrogen 98 ml of diisobutylaluminium hydride (20% in Toluoi) and stirred for 2 hours.

5 ml of isopropanol are then carefully added dropwise and the mixture is stirred for 10 minutes. Now water is added, the mixture is stirred at room temperature for 2 hours, the white precipitate is filtered off and washed well with ethyl acetate. After concentrating the filtrate in vacuo, 18.1 g of the title compound are obtained as a colorless oil.

IR (film): 3386 (wide), 2930, 2882, 1607, 1574, 1495, 1454, 1380, 1285,

1235, 1026, 924, 858, 797, 733 cm ^"1 .

1f) 7-benzyloxy-1-methyl-1, 2, 3,4-tetrahydronaphth-1-yl-methanol-tert-butyldimethylsilyl ether

To a solution of 18.1 g of the alcohol prepared in Example 1e) in 310 ml of N, N-dimethylformamide are added 11.4 g of imidazole followed by 12.6 g of tert-butyldimethylsilyl chloride and the mixture is stirred at room temperature under nitrogen for 20 hours . The mixture is then diluted 1: 1 with ether / hexane and the organic phase is washed with water and semi-concentrated

Sodium chloride solution. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. 26.1 g of the title compound are obtained as a colorless oil. IR (film): 3040, 2928, 2856, 1609, 1574, 1496, 1471, 1383, 1255, 1094, 837, 775, 733 cm- ¹ .

1g) 7-hydroxy-1-methyl-1, 2,3,4-tetrahydronaphth-1-yl-methanol-tert-butyldimethylsilyl ether

2.6 g of Pd / C (10%) are added to a solution of 26.1 g of the silyl ether prepared in Example 1f) in 261 ml of ethyl acetate and the mixture is stirred for 24 hours under hydrogen. It is then suction filtered through Celite, washed with ethyl acetate and the filtrate is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ether, 16 9 g of the title compound are obtained as a colorless oil

IR (film) 3420 (wide), 2930, 1611, 1565, 1495, 1371 1258 1084, 839

777, 735 cm " ¹

1 h) 8-methyl-8- (tert-butyldimethylsilyloxymethyl) -5,6,7,8-tetrahydronaphth-

2-yl-carboxylic acid methyl ester

16.0 g of nitrogen at 0 ° C. are added dropwise to a solution of 15.8 g of the phenol prepared in Example 1g) in 26.5 ml of pyridine

Trifluoromethanesulfonic acid anhydride and stirred for 20 hours at room temperature. Then the reaction mixture is poured into water and extracted with ether. The combined organic phases are washed with water, 10% hydrochloric acid, water and half-saturated sodium chloride solution, dried over sodium sulfate and after filtration in a Vacuum concentrated 21.2 g of the corresponding triflate are obtained as pale yellow-colored oil IR (film) 3010, 2930, 2880, 2837, 1607, 1581, 1490, 1472, 1424, 1362,

1211, 1044, 1006, 921, 838, 776, 730 cm " ¹

To a solution of 17.2 g of the previously prepared triflate in 40 ml of methanol and 59 ml of dimethyl sulfoxide, 4.38 g of tπethylamine are added, followed by 133 mg of palladium (II) acetate and 244 mg

Bιs (dιphenylphosphιno) propane CO gas is passed through this reaction mixture for 3 minutes and stirred for 18 hours under a CO atmosphere at 80 ° C. Subsequently, saturated sodium chloride solution is added and the mixture is extracted with ether. The combined organic phases are washed with half-concentrated sodium chloride solution , dried over sodium sulfate and concentrated in vacuo after filtration. The residue thus obtained is purified by chromatography on silica gel with hexane /

0-10% ether is obtained 7.1 g of the title compound as a colorless oil IR (film) 3020, 2929, 2843, 1728, 1610, 1573, 1434, 1409, 1386, 1361,

1250, 1191, 1108, 1006, 987, 939, 837, 776 cm- ¹ 1 i) 8-methyl-8- (tert-butyldimethylsilyloxymethyl) -5,6,7,8-tetrahydronaphth-

2-yl methanol

To a solution of 7.1 g of the ester prepared in Example 1 h) in 100 ml of toluene is added dropwise at -70 ° C under nitrogen 34 ml

Diisobutylaluminiumhydrid (20% in Toluoi) and stirred for 2 hours.

Then 1 ml of isopropanol is added dropwise and the mixture is stirred for 10 minutes.

Now water is added, the mixture is stirred at room temperature for 2 hours, the white precipitate is filtered off and washed well with ethyl acetate. After concentrating the filtrate in vacuo, 6.5 g of the title compound are obtained as a colorless oil.

IR (film): 3347 (broad), 2927, 2847, 1499, 1471, 1386, 1361, 1255, 1095,

939, 836.775.730 cm- ¹ .

1j) 8-methyl-8- (tert-butyldimethylsilyloxymethyl) -5,6,7,8-tetrahydronaphth-

2-yl carbaldehyde

17.6 g of manganese (IV) oxide are added to a solution of 6.49 g of the alcohol prepared in Example 1 i) in 1 12 ml of toluene and the mixture is stirred for 24 hours at room temperature under nitrogen. It is then filtered off with suction through Celite, washed with ethyl acetate and the filtrate is concentrated in vacuo. 5.83 g of the title compound are obtained as a pale yellow-colored oil. IR (film): 2930, 2840, 2720, 1698, 1602, 1570, 1470, 1385, 1360, 1255,

1210, 1097, 1006, 931, 901, 837, 776, 730 cm " ¹ .

1k) (E) -3- [8-Methyl-8- (tert-butyldimethylsilyloxymethyl) -5,6,7,8-tetrahydronaphth-2-yl -] - ethyl propenate

A solution of 8.18 g of triethyl phosphonoacetate in 27 ml of ethylene glycol dimethyl ether is added to a suspension of 1.34 g of sodium hydride (65% in mineral oil) in 27 ml of ethylene glycol dimethyl ether at 0 ° C. under nitrogen and the mixture is stirred for 30 minutes. A solution of 5.81 g of the aldehyde prepared in Example 1j) in 27 ml of ethylene glycol dimethyl ether is then added and the mixture is stirred at 50 ° C. for 4 hours. Now is added to saturated ammonium chloride solution and extracted with ether. The combined organic phases are washed with half-saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. The residue thus obtained is purified by chromatography on silica gel with hexane / 0-10% ether 6.54 g of the title compound are obtained as a colorless oil IR (film) 2931, 2870, 1713, 1636, 1605, 1470, 1409, 1388, 1366, 1316,

1254, 1 172, 1096, 1006, 983, 938, 837, 775 cm " ¹

11) 3- [8-Methyl-8- (tert-butyidιmethylsιlyloxymethyl) -5, 6,7,8-tetrahydronaphth-2-yl -] - ethyl propane

986 mg of palladium / carbon (10%) are added to a solution of 9 86 g of the ester prepared in Example 1 k) in 100 ml of ethyl acetate and the mixture is stirred for 18 hours at room temperature under an H2 atmosphere and the filtrate was concentrated in vacuo. 9.69 g of the title compound are obtained as a colorless oil

IR (film) 2929, 2843, 1736, 1499, 1471, 1371, 1255, 1 160, 1095, 939, 837,

775 cm " ¹

1 m) 3- (8-methyl-8-hydroxymethyl-5,6,7,8-tetrahydronaphth-2-yl -) - propanoic acid ethyl ester

To a solution of 8.61 g of the ester prepared in Example 11) in

90 ml of tetrahydrofuran are added at room temperature under nitrogen to 13.9 g of tetrabutylammoniumfluoπd tetrahydrate and stirred for 5 hours. The mixture is then diluted with ether and the organic phase is washed with water. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. The residue thus obtained is cleaned by Chromatography on silica gel With hexane / 0-25% ether, 5.31 g of the title compound is obtained as a colorless oil

IR (film) 3344 (wide), 2932, 1732, 1613, 1504, 1455, 1372, 1255, 1163,

1038.861.820.741 cm ^"1 1 n) ethyl 3- (8-formyl-8-methyl-5,6,7,8-tetrahydronaphth-2-yl -) - propanoate

A solution of 4.05 g of dimethyl sulfoxide in 15 ml of methylene chloride is carefully added dropwise to a solution of 3.04 g of oxalyl chloride in 23 ml of methylene chloride at -70 ° C. under nitrogen and the mixture is stirred for 10 minutes. In this

The reaction mixture is then added to a solution of 5.3 g of the alcohol prepared in Example 1 m) in 15 ml of methylene chloride and stirred for 1.5 hours at -60 ° to -70 ° C. 5.43 g of triethylamine are then added dropwise, the mixture is stirred for 1.5 hours and the reaction mixture is poured into water. It is then extracted with methylene chloride, the combined organic phases are washed with 1 N sulfuric acid, saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. 5.3 g of the title compound are obtained as a slightly yellow-colored oil. IR (film): 2933, 2857, 2706, 1732, 1613, 1573, 1504, 1455, 1372, 1346,

1250, 1 179, 1041, 935, 882, 860, 822, 741, 723 cm ^"1 .

1 o) (E) -3- [8- (2-Ethoxycarbonylethenyl) -8-methyl-5,6,7,8-tetrahydronaphth-2-yl] -propanoic acid ethyl ester To a suspension of 1.42 g sodium hydride (65% in mineral oil) in

28 ml of ethylene glycol dimethyl ether is added at 0 ° C. under nitrogen to a solution of 8.64 g of phosphonoacetic acid triethyl ester in 28 ml of ethylene glycol dimethyl ether and stirred for 30 minutes. A solution of 5.29 g of the aldehyde prepared in Example 1 n) in 28 ml of ethylene glycol dimethyl ether is then added at 0 ° C. and the mixture is stirred for 18 hours

40 ° C. Now it is added to saturated ammonium chloride solution and extracted with ether. The combined organic phases are washed with semisaturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-

10% ether gives 6.12 g of the title compound as a colorless oil. IR (film): 2980, 2932, 1732, 1710, 1644, 1500, 1454, 1372, 1305, 1270,

1 178, 1096, 1038, 988, 899, 857, 814, 726 cm ^"1 . 1 p) (E) -3- [8- (3-Hydroxypropenyl) -8-methyl-5,6,7,8-tetrahydronaphth-2-yl] propan-1-ol

60 ml of nitrogen are added dropwise at -70 ° C. to a solution of 6.1 g of the ester prepared in Example 10) in toluene

Diisobutylaluminiumhydrid (20% in Toluoi) and stirred for 2 hours.

6 ml of isopropanol are then added dropwise and the mixture is stirred for 10 minutes.

Now water is added, the mixture is stirred at room temperature for 2 hours, the white precipitate is filtered off and washed well with ethyl acetate. The filtrate is concentrated in vacuo. The residue obtained in this way is purified by chromatography on silica gel. With hexane / 0-60% ethyl acetate, 2.93 g of the title compound is obtained as a colorless oil.

IR (film): 3408 (wide), 2928, 2850, 1662, 1613, 1498, 1454, 1372, 1242,

1 1 1 1, 1047, 974, 816 cm- ¹ .

1q) (E) -3- [8- (2-Formylethenyl) -8-methyl-5,6,7,8-tetrahydronaphth-2-yl] propan-1-ol

14.3 g of manganese (IV) oxide are added to a solution of 4.29 g of the alcohol prepared in Example 1p) in 100 ml of toluene and the mixture is stirred for 5 hours at room temperature under nitrogen. It is then filtered off with suction through Celite, washed with ethyl acetate and the filtrate is concentrated in vacuo. 4.12 g of the title compound are obtained as a slightly yellow-colored oil. IR (film): 3417 (wide), 2932, 2842, 2731, 1682, 1629, 1498, 1454, 1375, 1 144, 1 105, 1057, 979, 897, 818, 732 cm " ¹ .

Example 2

3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-thmethylene-9-phenyl-1,3-nonadien-8-ynyl] - 5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

A suspension of 2 g of platinum dioxide in 28 ml of ethyl acetate is first stirred for 2 hours under a hydrogen atmosphere and then, carefully (oxyhydrogen), for 2 hours under an oxygen atmosphere. A solution is added to this suspension from 200 mg of the alcohol described in Example 1) in a little ethyl acetate and stirred for 18 hours in a 02 atmosphere. Then a G4

The frit is suctioned off and the filtrate is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-60% ethyl acetate, 93.3 mg of the title compound is obtained as a colorless oil.

IR (film): 3310 (wide), 3020, 2930, 2865, 1707, 1678, 1640, 1589, 1490, 1407,

1006, 756 cm ^-1 . This is the preferred embodiment.

In vivo test system

(ι) Production of human polymorphnuclerar leukocytes (PMN) PMNs from healthy volunteers are isolated from hepanized venous blood by dextran sedimentation and subsequent centrifugation via Ficoll-Histopaque®. The remaining erytrocytes are eliminated by hypotonic lysis in 0.2 percent sodium loosening The PMNs are resuspended in Hank ^'s banned salt solution (HBSS) and egg albumin from chickens (OVA) or cattle serum albumin (BSA) are added

(n) LTB4 receptor competition binding assay

Human PMNs are tritiated leukotriene B4 (LTB4) in the presence or

Absence of the tested substances in concentrations from 10 μmol / l to

0.05 mmol / l incubated in HBSS together with OVA. Zeil-bound tritium-labeled LTB4 is separated from the free ligands by vacuum filtration through a glass fiber filter and measured in a scintillation measuring device. The non-specific binding of tritium-labeled LTB4 is determined in the presence of one

Excess of unlabeled LTB4 (500 nmol / l) determined The competition factor (CF) is calculated from the ratio of the concentration of the substance to the concentration of LTB4, which leads to a 50% reduction in the tritium-labeled LTB4

Receptor binding leads

(111) LTB4 - induced chemotaxis experiment

The chemotaxis test is carried out with modified Boyden chambers, which consist of Transwell® modules with polyvinylpyrrolidone-coated polycarbonate filters with a pore size of 3 μm. The upper part of the chamber contains the human ones

PMNs in HBSS, which is supplemented with BSA or OVA. The lower part of the chamber is used alone with buffer or with the chemotactically active leukotriene B4 (LTB4) in one

Concentration within the range of 1 nmol / l to 100 nmol / l in the presence or absence of the test substance is added. The chamber is incubated for 60 minutes in a water-saturated atmosphere with 5% carbon dioxide. The number of PMNs that have migrated into the lower part of the chamber is shown by the Measuring the activity of the

Enzyme myeloperoxidase (MPO) determined in a calibrated experiment The enzyme activity is measured spectrometrically (450 n) by determining the rate of H2O2-dependent oxidation of the aromatic amine 3,3, ^' , 5,5 ^' -Tetramethylbenzιdιn (TMB) The EC50 value is determined graphically by the non-linear regression curve. The Kg value describes the ability of the competitive antagonist. The Kg value is determined as the concentration of antagonist required to obtain the EC50 value of the

Raise agonists by a factor of 2 The Kg value is calculated as follows

K _B = [LTB ₄ - receptor - antagonist] / (DR-1)

(DR = is the ratio of the LTB4 concentration required for half-maximum stimulation in the presence of the antagonist to the LTB4 concentration required for half-maximum stimulation in the absence of the antagonist)

(iv) LTB4 / lloprost-induced skin inflammation in the ears of mice

Female NMRI mice with a weight of 26 to 28 g and an age of 5 to 6 weeks are used for this in vivo experiment. Ten animals per group are randomly divided into the different treatment groups and kept individually. The animals had free access to the feed and water In order to avoid the oral intake of topically applied LTB4 / lloprost solutions, barrier collars are attached around the neck of the animals under ether anesthesia shortly before topical application

Leukotriene B4 (LTB4) and the stable prostacyclin derivative lloprost is dissolved in ethanol / isopropylmynstat (95 + 5 v / v) at a concentration of 0.003% (w / v). 10 μl of the LTB4 / lloprost solution is applied topically on the outside Surface of everyone

Ear (area about 1 cm2 / θhr) administered This corresponds to a dose of 0.3μg per ear or about 0.3 μg per crrι2 animals, which are treated with LTB4 / lloprost solution alone, develop the typical characteristics of an inflamed skin with formation of edema and infiltration of neutrophils These animals serve as a positive control. Animals treated with ethanol / isopropylmynstat (95 + 5 v / v) on the outer surface of each ear (area about 1 cm ^ / ear) serve as Negative - control

The effect of the LTB4 receptor antagonist on the LTB4 / lloprost induced

Inflammation reaction is determined by the test substance either with a topical or with an intragastric administration

For topical application, the test substance is dissolved in an LTB4 / lloprost solution in various concentrations. 10 μl of this solution is applied topically to the outer surface of the ear

For intragastric administration, the LTB4 receptor antagonist is dissolved in ethanol. After topical administration with LTB4 / lloprost, the LTB4 - Receptor antagonist or only the intragastric solvent administered at different doses with the aid of a probe. The highest final concentration of ethanol is 3%. The amount of ethanol decreases with further dilution barriers

The animals are sacrificed 24 hours after the inflammatory reaction has started. The ears are separated, weighed, shock-frozen and stored for further investigations. The peroxidase activity is determined spectrometrically in the homogenate of the ear skin. The tissue is in HTAB buffer (0 5% Homogenized hexadecyltrimethylammonium bromide (w / v) in 10 ^" 3 mol / l 3- [N-morpholinopropanesulfonic acid with pH 7.0) for 20 seconds with a Polytron® PT 3000 (Kinematica AG, Switzerland) at a rotation of 30000 revolutions per minute Homogenate is centrifuged for 20 minutes at 10 ° C and at 14500 revolutions per minute (20000g) in a Sorvall RC2-B centrifuge (SM-24 rotor). The aqueous supernatant is suctioned off and checked for its peroxidase activity at a dilution of 1 to 50 in HTAB buffer tested The peroxidase activity is determined by photometric measurement of the rate of H2O2-dependent oxidation of the aromatic amine 3,3 ^' , 5,5 ^' -tetramethylbenzide (TMB) The diluted supernatants are incubated in a 96-well microtiter plate with TMB solution and hydrogen peroxide (solution of 6.5 mg 3, 3 ^' , 5.5 ^' - tetramethylbenzidine dihydrochloride in 1 ml dimethylsulfoxide (DMSO), 1 100 (v / v) dissolved with 0.1 mol / l sodium acetate citrate buffer, pH 6.0, final concentration in the incubation mixture 1, 57 • 10 " ⁴ mol / l) (hydrogen peroxide 30% H202 1 16860 (v / v ) dissolved with 0 1 mol / l sodium acetate citrate buffer, pH 6.0, final concentration in the incubation mixture 4 93 • 10 ^"5 mol / l) After 30 minutes at room temperature, the reaction is carried out by adding 0.5 mol / l sulfuric acid stopped The absorbance is determined at 450 nm (maximum absorption) in a microtiter plate measuring device

Claims

3 patent claims

1. The invention relates to leukotriene B4 antagonists of the formula I,

wherein

Rl represents CH ₂ OH, COOR or CONR ₅ R ₆ , R2 H or an organic acid residue with 1-15 C atoms,

R3 H, optionally mono- or polysubstituted C 1 -C 14 -alkyl, C3-Cιo-cycloalkyl, optionally independently of one another singly or multiply by halogen, phenyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoromethyl , Chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy-substituted Cß- C- | o-aryl radical or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom,

R4 H, C-i-C-io-alkyl, C3-Cιrj-cycloalkyl, optionally by 1-3 halogen,

Phenyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl,

Carboxyl or hydroxy substituted Cß-Cirj-aryl radical, CH2-CO- (Cß-C-ιrj) aryl or a 5-6-membered aromatic heterocyclic ring having at least 1 heteroatom, B is a Ci-Cig straight or branched chain alkyl group, which, if appropriate can be substituted by fluorine or the group

symbolizes

D can mean a direct bond, oxygen, sulfur, -ClC-, -CH = CR7, or together with B also a direct bond,

Y is an optionally mono- or polysubstituted Ci-Cg-alkyl, C3-C-i rj-cycloalkyl, optionally substituted by aryl,

R5 and Rß are the same or different and represent H or optionally substituted by hydroxy groups C- | -C4-alkyl or Rß H and R5 Cι-C-15-alkanoyl or RßS02-, optionally substituted with OH, R7 H, Ci-Cß -Alkyl, chlorine or bromine, Rß has the same meaning as R3, m is 1-3, n is 2-5 and, if R4 is hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates

2 Process for the preparation of the compounds of general formula I, which is characterized in that an aldehyde of formula II,

wherein Y and m have the meaning given above, if appropriate after protecting free hydroxyl groups with an olefin reagent of the general formula III,

in which B, D and R3 have the meanings given above and Rg preferably denotes an alkyl group with 1-5 C atoms, is reacted in the presence of a base and the resulting keto function is reduced and, if appropriate, subsequently subsequently separates isomers in any order, protects free hydroxy groups and / or releases protected hydroxy groups and / or oxidizes the 1-hydroxy group to carboxylic acid and / or esterifies a carboxyl group and / or converts a free carboxyl group into an amide or converts a carboxyl group with a physiologically acceptable base into a salt

3 Pharmaceutical preparations consisting of a leukotriene B4-Derιvat or several Leukotrιen-B4-Derιvaten of formula I and usual auxiliaries and traαerstoffe