DE19722849A1 - Leukotriene B¶4¶ antagonists, especially 3-oxa-tetra-hydronaphthalene LTB¶4¶ antagonists - Google Patents

Abstract

The invention relates to leukotriene B4 antagonists of general formula (I) in which the contact of the chain O-(CH2)p-R1 can be situated at one of the free positions on the aromatic compound. R1 stands for CH2OH, COOR4, CONR5R6; R2 stands for H or an organic acid radical with 1-15 C atoms; R3 stands for H, C1-C14-alkyl, C3-C10-cycloalkyl, a C6-C10-aryl radical or a 5-6-link aromatic heterocyclic ring; R4 is H, C1-C10-alkyl, C3-C10-cycloalkyl, a C6-C10-aryl radical, CH2-CO-(C6-C10)aryl or a 5-6-link aromatic heterocyclic ring; A is a trans-, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group; B is a C1-C10-alkylene group or the group (a) or (b); D is a direct bonding, oxygen, sulphur, -CC-, -CH=CR7, or a direct bonding together with B; Y is a C1-C8-alkyl, C3-C10-cycloalkyl; R5 and R6 are identical or different and are H; R7 is H, C1-C5-alkyl, chlorine, bromine; R8 is the same as R3; p is 1-6; m is 1-3, n is 2-5. When R4 is hydrogen. The invention also relates to their salts with physiologically compatible bases and their cyclodextrin clathrates. The leukotriene antagonists are effective dermatological products.

Description

The invention relates to new leukotriene B ₄ antagonists, processes for their preparation and their use as medicaments. The new compounds are structural analogs of previously known leukotriene B ₄ antagonists which contain a six-membered ring as the basic structural element (DE 42 42 390).

Leukotriene B ₄ (LTB ₄ ) was discovered by B. Samuelsson and co-workers as a metabolite of arachidonic acid. In biosynthesis, the enzyme 5-lipoxygenase initially forms the leukotriene A ₄ as a central intermediate, which is then converted into the LTB ₄ by a specific hydrolase.

The nomenclature of leukotrienes 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 B ₄ is summarized in some recent work a) The Leukotrienes, Chemistry and Biology eds. LW Chakrin, DM Bailey, Academic Press 1984. b) JW Gillard et al., Drugs of the Future 12, 463 (1987). c) B. Samuelsson et al., Science 237, 1171 (1987). d) CW Parker, Drug Development Research 10, 277 (1987). It follows that LTB _{4 is} an important inflammation mediator for inflammatory diseases in which leukocytes migrate into the diseased tissue.

The effects of LTB ₄ are triggered at the cellular level by binding LTB ₄ to a specific receptor.

LTB ₄ is known to cause leukocyte adhesion to the blood vessel wall. LTB ₄ is chemotactically active, ie it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. In addition, it indirectly changes vascular permeability due to its chemotactic activity, a synergism with prostaglandin E _{2 being} observed. LTB ₄ obviously plays a crucial role in inflammatory, allergic and immunological processes.

Leukotrienes and especially LTB ₄ are involved in skin diseases that are associated with inflammatory processes (increased vascular permeability and edema, cell infiltration), increased proliferation of skin cells and itching, such as eczema, erythema, psoriasis, pruritus and acne. Pathologically elevated leukotriene concentrations are either causally involved in the development of many dermatids or there is a connection between the persistence of the dermatids and the leukotrienes. Significantly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic dermatitis, allergic contact dermatitis, bullous pemphigoids, delayed pressure urticaria and allergic vasculitis. Leukotrienes and especially LTB ₄ are also involved in diseases of internal organs for which an acute or chronic inflammatory component has been described, e.g. B .: joint diseases (rheumatoid arthritis); Respiratory tract disorders (asthma and chronic obstructive pulmonary disease (OPD)); inflammatory bowel diseases (ulcerative colitis and Crohn's disease); as well as reperfusion damage (to cardiac, intestinal or kidney tissue), which results from temporary pathological occlusion of blood vessels, such as glomerulonephritis, NSAID gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases.

Furthermore, leukotrienes and especially LTB _{4 are 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).

Leukotrienes and in particular LTB _{4 also} have an influence on the formation of white blood cells in the bone marrow, on the growth of smooth muscle cells, of keratinocytes and of B lymphocytes. LTB ₄ is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells.

Diseases with this appearance represent z. B. Leukemia or arteriosclerosis. Leukotrienes and especially LTB ₄ and derivatives are suitable for lowering elevated triglyceride levels and thus have an anti-arteriosclerotic and against obesity.

Due to the antagonization of the effects, in particular of LTB ₄ , the active substances and their forms of administration of this invention are specific remedies for the disease of humans and animals, in which leukotrienes in particular play a pathological role.

In addition to therapeutic options that can be derived from an antagonization of the LTB ₄ effect with LTB ₄ analogs, the usefulness and potential use of leukotriene B ₄ agonists for the treatment of fungal skin diseases could also be demonstrated (H. Katayama, Prostaglandins 34 , 797 (1988)).

The invention relates to leukotriene B ₄ antagonists of the formula I,

wherein
the linkage of the chain O- (CH ₂ ) _p -R _{1 can be} at one of the free positions on the aromatic and
R ₁ CH ₂ OH, COOR ₄ , CONR ₅ R ₆ , and
R _{2 represents} H or an organic acid residue with 1-15 C atoms,
R ₃ H, optionally mono- or polysubstituted C ₁ -C ₁₄ -alkyl, C ₃ -C ₁₀ - cycloalkyl, optionally independently mono- or polysubstituted by halogen, phenyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ - Symbolize alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy-substituted C ₆ -C ₁₀ aryl radical or a 5-6-membered aromatic heterocyclic ring with at least 1 hetero atom,
R ₄ H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ 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 ₆ -C ₁₀ aryl radical, CH ₂ -CO- (C ₆ -C ₁₀ ) aryl or a 5-6-membered aromatic heterocyclic ring with at least 1 hetero atom,
A is a trans, trans-CH = CH-CH = CH-, a -CH2-CH2-CH = CH- or a tetramethylene group,
B is a C ₁ -C ₁₀ straight or branched chain alkylene group which may optionally be substituted by fluorine or the group

symbolizes
D can mean a direct bond, oxygen, sulfur, -CC-, -CH = CR ₇ , or together with B also a direct bond,
Y is an optionally mono- or polysubstituted C ₁ -C ₈ -alkyl, C ₃ -C ₁₀ -cycloalkyl, optionally substituted by aryl,
R ₅ and R _{6 are} identical or different and represent H or C ₁ -C ₄ -alkyl which is optionally substituted by hydroxyl groups or R ₆ H and R ₅ C ₁ -C ₁₅ -alkanoyl or R ₈ SO ₂ - are optionally substituted by OH ,
R ₇ denotes H, C ₁ -C ₆ alkyl, chlorine, bromine,
R _{8 has} the same meaning as R ₃
p 1-6 means
m 1-3 means
n is 2-5 and, if R _{4 is} hydrogen, its salts with physiologically compatible bases and its cyclodextrin clathrates.

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

Suitable alkyl groups R ₄ are straight-chain or branched-chain alkyl groups with 1-10 C atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl.

The alkyl groups R ₄ 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 R ₄ ), dialkylamino and trialkylammonium with 1- 4 carbon 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 R ₄ are those with 1-4 C atoms.

The cycloalkyl group R ₄ can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl and methylcyclohexyl.

Suitable aryl groups R ₄ are both substituted and unsubstituted 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 with 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.

Suitable heterocyclic groups R ₄ are 5- and 6-membered aromatic heterocycles which contain at least 1 hetero atom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl and others

Such physiologically compatible acids are suitable as acid residue R ₅ . Preferred acids are organic carboxylic acids and sulfonic acids with 1-16 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 C _1-4 alkyl, hydroxy, C _1-4 alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br). 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, tridecyl acid, myristic acid, pentadecyl acid, diethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid , cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, Piperidinoessigsäure, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, with halogen (F, Cl, Br) or trifluoromethyl, hydroxy, C _1-4 alkoxy or carboxy groups substituted benzoic acids, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. Preferred arylsulfonyl radicals and alkanesulfonyl radicals R ₈ SO ₂ are those which are derived from a sulfonic acid having up to 10 carbon atoms. Examples of sulfonic acids are methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N, N-dimethylaminosulfonic acid, N, N-diisobutylaminosulfonic acid, N, N-dibutylaminosulfonic acid, pyrrolidino, piperazidone -Methylpiperazino- and morpholinosulfonic acid in question.

Suitable alkyl groups R ₃ are straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-14, in particular 1-10 C atoms, which are optionally substituted by optionally substituted phenyl (substitution see under aryl R ₅ ) could be. Examples include methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl , m- and p-chlorobenzyl groups. If the alkyl groups R _{3 are} halogen, halogen, fluorine, chlorine and bromine are suitable.

Examples of halogen-substituted alkyl groups R ₃ are alkyls with terminal trifluoromethyl groups.

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

Examples of suitable substituted or unsubstituted aryl groups R ₃ are:
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, C ₁ -C ₄ alkoxy or hydroxy group. The substitution in the 3- and 4-position on the phenyl ring is preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.

Suitable heterocyclic aromatic groups R ₃ are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 1-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, among others

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-methyltetramethylene, 1-methyl-tri-methylene, 1- Methylene-ethylene, 1-methylene-tetramethylene. The alkylene group B can also be the group

represent, where n = 2-5, preferably 3-5.

Suitable acid residues R ₂ 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 aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. Examples of the substituents are C _1-4 alkyl, hydroxy, C _1-4 alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br). 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, tridecyl acid, myristic acid, pentadecyl acid, diethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, trimethyl acetic acid, , Cyclohexylacetic acid, cyclohexane carboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, trichloric acid, with trifluoric acid, with trifluoric acid, with trifluoric acid, with trifluoric acid, with trifluoric acid, with fatty acids Hydroxy, C _1-4 alkoxy or carboxy groups substituted benzoic acids, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. Preferred acyl radicals R ₂ and R ₃ are those acyl radicals having up to 10 carbon atoms.

The alkyl radicals R ₅ and R ₆ , which optionally contain hydroxyl groups, are straight-chain or branched alkyl radicals, in particular straight-chain ones such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, particularly preferably methyl.

R ₇ as C _1-5 alkyl means straight-chain or branched-chain alkyl radicals as already mentioned for R ₃ or R ₄ . Preferred alkyl radicals R ₇ are methyl, ethyl, propyl and isopropyl.

Inorganic and organic bases, such as those known to the person skilled in the art, are suitable for salt formation for the formation of physiologically acceptable salts are known. Examples are mentioned Alkali hydroxides such as sodium and potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, Ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, Morpholine, tris (hydroxymethyl) methylamine, etc.

In order to arrive at the cyclodextrin clathrates, the compounds of formula I are added α-, β- or γ-cyclodextrin implemented. Β-Cyclodextrin derivatives are preferred.  

Preferred compounds of the present invention are compounds of the general formula I, where the attachment of the O- (CH ₂ ) _p -R ₁ group to the aromatics is represented by the formulas Ia and Ib and the radicals have the following meaning:

R ₁ is CH ₂ OH, CONR ₅ R ₆ , COOR ₄ with R ₄ 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 _1-4 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy-substituted phenyl radical.
Y is a methyl group
p is 1-3
m is 1-3
A is a trans-CH = CH-CH = CH or tetramethylene group;
B is a straight-chain or branched-chain saturated or unsaturated alkylene group with up to 10 C atoms, which may optionally be substituted by fluorine, or the group

D is a direct compound, oxygen, sulfur, a -C∼C group or a -CH = CR ₇ group with R ₇ as hydrogen, C _1-5 alkyl, chlorine or bromine;
B and D together are a direct link;
R _{2 represents} hydrogen or an organic acid residue with 1-15 C atoms;
R ₅ and R _{6 have} the meanings given above;
R ₃ is a hydrogen atom, C _1-10 allyl, cycloalkyl with 5-6 C atoms, optionally with 1-2 chlorine, bromine, phenyl, C _1-4 alkyl, C _1-4 alkoxy, chloromethyl, Fluoromethyl, trifluoromethyl, carboxy or hydroxy substituted phenyl and if
R _{4 represents} a hydrogen, its salts with physiologically compatible bases and cyclodextrin clathrates.

Particularly preferred compounds of the present invention are compounds of the general formula I, where the attachment of the O- (CH ₂ ) _p -R ₁ group to the aromatics is represented by the formulas Ia and Ib and the radicals have the following meaning:

R ₁ is CH ₂ OH, CONR ₅ R ₆ , COOR ₄ with R ₄ in the meaning of a hydrogen atom, an alkyl radical with 1-4 C atoms
R _{2 represents} hydrogen or an organic acid residue with 1-6 C atoms
R ₃ is a hydrogen atom or C _1-10 alkyl;
R ₅ and R _{6 have} the meanings given above;
A is a trans, trans-CH = CH-CH = CH or tetramethylene group,
B is a straight-chain or branched-chain alkylene group with up to 5 carbon atoms, or the group

D is a direct compound or a -C∼C group or a -CH = CR ₇ group with R ₇ as hydrogen or C _1-5 alkyl;
Y is a methyl group
p is 1-3
m is 1-2
B and D together are a direct link;
and if R _{4 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 a phenol of the formula II,

wherein A, B, D, R ₂ , R ₃ Y and m have the meaning given above, optionally after protecting free hydroxyl groups in R ₂ with a halide of the general formula III

Hal- (CH ₂ ) _p -R ₁ (III)

where Hal represents a chlorine, bromine or iodine atom and p, R _{1 has} the meaning given above, reacting in the presence of a base and then optionally separating isomers in any order, releasing protected hydroxyl groups and / or etherifying a free hydroxyl group and / or the 1- Hydroxy group oxidized to carboxylic acid and / or reduced and / or a carboxyl group esterified and / or a free carboxyl group converted into an amide or a carboxyl group with a physiologically compatible base converted into a salt. In the event that intermediately protected esters in the form of orthoesters (for example —C (OMe) ₃ or —C (OEt) ₃ ) for R ₁ in Formula III are used, it must subsequently be treated with acid.

The above process (II + III → I) is carried out in organic solvents such as. B. Dimethylformamide, dimethyl sulfoxide, acetone, tetrahydrofuran, toluene, at temperatures between 0 ° C and 100 ° C, preferably at temperatures between 20 ° C and 60 ° C below Stir for 5-24 hours in the presence of a base such as Sodium hydride, potassium tert.butylate, cesium, lithium or potassium carbonate carried out.

The reduction to the compounds of the formula I with R ₁ in the meaning of a CH ₂ OH group is carried out using a reducing agent suitable for the reduction of esters or carboxylic acids, such as, for example, lithium aluminum hydride, diisobutyl aluminum hydride, etc. Diethyl ether, tetrahydrofuran, dimethoxyethane, toluene, etc. are suitable as solvents. The reduction is carried out at temperatures from -30 ° C. to the boiling point of the solvent used, preferably 0 ° C. to 30 ° C.

The esterification of the alcohols of the formula I (R ₂ = H) takes place in a manner known per se. For example, the esterification is carried out by reacting an acid derivative, preferably an acid halide or acid anhydride, in the presence of a base such as sodium hydride, pyridine, triethylamine, tributylamine or 4-dimethylaminopyridine with an alcohol of the formula I. The reaction can be carried out without a solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, dimethyl sulfoxide, at temperatures above or below room temperature, for example between -80 ° C. to 100 ° C., preferably at room temperature.

The oxidation of the 1-hydroxy group is carried out according to the methods known to the person skilled in the art performed. The following can be used as oxidizing agents: pyridinium dichromate (Tetrahedron Letters, 1979, 399), Jones Reagenz (J. Chem. Soc. 1953, 2555) or Pla tin / oxygen (Adv. in Carbohydrate Chem. 17, 169 (1962) or Collins oxidation (Tetrahedron Letters 1968, 3363) and subsequent Jones oxidation. The oxidation with Pyridinium dichromate is at temperatures from 0 ° C to 100 ° C, preferably at 20 ° C to 40 ° C in a solvent inert to the oxidizing agent, for example Dimethylformamide.

Oxidation with Jones' reagent is preferred at temperatures from -40 ° C to + 40 ° C 0 ° C to 30 ° C in acetone as a solvent.

Oxidation with platinum / oxygen is preferred at temperatures from 0 ° C to 60 ° C 20 ° C to 40 ° C in an inert solvent against the oxidizing agent, such as. B. Ethyl acetate, carried out.

The saponification of the esters of the formula I is carried out by the methods known to the person skilled in the art carried out, such as with basic catalysts. The connections of the Formula I can be separated into the optical isomers by the customary separation methods (Asymmetric Synthesis, Vol. 1-5, Ed. J.D. Morrison, Acedemic Press. Inc. Orlando etc., 1985; Chiral Separations by HPLC, Ed. A. M. Krstulovic; John Wiley &Sons; New York etc. 1989).

The functionally modified hydroxy groups are released according to known methods methods. For example, the elimination of hydroxy protective groups, such as the tetrahydropyranyl radical, in an aqueous solution of an organic acid, such as. B. Oxalic acid, acetic acid, propionic acid and the like. a., or in an aqueous solution  inorganic acid, such as. B. performed hydrochloric acid. To improve solubility is expediently a water-miscible inert organic solvent added. Suitable organic solvents are e.g. B. alcohols such as methanol and Ethanol and ethers such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran will preferred applied. The cleavage is preferably at temperatures between 20 ° C and 80 ° C carried out. The silyl ether protecting groups are split off for example with tetrabutylammonium fluoride or with potassium fluoride in the presence of a Crown ether (such as Dibenzo [18] crown-6). As a solvent for example suitable tetrahydrofuran, diethyl ether, dioxane, dichloromethane, etc. The Cleavage is preferably carried out at temperatures between 0 ° C and 80 ° C.

The saponification of the acyl groups takes place, for example, with alkali or alkaline earth carbonates or hydroxides in an alcohol or in the aqueous solution of an alcohol. As alcohol are lower aliphatic alcohols, such as. B. methanol, ethanol, butanol etc., preferably methanol. As alkali carbonates and hydroxides are potassium and Called sodium salts. Potassium salts are preferred.

Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, calci umhydroxide and barium carbonate. The reaction takes place at -10 ° C to + 70 ° C, preferably at + 25 ° C.

The introduction of the ester group -COOR ₄ for R ₁ , in which R _{4 represents} an alkyl group with 1-10 C atoms, takes place according to the methods known to the person skilled in the art. The 1-carboxy compounds are reacted, for example, with diazo hydrocarbons in a manner known per se. The esterification with diazo hydrocarbons takes place, for. Example, that a solution of the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the 1-carboxy compound in the same or in another inert solvent, such as. B. methylene chloride mixed. When 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 -COOR ₄ for R ₁ in which R _{4 represents} a substituted or unsubstituted aryl group takes place according to the methods known to the person skilled in the art. For example, the 1-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine, dimethylaminopyridine, triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures between -30 ° C and + 50 ° C, preferably at 10 ° C.

If C = C double bonds contained in the primary product are to be reduced, the Hy takes place according to known methods.

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

The leukotriene B ₄ derivatives of the formula I with R ₄ meaning 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 stoichiometric amount of the base, after the water has been evaporated off or after the addition of a water-miscible solvent, for. As alcohol or acetone, the solid inorganic salt.

To produce an amino salt, LTB ₄ acid z. B. dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether, acetonitrile or benzene and at least the stoichiometric amount of the amine added to the solution. The salt is usually obtained in solid form or is isolated in a conventional manner after evaporation of the solvent.

The introduction of the amide group-CONHR ₅ with R ₅ in the meaning of alkanoyl takes place according to the methods known to the person skilled in the art. The carboxylic acids of the formula I (R ₄ = H) are first converted into the mixed anhydride in the presence of a tertiary amine, such as, for example, triethylamine, with isobutyl chloroformate. The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R ₅ = H) takes place in an inert solvent or solvent mixture, such as tetrahydrofutane, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide, at temperatures between -30 ° C and + 60 ° C , preferably at 0 ° C to 30 ° C. Another type of preparation for the amides is the amidolysis of the 1-ester (R ₁ = COOR ₄ ) with the corresponding amine.

A further possibility for the introduction of the amide group -CONHR ₅ consists in reacting a 1-carboxylic acid of the formula I (R ₄ = H), in which free hydroxyl groups are optionally protected as intermediates, with compounds of the formula IV,

O = C = NR ₅ (IV)

wherein R _{5 has} the meaning given above.

The reaction of the compound of formula I (R ₄ = H) with an isocyanate of formula IV, it optionally follows with the addition of a tertiary amine, such as. B. triethylamine or pyridine. The reaction can be carried out without a solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80 ° C to 100 ° C, preferably at 0 ° C to 30 ° C .

The desired amides can be prepared, for example, to produce the other amides React acid anhydrides with ammonia or the corresponding amines.

If the starting product contains OH groups in the leukotriene B ₄ residue, these OH groups are also reacted. If end products which contain free hydroxyl groups are ultimately desired, it is expedient to start from starting products in which they are temporarily protected by ether or acyl residues, which are preferably readily removable.

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

The compounds of the general formula II which serve as starting material can be prepared, for example, by known ketones of the general formula V,

wherein m has the meanings given above, reduced with sodium borohydride, the resulting alcohol converted to chloride with thionyl chloride, then hydrolyzed to nitrile with sodium cyanide and with sodium hydroxide solution followed by sulfuric acid to the acid of the general formula (VI). As an alternative to this route, it is also possible to add trimethylsilyl cyanide to the ketone of the general formula (V) and to react the resulting silylated cyanohydrin with zinc (II) chloride to give the acid of the general formula (VI).

The following ether cleavage is carried out with HBr, then the acid in the methyl ester and the phenolic OH group are reacted with a silyl chloride, for example with tert-butyldiphenylsilyl chloride, to give the silyl ether, and then the ester function in the α-position with a base, for example lithium diisopropylamide and a halide of the general formula (VII)

Hal-Y (VII),

wherein Hal is a chlorine, bromine or iodine atom and Y and m have the meaning given above, to convert to the ester of the general formula (VIII).

The ester of the general formula (VIII) is reduced with diisobutylaluminium hydride and then oxidized to the aldehyde of the general formula IX using the Collins reagent or by the Swern method (Tetrahedron Letters 34, 1651 (1978)).

The Wittig-Horner olefination of the aldehyde IX with the phosphonate of the formula X and a base and, if appropriate, subsequent hydrogenation and subsequent reduction of the ester group, oxidation of the primary alcohol, repeated Wittig-Horner olefination with the phosphonate of the formula X and, if appropriate, subsequent hydrogenation or Wittig-Horner reaction of the aldehyde IX with a phosphonate of the formula XI gives the ester of the general formula XII, where

wherein m, Y and A have the meanings given above. Suitable bases are, for example, potassium tert-butoxide, diazabicyclononane, diazabicycloundecane or sodium hydride. The reduction of the ester group, for example with diisobutyl aluminum hydride and subsequent oxidation of the primary alcohol obtained, for. B. with manganese dioxide or Collins reagent leads to the aldehyde of formula XIII.

The organometallic reaction of the aldehyde of the formula XIII with a Grignard reagent of the formula XIV, in which B, D

X-Mg-BDR ₃ (XIV)

and R _{3 has} the meanings given above and X denotes chlorine, bromine or iodine, optionally after protection of the hydroxyl groups (for example by acylation) and optionally diastereomer separation, leads to the compounds of the formula XV.

The compound of the formula XIV required for the organometallic reaction is prepared by reacting the corresponding terminal halide with magnesium. By reaction of the silyl ether XV with tetrabutylammonium fluoride, the phenol of the formula II is obtained, which can optionally be separated into the diastereomers:

The compounds of formula XV, in which B is a CH ₂ group and D is a -C∼C group or a CH = CR ₇ group, can be obtained, for example, by an organometallic reaction of a propargyl halide and subsequent alkylation with a corresponding one Alkyl halide and optionally subsequent Lindlar hydrogenation.

An alternative structure of the lower chain is based on the aldehyde of the formula XVI, which resulted from the Wittig-Horner reaction of the aldehyde IX and subsequent reduction and oxidation.

Wittig-Horner olefination of aldehyde XVI with a phosphonate of formula XVII

and reduction of the resulting ketone then led to the alcohol of formula XV can optionally be separated into the diastereomers. The now if necessary subsequent protection of the hydroxy group, for example by acylation, Silyl ether cleavage with tetrabutylammonium fluoride leads to the phenol of formula II.

The preparation of the phosphonates of the general formula XVII required for this reaction is described, for example, in DE 42 42 390 or is carried out in a manner known per se by reaction of an alkyl halide (which can be prepared from the corresponding alcohol by halogenation) of the general formula XVIII

Hal-DR ₃ (VIII)

with the dianion produced from phosphonate of the general formula XIX,

wherein B, D and R _{3 have} the meanings given above.

An alternative approach to the phosphonates of the general formula XVII is to react the anion of dimethyl methylphosphonate with an ester of the general formula XX,

R ₉ OOC-BDR ₃ (XX)

wherein R ₃ , B, D have the meanings given above and R _{9 is} an alkyl group having 1-5 C atoms. This ester can be obtained, for example, by alkylation with the corresponding halide.

The incorporation of the chemically and metabolically unstable cis-Δ ^6.7 double bond of the LTB ₄ into a cis-1,2-substituted cycloalkyl ring leads to stabilization, in particular by further derivatization of the functional groups and / or structural changes in the lower side chain, LTB ₄ derivatives were obtained which can act as LTB ₄ antagonists (DE-A 39 17 597 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 (LTB ₄ - nomenclature, counting starting from the carboxyl carbon atom with 1) in such leukotriene B ₄ 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 compounds are also suitable for lowering elevated triglyceride levels. They also have antifungal properties. Consequently, the new leukotriene B ₄ derivatives of the formula I are valuable pharmaceutical active ingredients. The compounds of the formula I are suitable for topical and oral administration.

The new leukotriene B ₄ 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, e.g. B .:
Contact dermatitis, various types of eczema, neurodermatoses, erythroderma, pruritis vulvae et ani, rosacea, erythermatodes cutaneus, psoriasis, lichen planus et verrucosus and similar skin diseases.

The new leukotriene B ₄ 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 adding the active ingredients to the desired application form with suitable additives, such as:
Solutions, ointments, creams or plasters, transferred.

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

In addition, the new compounds are optionally in combination with the usual carriers and auxiliaries also good for the production of inhalants suitable for the therapy of allergic diseases of the respiratory tract such as bronchial asthma or rhinitis.

Furthermore, the new leukotriene B ₄ 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 contained and 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 LTB ₄ derivatives are suitable not only for the treatment of diseases of internal organs with inflammatory processes, but also for the treatment of diseases in which, depending on the leukotriene, the focus is on increased growth and the formation of new cells. Examples are leukemia (increased growth of white blood cells) or arteriosclerosis (increased growth of smooth muscle cells from blood vessels).

The new leukotriene B ₄ derivatives can also in combination, such as. B. with lipoxygenase inhibitors, cyclooxygenase inhibitors, glucocorticoids, prostacyclin agonists, thromboxane antagonists, leukotriene D ₄ antagonists, leukotriene E ₄ antagonists, leukotriene F ₄ antagonists, phosphodiesterase inhibitors, calcium antagonists or other diseases, known antagonists, PAF therapies are used.

The following exemplary embodiments serve to explain the inventive method. The examples were not characterized in detail Diastereoisomers in the 12-position characterized as polar or non-polar.  

example 1 (±) -3-oxa-3 - {(3RS) -3-methyl-3 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl-1, 3-nonadien-8-ynyl] -indan-5-yl} -propanoic acid tert-butyl ester (diastereomer A)

521 mg of cesium carbonate followed by 0.26 ml of tert-butyl bromoacetate are added to a solution of 399 mg of the diol (diastereomer A) prepared in Example 1 n) in 3 ml of DMF and the mixture is stirred for 16 hours under argon at room temperature. Then the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is then washed with half-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, 231 mg of the title compound is obtained as a colorless oil.
IR (film): 3448, 2975, 2880, 1755, 1607, 1490, 1442, 1368, 1368, 1223, 1153, 992, 846, 757, 692 cm ^-1 .

The starting material for the above title compound is prepared as follows:

1a) (±) -6-methoxy-1-trimethylsilyloxy-indan-1-yl-carbonitrile

75 g of trimethylsilyl cyanide are carefully added dropwise to 44.9 g of 6-methoxy-1-indanone and 1.76 g of zinc iodide under nitrogen and the mixture is stirred at 22 ° C. for 20 hours. The reaction mixture is then carefully poured onto a saturated sodium hydrogen carbonate solution and extracted three times with methylene chloride. The combined organic phases are dried over sodium sulfate and, after filtration, is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-40% ether, 33.7 g of the title compound is obtained as a colorless oil.
IR (film): 3019, 2959, 2840, 2400, 1608, 1500, 1256, 1213, 1128, 1021, 902, 847, 764 cm ^-1 .

1b) (±) -6-methoxy-indan-1-yl-carboxylic acid

To a mixture of 33.6 g of the nitrile prepared in Example 1a) in 261 ml of a mixture of glacial acetic acid and concentrated hydrochloric acid in a ratio of 1: 1 are added 131 g of tin (II) chloride.2 H ₂ O and heated at 140 ° C for 6 hours Bath temperature. After cooling, the reaction mixture is poured into water and extracted three times with methylene chloride. The combined organic phases are washed with 2N potassium hydroxide solution, then this aqueous phase is extracted twice with ether and then acidified with cooling with dilute sulfuric acid. The acidified aqueous phase is extracted three times with methylene chloride. The combined organic phases are dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is mixed with toluene, heated and filtered hot from the residue. After concentrating the filtrate in vacuo, 25.7 g of the title compound are obtained as a colorless oil.
IR (film): 3100 (wide), 2938, 2850, 1713, 1610, 1504, 1413, 1261, 1124, 1039, 834 cm ^-1 .

1c) (±) -6-Hydroxy-indan-1-yl-carboxylic acid

25.7 g of the compound from Example 1b) prepared above is heated together with 134 ml of 47% HBr under reflux for 20 hours. After cooling, the reaction mixture is carefully poured onto ice water. It is extracted three times with ethyl acetate, the combined organic phases are washed once with semi-saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is recrystallized from hexane / toluene. 17.2 g of the crystalline title compound are obtained (melting point: 158 ° C.).
IR (CHCl ₃ ): 3570, 3320 (broad), 3008, 2955, 2860, 1705, 1610, 1498, 1429, 1256, 1191, 1035 cm ^-1 .

1d) (±) -6-Hydroxy-indan-1-yl-carboxylic acid methyl ester

14.6 g of potassium carbonate are added to a solution of 17.1 g of the hydroxy acid prepared in Example 1c) in 108 ml of acetone under nitrogen, followed by 6.55 ml of methyl iodide. After 19 hours of stirring at 22 ° C., the solid constituents are filtered off and the filtrate is concentrated in vacuo. The residue is taken up in ether and washed with half-concentrated sodium chloride solution. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is recrystallized from hexane / ether. 16.1 g of the crystalline title compound are obtained (melting point: 71 ° C.).
IR (CHCl ₃ ): 3580, 3300 (broad), 3008, 2955, 2860, 1727, 1609, 1498, 1429, 1255, 1193, 1039 cm ^-1 .

1e) (±) -6- (Diphenyl-tert-butyl-silyloxy) -indan-1-yl-carboxylic acid methyl ester

To a solution of 16.1 g of the hydroxy ester prepared in Example 1d) in 225 ml of dimethylformamide is added 13.8 g of imidazole under nitrogen at 22 ° C., followed by 27.7 g of diphenyl-tert-butyl-silyl chloride and the mixture is stirred for 20 hours at this temperature. The reaction mixture is then diluted with ether, washed with water and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-60% ether, 27.3 g of the title compound is obtained as a colorless oil.
IR (film): 3071, 2953, 2857, 1740, 1607, 1489, 1428, 1283, 1240, 1198, 1114, 967, 860, 821, 743, 701 cm ^-1 .

1f) (±) -1-methyl-6- (diphenyl-tert-butyl-silyloxy) -indan-1-yl-carboxylic acid methyl ester

A solution of 7.35 g of diisopropylamine in 36 ml of tetrahydrofuran is added dropwise to 45 ml of a 1.6 M solution of butyllithium in hexane under nitrogen at 0 ° C. and the mixture is stirred for 30 minutes at this temperature. The mixture is then cooled to -70 ° C. and a solution of 27.2 g of the compound prepared in Example 1e) in 40 ml of tetrahydrofuran is added dropwise. After stirring for one hour at -70 ° C., 31.3 g of methyl iodide in 108 ml of DMPU (N, N-dimethylpropyleneurea) are added, the mixture is allowed to warm to 0 ° C. in the course of one hour and stirred at this temperature for a further hour. Then the reaction mixture is poured onto a saturated ammonium chloride solution and extracted three times with ether. The combined organic phases are washed with half-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 / 10% ether, 22.3 g of the title compound is obtained as a colorless oil.
IR (film): 3071, 2932, 2857, 1732, 1607, 1582, 1487, 1428, 1284, 1114, 1055, 957,853, 822, 743, 704 cm ^-1 .

1g) (±) -1-methyl-6- (diphenyl-tert-butyl-silyloxy) indan-1-yl-methanol

96 ml of a 1.2M DIBAH solution in toluene are added to a solution of 22.2 g of the ester prepared in Example 1f) in 250 ml of toluene under nitrogen at -70 ° C. and the mixture is stirred for one hour at this temperature. Then carefully 34 ml of isopropanol followed by 48 ml of water are added to the reaction mixture, allowed to come to 22 ° C. and stirred at this temperature for 2 hours. The solid constituents are then suctioned off, washed well with ethyl acetate and the filtrate is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-70% ether, 17.8 g of the title compound is obtained as a colorless oil.
IR (film): 3596, 3400 (wide), 3070, 2930, 2858, 1609, 1482, 1427, 1293, 1107, 1030, 958, 844, 820, 739, 699 cm ^-1 .

1h) (±) -1-methyl-6- (diphenyl-tert-butyl-silyloxy) -indan-1-yl-carbaldehyde

5.54 ml of dimethyl sulfoxide in 30 ml of methylene chloride are slowly added dropwise to a solution of 3.08 ml of oxalyl chloride in 23.4 ml of methylene chloride at -70 ° C. under nitrogen. After 10 minutes, 12 g of the alcohol prepared in Example 1g) are rapidly added dropwise in 21 ml of methylene chloride and the mixture is stirred at -70 ° C. for 1.5 hours. Then 11.2 ml of triethylamine are added and, after stirring for 1.5 hours, the reaction mixture is poured into ice water. After phase separation, the aqueous phase is extracted three times with 100 ml each time with methylene chloride. The combined organic phases are washed once with 10% sulfuric acid, once with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. After drying over sodium sulfate, it is concentrated in vacuo after filtration. The crude product thus obtained crystallizes (melting point: 78-80 ° C.) and is used in the next step without further purification.
IR (film): 3072, 2931, 2858, 2707, 1724, 1607, 1485, 1428, 1285, 1191, 1114, 1057, 956, 845, 822, 741, 701 cm ^-1 .

1i) (±) - (E) -3- [1-methyl-6- (diphenyl-tert-butylsilyloxy) indan-1-yl] propenoic acid ethyl ester

7.87 ml of triethyl phosphonoacetate and 5.3 ml of DBU are added dropwise to a suspension of 1.69 g of lithium chloride in 120 ml of acetonitrile at 22 ° C. under nitrogen. After stirring for 10 minutes, a solution of 11.8 g of the aldehyde prepared in Example 1h) in 20 ml of acetonitrile is added dropwise to the reaction mixture and the mixture is stirred for 3 hours. The reaction mixture is concentrated in vacuo to about 30% of the volume and then poured into water. The aqueous phase is extracted four times with a mixture of hexane and ether in a ratio of 1: 1 and the organic phases are dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ether, 4.2 g of the title compound is obtained as a colorless oil.
IR (film): 3082, 2959, 2858, 1720, 1647, 1608, 1484, 1428, 1277, 1178, 1114, 1038, 959, 847, 822, 742, 701 cm ^-1 .

1j) (±) - (E) -3- [1-methyl-6- (diphenyl-tert-butylsilyloxy) indan-1-yl] prop-2-en-1-ol

To a solution of 4.2 g of the ester prepared in Example 1i) in 50 ml of toluene, 15 ml of a 1.2M DIBAH solution in toluene are added under nitrogen at -70 ° C. and the mixture is stirred for one hour at this temperature. Then carefully 10 ml of isopropanol followed by 7.5 ml of water are added to the reaction mixture, the mixture is allowed to come to 22 ° C. and the mixture is stirred at this temperature for 2 hours. The solid constituents are then suctioned off, washed well with ethyl acetate and the filtrate is concentrated in vacuo. This gives 4.0 g of the desired title compound, which is used in the next step without further purification.
IR (film): 3345, 3071, 2957, 2858, 1608, 1483, 1428, 1286, 1167, 1114, 1050, 970, 853, 822, 742, 701 cm ^-1 .

1k) (±) - (E) -3- [1-methyl-6- (diphenyl-tert-butylsilyloxy) indan-1-yl] propenal

7.85 g of manganese dioxide are added in portions to a solution of 4.0 g of the alcohol prepared in Example 1j) in 45 ml of toluene at 22 ° C. under nitrogen over the course of 2 hours. After stirring for a further 2 hours at this temperature, the mixture is filtered through Celite, washed well with ethyl acetate and the filtrate is concentrated in vacuo. In this way, 3.8 g of the desired title compound are obtained as a pale yellow-colored oil which is used in the next step without further purification.
IR (film): 3071, 2958, 2858, 1692, 1608, 1484, 1428, 1285, 1189, 1114, 1050, 960, 855, 822, 742, 701 cm ^-1 .

1l) (±) - (1E, 3E) -1- [1-methyl-6- (diphenyl-tert-butylsilyloxy) indan-1-yl] -6,6-trimethylene-9- phenyl-1,3-nonadien-8-in-5-one

A solution of 3.2 g of 2-oxo-3,3-trimethylene-6-phenyl-hex-5-in-1 is added dropwise at 0 ° C. to a suspension of 399 mg of sodium hydride (60% suspension in mineral oil) in 14 ml of dimethoxyethane. phosphonic acid dimethyl ester in 22 ml of dimethoxyethane and stirred for 1 hour at 0 ° C. A solution of 3.8 g of the aldehyde prepared in Example 1k) in 22 ml of dimethoxyethane is then added dropwise and the mixture is stirred at room temperature for 16 hours. The reaction mixture is poured onto saturated ammonium chloride solution and extracted with ether. The combined organic phases are washed once with a half-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 / 0-40% ether, 4.2 g of the title compound is obtained as a colorless oil.
IR (film): 3071, 2956, 2858, 1681, 1624, 1593, 1484, 1428, 1282, 1114, 1050, 1005, 959, 852, 822, 756, 743, 701 cm ^-1 .

1m) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-6- (diphenyl-tert-butyl-silyloxy) -indan-1-yl] -6.6- trimethylene-9-phenyl-1,3-nonadien-8-in-5-ol

364 mg of CeCl ₃ .6 H ₂ O are added to a solution of 4.18 g of the ketone prepared in Example 1l) in a mixture of 53 ml of methanol and 25 ml of tetrahydrofuran at -70 ° C. and the mixture is stirred for 20 minutes at this temperature . Then 369 mg of sodium borohydride are added, stirring is first carried out at -70 ° C. for 1.5 hours and at -40 ° C. for a further 30 minutes. Then 2.6 ml of acetone are added to the reaction mixture and after 20 minutes 0.55 ml of glacial acetic acid. After concentration in vacuo, the residue is mixed with water and extracted three times with ether. The combined organic phases are washed twice with 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 / 0-70% ether, 3.7 g of the title compound is obtained as a colorless oil.
IR (film): 3442 (wide), 3082, 2932, 2858, 1608, 1483, 1428, 1282, 1187, 1114, 1050, 991, 960, 851, 822, 756, 743, 701 cm ^-1 .

1n) (±) - (1E, 3E) - (5R or 5S) -1 - [(1RS) -1-methyl-6- (hydroxy) -indan-1-yl] -6,6-trimethylene-9- phenyl-1,3-nonadien-8-in-5-ol (diastereomer A)

5.48 g of tetrabutylammonium fluoride trihydrate are added to a solution of 3.7 g of the alcohol prepared in Example 1m) in 40 ml of tetrahydrofuran and the mixture is stirred for three hours at room temperature. It is then diluted with ether and washed once with water. The ethereal phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is separated and purified by repeated chromatography on silica gel. With hexane / 0-70% ethyl acetate, in addition to 630 mg of a mixed fraction of the following two compounds, 1.18 g of the title compound (diastereomer A) as a non-polar component and 407 mg (±) - (1E, 3E) - (5S or 5R) -1 - [(1RS) -1-methyl-6- (hydroxy) indan-1-yl] -6,6-trimethylene-9-phenyl-1,3-nonadien-8-in-5-ol (diastereomer B) as a polar component as colorless oils.
IR (film, diastereomer A): 3363 (broad), 3020, 2956, 2856, 1610, 1490, 1463, 1428, 1269, 1114, 991, 820, 756, 702 cm ^-1 .
IR (film, diastereomer B): 3358 (broad), 3020, 2956, 2856, 1610, 1490, 1461, 1428, 1269, 1114, 990, 820, 756, 702 cm ^-1 .

Example 2 (±) -3-oxa-3 - {(3RS) -3-methyl-3 - [(1E, 3E) - (5S or 5R) -5-hydroxy-6,6-trimethylene-9-phenyl-1, 3-nonadien-8-ynyl] -indan-5-yl} -propanoic acid tert-butyl ester (diastereomer B)

Analogously to Example 1), 397 mg of the diol (diastereomer B) prepared under Example 1n) gives 317 mg of the title compound as a colorless oil.
IR (film): 3498, 2980, 2934, 1753, 1607, 1490, 1368, 1223, 1154, 1095, 992, 846, 820, 757 cm ^-1 .

Example 3 (±) -5-oxa-5 - {(3RS) -3-methyl-3 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl-1, 3-nonadien-8-ynyl] -indan-6-yl} methyl pentanoate (diastereomer A)

244 mg of cesium carbonate followed by 0.13 ml of 1,1,1-trimethoxy-4-bromobutane are added to a solution of 199 mg of the diol (diastereomer A) prepared in Example 1n) in 2 ml of dimethylformamide, and the mixture is stirred for 20 hours under argon Room temperature. The reaction mixture is then poured into water, the pH is adjusted to between 5 and 6 using 10% strength sulfuric acid and the mixture is extracted three times 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 / 0-50% ether, 132 mg of the title compound is obtained as a colorless oil.
IR (film): 3462 (wide), 2980, 2951, 1738, 1607, 1490, 1441, 1287, 1173, 1117, 1060, 992, 757 cm ^-1 .

Example 4 (±) -3 - {{(3RS) -3-Methyl-3 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -indan-5-yl} -methyloxy} -benzoic acid methyl ester (diastereomer A)

Analogously to Example 1), from 201 mg of the diol (diastereomer A) prepared under Example 1n) and 172 mg of methyl 3-bromomethylbenzoate, 155 mg of the title compound are obtained as a colorless oil.
IR (film): 3500 (wide), 2950, 2865, 1716, 1607, 1488, 1434, 1383, 1285, 1208, 1107, 992, 818, 752 cm ^-1 .

Example 5 (±) -4 {{(3RS) -3-Methyl-3 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -indan-5-yl} -methyloxy} -benzoic acid methyl ester (diastereomer A)

Analogously to Example 1), from 200 mg of the diol (diastereomer A) prepared under Example 1n) and 172 mg of methyl 4-bromomethylbenzoate, 171 mg of the title compound is obtained as a colorless oil.
IR (film): 3440 (wide), 3065, 2919, 2855, 1732, 1652, 1614, 1455, 1384, 1263, 1157, 1100, 997, 818, 756 cm ^-1 .

Example 6 (±) -3-Oxa-3 {(5RS) -5-methyl-5 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid tert-butyl ester

Analogously to Example 1), from 300 mg of the diol prepared under Example 6n) and 213 mg of tert-butyl bromoacetic acid, 275 mg of the title compound are obtained as a colorless oil.
IR (film): 3500 (wide), 2932, 2859, 1755, 1607, 1494, 1442, 1369, 1223, 1151, 1078, 993, 844, 757 cm ^-1 .

The starting material for the above title compound is prepared as follows:

6a) (±) -6-methoxy-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphth-1-yl-carbonitrile

In analogy to Example 1a), 13.7 g of the title compound is obtained from 10.5 g of 6-methoxy-1-tetralone after recrystallization from hexane as colorless crystals.
Melting point: 68-70 ° C
IR (CHCl ₃ ): 3008, 2957, 2839, 2135, 1608, 1577, 1500, 1465, 1326, 1256, 1171, 1128, 1072, 1039, 1021, 902, 846 cm ^-1 .

6b) (±) -6-methoxy-1,2,3,4-tetrahydronaphth-1-yl-carboxylic acid

Analogously to Example 1b), from 34 g of the nitrile prepared in Example 6a), 13.9 g of the title compound are obtained as colorless crystals after recrystallization from methyl tert-butyl ether.
Melting point: 87-91 ° C
IR (film): 3100 (wide), 2938, 1713, 1610, 1504, 1413, 1261, 1165, 1124, 1039, 931, 836 cm ^-1 .

6c) (±) -6-Hydroxy-1,2,3,4-tetrahydronaphth-1-yl-carboxylic acid

Analogously to Example 1c), 20.3 g of the acid prepared in Example 6b) gives 16.3 g of the title compound after recrystallization from toluene / ether as colorless crystals.
Melting point: 131-133 ° C
IR (KBr): 3458, 3065 (broad), 2964, 2920, 1687, 1617, 1519, 1438, 1280, 1220, 1113, 914, 838, 796 cm ^-1 .

6d) (±) -6-Hydroxy-1,2,3,4-tetrahydronaphth-1-yl-carboxylic acid methyl ester

Analogously to Example 1d), 16.6 g of the acid prepared in Example 6c) gives 13.6 g of the title compound as a colorless oil.
IR (film): 3393, 3020, 2950, 2920, 1709, 1607, 1512, 1496, 1322, 1212, 1169, 994, 838 cm ^-1 .

6e) (±) -6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl- carboxylic acid methyl ester

Analogously to Example 1e), 27.5 g of the title compound are obtained as a colorless oil from 13.2 g of the ester prepared in Example 6d).
IR (film): 3075, 2933, 2863, 1738, 1607, 1500, 1428, 1261, 1162, 1114, 970, 823, 743, 701 cm ^-1 .

6f) (±) -1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl- carboxylic acid methyl ester

Analogously to Example 1f), 21.8 g of the title compound are obtained as a colorless oil from 22.0 g of the ester prepared in Example 6e).
IR (film): 3074, 2932, 2858, 1729, 1606, 1498, 1428, 1287, 1255, 1162, 1114, 988, 960, 823, 743, 701 cm ^-1 .

6g) (±) -1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl-methanol

Analogously to Example 1g), 20.6 g of the title compound are obtained as a colorless oil from 23.0 g of the ester prepared in Example 6f).
IR (film): 3585, 3410 (wide), 2932, 2858, 1607, 1495, 1428, 1285, 1161, 1114, 987, 959, 836, 822, 742, 701 cm ^-1 .

6h) (± -) - 1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl- carbaldehyde

Analogously to Example 1h), 19.0 g of the title compound are obtained as a colorless oil from 20.2 g of the alcohol prepared in Example 6g).
IR (film): 3071, 2932, 2858, 2707, 1723, 1605, 1496, 1472, 1428, 1286, 1256, 1114, 983, 954, 850, 823, 740, 701 cm ^-1 .

6i) (±) - (E) -3- [1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - ethyl propenate

Analogously to Example 1i), 17.5 g of the title compound are obtained as a colorless oil from 19.0 g of the aldehyde prepared in Example 6h).
IR (film): 3072, 2932, 2858, 1719, 1646, 1606, 1497, 1472, 1428, 1304, 1252, 1174, 1114, 1038, 987, 960, 850, 824, 743, 701 cm ^-1 .

6j) (±) - (E) -3- [1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - prop-2-en-1-ol

Analogously to Example 1j), 15.5 g of the title compound is obtained as a colorless oil from 17.35 g of the ester prepared in Example 6i).
IR (film): 3346 (wide), 3071, 2931, 2858, 1607, 1496, 1428, 1251, 1114, 986, 957, 824, 742, 701 cm ^-1 .

6k) (±) - (E) -3- [1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - propenal

Analogously to Example 1k), 3.38 g of the title compound is obtained from 4.42 g of the alcohol prepared in Example 6j) as a slightly yellow-colored oil.
IR (film): 3072, 2932, 2858, 2720, 1693, 1606, 1496, 1472, 1428, 1255, 1114, 986, 960, 824, 742, 702 cm ^-1 .

6l) (±) - (1E, 3E) -1- [1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - 6,6-trimethylene-9-phenyl-1,3-nonadien-8-in-5-one

Analogously to Example 1l), 3.38 g of the aldehyde prepared in Example 6k) and 3.09 g of 2-oxo-3,3-trimethylene-6-phenyl-hex-5-in-phosphonic acid dimethyl ester give 3.5 g of the title compound as a colorless oil .
IR (KBr): 3075, 2940, 2860, 1685, 1612, 1503, 1426, 1334, 1275, 1114, 989, 823, 756, 701 cm ^-1 .

6m) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-6- (diphenyl-tert-butyl-silyloxy) -1,2,3,4- tetrahydronaphth-1-yl -] - 6,6-trimethylene-9-phenyl-1,3-nonadien-8-in-5-ol

Analogously to Example 1m), 3.2 g of the title compound are obtained as a colorless oil from 3.5 g of the ketone prepared in Example 6l).
IR (KBr): 3435 (broad), 3075, 2935, 2860, 1605, 1496, 1427, 1296, 1277, 1253, 1113, 988, 824, 757, 702 cm ^-1 .

6n) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-6-hydroxy-1,2,3,4-tetrahydronaphth-1-yl -] - 6.6 - trimethylene-9-phenyl-1,3-nonadien-8-in-5-ol

Analogously to Example 1n), 1.36 g of the title compound is obtained as a colorless oil from 2.0 g of the alcohol prepared in Example 6m).
IR (film): 3375 (wide), 2931, 2865, 1610, 1582, 1490, 1442, 1374, 1249, 1154, 1099 1045, 992, 757 cm ^-1 .

Example 7 (±) -5-Oxa-5 - {(5RS) -5-methyl-5 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- - nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} pentanoic acid methyl ester

In analogy to Example 3), 320 mg of the diol prepared under Example 6n) and 248 mg of 1,1,1-trimethoxy-4-bromobutane are used to obtain 320 mg of the title compound as a colorless oil.
IR (film): 3500 (wide), 2930, 2850, 1732, 1607, 1494, 1442, 1367, 1312, 1241, 1169, 993, 838, 757 cm ^-1 .

Example 8 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-acetoxy-6,6-trimethylene-9-phenyl-1,3- tert-butyl nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoate

Analogously to Example 1), 5.5 g of the title compound are obtained as a colorless oil from 4.43 g of the phenol prepared under Example 8m) and 3.8 g of tert-butyl bromoacetic acid.
IR (film): 2978, 2933, 1754, 1609, 1492, 1442, 1369, 1303, 1233, 1153, 1085, 1020, 993, 845, 757 cm ^-1 .

The starting material for the above title compound is prepared as follows:

8a) (±) -7-methoxy-1,2,3,4-tetrahydronaphth-1-yl-carbonitrile

A solution of 60.38 g of 7-methoxy-1-tetralone in 2.3 l of methanol is added Argon at 0 ° C add 15.56 g sodium borohydride and stir for 2 hours at 0 ° C. Then it will be mixed with 100 ml of glacial acetic acid, concentrated in vacuo, diluted with 500 ml of water and extracted three times with ethyl acetate. The combined organic phases are washed once with semi-concentrated sodium chloride solution, dries over sodium sulfate and  after filtration in a vacuum. The alcohol thus obtained is used without further ado Cleaning in the next stage.

A solution of 60.5 g of the alcohol previously prepared in 650 ml of ether is added 40 ml of thionyl chloride slowly under argon at 0 ° C. After stirring for 18 hours, add the reaction mixture on 700 ml of ice water and extracted three times with ethyl acetate. The combined organic phases are washed once with semi-concentrated Sodium chloride solution, dries over sodium sulfate and, after filtration, evaporates in vacuo a. The chloride thus obtained is used in the next step without further purification.

32.9 g of sodium cyanide are added to a solution of 66.1 g of the previously prepared chloride in 137 ml of DMPU under argon and the mixture is heated at 85 ° C. for 18 hours. After cooling, it is diluted with ether, washed three times with water and once with semi-concentrated sodium chloride solution. It is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ethyl acetate, 42.75 g of the title compound is obtained as a colorless oil.
IR (CHCl ₃ ): 2950, 2841, 2221, 1613, 1503, 1464, 1323, 1284, 1248, 1034, 848 cm ^-1 .

8b) (±) -7-Hydroxy-1,2,3,4-tetrahydronaphth-1-yl-carboxylic acid methyl ester

145 ml of 40% potassium hydroxide solution are added to a solution of 42.75 g of the nitrile prepared in Example 8a) in 56 ml of ethanol and the mixture is heated under reflux for 20 hours. After cooling with conc. Acidified hydrochloric acid, stirred with ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic phases are washed once with half-concentrated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is recrystallized from hexane / toluene and 30.88 g of 7-methoxy-5,6,7,8-tetrahydronaphth-8-yl-carboxamide are obtained as a crystalline compound.
Melting point: 159 ° C
IR (CHCl ₃ ): 3518, 3400, 2998, 2935, 2839, 1673, 1610, 1575, 1502, 1464, 1255, 1036, 827 cm ^-1 .

A suspension of 15.3 g of the previously prepared amide in 300 ml of 20% sulfuric acid is heated under reflux for 18 hours. After cooling, add 250 ml of ice water and extract three times with ethyl acetate. The combined organic phases are washed once with half-concentrated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is used in the next step without further purification.
IR (CHCl ₃ ): 3080 (broad), 2945, 2840, 1706, 1612, 1504, 1466, 1409, 1283, 1255, 1124, 1037 cm ^-1 .

22.2 g of the acid prepared beforehand are mixed with 111 ml of 47% HBr solution and heated to 140-150 ° C. for 20 hours. After cooling, the reaction mixture is poured into 250 ml of ice water and extracted three times with ethyl acetate. The combined organic phases are washed once with half-concentrated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. (±) -7-Hydroxy-1,2,3,4-tetrahydronaphth-1-yl-carboxylic acid is obtained as a residue, which is used in the next step without further purification.
IR (CHCl ₃ ): 3600, 3310 (broad), 3020, 2945, 2865, 1707, 1612, 1508, 1450, 1290, 1260, 1193, 1038 cm ^-1 .

18.4 g of potassium carbonate and 8.3 ml of methyl iodide are added to a solution of 24.4 g of the acid previously prepared in 75 ml of DMSO and 170 ml of acetone, and the mixture is stirred at room temperature for 18 hours. It is then suctioned off from solid constituents, washed well with ethyl acetate and concentrated in vacuo. The residue is diluted with 300 ml of ether and washed once each with water and saturated sodium chloride solution. After drying over sodium sulfate, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-70% ethyl acetate, 16.68 g of the title compound is obtained as a colorless oil.
IR (CHCl ₃ ): 3600, 3330 (broad), 3008, 2955, 2865, 1728, 1612, 1503, 1451, 1436, 1258, 1194, 1165 cm ^-1 .

8c) (±) -7- (Diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl-carboxylic acid methyl ester

Analogously to Example 1e), 21.3 g of the title compound are obtained as a colorless oil from 11.7 g of the ester prepared in Example 8b).
IR (film): 2933, 2858, 1739, 1607, 1500, 1472, 1428, 1300, 1257, 1194, 1161, 1114, 997, 961, 822, 743, 702 cm ^-1 .

8d) (±) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl- carboxylic acid methyl ester

Analogously to Example 1f), 20.2 g of the title compound are obtained as a colorless oil from 16.7 g of the ester prepared in Example 8c).
IR (film): 3065, 2933, 2858, 1731, 1608, 1499, 1428, 1308, 1248, 1192, 1113, 983, 958, 824, 742, 701 cm ^-1 .

8e) (±) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl-methanol

Analogously to Example 1g), 14.9 g of the title compound are obtained as a colorless oil from 20.2 g of the ester prepared in Example 8d).
IR (film): 3587, 3406 (wide), 2931, 2859, 1606, 1494, 1428, 1306, 1245, 1191, 1114, 1035, 960, 835, 822, 742, 701 cm ^-1 .

8f) (±) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl-carbaldehyde

71.5 g of Collins reagent (Tetrahedron Letters 1968, 3363) are added to a solution of 14.3 g of the alcohol prepared in Example 8e) in 840 ml at 0 ° C. under argon and the mixture is stirred for 2 hours at this temperature. Then it is suctioned off through Celite, washed thoroughly with ether and the filtrate is concentrated in vacuo. In this way 14 g of the title compound are obtained as a slightly yellow colored oil, which is used in the next step without further purification.
IR (film): 3074, 2932, 2858, 2696, 1724, 1606, 1496, 1428, 1304, 1273, 1246, 1114, 971, 822, 731, 701 cm ^-1 .

8g) (±) - (E) -3- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - ethyl propenate

Analogously to Example 1i), 14.3 g of the aldehyde prepared in Example 8f) gives 11.3 g of the title compound as a colorless oil.
IR (film): 3071, 2932, 2858, 1719, 1646, 1607, 1494, 1428, 1306, 1270, 1244, 1177, 1114, 1038, 975, 957, 823, 742, 701 cm ^-1 .

8h) (±) - (E) -3- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - prop-2-en-1-ol

Analogously to Example 1j), 9.67 g of the title compound is obtained as a colorless oil from 11.28 g of the ester prepared in Example 8g).
IR (film): 3384 (wide), 3071, 2930, 2858, 1606, 1493, 1472, 1428, 1302, 1270, 1243, 1114, 974, 823, 742, 701 cm ^-1 .

8i) (±) - (E) -3- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - propenal

Analogously to Example 1k), 9.5 g of the title compound is obtained from 9.66 g of the alcohol prepared in Example 8h) as a slightly yellow-colored oil.
IR (film): 3068, 2931, 2858, 2720, 1691, 1606, 1495, 1428, 1272, 1246, 1114, 975, 956, 825, 732, 701 cm ^-1 .

8j) (±) - (1E, 3E) -1- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl -] - 6,6-trimethylene-9-phenyl-1,3-nonadien-8-in-5-one

Analogously to Example 1l), 9.58 g of the aldehyde prepared in Example 8i) and 5.52 g of 2-oxo-3,3-trimethylene-6-phenyl-hex-5-in-phosphonic acid dimethyl ester give 7.68 g of the title compound as a colorless oil.
IR (film): 3068, 2969, 2850, 1682, 1614, 1504, 1425, 1338, 1243, 1113, 1050, 1014, 969, 950, 822, 757, 706 cm ^-1 .

8k) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4- tetrahydronaphth-1-yl -] - 6,6-trimethylene-9-phenyl-1,3-nonadien-8-in-5-ol

Analogously to Example 1m), 6.86 g of the title compound is obtained as a colorless oil from 7.68 g of the ketone prepared in Example 8j).
IR (film): 3444 (wide), 3020, 2931, 2852, 1606, 1494, 1428, 1300, 1243, 1114, 992, 824, 756, 742, 701 cm ^-1 .

8l) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4- tetrahydronaphth-1-yl -] - 5-acetoxy-6,6-trimethylene-9-phenyl-1,3-nonadien-8-in

8.2 ml of acetic anhydride are added to a solution of 6.83 g of the alcohol prepared in Example 8k) in 16.4 ml of pyridine under argon and the reaction mixture is kept at 5 ° C. for 18 hours. The mixture is then concentrated in vacuo several times after the addition of toluene. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-10% ether, 6.73 g of the title compound is obtained as a colorless oil.
IR (film): 3069, 2932, 2858, 1733, 1606, 1492, 1428, 1370, 1267, 1240, 1114, 992, 958, 824, 739, 702 cm ^-1 .

8m) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7-hydroxy-1,2,3,4-tetrahydronaphth-1-yl -] - 5- acetoxy-6,6-trimethylene-9-phenyl-1,3-nonadiene-8-in

Analogously to Example 1n), from 6.71 g of the acetate prepared in Example 8l), 4.4 g of the title compound is obtained as a colorless oil.
IR (film): 3417 (wide), 3024, 2929, 2870, 1732, 1652, 1614, 1582, 1494, 1434, 1372, 1258, 1099, 992, 920, 870, 810, 757, 716 cm ^-1 .

Example 9 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-7- (p-biphenyl) - 1.3- heptadienyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid tert-butyl ester

Analogously to Example 1), 333 mg of the title compound are obtained as a colorless oil from 300 mg of the phenol prepared under Example 9e) and 151 mg of tert-butyl bromoacetic acid.
IR (KBr): 3340 (broad), 3027, 2938, 2861, 1752, 1608, 1487, 1366, 1218, 1152, 1082, 990, 843, 764, 738 cm ^-1 .

The starting material for the above title compound is prepared as follows:

9a) 2,2-Trimethylene-3- (p-biphenyl) propanoic acid ethyl ester

A solution of 14.1 g of diisopropylamine in 55 ml of tetrahydrofuran is added to 86.2 ml of a 1.6M solution of butyllithium in hexane at -10 ° C. After stirring for 30 minutes, 15.6 g of ethyl cyclobutane carboxylate in 36 ml of tetrahydrofuran are added at 60 ° C. and the mixture is stirred at this temperature for 1.5 hours. A solution of 30.0 g of the p-phenylbenzyl bromide in 36 ml of tetrahydrofuran is then added and the mixture is stirred for a further 2 hours. The reaction mixture is then added to 300 ml of saturated ammonium chloride solution and extracted three times with ether. The combined organic phases are washed once with water and once with half-concentrated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue obtained in this way is purified by double flash chromatography on silica gel. With hexane / 2% ether, 19.57 g of the title compound is obtained as a colorless oil.
IR (KBr): 3035, 2940, 2850, 1732, 1483, 1319, 1241, 1182, 1113, 1078, 847, 757 cm ^-1 .

9b) 2-Oxo-3,3-trimethylene-4- (p-biphenyl) -phosphonic acid dimethyl ester

A solution of 10.5 g of diisopropylamine in 9.7 ml of tetrahydrofuran is added to 59.2 ml of a 1.6M solution of butyllithium in hexane at -10 ° C. After stirring for 10 minutes, 8.24 g of dimethyl methanephosphonate in 9.4 ml of tetrahydrofuran are added at -60 ° C. and the mixture is stirred for 10 minutes. A solution of 19.56 g of the ester prepared in Example 9a) in 8.7 ml of tetrahydrofuran is then added dropwise, the temperature is brought to 0 ° C. in the course of one hour and the mixture is stirred at this temperature for one hour. The pH is then adjusted to 2 using half-concentrated hydrochloric acid, the phases are separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed once with half-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 / 60% ethyl acetate, 19.57 g of the title compound is obtained as a colorless oil.
IR (KBr): 3030, 2950, 2845, 1700, 1485, 1240, 1057, 1031, 1004, 944, 862, 850, 828, 762, 736 cm ^-1 .

9c) (±) - (1E, 3E) -1- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl- ] -6,6-trimethylene-7- (p-biphenyl) -1,3-heptadien-5-one

Analogously to Example 1l), 2.55 g of the title compound is obtained as a colorless oil from 2.0 g of the aldehyde prepared in Example 8i) and 1.88 g of 2-oxo-3,3-trimethylene-4- (p-biphenyl) butanephosphonate.
IR (KBr): 3022, 2927, 2830, 1675, 1620, 1588, 1490, 1423, 1268, 1240, 1112, 1004, 973, 955, 822, 758, 738 cm ^-1 .

9d) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4- tetrahydronaphth-1-yl -] - 6,6-trimethylene-7- (p-biphenyl) -1,3-heptadien-5-ol

Analogously to Example 1m), 2.34 g of the title compound is obtained as a colorless oil from 2.54 g of the ketone prepared in Example 9c).
IR (KBr): 3580, 3450 (broad), 3030, 2930, 2858, 1604, 1489, 1427, 1268, 1240, 1115, 988, 824, 765, 739 cm ^-1 .

9e) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7-hydroxy-1,2,3,4-tetrahydronaphth-1-yl -] - 6.6 - trimethylene-7- (p-biphenyl) -1,3-heptadien-5-ol

Analogously to Example 1n), 2.34 g of the alcohol prepared in Example 9d) gives 1.53 g of the title compound as a colorless oil.
IR (KBr): 3740, 3180 (broad), 3025, 2934, 2859, 1608, 1484, 1441, 1282, 1233, 1097, 991, 809, 767, 740 cm ^-1 .

Example 10 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-10-phenyl-1,3- decadien-9-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid tert-butyl ester

Analogously to Example 1), 300 mg of the phenol prepared under Example 10n) and 165 mg of tert-butyl bromoacetic acid give 282 mg of the title compound as a colorless oil.
IR (film): 3521 (wide), 3048, 2933, 2850, 1732, 1608, 1574, 1494, 1442, 1372, 1238, 1156, 1085, 1046, 933, 845, 810, 757 cm ^-1 .

The starting material for the above title compound is prepared as follows:

10a) 2,2-Trimethylene-4-pentenoic acid ethyl ester

A solution is added to 540 ml of a 1.6M solution of butyllithium in hexane at -10 ° C of 88.6 g diisopropylamine in 300 ml tetrahydrofuran. After stirring for 30 minutes 97.5 g of ethyl cyclobutane carboxylate in 200 ml of tetrahydrofuran are added at -70 ° C. and stirred for 1.5 hours at this temperature. Then a solution of 92.1 g Allyl bromide in 200 ml of tetrahydrofuran was added and the mixture was stirred for a further 2 hours. The reaction mixture is then made up to 400 ml of saturated ammonium chloride Given solution and extracted three times with ether. The combined organic phases once with water, once with semi-concentrated sodium chloride solution washed, dried over sodium sulfate and concentrated in vacuo after filtration.  

The residue thus obtained is distilled in vacuo, and 112 g of the title compound are thus obtained as a colorless oil. Boiling point: 110 ° C at 90 mbar
IR (film): 3078, 2981, 1728, 1641, 1444, 1367, 1324, 1247, 1205, 1141, 1099, 1052, 993, 916 cm ^-1 .

10b) 2,2-trimethylene-4-penten-1-ol

1.1 l of a 1.2M DIBAH solution in toluene are added under nitrogen at -70 ° C. to a solution of 92 g of the ester prepared in Example 10a) in 1.1 l of toluene and the mixture is stirred for one hour at this temperature. Then 325 ml of isopropanol is carefully added to the reaction mixture, followed by 222 ml of water, the mixture is allowed to come to 22 ° C. and the mixture is stirred at this temperature for 2 hours. The solid constituents are then suctioned off, washed well with ethyl acetate and the filtrate is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-30% ether, 54.4 g of the title compound is obtained as a colorless oil.
IR (film): 3355 (wide), 3075, 2975, 2850, 1639, 1434, 1273, 1025, 995, 912 cm ^-1 .

10c) 5- (Diphenyl-tert-butylsilyloxy) -4,4-trimethylene-1-pentene

106 g of imidazole are added to a solution of 54.4 g of the alcohol prepared in Example 10b) in 500 ml of dimethylformamide under nitrogen at 22 ° C., followed by 213 g of diphenyl-tert-butyl-silyl chloride and the mixture is stirred at this temperature for 20 hours. The reaction mixture is then diluted with ether, washed with water and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-10% ethyl acetate, 127 g of the title compound are obtained as a colorless oil.
IR (film): 3075, 2980, 2850, 1637, 1432, 1275, 1025, 997, 908, 824, 741, 701 cm ^-1 .

10d) (±) -5- (diphenyl-tert-butylsilyloxy) -4,4-trimethylene-1,2-pentanediol

356 mg of osmium tetroxide (solution in tert-butanol) are added to a mixture of 102 g of the alkene prepared in Example 10c) in a mixture of 1.0 l of acetone and 280 ml of water, followed by 39.3 g of N-methylmorpholine -N-oxide and then stirred for 20 hours at 22 ° C. It is then concentrated in vacuo, taken up in ice water and extracted three times with methylene chloride. The combined organic phases are washed once with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-60% ethyl acetate, 128 g of the title compound are obtained as a colorless oil.
IR (film): 3414 (wide), 3080, 2931, 2857, 1472, 1428, 1113, 1090, 823, 739, 702 cm ^-1 .

10e) 4- (Diphenyl-tert-butylsilyloxy) -3,3-trimethylene-butanal

81.5 g of sodium periodate are added to a solution of 127 g of the diol prepared in Example 10d) in a mixture of 1.28 l of tetrahydrofuran and 380 ml of water, and the mixture is then stirred at 22 ° C. for 1 hour. The precipitate is then filtered off and washed well with ether. After phase separation, the organic phase is washed twice with dilute sodium sulfide solution, twice with saturated sodium bicarbonate solution, three times with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the crude product thus obtained is used in the next stage without further purification.
IR (film): 3082, 2932, 2875, 2750, 1716, 1472, 1423, 1112, 825, 741, 703 cm ^-1 .

10f) 4- (Diphenyl-tert-butylsilyloxy) -3,3-trimethylene-1-butanol

19.1 g of sodium borohydride are added to a solution of 109 g of the aldehyde prepared in Example 10e) in 1.0 l of methanol under nitrogen at -10-0 ° C. and the mixture is stirred at 22 ° C. for 2 hours. Then 130 ml of acetone are added and the pH is adjusted to 7 with glacial acetic acid. It is concentrated in vacuo and diluted with water and ether. After phase separation, the aqueous phase is extracted three more times with ether. The combined organic phases are washed three times with half-concentrated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ethyl acetate, 105 g of the title compound are obtained as a colorless oil.
IR (film): 3362 (wide), 3075, 2930, 2856, 1472, 1428, 1112, 1093, 1048, 824.740, 701 cm ^-1 .

10g) 4- (diphenyl-tert-butylsilyloxy) -3,3-trimethylene-1-iodobutane

To a solution of 89 g of the alcohol prepared in Example 10f) in 500 ml of pyridine 184 g of p-toluenesulfonic acid chloride are added under nitrogen at 0 ° C. and the mixture is stirred 15 Hours at 22 ° C. Then the reaction mixture is poured onto ice water and stirred 2 Hours. Then ether is added, and the organic phase is added several times dilute sulfuric acid, twice with saturated sodium bicarbonate solution and washed three times with saturated sodium chloride solution and over sodium sulfate dried. After filtration, the mixture is concentrated in vacuo and the crude product thus obtained used in the next stage without further cleaning.

91.8 g of sodium iodide are added under nitrogen to a solution of 81.1 g of the previously prepared tosylate in 580 ml of acetone and the mixture is heated at 50 ° C. for 16 hours. The reaction mixture is poured into 600 ml of water and extracted three times with ether. The combined organic phases are washed once with semi-concentrated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-10% ether, 74.1 g of the title compound is obtained as a colorless oil.
IR (film): 3070, 2930, 2856, 1472, 1427, 1240, 1180, 1113, 1007, 824, 739, 701 cm ^-1 .

10h) 1- (Diphenyl-tert-butylsilyloxy) -6-phenyl-2,2-trimethylene-5-hexyne

145 ml of a 1.6M solution of butyllithium in hexane are added dropwise at -30 ° C. under nitrogen to a solution of 23.7 g of phenylacetylene in 124 ml of tetrahydrofuran and the mixture is stirred at 22 ° C. for 1 hour. Then 74.1 g of the iodide prepared in Example 10g) dissolved in 198 ml of DMPU are added at -30 ° C. and the mixture is stirred for 5 minutes at this temperature. The reaction mixture is then poured onto ice water and extracted three times with ether. The combined organic phases are washed once with half-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 / 0-5% ether, 74.5 g of the title compound is obtained as a colorless oil.
IR (film): 3070, 2930, 2855, 2232, 1598, 1490, 1472, 1427, 1360, 1112, 1007, 998, 824, 755, 739, 700 cm ^-1 .

10i) 6-phenyl-2,2-trimethylene-5-hexin-1-ol

54.5 g of tetrabutylammonium fluoride trihydrate are added to a solution of 39.1 g of the silyl ether prepared in Example 10h) in 350 ml of tetrahydrofuran and the mixture is stirred at room temperature for 18 hours. It is then diluted with ether and washed once with water. The ethereal phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ethyl acetate, 18.5 g of the title compound is obtained as a colorless oil.
IR (film): 3382 (wide), 3070, 2930, 2855, 1598, 1490, 1472, 1428, 1361, 1113, 1025, 821, 756, 741, 701 cm ^-1 .

10j) 6-phenyl-2,2-trimethylene-5-hexinic acid methyl ester

A solution of 14.7 ml of oxalyl chloride in 157 ml of methylene chloride is added dropwise -70 ° C under nitrogen slowly 25.3 ml of dimethyl sulfoxide in 103 ml of methylene chloride. After 28.3 g of the alcohol prepared in Example 10) are then added dropwise in 103 ml in 10 minutes Add methylene chloride quickly and stir for 1.5 hours at -70 ° C. Then you give 51.4 ml Triethylamine and after 1.5 hours stirring the reaction mixture Ice water. After phase separation, the aqueous phase is extracted three times Methylene chloride. The combined organic phases are washed once with 10% Sulfuric acid, once with saturated sodium bicarbonate solution and three times with  saturated sodium chloride solution. After drying over sodium sulfate is after Filtration concentrated in vacuo. The crude product thus obtained is without further Cleaning used in the next stage.

Dripped into a solution of 28 g of the aldehyde prepared above in 500 ml of acetone 98 ml of Jones reagent (J. Chem. Soc. 1953, 2555) are stirred at -30 ° C. and the mixture is stirred for 30 minutes at this temperature. Then 50 ml of isopropanol are added, the mixture is stirred at -20 ° C. for 10 minutes, sucks off through Celite and washes well with ether. After diluting the filtrate with 1 l The organic phase is washed ether twice with water and twice with semi-concentrated sodium chloride solution. After drying over sodium sulfate and Filtration is concentrated in vacuo. The crude product thus obtained is without further Cleaning used in the next stage.

18.1 g of potassium carbonate is added to a solution of 28.4 g of the acid prepared above in a mixture of 167 ml of acetone and 73 ml of dimethyl sulfoxide, followed by 8.15 ml of methyl iodide and the mixture is stirred at 22 ° C. under nitrogen for 18 hours. The solid constituents are then filtered off, washed with ethyl acetate and the filtrate is concentrated in vacuo. The residue is taken up in ether, the organic phase is washed once with water and once with half-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 / 0-10% ether, 18.5 g of the title compound is obtained as a colorless oil.
IR (film): 3070, 2950, 2857, 2235, 1732, 1598, 1490, 1428, 1330, 1199, 1112, 1070, 998, 821, 757, 700 cm ^-1 .

10k) 2-oxo-3,3-trimethylene-7-phenyl-hept-6-in-phosphonic acid dimethyl ester

Analogously to Example 9b), 9.59 g of the title compound is obtained as a colorless oil from 18.5 g of the ester prepared in Example 10j).
IR (film): 3075, 2955, 2875, 2235, 1708, 1598, 1495, 1427, 1331, 1198, 1113, 1068, 868, 807, 756 cm ^-1 .

10l) (±) - (1E, 3E) -1- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl- ] -6,6-trimethylene-10-phenyl-1,3-decadien-9-in-5-one

Analogously to Example 1l), 2.02 g of the title compound is obtained as a colorless oil from 2.0 g of the aldehyde prepared in Example 8i) and 1.72 g of 2-oxo-3,3-trimethylene-7-phenyl-hex-6-in-phosphonic acid dimethyl ester.
IR (film): 3025, 2934, 2850, 1682, 1594, 1494, 1472, 1428, 1348, 1271, 1243, 1191, 1114, 1058, 1005, 974, 956, 823, 757, 731 cm ^{²³⁰⁷⁸ ⁰⁰⁰⁷⁰ ⁵⁵² ⁰⁰¹⁰⁰⁰²⁸⁰⁰⁰⁰⁰00200012000285912296700040 0002019722 00004 22959-1} .

10m) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4- tetrahydronaphth-5-yl -] - 6,6-trimethylene-10-phenyl-1,3-decadien-9-in-5-ol

Analogously to Example 1m), 1.77 g of the title compound is obtained as a colorless oil from 2.0 g of the ketone prepared in Example 10l).
IR (film): 3565, 3452 (wide), 3070, 2932, 2850, 1606, 1494, 1471, 1428, 1242, 1190, 1114, 992, 823, 756, 742, 702 cm ^-1 .

10n) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7-hydroxy-1,2,3,4-tetrahydronaphth-1-yl -] - 6.6 - trimethylene-10-phenyl-1,3-decadien-9-in-5-ol

Analogously to Example 1n), 1.1 g of the title compound is obtained as a colorless oil from 1.75 g of the alcohol prepared in Example 10m).
IR (KBr): 3380 (broad), 3025, 2939, 2850, 2240, 1613, 1492, 1445, 1283, 1235, 996, 922, 810, 758, cm ^-1 .

Example 11 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-8-phenoxy-1,3- tert-butyl octadienyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoate

Analogously to Example 1), from 300 mg of the phenol prepared under Example 11g) and 168 mg of tert-butyl bromoacetic acid, 331 mg of the title compound are obtained as a colorless oil.
IR (film): 3500 (wide), 3050, 2933, 2850, 1732, 1600, 1505, 1372, 1242, 1150, 1086, 994, 845, 810, 754 cm ^-1 .

The starting material for the above title compound is prepared as follows:

11a) 2,2-Trimethylene-4-phenoxy-butanol-diphenyl-tert-butylsilyl ether

11.5 g of phenol followed by 39.9 g of cesium carbonate are added to a solution of 40 g of the tosylate prepared in Example 10g) in 300 ml of dimethylformamide and the mixture is stirred at 60 ° C. for 18 hours. Then the reaction mixture is poured onto ice water and extracted three times with a mixture of ether and hexane in a ratio of 1: 1. The combined organic phases are washed twice with half-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 / 0-10% ether, 28.5 g of the title compound is obtained as a colorless oil.
IR (film): 3070, 2930, 2857, 1600, 1587, 1497, 1472, 1428, 1300, 1244, 1172, 1112, 1073, 824, 753, 740, 701 cm ^-1 .

11b) 2,2-trimethylene-4-phenoxy-butanol

Analogously to Example 10i), from 28.5 g of the ether prepared in Example 11a) is obtained 13 g of the title compound as a colorless oil.
IR (film): 3400 (wide), 3075, 2934, 2856, 1600, 1497, 1473, 1301, 1244, 1171, 1113, 756 cm ^-1 .

11c) 2,2-Trimethylene-4-phenoxy-butanoic acid methyl ester

Analogously to Example 10j), 12.4 g of the title compound is obtained as a colorless oil from 13 g of the alcohol prepared in Example 11b).
IR (film): 3070, 2948, 2855, 1734, 1599, 1498, 1473, 1329, 1245, 1171, 1129, 1043, 883, 754 cm ^-1 .

11d) 2-Oxo-3,3-trimethylene-5-phenoxy-phosphonic acid dimethyl ester

In analogy to Example 9b), 9.79 g of the title compound is obtained as a slightly yellow-colored oil from 12.4 g of the ester prepared in Example 11c).
IR (film): 3075, 2953, 2868, 1705, 1599, 1497, 1472, 1247, 1175, 1032, 870, 805, 757 cm ^-1 .

11e) (± -) - (1E, 3E) -1- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1- yl -] - 6,6-trimethylene-8-phenoxy-1,3-octadien-5-one

Analogously to Example 1l), 2.42 g of the title compound is obtained as a colorless oil from 2.0 g of the aldehyde prepared in Example 8i) and 1.65 g of dimethyl 2-oxo-3,3-trimethylene-5-phenoxyphosphonate.
IR (film): 3027, 2931, 2850, 1682, 1599, 1494, 1471, 1428, 1339, 1242, 1172, 1114, 1070, 1030, 1004, 974, 936, 823, 754, 701 cm ^.1 .

11f) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4- tetrahydronaphth-1-yl -] - 6,6-trimethylene-8-phenoxy-1,3-octadien-5-ol

Analogously to Example 1m), 2.21 g of the title compound is obtained as a colorless oil from 2.4 g of the ketone prepared in Example 11e).
IR (film): 3452, 3075, 2933, 2850, 1600, 1494, 1471, 1428, 1392, 1242, 1172, 1114, 992, 823, 754, 700 cm ^-1 .

11g) (± -) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl -) - 6, 6- trimethylene-8-phenoxy-1,3-octadien-5-ol

Analogously to Example 1n), 1.37 g of the title compound is obtained as a colorless oil from 2.19 g of the alcohol prepared in Example 11f).
IR (KBr): 3380 (broad), 3030, 2938, 2865, 1598, 1583, 1497, 1288, 1237, 1076, 1032, 989, 916, 878, 804, 750 cm ^-1 .

Example 12 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-7,7-tetramethylene-10-phenyl-1,3- decadien-9-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid tert-butyl ester

Analogously to Example 1), from 300 mg of the phenol prepared under Example 12h) and 159 mg of tert-butyl bromoacetic acid, 353 mg of the title compound are obtained as a colorless oil.
IR (film): 3503 (wide), 3050, 2932, 2850, 1754, 1608, 1493, 1442, 1393, 1369, 1219, 1154, 1084, 1046, 992, 845, 757 cm ^-1 .

The starting material for the above title compound is prepared as follows:

12a) 2,2-tetramethylene-5-phenyl-4-pentic acid methyl ester

A solution of 40 g of 3-phenyl-2-propinol in 8.4 ml of pyridine is added very slowly 11.6 ml of phosphorus tribromide (internal temperature at approx. -10 ° C). Then you leave warm slowly to 25 ° C and add the reaction mixture to ice water. Man extracted three times with hexane / ether (1: 2) and washes the combined organic Phases once with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. Then it is dried over sodium sulfate and after Filtration concentrated at 25 ° C in a vacuum. 49.5 g of 1-bromo-3-phenyl-2-propyne are obtained as a crude product that is used in the next step without further purification.

41 ml of diisopropylamine in 140 ml of tetrahydrofuran are added dropwise to 180 ml of a 1.6 M solution of butyllithium in hexane at 0.degree. After 30 minutes, a solution of 32.5 g of methyl cyclopentane in 160 ml of tetrahydrofuran is added dropwise at -70 ° C. and the mixture is stirred at this temperature for a further 30 minutes. Then 49.5 g of the bromide prepared above are slowly added in a mixture of 31 ml of DMPU and 430 ml of tetrahydrofuran at -70 ° C. and allowed to warm to 10 ° C. in the course of 1.5 hours. 200 ml of saturated ammonium chloride solution are then added to the reaction mixture and the mixture is extracted three times with ether. The combined organic phases are washed once 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 / 0-30% ether, 43.1 g of the title compound is obtained as a colorless oil.
IR (film): 3075, 2948, 2863, 1728, 1601, 1487, 1320, 1039, 957, 757 cm ^-1 .

12b) 2,2-tetramethylene-5-phenyl-4-pentin-1-ol

Analogously to Example 10b), 25.25 g of the ester prepared in Example 12a) gives 20.25 g of the title compound as a colorless oil.
IR (film): 3358 (wide), 3056, 2950, 2866, 1598, 1490, 1442, 1322, 1041, 959, 912, 755 cm ^-1 .

12c) 3,3-tetramethylene-6-phenyl-5-hexonitrile

Add to a solution of 20 g of the alcohol prepared above in 200 ml of pyridine 43.5 g of p-toluenesulfonyl chloride at 0 ° C. and the mixture is then stirred for 7 hours 25 ° C. After adding a little ice, the mixture is stirred for a further hour, mixed with 1 l Ether and then wash once with 10% sulfuric acid, once with water, twice with saturated sodium bicarbonate solution and three times with saturated Sodium chloride solution. After drying over sodium sulfate is in vacuo constricted. 35.5 g of the corresponding tosylate are obtained without further purification is used in the next stage.

5.94 g of sodium cyanide are added to a solution of 34.4 g of the tosylate prepared above in 130 ml of dimethyl sulfoxide and the mixture is stirred at 80 ° C. for 3 hours. The reaction mixture is poured onto ice water and extracted five times with ethyl acetate. The combined organic phases are washed neutral 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 / 0-30% ethyl acetate, 14.4 g of the title compound is obtained as a colorless oil.
IR (film): 3055, 2955, 2869, 2245, 1598, 1490, 1442, 1322, 1070, 757 cm ^-1 .

12d) 3,3-Tetramethylene-6-phenyl-5-hexinic acid methyl ester

Add to a solution of 14.3 g of the nitrile prepared above in 130 ml of toluene one at -70 ° C 75 ml of a 1.2M solution of diisobutylaluminium hydride in toluene and stir for 2 hours at this temperature. Then carefully add 8 ml Isopropanol, followed by 40 ml saturated ammonium chloride solution and stirred 18 Hours at 25 ° C. The precipitate is then filtered off, and the residue is added Washed ethyl acetate and concentrated in vacuo. 13.78 g of 3.3- Tetramethylene-6-phenyl-5-hexinal as a crude product that without further purification in the next stage is used.

45 ml of Jones reagent (J. Chem. Soc. 1953, 2555) are added to a solution of 13.7 g of the aldehyde prepared above in 450 ml of acetone at -30 ° C. and the mixture is stirred for 30 minutes at this temperature. 25 ml of isopropanol are then added, the mixture is stirred at −20 ° C. for 10 minutes, filtered through Celite and washed well with ether. The filtrate is diluted with 500 ml of ether, washed three times with water and once with saturated sodium chloride solution. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. The crude product thus obtained is dissolved in 19 ml of acetone and mixed with 1.78 g of potassium carbonate and 1.83 g of methyl iodide. After stirring for 18 hours at 25 ° C., the precipitate is filtered off, washed with ethyl acetate and the filtrate is concentrated in vacuo. The residue is taken up in 150 ml of ether, washed once with water and once with half-concentrated sodium chloride solution. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-15% ether, 1.1 g of the title compound is obtained as a colorless oil.
IR (film): 3075, 2950, 2865, 1731, 1599, 1487, 1321, 1037, 958, 756 cm ^-1 .

12e) 2-oxo-4,4-tetramethylene-7-phenyl-hept-6-in-phosphonic acid dimethyl ester

Analogously to Example 9b), 741 mg of the title compound are obtained as a colorless oil from 1.1 g of the ester prepared in Example 12d).
IR (film): 3075, 2948, 2860, 1703, 1600, 1322, 1250, 1032, 870, 758 cm ^-1 .

12f) (±) - (1E, 3E) -1- [1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4-tetrahydronaphth-1-yl- ] -7,7-tetramethylene-10-phenyl-1,3-decadien-9-in-5-one

Analogously to Example 1l), 1.35 g of the title compound is obtained as a colorless oil from 1.11 g of the aldehyde prepared in Example 8i) and 741 mg of 2-oxo-4,4-tetramethylene-7-phenyl-hept-6-in-phosphonic acid dimethyl ester.
IR (film): 3071, 2931, 2850, 1689, 1626, 1591, 1494, 1472, 1428, 1361, 1303, 1271, 1245, 1190, 1114, 999, 974, 956, 823, 756, 743, 701 cm ^{- 1st}

12g) (±) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7- (diphenyl-tert-butyl-silyloxy) -1,2,3,4- tetrahydronaphth-1-yl -] - 7,7-tetramethylene-10-phenyl-1,3-decadien-9-in-5-ol

Analogously to Example 1m), 1.34 g of the ketone prepared in Example 12f) gives 1.03 g of the title compound as a colorless oil.
IR (film): 3442 (wide), 3075, 2931, 2850, 1606, 1494, 1472, 1428, 1271, 1243, 1114, 991, 958, 824, 756, 742, 701 cm ^-1 .

12h) (± -) - (1E, 3E) - (5RS) -1 - [(1RS) -1-methyl-7-hydroxy-1,2,3,4-tetrahydronaphth-1-yl -] - 7, 7- tetramethylene-10-phenyl-1,3-decadien-9-in-5-ol

Analogously to Example 1n), from 1.03 g of the alcohol prepared in Example 12g), 607 mg of the title compound is obtained as a colorless oil.
IR (KBr): 3390 (broad), 3020, 2930, 2859, 1608, 1489, 1442, 1288, 1232, 991, 810, 755 cm ^-1 .

Example 13 (±) -3-Oxa-3 - {(3RS) -3-methyl-3 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl- 1,3-nonadien-8-ynyl] -indan-5-yl} -propanoic acid (diastereomer A)

4 ml of 0.5N lithium hydroxide solution followed by 77 mg of lithium hydroxide are added to a solution of 231 mg of the ester prepared in Example 1) in a mixture of 4 ml of methanol and 2 ml of tetrahydrofuran and the mixture is stirred at 22 ° C. for 16 hours. Then the pH is adjusted between 4-5 with 1N sulfuric acid and extracted three times with ethyl acetate. The combined organic phases are washed with half-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 / 0-100% ethyl acetate, 167 mg of the title compound are obtained as a colorless oil.
IR (film): 3440 (wide), 3020, 2930, 2850, 1731, 1603, 1488, 1424, 1286, 1186, 1069, 992, 752 cm ^-1 .

Example 14 (±) -3-Oxa-3 - {(3RS) -3-methyl-3 - [(1E, 3E) - (5S or 5R) -5-hydroxy-6,6-trimethylene-9-phenyl- 1,3-nonadien-8-ynyl] -indan-5-yl} -propanoic acid (diastereomer B)

Analogously to Example 13), from 260 mg of the ester (diastereomer B) prepared under Example 2), 219 mg of the title compound is obtained as a colorless oil.
IR (film): 3420 (wide), 3020, 2930, 28 850, 1734, 1605, 1488, 1439, 1287, 1212, 1188, 1097, 1078, 988, 757 cm ^-1 .

Example 15 (±) -5-Oxa-5 - {(3RS) -3-methyl-1 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl- 1,3-nonadien-8-ynyl] -indan-5-yl} -pentanoic acid (diastereomer A)

0.26 ml of 0.5M sodium hydroxide solution followed by 10 mg of lithium hydroxide are added to a solution of 123 mg of the ester prepared in Example 3) in a mixture of 0.3 ml of methanol and 0.3 ml of tetrahydrofuran, and the mixture is stirred for 15 hours at room temperature. Then the pH is adjusted to 3 with 1N sulfuric acid and extracted three times with ethyl acetate. The combined organic phases are washed once 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 / 0-100% ether, 102 mg of the title compound is obtained as a colorless oil.
IR (film): 3420 (wide), 3020, 2945, 2860, 1720, 1607, 1489, 1442, 1322, 1285, 1201, 1189, 1058, 990, 753 cm ^-1 .

Example 16 (±) -3 - {{(3RS) -3-Methyl-3 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -indan-5-yl} -methyloxy} -benzoic acid (diastereomer A)

Analogously to Example 13), from 155 mg of the ester (diastereomer A) prepared in Example 4) is obtained 114 mg of the title compound as a colorless oil.
IR (film): 3420 (wide), 3025, 2955, 2835, 1696, 1617, 1490, 1423, 1377, 1286, 1224, 1019, 994, 758 cm ^-1 .

Example 17 (±) -4 - {{(3RS) -3-Methyl-3 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -indan-5-yl} -methyloxy} -benzoic acid (diastereomer A)

Analogously to Example 13), 155 mg of the title compound are obtained as a colorless oil from 170 mg of the ester (diastereomer A) prepared in Example 5).
IR (film): 3440 (wide), 3020, 2955, 2860, 1695, 1607, 1588, 1376, 1287, 1243, 1200, 1046, 993, 758 cm ^-1 .

Example 18 (±) -3-Oxa-3 - {(5RS) -5-methyl-5 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), 126 mg of the title compound are obtained as a colorless oil from 147 mg of the ester prepared in Example 6).
IR (KBr): 3430 (broad), 3020, 2930, 2862, 1747, 1608, 1497, 1490, 1392, 1231, 1180, 1163, 1083, 1046, 992, 754 cm ^-1 .

Example 19 (±) -5-Oxa-5 - {(5RS) -5-methyl-5 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} pentanoic acid

Analogously to Example 13), 167 mg of the title compound are obtained as a colorless oil from 200 mg of the ester prepared in Example 7).
IR (film): 3420 (wide), 3020, 2932, 2864, 1708, 1606, 1572, 1497, 1489, 1442, 1373, 1316, 1354, 1339, 1093, 994, 757 cm ^-1 .

Example 20 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-9-phenyl-1,3- nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), 733 mg of the title compound are obtained as a colorless oil from 1.0 g of the ester prepared in Example 8).
IR (KBr): 3440 (broad), 3020, 2955, 2860, 1730, 1604, 1490, 1429, 1274, 1223, 1079, 988, 757 cm ^-1 .

Example 21 3-Oxa-3 - {(8S or 8R) -8-methyl-8 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9- phenyl-1,3-nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

300 mg of the racemate / diastereomer mixture from Example 8) is by means of High pressure liquid chromatography on a Chiralcel OD (20 × 250 10 µm) with hexane / Isopropanol / ethanol (900: 4: 4) in a mixed fraction called Fr1 / Fr2 and two Pure substances called Fr3 (29.4 mg) and Fr4 (16.5 mg) separated. The mixed fraction Fr1 / Fr2 is added to the two by the same methodology with hexane / tert-butanol (900:10) Pure substances Fr1 (70.3 mg) and Fr2 (43.4 mg) separated.

In analogy to example 13), from 70.3 mg of the ester obtained in example 21) fraction Fr1, 46 mg of the title compound is obtained as a colorless oil.
IR (film): 3430 (wide), 3020, 2927, 2850, 1732, 1609, 1491, 1442, 1374, 1278, 1218, 1084, 992, 756 cm ^-1 .

Example 22 3-Oxa-3 - {(8S or 8R) -8-methyl-8 - [(1E, 3E) - (5S or 5R) -5-hydroxy-6,6-trimethylene-9- phenyl-1,3-nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

In analogy to example 13), 16 mg of the title compound is obtained as a colorless oil from 43.4 mg of the ester obtained in example 21) fraction Fr2.
IR (film): 3030 (wide), 3020, 2927, 2850, 1732, 1609, 1491, 1442, 1374, 1278, 1218, 1084, 992, 756 cm ^-1 .

Example 23 3-Oxa-3 - {(8R or 8S) -8-methyl-8 - [(1E, 3E) - (5S or 5R) -5-hydroxy-6,6-trimethylene-9- phenyl-1,3-nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), 20.2 mg of the title compound is obtained as a colorless oil from 29.4 mg of the ester obtained in Example 21) fraction Fr3.
IR (film): 3030 (wide), 3020, 2927, 2850, 1732, 1609, 1491, 1442, 1374, 1278, 1218, 1084, 992, 756 cm ^-1 .

Example 24 3-Oxa-3 - {(8R or 8S) -8-methyl-8 - [(1E, 3E) - (5R or 5S) -5-hydroxy-6,6-trimethylene-9- phenyl-1,3-nonadien-8-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), 12.6 mg of the title compound is obtained as a colorless oil from 16.5 mg of the ester obtained in Example 21) Fraction Fr4.
IR (film): 3030 (wide), 3020, 2927, 2850, 1732, 1609, 1491, 1442, 1374, 1278, 1218, 1084, 992, 756 cm ^-1 .

Example 25 (±) -3-Oxa-3 - {(8 RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-7- (p-biphenyl) -1.3- heptadienyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), 295 mg of the title compound are obtained as a colorless oil from 327 mg of the ester prepared in Example 9).
IR (KBr): 3430 (broad), 3035, 2930, 2860, 1738, 1608, 1492, 1486, 1434, 1287, 1218, 1190, 1083, 993, 852, 755, 739 cm ^-1 .

Example 26 (± -) - 3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-10-phenyl-1,3 - decadien-9-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), 218 mg of the title compound are obtained as a colorless oil from 270 mg of the ester prepared in Example 10).
IR (KBr): 3440 (broad), 3020, 2935, 2863, 1737, 1608, 1491, 1442, 1280, 1224, 1193, 1083, 993, 757 cm ^-1 .

Example 27 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-8-phenoxy-1,3- - octadienyli-5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), from 316 mg of the ester prepared in Example 11), 283 mg of the title compound is obtained as a colorless oil.
IR (KBr): 3430 (broad), 3035, 2935, 2865, 1737, 1600, 1586, 1496, 1473, 1436, 1287, 1243, 1192, 1173, 1080, 994, 880, 754 cm ^-1 .

Example 28 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-7,7-tetramethylene-10-phenyl-1,3- decadien-9-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid

Analogously to Example 13), from 348 mg of the ester prepared in Example 12), 310 mg of the title compound are obtained as a colorless oil.
IR (KBr): 3430 (broad), 3018, 2930, 2865, 1735, 1608, 1573, 1488, 1441, 1432, 1372, 1276, 1225, 1191, 1068, 991, 755 cm ^-1 .

Example 29 (±) -3-Oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-10-phenyl-1,3- decadien-9-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoic acid methyl ester

An ethereal diazomethane solution is added to a solution of 200 mg of the acid prepared in Example 26) in ethyl acetate until the yellow color remains. After stirring for 15 minutes, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-15% ethyl acetate, 197 mg of the title compound is obtained as a colorless oil.
IR (film): 3460 (wide), 3020, 2935, 2865, 2232, 1763, 1740, 1610, 1492, 1441, 1374, 1283, 1212, 1087, 994, 757 cm ^-1 .

Example 30 (±) -Lithium- {3-oxa-3 - {(8RS) -8-methyl-8 - [(1E, 3E) - (5RS) -5-hydroxy-6,6-trimethylene-10- phenyl-1,3-decadien-9-ynyl] -5,6,7,8-tetrahydronaphth-2-yl} propanoate}

0.5 ml of 0.5N lithium hydroxide solution is added to a solution of 124 mg of the ester prepared in Example 10) in 1 ml of a mixture of methanol and tetrahydrofuran in a ratio of 1: 1 and the mixture is stirred at 25 ° C. for 24 hours. Then 102 mg of the crystalline title compound are obtained by freeze-drying (melting point: 116 ° C.).
IR (KBr): 3430 (broad), 3020, 2935, 2865, 1625, 1490, 1430, 1338, 1277, 1228, 1068, 993, 757 cm ^-1 .

Claims (3)

1. Leukotriene B ₄ antagonists of the formula I.
wherein
the linkage of the chain O- (CH ₂ ) _p -R _{1 can be} at one of the free positions on the aromatic and
R ₁ CH ₂ OH, COOR ₄ , CONR ₅ R ₆ , and
R _{2 represents} H or an organic acid residue with 1-15 C atoms,
R ₃ H, optionally mono- or polysubstituted C ₁ -C ₁₄ -alkyl, C ₃ -C ₁₀ - cycloalkyl, optionally independently mono- or polysubstituted by halogen, phenyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ - Symbolize alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy-substituted C ₆ -C ₁₀ aryl radical or a 5-6-membered aromatic heterocyclic ring with at least 1 hetero atom,
R ₄ H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ 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 ₆ -C ₁₀ aryl radical, CH ₂ -CO- (C ₆ -C ₁₀ ) aryl or a 5-6-membered aromatic heterocyclic ring with at least 1 hetero atom,
A is a trans, trans-CH = CH-CH = CH-, a -CH2-CH2-CH = CH- or a tetramethylene group,
B is a C ₁ -C ₁₀ straight or branched chain alkylene group which may optionally be substituted by fluorine or the group
symbolizes
D can be a direct bond, oxygen, sulfur, -C∼C-, -CH = CR ₇ , or together with B can also be a direct bond,
Y is an optionally mono- or polysubstituted C ₁ -C ₈ -alkyl, C ₃ -C ₁₀ -cycloalkyl, optionally substituted by aryl,
R ₅ and R _{6 are} identical or different and represent H or C ₁ -C ₄ -alkyl which is optionally substituted by hydroxyl groups or R ₆ H and R ₅ C ₁ -C ₁₅ -alkanoyl or R ₈ SO ₂ - are optionally substituted by OH ,
R ₇ denotes H, C ₁ -C ₅ alkyl, chlorine, bromine,
R _{8 has} the same meaning as R ₃
p 1-6 means
m 1-3 means
n is 2-5 and, if R _{4 is} hydrogen, its salts with physiologically compatible bases and its cyclodextrin clathrates. 2. Pharmaceutical preparations characterized by a content of leukotriene B ₄ - antagonists of the general formula I according to claim 1. 3. Process for the preparation of leukotriene B ₄ antagonists of the general formula according to claim 1, characterized in that a phenol of formula II
wherein A, B, D, R ₂ , R ₃ Y and m have the meaning given above, optionally after protecting free hydroxyl groups in R ₂ with a halide of the general formula III
Hal- (CH ₂ ) _p -R ₁ (III)
where Hal represents a chlorine, bromine or iodine atom and p, R _{1 has} the meaning given above, reacting in the presence of a base and then optionally separating isomers in any order, releasing protected hydroxyl groups and / or etherifying a free hydroxyl group and / or the 1- Hydroxy group oxidized to carboxylic acid and / or reduced and / or a carboxyl group esterified and / or a free carboxyl group converted into an amide or a carboxyl group with a physiologically compatible base converted into a salt and optionally the intermediately protected esters then treated with acid.