IE66248B1 - Novel alkanophenones - Google Patents

Abstract

Substituted alkanophenones of the general formula <IMAGE> in which R1 denotes optionally fluorinated lower alkyl, R2 represents hydrogen, optionally fluorinated lower alkyl or lower alkenyl, X denotes lower alkylene, oxy, thio or a direct bond, alk represents lower alkylene, n stands for 1 or 2, R3 denotes phenyl which is unsubstituted or substituted by optionally fluorinated lower alkyl, etherified or esterified hydroxyl, optionally lower alkylated amino and/or optionally esterified or amidated carboxyl or denotes lower alkyl which is optionally fluorinated or substituted by optionally esterified or amidated carboxyl, R4 represents optionally esterified or amidated carboxyl or 5-tetrazolyl and R5 stands for hydrogen or lower alkyl, have leukotriene-antagonist properties and can be used as antiallergic pharmaceutical active compounds. The process for their preparation is characterised in that an epoxide of the formula <IMAGE> in which R1, R2, X, alk, n and R3 have the above meanings, is reacted with a thiol of the formula <IMAGE> in which R4 and R5 have the above meanings, or a salt thereof and, if desired, a compound obtainable according to the process is converted into another compound of the formula I, a stereoisomer mixture obtainable according to the process is resolved into the components and/or a free compound obtainable according to the process is converted into a salt or a salt obtainable according to the process is converted into the free compound or into another salt.

Description

EP-A-228 045 discloses asymmetric alpha-hydroxythio ethers that are effective as leucotriene antagonists and are suitable for the treatment of allergic conditions.

The documents EP-A-017 332, EP-A-079 637, US-A-4 546 194, EP-A-139 809 and EP-A-150 447 describe SRS-A or leucotriene antagonists that contain as a common structural feature an alkanophenone radical which is bonded via a chain to a 4-oxo-4H-l-benzopyrane group.

The invention relates to novel substituted alkanophenones of general formula I in which is lower alkyl or mono-, di- or poly-fluorolower alkyl, R2 is hydrogen, lower alkyl, lower alkenyl or mono-, di- or poly-fluoro-lower alkyl, X is Cj-C-jalkylene, oxy or thio, alk is lower alkylene, n is 1 or 2 , R3 is phenyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl, amino, N-mono- or N,N-di-lower alkylamino, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl and/or by trifluoromethyl, or is lower alkyl, mono-, dior tri-fluoro-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl or Nmono- or N,N-di-lower alkvlcarbamoyl-lower alkyl, R4 is carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, or N~(benzenesulfonyl )-carbamoyl that is unsubstituted or is substi2 tuted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl, and R5 is hydrogen or lower alkyl; radicals designated "lower' having not more than 7 carbon atoms; and salts thereof, to processes for their preparation, to pharmaceutical preparations comprising them as active ingredient, and to their use as active ingredients in medicaments.

The spatial arrangement shown in the above formula I for the preferred compounds in which the O atom of the hydroxy group is in the relative trans-configuration with the S atom is to be understood as follows; the symbols in the first line lie above the plane of the drawing and the symbols in the third line therefore lie below the plane of the drawing (or vice versa), which for the formula shown corresponds to the opposite configuration, (RS)(SR), according to the Kahn-Ingold-Prelog convention at the carbon atom bonded to the sulfur atom, (C-S-), and the carbon atom carrying the hydroxy group, (C-OH). when n is 2, the enantiomers having the S(C-S-), R(COH)configuration and, when n is 1, the enantiomers having the R(C-S-), S(C-OH)-configuration are especially preferred. In a vinylene or buta-1,3-dienvlene radical represented by the symbol "(CH=CHjyj-, the double bond or the double bond of the butadienylene radical originating from the carbon atom bonded to the radical alk is preferably, but not necessarily, in the cis-conficyuration, usually designated (Z), the other double bond then preferably, but again not necessarily, having the transconfiguration, usually designated (E).

N-(Benzenesulfonyl)-carbamoyl that is unsubstituted or substituted in the phenyl moiety as indicated is, for example, unsubstituted or monosubstituted, preferably in the ortho-position.

Hereinbefore and hereinafter lower5' radicals and compounds are to be understood as being those radicals and compounds containing no more than 7 and, unless otherwise indicated, preferably no more than 4 carbon atoms (C atoms).

Lower alkyl is, for example, Cj-C7alkyl, especially straight-chain Cj-C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or sec-butyl, but may also be a branched-chain Cj-C4alkyl, such as isobutyl or tertbutyl, or a pentyl, hexyl or heptyl radical. Lower alkyl Rj, R5 and as a substituent of phenyl or N-(benzenesulf onyl)-carbamoyl is preferably Cj-C4alkyl, for example methyl,· lower alkyl R2 is preferably C2-C5alkyl, for example propyl, and lower alkyl R3 is preferably C3-C7alkyl, for example propyl, butyl or pentyl.

Mono-, di- or poly-fluoro-lower alkyl has, for example, up to and including 5 fluorine atoms and is, for example, mono-, di- or tri-fluoro-Cj-C7alkyl, especially w-fluoroor cu,uj,fe>"trifluoro-Cj-C4alkyl, such as trifiuorornethyl, 2.2.2- trifluoroethyl or 3,3,3-trifluoropropyl. Fluorinated lower alkyl Rj and as a substituent of phenyl R3 is especially trifiuorornethyl, and fluorinated lower alkyl R3 is preferably &J,iU?6J-trif luoro-C2-C4alkyl, for example 3.3.3- trifluoropropyl.

Lower alkenyl R2 is, for example, c2-C4alkenyl, such as vinyl, prop-l-enyl or especially prop-2-enyl (allyl).

Lower alkylene is, for example, straight-chain Cj-C7alkvlene, and in the case of X especially C3-C3alkylene, such as Methylene or ethylene, and in the case of alk especially C2"C6alkylene, such as ethylene, 1,3-propylene, 1,4-butylene, also 1,5-pentylene or 1,6-hexylene.

Lower alkoxy is, for example, Cj-C^alkoxy, such as methoxy.

Lower alkoxycarbonyl is, for example, Ci~C4alkoxycarbonyl, such as methoxy-, ethoxy-, propoxy- or butoxycarbonyl .

Lower alkylamino is, for example, C1-C4alkylamino, such as methyl-, ethyl-, propyl- or isopropyl-amino.

Di-lower alkylamino is, for example, di-C1-C4alkylamino, such as dimethylamino, diethylamino or N-ethyl-N-methylamino.

N-mono- or N,N-di-lower alkylcarbamoyl is, for example, N-Ci-C4alkyl- or N,N-di-C1"C4alkyl-carbamoyl, such as lime thy 1-, N-ethyl- or Ν,Ν-dimethyl-carbamoyl.

Halogen is, for example, halogen having an atomic number of up to and including 35, such as fluorine, chlorine or bromine.

Host of the compounds of formula I can, depending upon their individual character, also be in the form of salts. Those compounds which have sufficient acidity, such as, especially, those having carboxy, tetrazolvl or sulfamoyl groups, can form salts with bases, such as, especially, inorganic bases, preferably physiologically tolerable alkali metal salts, especially sodium and potassium salts. However, ammonium salts with ammonia or physiologically tolerable organic amines, such as mono-, di- or tri-lower alkylamines, for example diethylamine, mono-, di- or tri-(hydroxyalkyl)-amines, such as tris(hydroxymethyl) -methylamine, or D-glucosamine, also come into consideration.

The compounds of formula I and their salts exhibit advantageous pharmacological properties, especially a pronounced leucotriene-antagonism.

For example, in vitro in a concentration range of approximately from 0.001 to 1.0 pmol/l, they inhibit the contraction of a smooth muscle induced by leucotriene-D4 (LTD4). This so-called LTD4-antagonism is detected experimentally, for example, as follows: in segments which have been removed from the ileum of a guinea pig weighing 300-400 g and which have been incubated in an organ bath in Tyrode's solution at 38°C and while being gassed with a mixture of 95 % oxygen and 5 % carbon dioxide at a load of 1 g, contractions are induced with synthetic leucotriene D4 (in potassium salt form) and are registered isotonically. The extent of the inhibition by the test compound is detected after a preliminary incubation of 2 minutes and is evaluated as IC5Q, that is to say the concentration which reduces the test contraction by 50 %. The compounds of formula I also have excellent activity in vivo. In addition, they have a relatively long duration of action which is a very significant advantage both specifically and therapeutically. For example, in an in vivo bronchoconstriction standard test on guinea pigs, with aerosol administration of a solution comprising from 0.0001 to 1 % by weight of the test compound, a marked LTD4-antagonistic effect was demonstrated. (A description of the test method can be - δ found in the appendix after the Examples).

Surprisingly, many compounds of formula I also exert a pronounced inhibitory action on other physiologically important enzyme systems. For example, the inhibition of phospholipase A 2 obtained from human leucocytes was observed in the tested concentration range of approximately 0.5-50 Mmol/1. (The experimental procedure for this determination is described in more detail in the appendix after the Examples.) Likewise, the inhibition of phospholipase C obtained from human thrombocytes was observed in the tested concentration range of approximately 1-100 μπιοί/ΐ.

Owing to these valuable pharmacological properties, the compounds of formula I according to the invention can be used therapeutically in all cases where the action of leucotrienes results in pathological conditions, and alleviate or eliminate these conditions. Accordingly, they can be used, for example, for the treatment of allergic conditions and diseases, such as, especially, asthma, but also hay fever and obstructive pulmonary diseases, including cystic fibrosis. Owing to their anti-inflammatory activity, they are also suitable as inflammation-inhibiting agents, especially as external (topical) skin phlogistatics for the treatment of inflammatory dermatoses of any origin, as in mild skin irritations, contact dermatitis, exanthemas and burns, and also as mucous membrane phlogistatics for the treatment of inflammation of the mucosa, for example of the eyes, nose, lips, mouth and genital or anal region. They can also be used as sun screens. The high inhibitory effect on various blood factors also points to the possibility of the therapeutic use of the compounds of formula I where thrombosis and blood coagulation are indicated.

The invention relates preferably to compounds of formula I in which Rj is Ci~C4alkvl or 2 is hydrogen, Cj-C^alkyl, C2-C4alkenyl or όύ,ο,ιο-χΓίί luoro-Cj-C^alkvl, X is C1-C3alkvlene, oxy or thio, alk is straight-chain C2~C6alkylene, n is 1 or 2, R3 is phenyl that is unsubstituted or is substituted by Cj-C^alkyl, C^-C^alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, carboxy and/or by C1-C4alkoxycarbonyl, or is Cj-Cyalkyl, ω,ω,ωtrifluoro-C2-C5alkyl, carboxv-C2=C5alkvl or C1-C4alkoxycarbonyl-C2"C5alkvl, r4 is carboxy or N-(benzenesulfonyl )-carbamoyl, and R5 is hydrogen, and salts thereof, especially the pharmaceutically acceptable salts thereof.

Of the above-mentioned compounds of formula I preference is given especially to those wherein is Cj-C4alkyl or (4,0)f(3—crirluoro-Cj =C4alky 1, R2 is Cj—C4alkvl, C2—C4— alkenyl or 4>, Special preference is given to the compounds of the formula la in which Ri is (^--04 alkyl, R2 is C^-^alkyl, C2"C4alkenyl or ω,ω--trifluoro-Cj-C^aIky 1, X is C1-C3alkylene, oxy or thio, alk is straight-chain C2~C6alkylene, n is 1 or 2, R3 is a group of formula -A-=R3f in which -A- is Cχ-Chalky lene, phenylene or a direct bond and R3Z is alkvl, trifluoromethyl, carboxy or C1-C4alkoxycarbonyl, R4 is carboxy or N-(benzenesulfonyl)-carbamoyl, and R5 is hydrogen, and salts thereof, especially the pharmaceutically acceptable salts thereof.

The invention relates preferably to the compounds of formula la in which R3 is C1-C4alkyl, R2 is C^-C^alkyl, X is oxy, alk is C2-Cgalkylene, n is 1 or 2, R3 is phenyl substituted by C1-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl or by C^-C^alkoxycarbonyl, or is C2-C8alkyl, ω,ωρύtrifluoro-C3-C5alkyl or Cj -Cysalkoxycarbonyl-Cj-C^alkyl, R4 is carboxy, and R5 is hydrogen, and salts thereof, especially the pharmaceutically acceptable salts thereof.

The invention relates especially to the compounds of formula la in which R3 is Ci-C4alkyl, R2 is C1-C4alkyl, X is oxy, alk is C2-C6alkylene, n is 2, R3 is a group of the formula -A-R3Z in which -A- is C^-C^s Iky lene or phenylene, and R3Z is CjL-C4alkyl, trifluoromethyl or C1-C4alkoxycarbonyl, R4 is carboxy or N-(benzenesulfonyl) -carbamoyl, and R5 is hydrogen, and salts thereof, especially the pharmaceutically acceptable salts thereof.

Preference is given generally to compounds of formula I or la in which X is oxy, and salts thereof, especially the pharmaceutically acceptable salts thereof.

Preference is also given generally to compounds of formula I or la in which n is 2, and salts thereof, especially the pharmaceutically acceptable salts thereof.

Preference is given generally also to compounds of formula I or la in which R3 is m-c1-C4alkylphenyl or mtrifluoromethylphenyl, R4 is carboxy and R5 is hydrogen, and salts thereof, especially the pharmaceutically acceptable salts thereof.

Preference is given generally also to compounds of formula ϊ or la in which in the radical -(CH=CH)n- the double bond adjacent to the radical alk is in the (Z)~, that is to say the cis-confiouration. and the additional double bond which may be present in the radical "(CH=CH)n- is in the (Ξ)-, that is to say the transconfiguration, and salts thereof, especially the pharmaceutically acceptable salts thereof.

Finally, preference is given generally to compounds of formula I or la in which the chain carbon atom bonded to the sulfur atom has the (S)-configuration and the chain carbon atom carrying the hydroxy group has the (R)configuration, and salts thereof, especially the pharmaceutically acceptable salts thereof.

The invention relates specifically to the compounds of formula I mentioned in the Examples and to their salts, especially pharmaceutically acceptable salts.

The process according to the invention for the preparation of compounds of formula I and their salts is based on methods known per se and is carried out as follows: an epoxide of formula II ί R ' Χ· z°\ 1 I Ή—X-alk-(-CH=CH) -CH—-CH—Rj z\ z n (II), HO in which Ri , R2/ alk. n and R3 are as defined above, is reacted with a thiol of formula III hs \/\ z°\ ZRs—+ 11 11 \ z\ z* ΰ (III), in which R4 and R5 are as defined above, or with a salt thereof, and, if desired, a compound obtainable in accordance with the process is converted into a different compound of formula I, a stereoisomeric mixture obtainable in accordance with the process is separated into the components, and/or a free compound obtainable in accordance with the process is converted into a salt, or a salt obtainable in accordance with the process is converted into the free compound or into a different salt.

In the reaction of epoxides II with thiols III, the configuration at the carbon atom bonding with the thio group is reversed and the configuration at the carbon atom carrying the hydroxy group is retained. In order to obtain the preferred compounds having the opposite confi5 guration at these two carbon atoms, it is therefore preferable to use the corresponding trans-epoxides 11 as starting materials. Starting from R,R-epoxides II there are obtained compounds I having the S(C-S-), R(COH)configuration, and starting from S,S-epoxides II there are obtained compounds I having the R(C-S-), S(C-OH)· configuration. The reaction is effected under conditions known per se at a temperature of from approximately -20°C to approximately +50°C, preferably at room temperature, that is to say from 18°C to 25°C, and especially in a basic medium, for example in the presence of an amine, especially a tertiary aliphatic, arvlaliphatic or saturated heterocyclic amine, such as a trialkylamine (for example triethylamine or ethyldiisopropylamine), a dialkylbenzvlamine (for example N,N-dimethylbenzvlamine) , an Ν,Ν-dialkylaniline (for example N,N-dimethylaniline) or N-methyl- or N-ethyl-piperidine or N,N*-dimethy1piperazine. The reaction is usually carried out in an inert organic solvent, such as a lower alkanol, for example methanol or ethanol.

In a preferred form, components II and III in which R4 is esterified carboxy or tetrazolvl and R3 is as defined above and is, for example, esterified carboxy or unsubstituted or fluorinated lower alkyl are used as starting materials and R4 is hydrolysed (optionally selectively) to carboxy, which is then converted, if desired, into amidated carboxy.

Starting materials for the process according to the invention are either known per se or can be obtained in a manner known per se by known analogy processes.

The epoxide of the above-defined formula II used as starting material can be prepared especially by means of the same processes as those used in the synthesis of leucotrienes. In a typical general method of synthesis for compounds II in which n is 1, for example, an aldehyde of formula o=ch-r3 (IV) in which A and R3 are as defined above, is used as starting material, a free carboxy group R3 uhich may be present being protected in the form of an ester, for example a lower alkyl ester. This compound is condensed with formvlmethylenetriphenylphosphorane (or an equivalent reagent), the corresponding t£ans-3-R3-prop~2~enal of formula O=CH, (V) being formed. This compound is then epoxidised in a manner known per se. preferably under weakly alkaline conditions (for example in the presence of alkali metal carbonates), with aqueous hydrogen peroxide, to produce a trans-. that is to say 2(RS),3(RS)-epoxy-3-R3-propanal of formula The epoxyaldehyde VI can then be reacted to form the corresponding epoxide II in which R4 is esterified carboxy and n is 1 by condensation with a phosphonium halide fl z’\ Rl j H-X-alk-CHz-PCCtHs)jHal® (VII), HO in which Rj, R2and alk are as defined above and Hal is a halogen atom, preferably bromine, and with a base, for example sodium amide, in tetrahydrofuran.

Compounds VII are prepared especially by reaction of a corresponding compound of formula fl R / \ 1 I fl—X-alk—CH2-Ha 1 (VIII) H0Z h with triphenylphosphine in customary manner. Compounds VIII in which X is oxy or thio are obtained, for example, by condensing with one another corresponding compounds of formulae fl R/\/\ 1 ι fl—XH (IX) and Hal-alk-CH2-Hal (X), in customary manner.

In another method of preparing compounds II, trans-3-R3prop-2-enol of formula HOCH2 ZCH (xi), in which r3 is as defined above, but free carboxy as a substituent of R3 is preferably in an ester form, is epoxidised, for example, by means of tert-butyl hydroperoxide in the presence of titanium tetraisopropanolate and a D- or L-tartaric acid di-lower alkyl ester, and when a D-tartaric acid ester is used there is obtained predominantly 2R,3R~epoxy~3-R3~propanol Xlla, and when an L-tartaric acid ester is used there is obtained predominantly the corresponding 2S,3S-epoxy~3-R3~propanol Xllb HOCH2 Ο H This compound is then oxidised, for example by treatment with oxalyl chloride/dimethyl sulfoxide and then with triethylamine, to the corresponding epoxyaldehyde VI which can then be reacted with the corresponding phosphonium salt VII to form the corresponding epoxide II in which R3 is esterified carboxy and n is 1.

In that reaction there are obtained predominantly epoxides II in which the double bond has the preferred cis-stereoconfiquration. If a D-tartaric acid ester is used, then, as mentioned above, there are obtained predominantly compounds II in which the epoxy group has the R,R-configuration, or S,S-enantiomers when the reaction is carried out in the presence of L-tartaric acid esters.

For the preparation of epoxides II in which n is 2, for example the epoxy alcohol Xlla or Xllb is first converted by treatment with Ν,Ν*-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of trifluoroacetic acid and pyridine and then with triphenylphosphoranylideneacetaldehyde into the corresponding 4R,5R- or 4S,5S4,5-epoxy—5—R3—pent-2-enal of formula Xllla or XHIb, respectively O=HC-CH=CHx .0. zH O=HC-CH=CH 0χ H Λ—-cz (XI Ia) or ,C——Cx (Xllb) , HZ H* which is then reacted further with the phosphonium halide VII to form the corresponding epoxide II in which n is 2. It is preferable to obtain those epoxides in which the double bond joined to the radical alk has cis-stereo10 configuration and the double bond joined to the oxirane ring has trans-stereo-conf iguration.

Compounds obtainable in accordance with the process can, if desired, be converted into other compounds of formula I.

For example, esterified or amidated carboxy groups can be hydrolysed to free hydroxy, preferably under basic conditions, for example in the presence of sodium hydroxide solution, and preferably in a water-miscible organic solvent, such as tetrahydrofuran, dioxane or a lower alkanol, such as methanol or ethanol. Starting from compounds I in which R4 is esterified carboxy, such as lower alkoxycarbonyl, and R3 contains such a group as substituent, the hydrolysis can be controlled in such a manner that selectively only r4 or both R4 and the lower alkoxycarbonyl substituent of R3 are hydrolysed to carboxy. If an equimolar sodium hydroxide solution is used and mild reaction conditions are chosen, for example stirring at room temperature for about 0.5 to 2 hours, virtually only alkoxycarbonyl R4 is hydrolysed, whilst under extreme conditions, for example with prolonged reaction periods or with heating, both R4 and the alkoxycarbonyl group in R3 are hydrolysed to carboxy.

Conversely, carboxy R4 and a carboxy substituent of R3 can be esterified in customary manner.

Furthermore, free or esterified carboxy R4 and such a group as a substituent of R3 can be amidated in customary manner, for example by treatment with ammonia or with a mono- or di-lower alkylamine. For example, carboxy R4 can be converted in customary manner, for example in the presence of a carbodiimide salt, for example N-ethvl-N^(3-dimethylaminopropyl)-carbodiimide hydrochloride, and 4-dimethylaminopyridine, with an unsubstituted or substituted benzenesulfonamide into the corresponding Nbenzenesulfamidoylcarbamoyl groups.

Of course, it is also possible to separate resulting diastereoisomeric mixtures into the individual components on the basis of the different physical properties of the components and/or to separate resulting mixtures of enantiomers into the individual enantiomers according to customary racemate separation processes.

If individual diastereoisomers are desired, then advantageously an individual diastereoisomer of a starting material can be used at any stage or one diastereoisomer can be formed preferentially from a starting material in diastereoisomer form by means of stereoselective reaction conditions or optically active reagents, or racemic diastereoisomeric mixtures can be separated into the individual diastereoisomers by physical separation methods, optionally using optically active auxiliaries.

From the stereochemical standpoint, however, both the condensation according to the invention of components II and III and the preparation of the starting materials are preferably carried out using starting materials that are uniform in stereo-configuration in each case, where possible carrying out the reactions stereoselectively, for example by the use of configurativelv uniform, optically active reagents and/or auxiliaries, and isolating configurativelv uniform products from reaction mixtures immediately after the reaction. For example, in the preparation of the unsaturated starting materials, cis- and trans-isomers which may be formed are separated from one another immediately, for which purpose the customary physical separation methods, such as, espe15 cially, chromatography, are suitable. In the main reaction there is used especially the stereoisomeric epoxide II having the stereoconfiguration of the double bond(s) that is preferred in the end product and in racemic form (which is often formed in the variant of the epoxidisation of the compound V with hydrogen peroxide) or preferably in the form of an individual diastereoisomer in which the configuration at the oxirane carbon atom making a bond with the S atom is opposite to the configuration at the (C-S-) carbon atom preferred in the end product I.

Likewise, resulting salts can be converted, for example by treatment with an acid, into the free acids, and resulting free acids can be converted by treatment with a base into salts.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter the free compounds and their salts should be understood, where appropriate, as meaning also the corresponding salts and free compounds, respectively.

The invention relates also to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is used in the form of a salt or is formed under the reaction conditions.

The invention relates also to the novel starting materials and intermediates occurring in the processes according to the invention and their preliminary stages.

Preferably, the starting materials used and the reaction conditions chosen are such that the compounds listed above as being especially preferred are obtained.

The present invention relates also to pharmaceutical preparations and medicaments that comprise one of the compounds of formula I according to the invention or a pharmaceutically acceptable salt thereof. The pharmaceutical preparations according to the invention are especially those which are intended for local administration and especially for administration by inhalation, for example in the form of an aerosol, a micronised powder or a fine spray solution, to mammals, especially humans, and which comprise the active ingredient on its own or together with a pharmaceutically acceptable carrier.

Pharmaceutical preparations for topical and local use are, for example, for the treatment of the skin, lotions and creams which comprise a liquid or semi-solid oil-inwater or water-in-oil emulsion, and ointments (which preferably comprise a preservative). Suitable for the treatment of the eyes are eye drops which comprise the active ingredient in aqueous or oily solution, and eye ointments which are preferably manufactured in sterile form. Suitable for the treatment of the nose are aerosols ©nd sprays (similar to those described below for the treatment of the respiratory tract), coarse powders which are administered by rapid inhalation through the nostrils, and especially nose drops which comprise the active ingredient in aqueous or oily solution; suitable for local treatment of the buccal cavity are lozenges which comprise the active ingredient in a mass generally formed of sugar and gum arabic or tragacanth, to which flavourings may be added, and pastilles which comprise the active ingredient in an inert mass, for example of gelatine and glycerine or sugar and gum arabic.

Pharmaceutical preparations suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compound of formula I according to the invention with a suitable pharmaceutically acceptable solvent, such as, especially, ethanol and water, or a mixture of such solvents. They may,, as necessary, comprise other pharmaceutical adjuncts, such as non-ionic or anionic surface-active agents, emulsifiers and stabilisers, and also active ingredients of other kinds, and especially advantageously they can be mixed with a propellant gas, such as an inert gas under elevated pressure or especially with a readily volatile liquid, preferably a liquid that boils under normal atmospheric pressure below customary room temperature (for example from approximately -30 to +10°C), such I - 20 10 as an at least partially fluorinated polyhalogenated lower alkane, or a mixture of such liquids. Such pharmaceutical preparations, which are used predominantly as intermediates or stock mixtures for the preparation of the corresponding medicaments in finished form, comprise the active ingredient customarily in a concentration of from approximately 0.1 to approximately 10 % by weight, especially from approximately 0.3 to approximately 3 % by weight. For the preparation of medicaments in finished form, such a pharmaceutical preparation is introduced into suitable containers, such as flacons and pressurised bottles, which are provided with a spray device or valve suitable for such purposes. The valve is preferably constructed in the form of a metering valve which on operation releases a predetermined amount of liquid, corresponding to a predetermined dose of the active ingredient. In the preparation of the finished medicament form, it is also possible for corresponding amounts of the pharmaceutical preparation in stock solution form and of the propellant to be introduced separately into the containers and to be mixed with one another only at that stage. The dosage of the compound of formula I to be administered and the frequency of administration depend upon the effectiveness and the duration of action of each individual compound, upon the severity of the disease to be treated and its symptoms, and upon the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the recommended daily dose of a compound of formula I according to the invention for a mammal (especially a human) weighing 75 kg might be in the region of from approximately 10 to approximately 500 mg, preferably from approximately 25 to approximately 250 mg, which can advantageously be administered in several doses per day, as necessary.

The following Examples illustrate the present invention in more detail but do not limit the scope thereof. All temperatures are given in degrees Celsius.

Example 1; (IR,2S)-1-hydroxy-1-(3-trifluoromethylphenylt8-(4-acetyl-3-hydroxy-2-propvlohenoxv)-octa3(E), 5(2;1-dien-2-yl-7~thio-4-oxo-4H-l-benzo~ pyrane~2-carboxylΐc acid methyl ester A solution of 0,93 g of (lR,2R)-l,2-epoxy-l-(3-trifluoromethylphenyl)-8-(4~acetyl~3~hydroxy-2-propylphenoxy)octa-3(E),5(Z)-diene in 25 ml of methanol is stirred under argon with 0.80 g of triethylamine and 0.62 g of 7mercaptochromone-2-carboxylic acid methyl ester for 20 hours at room temperature and concentrated by evaporation. The residue is dissolved in ethyl acetate and filtered over silica gel- The filtrate is washed once with 2N hydrochloric acid and 3 times with brine, dried over magnesium sulfate and concentrated by evaporation. Purification of the residue by chromatography on silica gel with hexane/ethyl acetate (1:1) yields the title compound having a melting point of 82-63°; [c]D (methanol, 0.135 %) = 103 ± 7.4°; UV (methanol): λ max (£) = 216 (50,000), 235/sh, 271 (27,940), 285/sh; 325 (12900).

The starting material is prepared, for example, as follows: a) (2R 3R)-2-3-eooxy-3-(3-trifluoromethylohenvl1-propanol Under totally anhydrous conditions and an argon atmosphere, a solution of 4.62 ml of tetraisopropyl orthotitanate in 100 ml of methylene chloride is cooled to -70°, and 3.2 ml of D(-)-tartaric acid diethyl ester and .45 g of 3-(3-trifluoromethvlphenyl)-prop-2(E)-enol in a small amount of methylene chloride are added. After stirring for 10 minutes at -70°, 21.5 ml of 3-molar tert-butyl hydroperoxide solution in toluene are added, the temperature rising to -60°C. The temperature is allowed to rise to 0° within a period of 2 hours, and the resulting yellow solution is poured slowly into a solution of 14.5 g of iron(II) sulfate and 5.8 g of L(-r)tartaric acid in 60 ml of water (cooling!, exothermic) and the mixture is stirred for 30 minutes at 5-10°. The aqueous phase is separated off and extracted with ether. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in 90 ml of ether, cooled to 0-5°, and a suspension of 2.32 g of sodium hydroxide in 60 ml of brine is added and the mixture is stirred for 1 hour at 0-5° . The aqueous phase is separated off and extracted with ether. The combined ether phases are dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel with hexane/ethyl acetate (3:2). The title compound is thus obtained in the form of a colourless oil; IR (CH2C12): 3550, 3430, 2950, 2880, 2830, 1310, 1150, 1110, 1050 cm1; [a]θθ (methanol, 0.175 %) - 42.3 ± 5.7°; Rf = 0.30 (hexane/ethyl acetate 3:2). b) (4R,5R1-4,5-eooxy-5-(3-trifluoromethvlphenvll-oent2(E)~enal A solution of 4.5 g of (2R,3R)-2,3-epoxy-3-(3-trifluoromethvlphenyl)-propanol in 105 ml of dimethyl sulfoxide is stirred under argon with 1.7 ml of pyridine, 0.77 ml of trifluoroacetic acid and 12.75 g of N,N-dicyclohexylcarbodiimide for 6 hours at room temperature. After the addition of 8.25 g of formvlmethylenetriphenylphos23 phorane, stirring is continued for a further 20 hours at room temperature; 320 ml of ethyl acetate are added and after 10 minutes the mixture is poured onto 320 ml of brine. The resulting suspension is stirred for 5 minutes and filtered. In the filtrate the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed 3 times with brine, dried over sodium sulfate and concentrated by evaporation. The residue is filtered over silica gel with ether/hexane = (4:1). The filtrate is concentrated by evaporation and the residue is purified by chromatography on silica gel with hexane/ethyl acetate (3:1). The title compound is thus obtained in the form of a light-yellow oil; IR (CH2C12): 2780, 2695, 1670, 1520, 1305, 1145, 1105 cm-1; Rf = 0.31 20 (hexane/ethvl acetate 3:1) [σ]θ (chloroform, 0.245 %) = 144.5 ± 4.1°. c) 3-(4-acetyl-3-hvdroxy-2-propylphenoxy)-prooyltriPhenylphosohonium bromide A solution of 27 g of 3-(4-acetyl-3-hvdroxy-2~propyl~ phenoxy)-propyl bromide in 50 ml of toluene is heated at reflux with 21.85 g of triphenylphosphine for 20 hours. The resulting suspension is cooled to room temperature; 200 ml of ether are added and the mixture is stirred for 1 hour. The colourless precipitate is filtered off with suction, washed with ether and dried. The title compound has a melting point of 211-212°. d) (1R^2R1.-L·, 2-epoxy-l-( 3-trifluoromethvlphenyl)-8-(4acetyl-3-hvdroxv-2.-propylDhenoxv)-octa-3(E), 5(2)diene A suspension of 5.55 g of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl-triphenylphosphonium bromide in 80 ml of tetrahydrofuran is stirred under argon with 0.78 g of ·· NaNH2 and 60 mg of potassium tert-butanolate for 1 hour at room temperature, then cooled to 0-5°; 1.7 g of (4R,5R)-4,5-epoxy-5~(3-trifluoromethylphenyl)-pent-2(E)= enal in 20 ml of tetrahydrofuran are added within a period of 5 minutes and the mixture is then stirred for 2 hours at room temperature. The resulting suspension is poured onto phosphate buffer (pH 7) and extracted with ether. The combined ether extracts are washed with phosphate buffer pH 7, dried over sodium sulfate and concentrated by evaporation. The residue is taken up in hexane/ethyl acetate/triethylamine (24:71:5) and filtered over silica gel that has been prewashed with that solvent mixture. The filtrate is concentrated by evaporation and yields the title compound in the form of a light-yellow oil; Rf = 0.75 (hexane/ethyl acetate 3:2).

Example...2: Sodium salt of (lR,2S)-l-hvdroxy-l-(3-trifluoromethylohenvl)-8-(4-acetvl~3-hvdroxy-2nroovlphenoxv)-octa-3fΞ).5(Z)-dien-2-vl-7thio-4-oxo-4H-lbenzopyrane-2-carboxylic acid 0.7 g of (lR,2S)-i-hydroxy-l-(3"trifluoromethylphenyl)-8(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(Ε),5(Z)-dien2-yl-7-thio-4-oxo-4H-l-benzopvrane-2-carboxylic acid methyl ester is dissolved under argon in 20 ml of tetrahydrofuran; 5.1 ml of 0.2H sodium hydroxide solution are added and the mixture is stirred for 1 hour at room temperature. Concentration by evaporation and purification of the residue by chromatography on a Reversed Phase silica gel column (for example Merck Lichroprep® RP—8) with methanol/water (3:1) yield the title compound, m.p. 207-208°, [g]q° (0.54 %, methanol) = 96.3 ± 1.9° UV (methanol): Λ max (£) = 220 (488840), 235/sh, 267 (25940), 285 (22900), 324/sh.

Example 3; (IS,2R)-l-hvdroxy-l-(3-trifluoromethylphenyl)8-(4-acetyl-3-hydroxy-2-propvlphenoxv)-octa3(El , SiZ^dien^-yl^-thio-a-oxo-^H-l-benzopyrane-^-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IS,2S)-1,2~epoxy-l-(3-trifluoromethylphenyl)-8-(4acety l-3-hydroxy-2-propv lphenoxv)-octa-3 (Ξ), 5(Z)-diene; m.p. 68-69’.

The starting material is prepared, for example, as follows: a) (2§^35)-2,3epoxv-3-(3-trifluoromethylPhenylL-propanol The title compound is prepared as described in Example la) but using L(+)-tartaric acid diethyl ester; colourless oil; IR (CH2C12): 3590, 3480, 2920, 2870, 1330, 1165, 1125, 1070 cm-1; [a]θ° (methanol, 0.175 %) = -41.7 ± 5.7°; Rf = 0.34 (hexane/ethyl acetate 1:1). b) (4S?_5S) —4.5-epoxy-5-(3—trif luoromethvlohenvl)-pent2(E)-enal The title compound is prepared analogously to Example lb) from the epoxy alcohol according to a); light-yellow oil; IR (CH2C12). 2780, 2695, 1670, 1620, 1305, 1145, 1110 cm-1; [α]θ° (chloroform, 0.15 %) = -158.0 ± 6.7°; Rf = 0.4 (hexane/ethyl acetate 4:1). c) (lS-,2S)-l,2-epoxy-l-(3-trifluoromethylphenyll"8-(4apetyl-3-hvdroxy-2-oropy lphenoxv) -octa-3(E),5(Z) diene The title compound is prepared analogously to Example Id) from the epoxvaldehyde according to b); light-brown oil; Rf = 0.61 (hexane/ethyl acetate 3:2).

Example 4: Sodium . salt of (lS?2R)-l_hyd.roxy-.l".(,3-trifluoromethylphenyl)-8-(4-acetvl-3-hydroxv-2propvlphenoxv) -octa-3 (E_) ,.5( ZJ -disn -2-wl~7thio-4-oxo-4H~l°benzopvrane-2-carbQxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 3; m.p. 210-212°, [α]ρθ (MeOH, 0.18 %) = -86.1 ± 5.6° UV (MeOH) : A j5jax( £) = 220 (42820); 235/sh; 267 (26660); 285 (23760); 320 (15800).

Example 5; (IR,2S)-l-hydroxy-l-(3-trifluoromethylphenvl)6- (4-acetvl-3-hydroxy-2-_pronvlDhenoxy) -hex3(Z)-en-2-yI-7thio-4-QXO-4H-l-bengopyrane-2carboxvlic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-(3-trifluoromethylphenyl)-6-(4acetyl-3-hydroxy-2-propy1phenoxy)-hex-3(Z)-ene; 1ightyellou viscous oil; [a](MeOH, 0.115 %) = 57.4 ± 8.7°; UV (MeOH): Amax(e) = 220/sh; 271 (5280); 285/sh; 320 (2800).

The starting material is prepared, for example, as follows: a) (2S,3R)-2„3-epoxy-3-(3-trifluoromethylphenyl)-prooanal A solution of l.l g of oxalyl chloride in 15 ml of methylene chloride is cooled to -65-70° under argon and within a period of 2 minutes 1.5 g of dimethyl sulfoxide in 5 ml of methylene dichloride are added. After stirring for 10 minutes at -65-70°, 1.7 g of (2R,3R)-2,3epoxy-3-(3-trifluoromethylphenyl)-propanol in 15 ml of methylene chloride are added dropwise. After stirring for a further 30 minutes, 4 g of triethylamine are added dropwise, the temperature rising to -40°. The tempera27 ture is allowed to rise to 0° and the reaction mixture is poured onto phosphate buffer (pH 8). The organic phase is separated off and the aqueous phase is extracted with methylene chloride. The combined organic extracts are washed twice with brine, dried over sodium sulfate and concentrated by evaporation. Chromatography of the residue on silica gel with hexane/ethyl acetate (7:3) yields the title compound in the form of a colourless oil; IR (methylene chloride): 2820, 1730, 1330, 1165, 1125, 1070 cm1. Rf = 0.36 (hexane/ethyl acetate 3:2). [α]θθ (chloroform, 0.20 %) = -17.5 ± 5*. b) (1R2R1-1,2-eooxv-l-(3-trifluoromethvlphenvl)-6-(4acetvl-3-hydroxy-2-oropvlphenoxy)-hex-3 (Z)-ene The title compound is prepared analogously to Example id) from the epoxyaldehyde according to a); light-yellow oil; Rf = 0.69 (hexane/ethyl acetate 3::2).

Example 6: Sodium salt of (1R.2S)-i-hvdroxv-l-(3-trifluoromethylohenvl)-6-( 4-acetyl-3-hvdroxy-2oropvlphenoxv)-hex-3 (Z1-en-2-vl-7-thio-4-oxo~ 4H-l-benzopyrane~2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 5; m.p. 222-224°; [σ]θ° (MeOH, 0.135 %) = 62.2 ± 7.4°.

UV (MeOH): Amax(e) = 267 (22060); 285 (21140); 318/sh.

Example 7; (IS.2R)-l-hvdroxv-l-(3-trifluoromethvlphenvl)6-(4-acetyl-3-hvdroxy-2-proovlphenoxy)-hex3(Z)-en-2-vl-7-thio-4-oxo-4H-l-benzopyrane-2carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IS,2S)-1,2-epoxy-l~(3-trifluoromethylphenvl)-6-(4acetyl-3-hydroxy-2-propylphenoxy)-hex-3 (Z)-ene; colour- 28 less powder having a melting point of 69-71°.

The starting material is prepared, for example, as follows: a) f2R.3S1-2.3-epoxv-3-(3-trifluoromethvlphenvl)-orooanal The title compound is prepared analogously to Example 5a) from (2S,3S)-2,3-epoxv-3-(3-trifluoromethylphenyl)propanol. Light-yellow liquid; IR (CH2C12): 2820, 1730, 1330, 1165, 1130, 1070 cm1; [α]θ (chloroform, 0.20 %) = 0.0 ± 5°; (chloroform, 0.20 %) = 475.0 ± 5.0°; Rf = 0.44 (hexane/ethyl acetate 7:3). b) (IS, 2S )-1.2-epoxv-l- (3-trifluoromethvlphenvl 1 -6- (4acetyl-3-hvdroxv-2-oroovlohenoxy1-hex-3(Z1-ene The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to a). Light-yellow oil; Rf = 0.43 (hexane/ethyl acetate 3:2).

Example 8: Sodium salt of (IS,2R)-l-hydroxv-l-(3-tri° fluoromethylphenyl)-6-(4-acefcyl-3-hydroxv-2propvlphenoxv)-hex-3(Z)~en-2-yl~7-thio-4~oxo4H-l-benzooyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 7; m.p. 239-241°; [a]θ (methanol, 0.15 %) = -60.7 ± 6.7°; UV (methanol): λ Jliax(£) = 216 (44080); 268 (22520); 285 (21640); 320/sh.

Example 9: (IR.2S)-l°hvdroxy-l-(3-methylphenvl)-8-(4acetyl°3-hydroxy-2-propylphenoxy)-octa3(E),5(Z)-dien°2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR, 2R)-1,2-epoxy-l~(3-methylphenyl)-8-(4-acetyl-3~ hydroxy-2-propylphenoxy)-octa-3(S),5(Z)-diene; lightyellow powder having a melting point of 71-72°; [α]θ° = 81.7 ± 8.7° (MeOH, 0.115 %); UV (MeOH): λraax(£) = 217 (53680); 235/sh; 271 (29120); 285/sh; 325 (13200).

The starting material is prepared, for example, as follows: a) (2R„3R)-2,3-epoxy-3-(3-methvlphenyl)-propanol The title compound is prepared analogously to Example la) from 3-(3-methylphenyl)™prop-2(E)-enol; colourless, viscous oil; IR (CH2Cl2)". 3560, 3410, 2880, 2830, 1590, 1050 cm1; Rf = 0.39 (hexane/ethyl acetate 1:1); [β]θ = 38.9 ± 5.3° (chloroform, 0.19 %). b) (4R.5R)-4.5-epoxv-5-(3-methylohenyl)-pent-2(E)-enal The title compound is prepared analogously to Example lb) from the epoxy alcohol according to a); light-yellow powder, m.p. 60-61°; IR (CH2C12): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1130 cm1; Rf = 0.34 (hexane/ethvl acetate 4:1). c) (IR.2Π)-1. 2-epoxy-l-_i3-me_thvlphenyl) -8- (4-acetyl-3hydroxy-2-propvlPhenoxv) -octa_-3_LE 15 f Ζ1 -diene The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to a); light-yellow oil; Rf = 0.63 (hexane/ethyl acetate 3:2).

Example 10: Sodium salt of (IR.2S)-l-hydroxv-l°(3methylphenvlJ -8-(4-acetvl-3-hydroxv-2aropyIphenoxy)-octa-3(E),5(Z)-dien-2-yl7thio-4-oxo-4H-l-benzopyrane-2°carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 9; beige powder having a melting point of 217° (decomp.),· [a]|° (methanol, 0.15 %) = 71.3 ± 5.7°; UV (methanol): Amax(£) = 219 (51520); 234/sh; 267 (26460); 284 (23280); 322/sh.

Example 11: (IS,2R)-l-hvdroxv-l-(3-methylphenyl 1-8-(4acetvl-3-hvdroxy-.2rLprooyl_phenoxv.biQC-ta 3(E),5(Z)-dien-2-yl-7-thio-4-oxo-4H-l-benzoT pyrane-2-carboxylic acid methvl ester The title compound is prepared analogously to Example 1 from (IS,2S)-1,2-epoxy-l-(m-tolyl)-8-(4-acetvl-3-hydroxy20 2-propylphenoxy)-octa-3(E),5(Z)-diene; [α]θ (MeOH, 0.148 %) = -75.7 ± 6.8°; UV (MeOH): AMax(e) = 217 (51760); 240/sh; 271 (27860); 290/sh; 328 (12600).

The starting material is prepared, for example, as follows: a) (2S ,3S)°2,3-ePoxy°3-(3-methylphenvl)-propanol The title compound is prepared analogously to Example la) from 3-(3-methylphenyl)-prop-2(E)-enol but using 1.( + ) = tartaric acid diethyl ester; colourless oil; IR (CH2C12): 3550, 3470, 2940, 2880, 2830, 1590, 1050 cm1; Rf = 0.31 (hexane/ethvl acetate 3:2). b) (4S,5S)-4,5-ePoxv-5-(3-methvlPhenvl)-oent-2(E)-enal The title compound is prepared analogously to Example lb) from the epoxy alcohol according to a); light-yellow oil; IR (CH2C12): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1130, 1085 cm"1; Rf = 0.29 (hexane/ethyl acetate 4:1). c) (is,2S)-1.2-epoxy-1-(3-methylPhenyl)-8-(4-acetyl-35 hydroxy-2-proovl phenoxy) -octa^3jLE) , 5 f Z) -diene The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to b); light-yellow oil; Rf = 0.51 (hexane/ethyl acetate 7:3).

Example 12: Sodium salt of (IS,2R)-l-hydroxy-l-(31 0 methylphenyl)-8-(4-acetyl-3-hydroxv-2oropvlohenoxy)-octa-3(E) , 5 (Z)-dien-2-yl-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 1 <15 from the corresponding methyl ester according to Example 2Ω 11; m.p. 197-198°; [a ] θ (0.14 %, methanol) = -72.1 ± 7.1°; UV (MeOH):Amax(£) = 218 (50700); 235/sh; 267 (25780); 285 (22600); 321 (15000).

Example 13: (IR,2S)-1-hydroxy-1-(3-methvlphenyl)-6-(42o acetyl-3-hvdroxy-2-propylphenoxvl-hex-3 (Z) ~ en-2-yl-7-thio-4-oxo-4H-3.-benzopyrane-2carboxvlic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)1,2-epoxy-l-(3-tolvl)-6-(4-acetyl-3-hydroxy~ 2-propylphenoxy)-hex-3(Z)-ene; colourless powder having a melting point of 136-138°; [α]θ° = 28.1 ± 7.4° (methanol, 0.135 %); UV (methanol): Λmax(£) = 271 (26020); 282/sh; 323 (13700).

The starting material is prepared, for example, as on follows: a) (2S.3R)-2,3-epoxv-3-(3-methvlphenvl)-oropanal, The title compound is prepared analogously to Example 5a) from (2R,3R)-2,3-epoxy-3-( 3-methyIpheny 1)-propanol; light-yellow oil. IR (methylene chloride): 2920, 2820, 5 1730, 1610, 1140, 1070 cm-1; Rf = 0.49 (hexane/ethyl acetate 3:2). b) (IR, 2R) -1,2-epoxv-l-(3-methylphenv 1) -6- (4-acetvl-3hydroxy-2-propylphenoxv)-hex-3 (Z)-ene The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to a); light-yellow oil; Rf = 0-73 (hexane/ethyl acetate 3:2).

Example......14: Sodium salt of (IR, 2S)-l-hvdroxv-l-(3methyIpheny1)-6-(4~acetyl-3-hvdroxy-2pr.op.ylphenoxvj -hex-3 (Z) -en-2-yl-7-thi_o-4 oxo-4H-l-benzopyrane~2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 13; beige powder having a melting point of 238-240°; [α]θ (methanol 0.135 %) = 31.1 ± 7.4°; UV (methanol): Amax^) = 268 (21800); 285 (20860); 322/sh.

Example 15: (lR,2S)-l-hvdroxy-l-(3~methoxvcarbonvlphenvl)-8-(4-acetyl-3-hvdroxv-2-propvlphenoxy)-octa-3(E) ,5(Z)-dien-2-yI-7-thio-4oxo-4H-l-benzooyrane-2-carboxylic acid 25 methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-(3-mefhoxycarbonylphenvl)-8-(4~ acetyl-3-hydroxy~2-propylphenoxy)-octa-3 (E),5(Z)-diene; [α]θ° (methanol, 0.14 %) = 27.9 ± 7.1°; UV (methanol): Amax(£) = 221 (53560); 234/sh; 270 (28980); 285/sh; 326 (13860).

The starting material is prepared, for example, as follows: a) (2R,3R)-2,3-epoxy-3-(3-methoxycarbonylphenvl)-propanol The title compound is prepared analogously to Example la) from (E)-3-methoxycarbonylcinnamic alcohol; slightly yellowish oil; Rf = 0.3 (hexane/ethyl acetate 1:1). b) (4R,5R)-4.5-epoxv-5-(3-methoxvcarbonylphenyJJ -pentr 2(El-enal -] θ The title compound is prepared analogously to Example lb) from the corresponding epoxy alcohol; light-yellow oil; Rf = 0.35 (hexane/ethyl acetate 3:2).

C) (IR,2R)-1,2-epoxv-(3-methoxvcarbonvlphenvl)-8-(4acetvl-3-hvdroxy-2-propvlphenoxv)-octa-3(E),5(Z)1 5 diene The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to b); viscous yellow oil; Rf = 0.50 (hexane/ethyl acetate 3:2).

Example 16: Sodium salt of (lR«2S)-l-hy.droxyrl~:i_2r: methoxycarbonylphenvl)-8-(4-acetvl-3hydroxv-2-propvlphenoxv)-octa-3(£),5(2)dien-2-vl-7-thio-4-oxo-4H-l-benzopyrane-2carboxvlic acid The title compound is prepared analogously to Example 2 from (IR,2S)-1-hydroxv-l-(3-methoxycarbonvlphenyl)-8-(4acetyl~3-hydroxy-2~propylphenoxy)-octa-3(E),5(Z)-dien-2yl-7~thio~4~oxo~4H-l-foenzopvrane-2-carboxylic acid methyl ester according to Example 15; light-brown powder having a melting point of 181° (decomp.); [c-]q (methanol, 0.15 %) = 32.0 ± 6.7°; UV (methanol) : λ inax (e) = 222 (51600); 232/sh; 267 (24160); 284 (22940); 320/sh; 400/sh.

Example 17: (IS, 2R)-l-hydroxy-l-(3-methoxycarbonylphenyl )-8-(4-acetyl-3~hydroxy-2~propvl~ phenoxv)-octa-3(E).5fZ)dien-2-vl-7-~thio-4oxo-4H-l-benzoovrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from the (IS,23)-1,2-epoxy~l-(3-methoxycarbonylphenyl)=8~ (4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(Ξ),5(Z)diene; m.p. 77-78° (colourless powder); [α]θ (methanol, 0.15 %) = -52.7 ± 6.7°; UV (methanol): λ ϊί1βχ(e) = 221 (57420); 235/sh; 271 (29980); 288/sh; 326 (14320).

The starting material is prepared, for example, as follows: a) (2S,3S)-2,3-eooxv~3-(3-methoxycarbonyIphenvl)-propanol The title compound is prepared analogously to Example la) from (E)-3-methoxycarbonylcinnamic alcohol but using L(-r)-tartaric acid diethyl ester; colourless oil; Rf = 0.48 (hexane/ethyl acetate 1:1). b) (4S,55)-4,5-epoxy-5-f3-methoxycarbonylphenyl)-pent2-(E)-enal The title compound is prepared analogously to Example lb) from the corresponding epoxy alcohol; colourless oil; IR (methylene chloride); 3050, 2990, 2945, 2820, 2730, 1725, 1695, 1640, 1290, 1255 cm1; Rf = 0.34 (hexane/ethvl acetate 3:2). c) fIS,2S)-1.2-eooxy-l- (3-methoxycarbonylphenyl) -8-.( 4^acetyl-3-hydroxv-2-propylphenpxyJ"Qctg-JJE) ,5.,(Z)diene The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to b); light-yellow oil; Rf = 0.54 (hexane/ethyl acetate 3:2).

Example 18: Sodium salt of (lS„2R)-l-hydroxv-l-(3methoxycarbonvlphenyl) -8- (4-acety 1-,3.hydroxy^2r.propy lphenoxv) -octa-3,(.g t.5(Z) o dien-2-vl-7-thio-4-oxo-4H-l°benzopyrane-2carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 17; beige powder having a melting point of 174-176°; [α]θ° (methanol, 0.155 %) - -80.6 ± 6.5°; UV (methanol): A -max(e) = 223 (59300); 235 sh; 267 (27300); 284 (24800); 321 (16200).

Example 19: (IR.2S)-l-hydroxy-l-(3°methoxvcarbonylphenyl),-.fcJ.4^3^etyl-3-hydr^.xy-2rPrppy_lr phenpxv) -hex-3 ,(.Z)-e.n-2-yl-7-thio-4-Qxp-4H-.ljz benzopvrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)=1,2-epoxy-l-(3-methoxycarbonylphenyl)-6-(4acetyl-3-hydroxy-2-propylphenoxy)-hex-3 (Z)-ene; colour25 less oil; [σ]θ° (methanol, 0.11 %) = 24.5 ± 9.1°; UV (methanol):-X max( £) = 270 (22400); 322 (12000).

The starting material is prepared, for example, as follows: a) (2S...3R)-2 3 3-eoox.y-.3rJ 3-methoxycarbonylphenyl 1-prooanal The title compound is prepared analogously to Example 5a) from (2R, 3R) -2,3-epoxy~3- (3-methoxycarbonvlphenyl) propanol; light-yellow oil; IR (methylene chloride): 2950, 2820, 1725, 1610, 1590, 1430, 1290, 1255 cm-1; Rf = 0.33 (hexane/ethyl acetate 3:2). b) (IR, 2R) -1 , 2-eooxv-l- (3-methoxycaybornylohenvl) -6,-( 4acetyl°3-hydroxv-2-orooylphenoxy)-hex-3 (Z)-ene The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to a); light-yellow oil; Rf = 0.39 (hexane/ethyl acetate 3:2).

Exampl.e_2.0: Sodium salt of (IR, 2S)-l-hvdroxv-l-( 3° methoxycarbonylohenyl)-6-(4~acetyl~3~ hvdroxv-2-proovlohenoxy) -hex-3 (Z) ~en-2~yl-7_thio-4-oxo-4H-l-benzop_ygane-2-carboxyli_c acid (A), and disodium salt, of (1R,2S)-Ir hvdroxv-l-( 3-carboxvohenyn_-6-( 4-acetvl-3_r hvdroxv-2''3roovl33hgnoxylshex·-3 (Z)-en-2-vlr7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid.(BI A solution of 0.5 g of (lR,2S)-l-hydroxy-l-(3-methoxy* carbonylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)hex-3 (Z)-en-2~yl-7-thio~4-oxo-4H-l~benzopyrane-2-carboxylic acid methyl ester according to Example 19 in 20 ml of tetrahydrofuran is stirred under argon for 40 hours with 7.5 ml of 0.2N sodium hydroxide solution at room temperature and is then concentrated by evaporation. The residue is purified by chromatography on Lichropre^) RP-8, Merck, with methanol/water (3:1) and yields in 20 fractions 2-5 title compound B; m.p. 262-264°; [α]θ (methanol, 0.105 %) = 17.1 ± 9.5°; UV (methanol): A €) = 268 (19680); 284 (19060); 325/sh; and in fractions 8-12 title compound A; m.p. 155° (decomp.); [α]θ (methanol, 0.12 %) = 22.5 ± 8.3°; UV (methanol): A jnax( e) = 268 - 37 (26200); 286 (29220); 325/sh.

Example..21: (IS, 2R)-1-hvdroxy-1-( 3-methoxycarbonvl~ phenyl) -6- (4-acetvl-3-hydroxy-2-propylr phenoxy)-hex-3(Z) -en-2-yl-7-thio-4-oxp-4H-l5 benzopyrane-2-carboxvlic acid methyl ester The title compound is prepared analogously to Example 1 from (IS, 2S) -1,2 - epoxy-1- (3-carboxymethylphenyl) -6- (4acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene; colourless oil which hardens in the refrigerator, m.p. 90-91°; [<χ]θ° =415 ± 7-7° (0.13 % methanol); UV (methanol): Amax(£) = 271 (25120); 322 (13280).

The starting material is prepared, for example, as follows: a) (2R 3S)-2,3-epoxy-3-(3-methoxycarbonvlPhenyl)-Propanal 1 5 The title compound is prepared analogously to Example 5 from (2S, 3S)-2,3-epoxy-3-(3-methoxycarbonylphenyl)propanol; colourless oil; IR (methylene chloride): 2910, 2780, 1705, 1590, 1570, 1415, 1270, 1235 cm-1; Rf = 0.36 (hexane/ethyl acetate 3:2). b) (IS,2S)-1,2-epoxy-l-(3-methoxvcarbonylPhenyl)-6-(4acetyl_-3-hydroxy-2-propyl phenoxy 1 -hex-3 (Z) -ene The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to a); colourless oil, not characterised in more detail.

Example 22: Sodium salt of (IS,2R)-lhydroxy-l-(3^ methoxycarbonvlphenvl) -6-( 4°acetyl2i3r hydroxy-2-oropylphenoxv) -hex-3£Z) -en-2-y 1.^.7^ thio-4-oxo-4H-l-benzopvrane°2=carboxy.lic 5 acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 21; beige powder having a melting point of 208-210°; [c]2° (methanol, 0.12 %) = -41.7 ± 8.3°; UV (methanol): ^max(£) = 268 (21060); 285 (21540); 325/sh.

Example 23: (4R, 5S_).-1^L·, 1-trifluoro-4-hydroxv-l1-(4acetyl-3-hvdroxy-2-propylphenoxv) -undeca6(E) ,8( Z)-dien-5-vl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester 15 The title compound is prepared analogously to Example 1 from (4R,5R)-4,5-epoxy-l,1,1-trifluoro-11-(4-acetyl-3hydroxy~2~propy1phenoxy)-undeca-6(Ξ),8(Z)-diene; beige powder having a melting point of 64-66°, [α]θ (methanol, 0.15 %) = 147.3 ± 6.7°. UV (methanol): Λmax(e) = 220 (48960); 270 (28500); 283/sh; 325 (13400).

The starting material is prepared, for example, as follows: a) (2R, 3RJL-2,3-epoxv-6,6,6-trif luoro-hexanol The title compound is prepared analogously to Example la) 25 from 6,6,6-trifluoro-hex-2(E)-enol; colourless oil; [α]θ° (chloroform, 0.17 %) = 35.9 ± 5.9°; IR (methylene chloride): 3550, 3420, 2950, 2890, 2830, 1125 cm"1. b) (4R, 5R) —4,5-epoxv-8 ., 8.8-trifluoro-oct-2 (E)-enal The title compound is prepared analogously to Example lb) 30 from the corresponding epoxy alcohol according to a); light-yellow oil; IR (CH2Cl2): 3050, 2980, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 ca1; Rf = 0.41 (hexane/ethyl acetate = 3:2). c) (4R,5R)-4,5-eooxy-l,1.1-trifluoro-ll-(4-acetvl-35 hvdroxv-2-propylphenoxy)-undeca-6(E), 8 (zL-diene The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to b); light-yellow oil; Rf = 0.48 (hexane/ethyl acetate 3:2).

Example 24: Sodium salt of (4R,5S)-1,1.1-trifluoro-41 0 hydroxy-11- (4-acetvl-3-hydroxy-2-propy_l_phenoxv)-undeca-6(E),8(Z)-dien-5-vl-7-thio4-oxo-4H-l-benzopyrane-2~carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 23; beige powder having a melting point of 198-200°; Ω [α]θ (methanol, 0.15 %) = 127.3 ± 6.7°; UV (methanol); Amax(e) = 221 (48820); 230/sh; 267 (25440); 285 (23080); 322/sh.

Example 25: (4S,5R)-1,1,1-trifluoro-4-hydroxv-l1-(420 acetyl - 3 -hydroxy- 2 -propylphenoxy) -undeca6(E)„8(Ζ)-dien-5-yT~7-thio-4-oxo~4H-l-benzopvrane-2-carboxvlic acid methyl ester The title compound is prepared analogously to Example 1 from (4S,5S)-4,5-epoxy-1,1,1-trifluoro-ll-(4-acetvl-325 hydroxy-2-propyIphenoxy)-undeca-δ(E),8(Z)-diene; colourless powder having a melting point of 69-71°; [α]θ = -153.3 ± 6.7° (methanol, 0.15 %). UV (methanol): Amax(e) = 220 (49560); 235/sh; 270 (29220); 285/sh; 325 (12990).

The starting material is prepared, for example, as follows: a) (2S,3S)-2,3-epoxy-6.6,6-trifluoro-hexanol The title compound is prepared analogously to Example la) from 6,6,6-trifluoro-hex-2(E)~enol but using L( + )20 tartaric acid diethyl ester; colourless oil; [σ]θ (chloroform, 0.17 %) = -25.9 ± 5.9°; IR (methylene Chloride): 3550, 3430, 2940, 2880, 2830, 1125 cm-1. b) (4S,5S)-4.5-epoxy-8,8„8-trifluoro-oct-2(Ξ)-enal The title compound is prepared analogously to Example lb) from the corresponding epoxy alcohol according to a); light-yellow oil; IR (methylene chloride): 3050, 2990, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm1; Rf = 0.36 (hexane/ethyl acetate 3:2). c) (4SJ5S)-4,5-epoxy-l.l,ltrifluoro-ll-(4-acetvl-3hydroxy-2-propylPhenoxy1-undeca-6(E),8(Z)-diene Ί5 The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to b); light-yellow oil.

Example 26: Sodium salt of (4Si_5R)-1,1.1-trifluoro-4_hydroxy-ll-(4-acetyl-3°hydroxy-2~oropyl20 phenoxy1-undeca-6(E) ,8(Z)-dien-5-yl-?rjhio4-oxo-4H-l-benzopyrane-2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 25; beige powder having a melting point of 201203°; [a]^0 (metheino1 °-15 %) = "117.3 ± 6.7°; UV (methanol): Amax(€) = 222 (48320); 233/sh; 267 (26440); 285 (24440); 330/sh.

Example 27: (4K,5S)-1.1,l-trifluoro-4-hydroxy-9-(4^ acetyl-3~hydroxv-2-propylphenoxy)-norv^S (Z)en-5-yl-7-thio-4-oxo-4H-l-benzopyrane-2carboxvlic acid methvl ester The title compound is prepared analogously to Example 1 from (4R,5R)-4,5-epoxy-l,1,l-trifluoro-9-(4-acetvl-3hydroxy-2-propylphenoxy)-non-6(Z)-ene; colourless, viscous oil; IR (methylene chloride): 3530, 2920, 2890, 2820, 1720, 1640, 1605, 1585 cm1.

The starting material is prepared, for example, as follows: a) (2S,3R)-2.3-epoxy-6,6,6-trifluoro-hexanal The title compound is prepared analogously to Example 5a) from (2R,3R)-2,3-epoxv-6,6,5-trifluoro-hexanol; colourless liquid having a boiling point of 80-81°/26 mbar.; on [G)D (chloroform, 0.15 %) = -10.7 ± 6.7°. b) (4R,5R)-4.5-eooxv-l„1.l-trifluoro-9-(4-acetyl-3hvdroxy-2-propylphenoxy)-non-6(Zj-ene The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to a); light-yellow oil.

Example_28: Sodium salt, of (4R.5S)-1,1.l-trifluoro-4hydroxy-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-non-6(Z)-en-5-yl-7-thio-4-oxo-4H-lbenzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 27; light-yellow powder having a melting point of 20420 206°; [α]θ (methanol, 0.15 %) = 42.7 ± 6.7°; UV (methanol): > max(e) = 218 (36920); 268 (20280); 285 (20180); 325/sh.

Example 29: (5R, 6S)-5-hvdroxyrl2-(4-acetvl-3-hydroxy-2-_ propylphenoxy)-dodec-7 (Z) -en-6-yl-7-thior4oxo-4H-l-benzopyra.ne-2-carboxy.lic .acid methyl ester The title compound is prepared analogously to Example 1 from (5R,6R)-5,6-epoxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)~dodec-7(Z)-ene; light-yellow oil; Rf = 0,37 (hexane/ethyl acetate 1:1).

The starting material is prepared, for example, as follows: a) 5-(4-acetyl-3-hydroxy-2-propy1phenoxy)-penty1- triphenvlphosphonium bromide The title compound is prepared as in Example lc) from 5(4-acetyl3~hydroxy-2-propylphenoxy)-pentyl bromide; colourless crystals having a melting point of 82-85°. b) (2S, 3R1-2.3-e3oxv-naor3.nal The title compound is prepared analogously to Example 5a) 2 0 from (2R,3R)-2,3-epoxy-heptanol; [g]d = -99.,4 ± 0.1°. c) (5R,6R)-5,6-epoxy-l2~(4-aeetyl-3-hydroxv-2-propylphenoxy) -dodec-7 (_Zj -ene The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to a), light-yellow oil.

Example 30: Sodium salt of (5R.6S)-5-hydroxv-l2-(4acetyl-3-hydroxy-2-propvlphenoxv)-dodec7(Z1-en-6-yl-7-thio-4-oxo-4H-l-benzoPvrane2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 29; m.p. 192-194°; [α]θ (methanol, 0,125 %) = +5.6 ± 8.0°; UV (methanol) -. Λ max(e) = 218 (38000); 268 (22040); 285 (21120); 325 sh.

Example 31: (5S,6R)-5-hvdroxv-12-(4-acetyl-3hvdroxy-2oroovlphenoxy)-dodec-7(Z)-en-6-vl-7-thio~4~ oxo-4H-l-ben2opyrane-2-carboxvlic acid methyl ester The title compound is prepared analogously to Example 1 from (5S,6S)-5,6~epoxy-12-(4-acetyl~3-hydroxy-2~propylphenoxy)-dodec=-7( Z)-ene; light-yellow oil; Rf = 0.41 (hexane/ethyl acetate 1:1).

The starting material is prepared, for example, as follows: a) (2R,3S)-2,3-epoxv-heptanal The title compound is prepared analogously to Example 5a) from (2S,3S)-2,3-epoxy-heptanol; [α]θ = +104.3 ± 0.4°. b) (5S.6S)~5,6-epoxy-i2-(4-acetvl-3-hydroxy-2-propylphenoxy)-dodec°7 f Z)-ene The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to a); light-yellow oil, Rf = 0.42 (hexane/ethyl acetate 3:2).

Example 32: Sodium salt of (5S,6R)°5-hydroxy-12-(4~ acetvl-3-hydroxy-2-propy1phenoxv)-dodec7(Z)-en-6-yl~7-thio-4-oxo-4H-l-benzopyrane2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 31; m.p. 192-194°; [α]θθ (methanol, 0.145 %) = 0 + 6.9°; UV (methanol): A max(e) = 218 (37060); 268 (21760); 286 (20520) ; 325 sh.

Example 33: f4R,5S)-1,1,1-trifluoro-4-hydroxy-ll-(4acetyl-3-hydroxy-2-propy lphenoxv 1 -undec6 f Z) -en-5-yl°7-thio-4-oxo-4H-l-benzopvrane2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (4R,5R)-4,5-epoxy-l, 1,1-trifluoro-ll-(4-acetyl-3hydroxy-2-propylphenoxv)-undec-6(Z)-ene, light-yellow oil; Rf = 0-47 (hexane/ethyl acetate 1:1).

The starting material is prepared, for example, analogously to Example Id) from (2S,3R)-2,3-epoxy-6,6,6trifluoro-hexanal; light-yellow oil.

Example 34: Sodium salt of (4R,5S)-1,1,1-trifluoro-4hydroxy-11-(4-acetyl°3°hydroxy-2-propvIphenoxv1-undec-6(Z)-en-5-yl-7-thio-4-oxo-4Hl-benzopvrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 33; m.p. 193-195°; [α]θ° (methanol, 0.135 %) = +16.3 + 7.4°; UV (MeOH): Amax(e) = 218 (37380); 267 (21380); 286 (21020); 325/sh.

Example 35: (5R,5Sl~5~hvdroxy-10-(4-acetyl°3-hydroxv-2propvlphenoxv1-dec-7 (Z1-en-6-vl-7-thio-4oxo-4H-l-benzoovrane~2-carboxylic acid methvl ester The title compound is prepared analogously to Example 1 from (5R,6R)-5,6-epoxy-10-(4-acetyl-3-hydroxy-2-propvl20 phenoxy)-dec-7(Z)-ene, light-yellow oil; [α]θ (methanol, 0.135 %) = +48.9 + 7.4°; UV (methanol): A max(e) = 216 (38140); 271 (24040); 285 sh, 322 (12700).

The starting material is prepared, for example, analogously to Example Id) from (2S, 3R)-2,3-epoxy-heptanal; light-vellow oil. Rf = 0.45 (hexane/ethyl acetate = 7:3).

Example 36: (5R,6S)-5-hydroxy-10~(4~acetyl-3-hydroxy-2propylphenoxv)-dec-7 (Z)-en-6-vl-7-thio-4oxo-4H-l-benzopvrane-2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 35 and is converted into the free acid with hydrochloric β 20 acid; m.p. 58-60°; [a]θ (methanol, 0.130 %) - +36.2 + 7.7°; UV (methanol): Λ max(£) = 218 (35240); 269 (20750); 283 (19800); 330 sh.

Example 37: (5S.6R1-5-hvdroxv-10°(4-acetyl-3-hydroxv-2propylphenoxv1-dec-7 (Ζ1-en-6-vl-7~thio-4oxo-4H-l-ben2ony.rane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (5S,6S)-5,6-epoxy-10-(4-acetyl-3-hvdroxy-2-propyl20 phenoxy)-dec-7(Z)-ene, light-yellow oil; [α]θ (methanol, 0.115 %) = -50.4 ± 8.7°; UV (MeOH):> max(£) = 217 (38000); 271 (24100); 285 sh, 321 (12800).

The starting material is prepared, for example, analogously to Example Id) from (2R,3S)-2,3-epoxy-heptanal; light-brown oil; Rf - 0.52 (hexane/ethyl acetate 7:3). - 46 Example 38; Sodium salt of (5S.6R)-5-hydroxv-10-(4acetvl-3-hvdroxv°2-propylphenoxy)-dec-7(Z)° en-6-yl-7-thio-4-oxo-4H-l-benzopyrane-2carboxvlic acid 5 The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 2 0 37; m.p. 224-226°, [α]θ (methanol, 0.145 %) = -29.0 ± 6.9°; UV (methanol): Λ max(e) = 219 (38760); 268 (21880); 285 (21260); 325 sh. 0 Example 39; (5S,6R)-5-hvdroxy-10-(4-acetyl-3-hydroxy-2propvIphenoxy)-dee-7(Z)en-6-yl-7-thio-4 oxo-4H-l-benzopvrane-2-f H-benzenesulfonamidyl )-carboxamide A solution of 0.20 g of (5S,6R)-5-hydroxy-T0-(4-acetyl-31 5 hydroxy-2-propylphenoxy)-dec-7 (Z)-en-6-yl-7-thio~4~oxo4H-l-benzopyrane~2~carboxylic acid in 10 ml of methylene chloride is stirred under argon at room temperature with 60 mg of benzenesulfonamide, 44 mg of 4-dimethvlaminopvridine and 70 mg of N-ethyl-Ni'-(3-dimethylaminopropyl)20 carbodiimide hydrochloride for 24 hours. The resulting solution is diluted with 30 ml of methylene chloride, washed twice with IN hydrochloric acid and twice with brine, dried over magnesium sulfate and concentrated by evaporation. Chromatography of the residue on silica gel with methylene chloride/methanol (9:1) yields the title compound having a melting point of 140-142*.

Example 40; (4RS,5SR)-l-methoxycarbonyl-4-hydroxy-9-(4acetyl-3-hydroxv-2-propvlPhenoxy)-non-6(Zien- 5-yl-7-thio-"4-oxo°4H-l-benzopyrane-230 carboxylic acid methvl ester The title compound is prepared analogously to Example 1 from (4RS,5RS)-4,5-epoxy-l-methoxycarbonyl-9-(4-acetyl-3- 47 hydroxy-2-propylphenoxy)-non-6(Z)-ene; colourless oil; [α]θ° (methanol, 0.125 %) = 0.0 ± 8.0°; UV (methanol): Amax(e) = 270 (24000); 340 (13200).

The starting material is prepared, for example, analogously to Example Id) from 5,6-epoxy-6-formylhexanoic acid methyl ester; light-yellow oil; Rf = 0.35 (hexane/ethyl acetate 3:2).

Example 41: Disodium salt of (4RS,5SR)-l-carboxy-4hydroxy-9-(4-acetyl-3~hvdroxy-2-propyl~ phenoxy 1 -non-5 (Z) °en-5-yl~7-thio-4-oxo-4H-l~ benzopyrane-2-carboxylic acid 0.24 g of the methyl ester according to Example 40 is dissolved under argon in 15 ml of tetrahydrofuran; 3.8 ml of 0.2N sodium hydroxide solution are added and the mixture is stirred for 20 hours at room temperature. Concentration by evaporation and purification of the residue by chromatography on a ’’Reversed Phase" silica gel column (for example Merck Lichroprep© RP-8) with methanol/water (7:3) yield the title compound having a melting point of 248-250° (decomp.); UV (methanol): AmaK(e) = 218 (33900); 268 (18580); 284 (18240); 330 sh.

Example 42: (IR,2S)-1-hydroxy-1-(3-trifluoromefchylphenvl)-10-(4-acetyl-3~hydroxy-2-propylphenoxv)-deca-3(El.5(Z)-dien-2-vl°7-thio-4oxo-4H-l-benzopyrane-2-°carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-1-(3-trifluoromethvIpheny1)-10-(4acetyl-3-hvdroxy-2-propy 1 phenoxy)-deca-3 (E), 5(Z) -diene; on light-yellow oil. [α]θ (CHC13, 0.363 %) = 46.6 ± 2.8° ; UV (CHC13) : Λϊη3χ( e) = 270 (26500); 285 (24240); 322 (15200)The starting material is prepared, for example, as follows: a) (1R,2R)-1,2-epoxv-l-(3-trifluoromethvlphenyl1-10°(4acetvl-3-hydroxy-2-propvlnhenoxv)-deca-3(E), 5 (Z) diene The title compound is prepared analogously to Example Id) from 5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentv1triphenylphosphonium bromide (Example 29a) and (4R,5R)-4,5epoxy-5-(3-trifluoromethylphenyl)-pent-2(E)-enal (Example on lb); light-brown oil; [c]θ (CHC13, 0.224 %) = 70.8 ± °; Rf = 0.50 (hexane/ethyl acetate = 1:1); IR (CH2C12): 2960, 2930, 2865, 1735, 1625, 1330, 1125 cm1.

Example 43: Sodium salt of (IR,2S)-l-hvdroxy°l=(3-trifluoromethylphenvl)-10-(4-acetyl-3-hvdroxy2~propylphenoxv)-deca-3(S).5(Z)-dien-2-vl-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 42); m.p. 217-219°; [g]q° (MeOH, 0.160 %) = 145.6 ± 6.3°; UV (MeOH): Λ max(£) = 220 (50480), 230 (sh), 267 (26240), 284 (23000), 320 sh.

Example 44: (IR,2S)-l-hydroxv-l-(3-methvlphenyl)-10-(4acetvl-3-hydroxy-2-propylphenoxy)-deca~ 3(E).5(z)-dien-2-yl-7-thio~4-oxQ"4H-l-benzopvrane-2-carboxyIic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-(3-methylphenvl)-10-(4-acetyl-3hydroxy-2-propylphenoxy)-deca-3(Ξ)„5(Z)-diene; m.p. 59-60°; [α]θ (CHC13, 0.163 %) = 31.9 ± 6.1°; UV (CHC13): Λ max(e) = 241 (31420); 286 (23060).

The starting material is prepared, for example, as follows: a) (1R,2R)-1,2-epoxv-l-(3-methylphenyl)-10-(4-acetvl-3hydroxy-2-propylphenoxy)-deca-3(E) .SfZbdiene The title compound is prepared analogously to Example Id) from 5-( 4-acetyl-3~hydroxy-2-propylphenoxy)~pentyltripheny1phosphonium bromide (Example 29a) and (4R,5R)-4,510 epoxv-5-(3-methylphenyl)~pent-2(E)*-enal (Example 9b); light-yellow oil; (a]20 (CHC13, 0.273 %) = 118.7 ± 3.7°. Rf = 0.62 (hexane/ethvl acetate = 3:2).

Example 45: Sodium salt of (lR,2S)-l-hvdroxy-l-(3methylphenyl) -10- (4-acety l-3-hydroxv-21 5 propvlphenoxy)-deca-3(E),5(Z)-dien-2~vl-7thio-4-oxo-4H-l-henzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 44); m.p. 208-210°; [α]θθ (MeOH, 0.30 %) = 50.7 ± 3.3°.

UV (MeOH): Λmax(e) - 219 (52420), 230 (sh), 267 (26620), 285 (23520), 325 (sh).

Example 46: (IS,2R)-l-hydroxy-l-(3-trifluoromethylphenvl )-10-( 4-acety l-3-hydroxv-2-propyl2 5 phenoxy)-deca-3(E) ,,5(Z)~dien-2-yl-7-thio~4~ oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IS,2S)-1,2-epoxy-l-( 3-trif luoromethylphenyl )-10-( 450 acetyl-3~hydroxy~2-propylphenoxy)-deca-3(E) , 5(Z)-diene; viscous mass; Rf = 0.48 (hexane/ethyl acetate = 1:1).

The starting material is prepared, for example, as follows: a) (IS ,25)-1,2-epoxy-l-(3-trifluoromethvlphenvl)-10-(4acetvl-3-hvdroxy-2°propylphenoxv)-deca-3(Ξ), 5 (Z) ~ diene The title compound is prepared analogously to Example Id) from 5-(4~acetyl-3-hydroxy-2-propylphenoxy)~pentyltriphenylphosphonium bromide (Example 29a) and (4S,58)-4,5epoxy-5-(3-trifluoromethylphenvl)-pent-2(E)-enal (Example . 20 3b); light-yellow oil; [α]θ (chloroform, 0.454 % = -86.8 ± 2.2°; Rf = 0.46 (hexane/ethyl acetate = 1:1).

IR (methylene chloride): 2960, 2930, 1730, 1625, 1330, 1130 cm1.

Example 47: Sodium salt of (IS,2R)-l-hydroxy-l-(3-trifluoromethylphenvl)-10-(4-acetvl-3-hydroxy2-propvlphenoxv)-deca-3(E),5(Z)-dien-2-yl-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 46); Ω m.p. 168-170°; [a]θ (methanol, 0.150 %) = -66.7 ± 6.7°; UV (MeOH): Λ TOax(£) = 220 (49640), 230 (sh), 266 (25640), 285 (22140), 320 (sh).

Example 48: (1R,2S1-I°hydroxy-1( 3-trifluoromethylτ phenyl)-8-Γ 4-acetvl-3-hydroxy-2-( 3,3 ,.3trifluoropropyl 1 -phenoxy1-octa-3 (E],5f ZJL·. dien-2-yl-7-thio-4-oxo~4H-l-benzopvrane<2_carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-(3-trifluoromethylphenyl)-8-[4acetyl-3-hydroxy-2- (3,3,3-trif luoropropyl) -phenoxy ] -octa3(E),5(Z)-diene; light-yellow oil; Rf = 0.34 (hexane/ethyl acetate = 1:1).

The starting material is prepared, for example, as follows: a) (IR, 2R) —1,2-epoxy-l-(3-trif luoromethylphenyl) -8- Γ 4acetyl-3-hvdroxy-2-( 3,3,3-trifluoropropyl) -phenoxy 1 octa-3(E),5(Z)-diene The title compound is prepared analogously to Example Id) from 3—[4—acetyl—3—hydroxy-2—(3,3,3-trifluoropropyl)phenoxy]-propyl triphenylphosphonium bromide and (4R,5R)4,5-epoxy~5- (3-tr if luoromethy lpheny 1) -pent-2 (E) -enal 20 (Example lb); light-yellow oil; [σ]θ (chloroform, 0.406 %) = -58.6 ± 2,5°; Rf = 0.45 (hexane/ethyl acetate = 7:3). IR (methylene chloride): 2945, 1670, 1610, 1310, 1055 cm"1. b) 3-Γ 4-acetyl-3-hvdroxy-2-( 3,3,3-trifluoropropyl)phenoxv 1 -propyl-triphenvlphosphonium bromide The title compound is prepared analogously to Example Ic) from 3-[4~acetyl-3-hydroxv-2-(3,3,3-trifluoropropyl)phenoxy]-propyl bromide. M.p. 184-185°.

Example 49: Sodium salt of (lR,2Sl-l-hydroxy-l-(3-trifluoromethylphenyl1-8-Γ 4-acetyl-3-hydroxy°2(3,3,3-trifluoropropyl1-phenoxy1-octa3(E1.5(Z1-dien-2-yl7-thio~4-oxo-4H-lbenzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 48); m.p. 238—240°; [α]θ° (methanol, 0.150 %) = 208 ± 6.6°; UV (MeOH): A Max(£) = 216 (50040), 230 (sh), 267 (28960), 280 (sh), 320 (16020).

Example 50: (IR,2S1-1-hydroxv-l-(3-methylphenyl)-8-Γ4~ acetvl-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy1-octa-3(El,5(Z)-dien-2-yl-7~thio-4oxo-4H-l-benzopyrane-2-carboxylic acid methvl ester The title compound is prepared analogously to Example 1 from (1R,2R)-1,2-epoxy-l-(3-methylphenyl)-8-[4-acety1-3hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-octa3(E),5(Z)-diene; light-yellow, viscous oil; Rf = 0.41 20 (hexane/ethyl acetate = 1:1). [α]θ (chloroform, 0.155 %) = 32.3 ± 6.5°. UV (chloroform): A max(ε) = 271 (32320), 318 (16100).

The starting material is prepared, for example, as follows: a) (IR,2R)-1,2-epoxy-l-(3-methy lphenyl 1--8-Γ4-acetyl~3hydroxv-2°(3,3,3-trifluoropropyl1-phenoxv1-octa3LE),_5(Z.)-diene The title compound is prepared analogously to Example id) from 3-[4-acety1-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy]-propyltriphenylphosphonium bromide (Example 48b) and (4R,5R)-4,5~epoxy-5-(3-methylphenyl)-pent-2(Ξ)-enal (Example 9b), light-yellow oil; R« = 0.38 (hexane/ethyl acetate = 3:2).

Example 51: Sodium salt of (IR,2S)-l-hvdroxv-l-(3methylphenvl) -8- Γ 4-acetyl-3-hydroxy-2(3,3„3-trifluoropropvl)-phenoxv1-octa3(E), S^^dien^-vl-y-thio^-oxo^H-lbenzopyrane-^-carboxvl ic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 50); m.p. 233-235*; [α]θ° (methanol, 0.195 %) = 69,,7 ± 5.1°; UV (MeOH): λ raax(£) - 218 (52320), 230 (sh), 267 (29040), 280 (sh), 320 (16000).

Example 52; (IR,2S)-l-hvdroxv-l-(2-trifluoromethylphenyl)-8-(4-acetyl-3-hvdroxy-2-propylphenoxv)-octa-3(E),5(Z)-dien-2-vl-7-thio-4oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)~1,2-epoxy-l-(2-trifluoromethylphenyl)-8-(4acetyl-3"hydroxy-2-propylphenoxy)-octa-3(E),5(Z)-diene; m.p. 66-68°; Rf = 0.23 (hexane/ethyl acetate = 3:2). 2Ω [α]θ (methanol, 0.150 %) = 22.0 ± 6.7*; UV (MeOH), Amax(e) = 216 (50000), 238 (sh), 271 (27860), 285 (sh), 324 (13900).

The starting material is prepared, for example, as follows: a) (IR.2R)-1,2-epoxv-l-(2-trifluoromethvlphenvl)-8-( 4acetvl-3-hvdroxy-2-propylphenoxv)-octa-3(E) ,5(Z)diene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyltriphenylphosphonium bromide (Example lc) and (4R,5R)-4,5epoxy~5-(2-trifluoromethylphenyl)~pent-2(E)"enal; lightbrown oil; [c]^° (chloroform, 0.207 %) = -5.8 ± 4.8° Rf - 0.25 (hexane/ethyl acetate = 4:1). b) (4R,5R)-4,5-eooxy-5-(2-trifluoromethylphenyl)-pent2(El-enal The title compound is prepared analogously to Example lb) from (2R,3R)-2,3-epoxy-3-(2-trifluoromethylphenyl)propanol; yellow crystals; Rf = 0.36 (hexane/ethyl 20 acetate = 4:1). [α]θ (methanol, 0.165 %) = 23.0 ± 6.1; UV (MeOH): ^^^(£) = 216 (14400), 235 (17240). c) (2R,3R)-2.3-epoxy-3-(2-trifluoromethylphenyl)-propanol The title compound is prepared analogously to Example la) from 3-(2-trifluoromethylphenyl)-prop-2(E)-enol; colourless crystals; Rf = 0.38 (hexane/ethyl acetate = 3:2); IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm-1.

Example 53: Sodium salt of (lR,2S)-l-hydroxy-l-(2~trifluoromethylphenyl1-8-(4-acetyl-3-hydroxv-2propylnhenoxy1-octa-3(El,5(Z1-dien-2-vl-7thio~4-oxo-4H-l~benzopyrane-2-carfaoxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 52); m.p. 155-157°; [ο:]θΟ (methanol, 0.180 %) = 12.8 ± 5.6°; UV (MeOH) : Λ snax(e) = 219 (48400), 230 (sh), 266 (25480), 284 (22540), 325 (sh).

Example 54: (IS,2R)-l-hvdroxy-l-f2-trifluoromethvlphenyl)-8-(4-acetyl-3-hvdroxv-2-propylphenoxv)-octa-3(E),5(Z)-dien-2-yl-7-thio~4oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IS,2S)-1,2-epoxy-l~(2-trifluoromethylphenyl)-8-(4acetyl-3-hydroxy-2-propyIphenoxy) octa-3(E),5(Z)-diene ; m.p. 71-73°; Rf = 0.25 (hexane/ethyl acetate = 3:2). [α]θθ (methanol, 0.170 %) =-27.1 ± 5.9°; UV (MeOH): Amax(e) = 216 (51040), 235 (sh), 271 (28140), 285 (sh) , 324 (13500).

The starting material is prepared, for example, as follows: a) (IS,2S)-1,2-epoxv-l-(2-trifluoromethylphenyl)-8-(4acetvl-3-hydroxy-2-propylphenoxy)-octa-3(E),5(Z) diene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl-triphenyIphosphonium bromide (Example lc) and (4S,5S)-4,5epoxy-5-(2-trifluoromethylphenyl)-pent-2(E)-enal; reddish oil; [c]D (chloroform, 0.207 %) = 5.4 ± 4.8°; Rf = 0.29 (hexane/ethyl acetate = 4:1). b) (4S,5S)-4 a5-epoxv-5-(2-trifluoromethylphenyl)-pent2(E)-enal The title compound is prepared analogously to Example lb) from (2S,3S)-2,3-epoxy-3-(2-trifluoromethylphenyl)propanol; yellow crystals; Rf = 0.38 (hexane/ethyl on acetate = 4:1); [α]θ (methanol, 0.180 %) = -25.0 ± 5.5°; UV (MeOH): Amax(e) = 215 (13960), 236 (17060). c) (2S,3S)-2^ 3-epoxy-3-(2-trifluoromethylphenvl)-propanol The title compound is prepared analogously to Example la) from 3-(2~trifluororaethylphenyl)-prop-2(E)-enol; colourless crystals; Rf = 0.35 (hexane/ethyl acetate = 3:2).

IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm1.

Example 55: Sodium salt of (IS, 2R)"l-hydroxvrlri2rtrirfluoromethylphenvl)-8-(4-acetyl-J-hydroxy-2propvlphenoxy) -octa-3 (E) , 5 (Z) -dienr_2_-_Ylr 7_-_ Ί0 thio-4-oxo-4H-l-benzopyrane-2~carboxYlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 54); m.p. 182-184°; [α]θθ (methanol, 0.205 %) = -16.6 ± 4.9°; UV (MeOH): Jlmax(e) = 219 (47680), 235 (sh), 266 (24960), 284 (22100), 330 (sh).

Exa.mp.le_5 6: (IR,2S)-l-hvdroxy-lr(4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propylοΗθηοχνΙ^οΡΐει^ΧΕ-Ι^δΙΖ^ -dien-2~ylr7.rthAQ.-4r 20 oxo-4H»l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-l,2-epoxy-l-(4-trifluoromethylphenvl)-8-(4acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E),5(Z)-diene; m.p. 68-70°; Rf = 0.16 (hexane/ethyl acetate = 3:2). on [C]D (methanol, 0.155 %) = 110.3 ± 6.5°; UV (MeOH): ΑΜχ(£) = 217 (52880), 236 (sh), 270 (28880), 285 (sh), 326 (13700).

The starting material is prepared, for example, as 30 follows: a) (IR, 2R)-1,2-epoxV"-l-(4-trif luoromethylphenyl )-8-( 4_t acetvl-3-hvdroxy-2-propylphenoxy )-qcta~3( E) ,5_J ZLz diene The title compound is prepared analogously to Example id) from 3-(4-acetyl-3-hydroxv-2-propylphenoxy)-propyltri~ phenylphosphonium bromide (Example lc) and (4R,5R)-4,5epoxy-5-(4-trif luoromethylphenyl)-pent-2 (S) -enal; yellow oil; [α]θθ (chloroform, 0.220 %) = 6.5 ± 4.5°; Rf = 0.35 (hexane/ethyl acetate = 4:1). b) (4R, 5R)-4,5-epoxy-5-( 4-trif luoromethylphenyl)-pent2(E)-enal The title compound is prepared analogously to Example lb) from ( 2R, 3R)-2,3-epoxy-3-( 4-trif luoromethylphenyl) propanol; yellow crystals; m.p. 67-70°; Rf = 0.24 20 (hexane/ethyl acetate = 4:1). [α]θ (methanol, 0.150 %) = 171.3 ± 6.7°; UV (MeOH): AmaK(e) = 237 (19660). c) (2R,3R)-2,3-e~ooxy-3-(4-trifluoromethylphenvl)-propanol The title compound is prepared analogously to Example la) from 3-(4-trif luoromethylphenyl) -prop-2 (E) -enol; colourless crystals; Rf = 0.25 (hexane/ethyl acetate = 3:2).

IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm-1.

Example 57: Sodium salt of (IR,2S)-l-hydroxv-l-(4-trifluoromethvlphenyl)-8-(4-acetvl-3-hydroxy-2propyIphenoxv)-ocrs-3(E),.5(Z)-dien-2-vl-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 56); m.p. 229-231°; [σ]θ° (methanol, 0.160 %) = 118.8 ± 6.3°; UV (MeOH):Araax(e) = 220 (53060), 235 (sh), 267 (27280), 284 (23880), 320 (16300), Example 58: (IS,2R1-l-hydroxv-l-(4-trifluoromethylphenyl )-8-( 4-acetyl-3-hydroxy-3propyl°phenoxv)-octa-3(E),5(Z)-dien-2-yl7-thio~4oxo-4H-l-benzopyrane-2-carhoxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IS,2S)-l,2-epoxv-l-(4-trifluoromethylphenyl)-8-(4acetyl-3-hydroxy-2-propylphenoxv)-octa-3(E),5(Z)-diene; m.p. 67-69°; Rf = 0.13 (hexane/ethyl acetate = 3:2); [α]θ° (methanol, 0.155 %) = -109.7 ± 6.5°; UV (MeOH): Amax(£) = 217 (52640), 235 (sh), 270 (28660), 285 (sh) , 326 (13680).

The starting material is prepared, for example, as follows: a) fIS.2S)-1,2-epoxv-l-(4-trifluoromethylphenyl)-8-(4° acetyl-3-hydroxy-2-propylphenoxv)-octa-3(E).5(Z)diene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl-triphenyl phosphonium bromide (Example lc) and (4S,5S)-4,5epoxy-5-(4-trifluoromethylphenyl)-pent-2(E)-enal; reddish oil; [a]θ (chloroform, 0.199 %) = -5.4 ± 5.0°; Rf = 0.23 (hexane/ethyl acetate = 4:1). b) (4S„5S)-4 ,5-epoxy-5-(4-trifluoromethylphenyl)-pent2(E)-enal The title compound is prepared analogously to Example lb) from (2S,3S)-2,3-epoxy~3~(4-trifluoromethylphenyl)propanol; yellow crystals; m.p. 67-69°. Rf = 0.18 20 (hexane/ethyl acetate = 4:1). [a]θ (methanol, 0.150 %) = - 59 -180.0 ± 6.7°; UV (MeOH): Λ max(e) = 236 (19740). c) (2S,3S)-2,3-epoxy-3-( 4-trifluoromethylphenyl)-propanol The title compound is prepared analogously to Example la) from 3-(4-trifluoromethylphenyl)-prop-2(E)-enol; colourless crystals; Rf = 0,23 (hexane/ethyl acetate = 3:2).

IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm-1.

Example 59: Sodium salt of (lS,2R)-l-hydroxy-l-(4-trifluoromethyIphenvl)-8-(4-acetyl-3-hydroxy-2propylphenoxy)-octa-3(E) ,5(Z)-dien-2-yl-7thio-4"Oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 58); m.p. 228-230°; [α]θ° (methanol, 0.175 %) = -99.4 ± 5.7°; UV (MeOH): A max(e) = 220 (49800), 235 (sh), 267 (25320), 284 (22200), 320 (15600).

Example 60: (IR,2S)-l-hvdroxy-l-(3-trifluoromethvlphenyl )-8-( 4-acetvl-3-hydroxv-2-propylphenoxy)-octa-3(Z)-en-2-vl-7-thio-4-oxo-4Hl-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-(3-trifluoromethylphenyl)-8-(4acetyl-3-hydroxy-2-propylphenoxy)-octa-3(Z)-ene; colour. 20 less oil; Rf = 0.41 (hexane/ethyl acetate = 1:1); [α]θ (chloroform, 0.150 %) = 45.7 ± 6.7°; UV (MeOH): Λmax(e ) = 271 (22760), 288 (20060), 270 (28880), 324 (14460).

The starting material is prepared, for example, as follows: a) (IR,2R)-1,2-epoxv-l-(3-trif luoromethvlphenvl)-8_-_( 4acetvl-3 -hydroxv-2-propyl phenoxv) -octa-3 (Z) -ene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentyl-triphenylphosphonium bromide (Example 29a) and (2S,3R)-2,3epoxy-3-( 3-trif luoromethvlphenvl )-propanal (Example 5a); light-yellow oil; [a]θ (chloroform, 0.221 %) = .3 ± 4.5°; Rf = 0.56 (hexane/ethyl acetate = 3:2).

Example 61: Sodium salt of (IR,2S)-1-hydroxy-1-(3-trifluoromethvlphenvl)8-(4-acetyl3-hvdroxy-2propvIphenoxy)-octa-3(Z)-en-2-yl-7-thio-4oxo-4H-l~benzopyrane-2~carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 60); m.p. 231-233"; [a]D (methanol, 0.190 %) = 51.1 ± 5.3°; UV (MeOH):Ά max(e) = 215 (42320), 267 (22220), 286 (20800), 320 (sh).

Example_62: (IR, 2S)-l-hydroxy-l-(3~trifluorometh_ylphenvl )-9-( 4-acetyl-3-hydroxy-2~proioyl·: phenoxv)-nona-3(E),5(Z)-dien-2-yl-7-thio-4oxo-4H-l-benzopyrane~2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy~l-(3-trifluoromethvlphenvl)-9-(4~ acetyl-3-hydroxy-2--propyIphenoxy) -nona-3 (E), 5 (Z) -diene; . . 20 light-yellow viscous oil; [σ]θ (chloroform, 0.155 %) = 44.5 ± 6.5°; Rf = 0.50 (hexane/ethyl acetate = 1:1); UV (CHC13):Amax(£) = 270 (26800), 284 (23100), 323 (14480).

The starting material is prepared, for example, as follows; a) 3—(4-acetyl-3—hydroxy—2-propylphenoxy)—butvl—triphenylphosphonium bromide The title compound is prepared analogously to Example lc) from 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-butyl bromide; m.p. 167-169°. b) (IR,2R)-1 , 2-epoxv-l- ( 3-trif luoromethylphenyl)-9- (_4_r acetyl-3-hydroxy-2-propylphenoxy)-nona-3 (E) . 5 (Z) diene The title compound is prepared analogously to Example Id) from 5-(4-acetyl-3-hydroxv-2-propylphenoxy)-butyl-triphenylphosphonium bromide and (4R,5R)-4,5-epoxy-5-(3trifluoromethylphenyl)-pent-2(E)-enal (Example lb); on light-yellow oil; [a]^ (chloroform, 0.308 %) = 40.7 ± 3.2°; Rf = 0.70 (hexane/ethyl acetate = 3:2); IR (methylene chloride): 2950, 2860, 1625, 1325, 1120 cm"1.

Example, 63: Sodium salt of ilR.2S)-l-hvdroxy-l-(3~trifluoromethylphenyl)-9-(4-acetvl-3-hvdroxy~2propylphenoxy)-nona-3(E),5(Z)-dien°2-vl-7thio-4-oxo-4H-l-benzopyrane-2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 62); m.p. 204-206°; (a](chloroform, 0.289 %) = 8.0 ± 3.5°; [α]θ = 55.5 ± 6.5° (methanol, 0.155 %); UV (methanol); Amax(e) = 219 (49320), 232 (sh), 266 (25800), 285 (22060), 330 (sh).

Example 64: (IR,2S)-l-hydroxy-l-(3-trifluoromethylphenyl )-11-( 4-acetyl-3-hydroxy-2-propy_lphenoxy)-undeca-3(E),5(Z)-dien-2-yl-7-thipr 4-oxo-4H-l-benzopvrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxv-l-(3-trifluoromethylphenyl)-11-(4acetyl-3-hydroxy-2-propylphenoxv)-undeca-3(E), 5 (Z)-diene; light-yellow viscous oil; [ο:]θ (chloroform, 0.160 %) = 48.1 ± 6.3°; Rf = 0.50 (hexane/ethyl acetate = 1:1).

UV (CHC13):Amax(e) = 270 (27120), 286 (23300), 323 (14740).

The starting material is prepared, for example, as follows: a) 3°(4-acetyl-3-hydroxy-2-propvlphenoxy)-hexyl-triphenyl Phosphonium bromide The title compound is prepared analogously to Example lc) from 3-(4-acetyl-3-hydroxy-2-propylphenoxv)-hexyl bromide; the compound crystallises very slowly. b) (IR,2R)-1,2-eooxy-l-(3-trifluoromethylphenyl)-11-(4acetyl-3-hydroxy-2-propylohenoxv1-undeca-3(E),5( Z)diene The title compound is prepared analogously to Example Id from 5-(4-acetyl-3-hydroxy-2-propylphenoxv)-hexyl~triphenylphosphonium bromide and (4R,5R)~4,5-epoxv-5-(3trifluoromethylphenyl)-pent-2(E)-enal (Example lb); light-yellow oil; [α]θ (chloroform, 0.450 %) = 41.1 ± 2.2°; Rf = 0.66 (hexane/ethyl acetate = 3:2); IR (methylene chloride): 2960, 2860, 1625, 1325, 1120 cm-1.

Example 65: Sodium salt of (lR,2Sl-l~hvdroxy-l-(3-trifluoromethylphenvl)-ll-(4-acetyl-3-hydroxv2-propylphenoxv] -undeca-3_(_El_, 51Z) -djen-2-yl7-thio-4-oxo-4H-i-benzopyrane-2-carboxvlic 5 acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 64); m.p. 216-218°; [a]1° (chloroform, 0.258 %) = 34.9 ± 3.9°; 9Π [α]θ = 73.8 ± 6.3° (methanol, 0.160 %); UV (methanol): ^max(£) = 219 (50140), 232 (sh) , 266 (26120), 286 (22460), 320 (15600).

Example 66: (IR,2S)~l"hvdroxy-l-phenyl-8-(4-acetyl-3hy_droxy-2-propylphenoxy) -octa-3 (E) , 5 ( Z) dien-2-vl-7-thio-4-oxo-4H-l-benzopvrane-21 5 carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-phenyl-8-(4-acetyl-3-hydroxy~2propylphenoxy)-octa-3(E),5(Z)-diene; light-yellow foam; Rf = 0.41 (hexane/ethvl acetate =1:1); [a]θ = 47.3 ± 2q 2.6° (chloroform, 0.385 %).

The starting material is prepared, for example, as follows: a) (1R.2R1-1,2-epoxy-l-phenyl-8-(4~acetyl-3~hvdroxy~2~ propylphenoxy)-octa-3(E).5(Z)-diene The title compound is prepared analogously to Example Id) from 3~(4-acetyl~3-hydroxy~2~propylphenoxy)-propy1-triphenylphosphonium bromide (Example lc) and (4R,5R)-4,5epoxv-5~phenyl-pent"2(E)-enal; light-yellow oil; Rf = 0.60 (hexane/ethyl acetate = 3:2). b) (4R, 5R)-4,5-epoxv-5-phenyl-pent-2(E)-enal The title compound is prepared analogously to Example lb) from (2R, 3R)-2,3-epoxy-3-phenyl-propanol; yellow oil which crystallises on standing; Rf = 0.38 (hexane/ethyl acetate = 3;2); [σ]θ° = 185 ± 5.0° (chloroform, 0.200 %). c) (2R ,3R)-2„3~epoxv-3-ohenyl-propanol The title compound is prepared analogously to Example la) from 3-phenyl~prop-2(E)-enol; colourless oil which crystallises at low temperature. Rf = 0.49 (hexane/ethyl acetate = 1:1); IR (methylene chloride): 3590, 3040, 2980, 2920, 2870, 1605, 1080, 1070 cm1. [α]θ (chloroform, 0.279 %) = 47.7 ± 3.6°.

Example 67: Sodium salt of (lR,2S)-l-hydroxv-l-phenyl-8(4-acetyl-3-hydroxv-2-propylphenoxy) -octa3(E) .5(Z )-dien-2-yi-7-thio~4-oxo~4H-l-ben2opyrane-2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 66); m.p. 219-221°; [α]θ° (chloroform, 0.160 %) = 103.1 ± 6.3°; UV (methanol): max(e) = 221 (51180), 232 (sh), 267 (27040), 284 (23840), 321 (16200); UV (chloroform): -^max(£) = 274 (26080), 286 (sh), 330 (sh).

Example 68: (IR,2S)-l-hydroxv-l-i3-trifluoromethvlphenyl)8-(3-acetyl-4-hydroxy-5-propylphenoxy)-octa-3(B),5(Z)-dien-2-yl-7-thio-4oxo-4K~l-benzopyrane-2-carboxylic acid methvl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-(3-trifluoromethylphenvl)-8-(3acetyl-4~hydroxy~5~propylphenoxy)-octa-3 (E) , 5(Z) -diene; Rf = 0,21 (hexane/ethyl acetate, 3:2).

The starting material is prepared, for example, as follows: a) 3-(3-acetyl-4~hydroxy-5-propylphenoxy)~Propyl bromide 6.2 g of potassium carbonate and 0.5 g of potassium iodide are added to a solution of 5.8 g of 2,5-dihydroxy3-propvl-acetophenone and 6.1 ml of 1,3-dibromopropane in 60 ml of methyl ethyl ketone. The reaction mixture is heated at reflux for 24 hours, and then poured onto 300 ml of ice-water, rendered acidic with hydrochloric acid and extracted with dichloromethane (3 x 150 ml).

The combined extracts are washed with 50 ml of water and dried over sodium sulfate. After filtration and concentration by evaporation in vacuo. the residue is chromatographed on 400 g of silica gel with dichloromethane. In the first fraction the title compound is eluted which, after concentration by evaporation, is obtained in the form of light-yellow crystals having a melting point of 69-70’. b) 3-(3-acetyl-4-hvdroxy-5-propylphenoxy)-propvl-triphenvlPhosphonium bromide The title compound is prepared analogously to Example lc) from 3-(3-acetyl-4-hydroxy-5-propy1phenoxy)-propyl bromide and triphenylphosphine; m.p. 103-105°. c) (1R,2R)-1,2-sooxv-l-(3-trifluoromethylphenyl)-8-(3acetvl-4-hydroxv-5-propylphenoxy)-octa-3(E),5(Z)~ diene The title compound is prepared analogously to Example Id) from 3-(3-acetvl-4-hydroxy-5-propylphenoxy)"propyl-triphenylphosphonium bromide and (4R,5R)-4,5~epoxy-5-(3trifluoromethylphenyl)-pent-2(E)-enal; Rf = 0.54 (hexane/ethyl acetate 2:1).

Example 69: Sodium salt of (IR, 2S)-l-hydroxy-l-(3-trif luoromethylphenyl )-8-( 3-acetyl-4-hydroxy-5propylphenoxy)-octa-3(£) , 5 (Z)-dien-2-vl-7thio-4-oxo"4H-l-benzopyrane-2-carhoxylic acid The title compound is prepared analogously to Example 2 from (IR, 2S)-l~hydroxy-l-( 3-trif luoromethylphenyl )-8-( 3acetyl-4~hydroxy--5-propylphenoxy)-octa-3 (Ε), 5(Z)-dien-2yl-7-thio"4-oxo"4H-l~benzopyrane-2-carboxylic acid methyl ester; yellow foam; 1H-NMR (CD3OD): δ = 7.91, 7.76-7.56, 7.50, 7.36, 7.05, 6.82, 6.41, 6.00, 5.75, 5.47, 5.12, 4.45, 3.78, 2.65-2.35, 1.88, 1.58, 0.94 ppm.

Example 70: (lR,2S)-l-hvdroxy-l-(3-chlorophenvl)-8-(4ace tv 1-3 -hvdr ox v-2-prooylj>henox.y_) -oc ta 3(E),5(Z)-dien-2-yl-7-thio-4-oxo-4H-l-benzopvrarie- 2 -carboxylic.. ac id._methy l.._ester The title compound is prepared analogously to Example 1 from (IR,2R)~1,2-epoxy-l-(3-chlorophenyl)-8-(4-acetyl-3hydroxy-2-propylphenoxy)-octa-3(E),5(Z) -diene; m.p. 76-77°; [α]θ° (chloroform, 0.215 %) = 51.2 ± 4.7°; UV (chloroform): Λ max(e) = 271 (28160), 285 (sh), 321 (15380).

The starting material is prepared, for example, as follows: a) (IR,2R)-1,2-epoxy-l-(3-chlorophenyl)-8-(4-acetyl-3hydroxy-2-propylphenoxy) -octa-3 (£).5(2) -diene The title compound is prepared analogously to Example Id) from 3-( 4-acetyl-3-hydroxy-2-propylphenoxy)-propyl-triphenylphosphonium bromide (Example Ic) and (4R,5R)-4,561 epoxy-5-(3-chlorophenyl)-pent-2(E)-enal; light-yellow oil; [α]θ° (chloroform, 0.541 %) = 63.9 ± 1.8°. b) (4R,5R)-4,5-epoxy-5-(3-chlorophenyl)-pent-2(E)-enal The title compound is prepared analogously to Example lb) from (2R,3R)-2,3-epoxy-3-(3-chlorophenyl)-propanol; darkyellow oil; Rf = 0.23 (hexane/ethyl acetate - 4:1). [α]θ (chloroform, 0.30 %) = 184.7 ± 3.3. c) (2R,3R)-2,3-epoxy-3-(3-chlorophenvl)-propanol The title compound is prepared analogously to Example la) 10 from 3-(3-chlorophenyl)-prop-2(E)-enol; light-yellow oil; Rf - 0.22 (hexane/ethyl acetate = 7:3). IR (methylene chloride): 3580, 3040, 2980, 2910, 2860, 1600, 1570, 1070 cm1. [g]q° (chloroform, 0.334 %) = 47.3 ± 3.0°.

Example 71: Sodium salt of (lR,2S)-l-hydroxy-l-(3~ chlorophenyl)-8-(4-acetyl~3~hydroxy-2propylphenoxv)-octa-3(E),5(Z)-dien-2-vl-7thio-4-oxo-4H-l-benzopvrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 70); m.p. 217-219°; [c]D = (methanol, 0.160 %) = 107.5 ± 6.3°; UV (methanol):Amax(e) = 219 (55060), 235 (sh), 267 (27340), 284 (23920), 320 (16500).

Example 72: (1R;2S)-l-hydroxy-l-(3-chlorophenyl)-10-(425 acetyl-3-hydroxy-2-propylphenoxv)-deca3 (Ε)^5_( Z)-dien-2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid methvl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l~(3-chlorophenyl)-10-(4-acety1-330 hydroxy-2-propylphenoxy)-deca-3(E),5(Z)-diene; m.p. 61-62°. [α]θ (chloroform, 0.170 %) = 52.9 ± 5.9°; UV (chloroform): Amax(e) = 271 (27120), 286 (24800), 322 (15400).

The starting material is prepared, for example, as 5 follows: a) (IR,2R)-l,2-eaoxy-l°(3-chlorophenyl)-10-(4-acetvl-3hydroxy-2-propylphenoxv)-deca-3(Ξ) ,5(Z)-diene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy~2"propylphenoxy)-pentyl-tri10 phenylphosphonium bromide (Example 29a) and (4R,5R)-4,5epoxy-5-(3-chlorophenyl)--pent-2(E)-enal (Example 70b); light-yellow oil; [α]θ (chloroform, 0.391 %) = 61.4 ± 2.5° .

Example 73: Sodium salt of (IR,2S)-1-hvdroxv-1-(315 chlorophenvl)-10-(4-acetyl-3-hydroxv-2oropylphenoxv)-deca-3(E),5(Z)-dien-2-yl-7thio-4-oxo-4H-l-benzopyrane~2-earboxvlic acid The title compound is prepared analogously to Example 2 20 from the corresponding methyl ester (Example 72); m.p. 204-206°; [α]θ° (methanol, 0.205 %) = 58.5 ± 4.9°; UV (MeOH):Araax(£) = 218 (27940), 267 (13140), 285 (11600), 320 (sh).

Example 74: (IR,2S)-l-hvdroxy-l-(3-methoxvohenyl)-8-(425 acetv1-3-hydroxy-2-propy1phenoxv)-octa3(E),5(Z)-dien~2-yl-7-thio-4°oxo-4H°l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)"1,2-epoxy-l-(3-methoxypheny1)-8-(4-acetyl-369 hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene; m.p. 65-67°; UV (chloroform): Amax(e) = 271 (30360), 285 (sh), 323 (16600).

The starting material is prepared, for example, as follows: a) (IR,2R)-1,2-epoxy-l-(3-methoxyphenvlJ-8-(_4-acety_l_-3r hydroxy-2-propylohenoxy)-octa-3(Ξ) ,5(Z)-diene The title compound is prepared analogously to Example Xd) from 3-(4—acetyl—3-hydroxy—2-propylphenoxy)-propvl-triphenyl phosphonium bromide (Example Xc) and (4R,5R)-4,5epoxy-5-(3-methoxypheny1)-pent-2(E)-enal; light-yellow 20 oil; [c]q (chloroform, 0.315 %) = 78.4 ± 3.2. b) (4R,5R)-4,5-epoxv-5-( 3-methoxvnhenyl)-pent-2(E)-enal The title compound is prepared analogously to Example lb) from (2R,3R)-2 , 3-epoxv-3-(3-methoxypheny1)-propanol; yellow oil; Rf = 0.41 (hexane/ethyl acetate = 3:2); [α]θθ (chloroform, 0.567 %) = 168.9 ± 1.8°. c) (2R,3R)-2,3-epoxy-3-( 3-methoxypheny1)-propanol.

The title compound is prepared analogously to Example la) from 3-(3-methoxypheny1)-prop-2(E)-enol; light-yellow oil; Rf = 0.31 (hexane/ethyl acetate = 3:2).

IR (methylene chloride): 3550, 2890, 1580, 1565, 1465, 1445, 1130 cm-1.

Example 75: Sodium salt of (lR,2S)~l-hydroxv-l-(3methoxvphenyl)-8-(4-acetvl-3-hydroxy-2propvlphenoxy)-octa-3(_£) ,5(Z)_Tdien-2-y.I-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 74); m.p. 206-208°; [α]θ° (methanol, 0.293 %) = 99.7 ± 3.4°; UV (methanol) : Amax(e) = 221 (57840), 235 (sh), 268 (29360), 282 (26400), 320 (16800).

Example 75: (IR,2S1-1-hydroxv-l-(3-methoxyPhenyl)-10-/4acety1-3-hvdroxv-2-prooylphenoxv)rdeca3(E),5(Z)-dien-2°yl-7-thio-4-oxo-4H-l°benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (1R,2R)~1,2-epoxy-l~(3-methoxyphenyl)-10-(4-acetyl3-hydroxy-2-propylphenoxy)-deca-3(B),5(Z)-diene; m.p. 53° (partly sublimes); UV (chloroform): Amax(e) = 272 20 (29920), 285 (sh), 323 (15540); [α]θ (chloroform, 0.180 %) = 44.4 ± 5.6°.

The starting material is prepared, for example, as follows: a) (1R,2R)-1 J2-eooxv-l-(3-methoxyphenyl1-10-(4-acetvl3-hydroxy-2-propylp.henoxy) -deca-3 (E),5(Z ) -dieng The title compound is prepared analogously to Example Id) from 3-(4-acety1-3-hydroxy-2-propv1phenoxy)-penty1-tri~ phenylphosphonium bromide (Example 29a) and (4R,5R)-4,5epoxy-5~(3-methoxyphenyl)-pent-2(E)-enal (Example 74b); light-yellow oil; [α]θ (chloroform, 0.375 %) = 72.5 ± 2.7.

Bxampl,e__77: Sodium salt of (1R.2S)-1-hydroxv-l-(3methoxyphenyl)-10-(4-acetyl-3-hvdroxy-2orooylohenoxy) -deca-3 (El,5(Z) -dien-2°yl-7thio-4rOXO4Hrl-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 76); m.p. 187-188°; [α]θθ (methanol, 0.150 %) = 72.0 ± 6.7°; UV (methanol):Araax(e) = 222 (55780), 268 (27820), 282 (25200), 321 (16200).

Example 78: (IR.2S)-1-hydroxy-l-(3-trifluoromefchylphenvl)-8-(4-trifluoroacetyl-3-hydroxyphenoxy)rocta-3(E) ,5(Z)-dien.r 2r.y 1=7-.thio-4oxo-4H-l-benzopvrane-2-carboxvlic acid methyl ester The title compound is prepared analogously to Example 1 from (IR, 2R) -1,2-epoxy-l- ( 3-trif luoromethylphenvl) -8- (4trifluoroacetyl-3-hydroxyphenoxy)-octa-3(E),5(Z)-diene; Rf = 0.23 (hexane/ethyl acetate 3:2).

The starting material is prepared, for example, as follows: a) 3 - (4 - tr i f luoroacety 1-3 -hydroxy phenoxy) -propyl- bromide The title compound is prepared analogously to Example 68a) from 2,4-dihvdroxytrifluoroacetophenone and is obtained in the form of a light-yellow oil; IR (dichloromethane): 3150, 2940, 1645, 1625, 1380, 1210, 1150, 1125, 1020, 940 cm’1. b) 3-(4-tr i fluoroacety 1-3-hvdroxvphenoxy)-propyl-tr ί phenylphosphonium bromide The title compound is prepared analogously to Example lc) from 3-(4-trifluoroacetyl-3-hvdroxyphenoxy)-propyl bromide and triphenylphosphine; m.p. 125-130°C. c) (IR,2R)-1,2-epoxv-l-(3-trifluoromethylphenyl)-8-(4trifluoroacetyl-3-hydroxyphenoxy)-octa-3(E) .5(2)diene The title compound is prepared analogously to Example Id) from 3-(4~tri fluoroacety1-3-hydroxyphenoxy)-propy1-1riphenylphosphonium bromide and (4R,5R)-4,5-epoxv-5-(3trifluoromethylphenyl)-pent-2(E)-enal; Rf = 0.56 (hexane/ethyl acetate 2:1).

Example 79: Sodium salt of (lR,2S)-l-hydroxy-l-(3-tri~ fluoromethylpheny1)-8-(4-trifluoroacetyl-3hydroxyphenoxy)-octa-3(E)a5(Z)-dien-2-yl-7thio-4OXO-4H-l°benzopyrane-2-carboxylic acid ml of 0. IN aqueous sodium hydroxide solution are added to a solution, cooled to 10°C, of 708 mg of the methyl ester of the title compound (see Example 78) in 25 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 24 hours, freed of solvent in vacuo and the residue is taken up in water. After filtration until clear, the solution is lyophilised. The title compound is obtained in the form of an olive-green amorphous powder. iH-NMR (CD3OD): & = 7.94, 7.78-7.46, 7.36, 6.90, 6.36, 6.04, 5.74, 5.42, 5.12, 4.42, 3.86 ppm.

Example 80: (IR, 2S)-1-hydroxy--1-( 3-trif luoromethylphenyl ) -8-(4-trifluoroacetyl-3-hvdroxy-2propylphenoxy)-octa-3(Ξ),5(Z)-dien°2-yl-7thio-4-oxo-4H-l-benzopyrane-2°carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2R)-1,2-epoxy-l-(3-trifluoromethylphenyl)-8-(4tri fluoroacetyl-3-hydroxy-2-propylphenoxy)-octa3(E),5(Z)-diene; Rf = 0.18 (toluene/ethyl acetate 5:1). - 73 The starting material is prepared, for example, as follows: a) 3-(4-trifluoroacetvl-3-hvdroxv-2~propylphenoxy)propyl bromide The title compound is prepared analogously to Example 58a) from 2,4-dihydroxy-3-propyl-tri£luoroacetophenone and is obtained in the form of a yellow oil; IR (dichloromethane): 3150, 2950, 2860, 1640, 1620, 1500, 1295, 1210, 1150, 1120, 1070 cm-1. b) 3-(4-trif luoroacety l-3-hydroxv~2-~propy lphenoxy)propvl-triphenylphosphonium bromide The title compound is prepared analogously to Example lc) from 3-(4-trifluoroacetvl-3~hydroxy-2-propylphenoxy)propyl bromide and triphenylphosphine; m.n. 170-190°C. c) (1R,2R)-1,2-epoxv-l-(3-trifluoromethylphenyl)-8^( 4trifluoroacetyl-3-hydroxy-2-propylphenoxy)-octa3(E),5(Z)-diene The title compound is prepared analogously to Example Id) from 3-(4-trifluoroacetyl-3-hydroxy-2-propylphenoxv)20 propvl-triphenylphosphonium bromide and (4R,5R)-4,5epoxv-5-(3-trifluoromethylphenyl)-pent-2(E)-enal; Rf = 0.55 (hexane/ethyl acetate 2:1).

Example ..81: Sodium salt of (lR ,2S)-l-hydroxy-l-(3-trifluoromethylphenyl)-8-(4-trifluoroacetyl-325 hygroxy-2-propvlphenoxy)-octa-3(Ξ),5(Z)dien-2-vl-7~thio-4-oxo-4H-l-benzopvrane~2carboxylic acid .5 ml of 0.1N aqueous sodium hydroxide solution are added to a solution, cooled to 10°C, of 500 mg of the methyl ester of the title compound (see Example 80) in ml of tetrahydrofuran. The reaction mixture is stirred for 1 hour at 10°C, freed of tetrahydrofuran in vacuo and the solution that remains is lyophilised. The title compound is obtained in the form of a yellowishgreen amorphous powder; -’-H-NMR (CD3OD); δ = 7.93, 7.777.60, 7.50, 7.36, 6.92, 6.43, 6.04, 5.73, 5.47, 5.13, 4.47, 4.00, 2.50, 2.38, 0.72 ppm.

Example 82: (IR,2S1-1-hydroxy-1-(3rtrifluoromethvl10 phenyl)-8-(4-acetyl-3-hydroxy°2-propvlphenvlthio)-octa-3(Ξ).5(Z)-dien-2-vl-7-thio4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (1R,2S)-1,2-epoxy-l-(3-trifluoromethylphenyl)-8-(4acetyl-3~hydroxy-2-propylphenylthio)-octa-3(E),5(Z)diene; Rf = 0.19 (hexane/ethyl acetate 3:2).

The starting material is prepared, for example, as follows: a) 3-( 4-acetyl-3-hvdroxy-2-oropylohenylthi_o) -propyl bromide The title compound is prepared analogously to Example 68a) from 2-hydroxy-4-mercapto-acetophenone; light-yellow oil. b) 3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propyl° triphenylphosphonium bromide The title compound is prepared analogously to Example 1 from 3-(4-acetyl=3~hydroxy-2"propylphenylthio)-propyl bromide and triphenylphosphine. c) (lR,2S)-l,2-epoxy-l-( 3-trif luoromethvlphenvl )-8-1-4^ acetyl-3-hydroxy-2-propvlphenylthio)-octa-3(E),5(Z)~ diene The title compound is prepared analogously to Example Id) from 3-(4—acetyl—3-hydroxy—2-propylphenylthio)-propyl— triphenylphosphonium bromide and (4E.5R)4,5epoxy-5~(3trifluoromethylphenyl)-pent-2(E)-enal.

Example 83; Sodium salt of (IR,2S)-l-hvdroxv-l~(3-trif luoromethvlphenvl) -8- (4-acgtvlrL3-_hydrox.y-2propylphenvIthio)-octa-3(E),5(Z)-dien-2-yl7-thio-4-oxo-4H-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 82).

Example 84: (lR,2S)-l-hydroxy-l-(3-trifluoromethvlphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenylthio)-deca-3(E) ,, 5 (Z)-dien-2-yl-7-thio4-oxo-4H°benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (IR,2S)-1,2-epoxy-l-(3-trifluoromethylphenyl)-10-(4acetyl~3-hydroxy-2-propylphenylthio)-deca-3(Ξ),5(Z)diene; Rf = 0.17 (hexane/ethyl acetate 3:2).

The starting material can be prepared, for example, as follows: a) 5-(4-acetyl-3-hydroxy-2-prooylphenylthio)-pentyl bromide The title compound is prepared analogously to Example 68a) from 2-hvdroxy-4-mercapto-acetophenone; light-yellow oil. b) 5-(4°acetyl-3-hydroxy-2-propylphenvlthip)rP.entylr· triphenylphosphonium bromide The title compound is prepared analogously to Example 1 from 5-( 4-acetyl-3-hydroxy-2—propylphenyl thio)-pentyl bromide and triphenylphosphine. c) (IR, 2S)-1,2-epoxy-l- ( 3-trifluoromethylphenyl L-10- (4acetyl-3-hydroxy-2-propylphenylthio)-deca-3(Ξ) ,_5_(Z)diene The title compound is prepared analogously to Example Id) from 5-( 4-acetyl=3—hydroxy-2—propylphenylthio) -pentyltriphenylphosphonium bromide and (4R,5R)-4,5-epoxy-5-(3tr if luoromethylphenyl) -pent-2 (E) -enol.

Example 85: Sodium salt of (lR.2S)-l-hydroxv-l-(3-trifluoromethylphenvl )-10-(4-acetvl~3-hydroxy2xP,r_opyl phenyl thio),-deca-3 (E) , 5 (, Z X^.dien-2yl~7-thio4~oxo-4H~benzopyrane-2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 84).

Example 86: 15R, 6S)-1,1,1-trif luoro-5-hydroxy^l_2-( 4^ acetyl-3"hydroxy-2-propvlphenoxyj-dodeca7(E),9(Z)-dien-5-vl-7-thio-4-oxo-4H-l-benzor pyrane-2-carboxylic acid methvl aster The title compound is prepared analogously to Example 1 from (5R, 6R) -5 , 5-epoxy-l, 1,1-trif luoro-12-(4-acetvl-3hydroxy-2-propylphenoxy)-dodeca-7 (Ξ), 9(Z)-diene; lightyellow foam; Rf = 0.24 (hexane/ethyl acetate = 3:2).

The starting material is prepared, for example, as follows: ΊΊ a) (2R,3R)-2.3-eooxv-7,Ί,7-trifluoro-heptanol The title compound is prepared analogously to Example la) from 7,7,7-trifluoro-hept-2(E)-enol; light-yellow oil; Rf = 0.38 (hexane/ethyl acetate = 3:2). [c:]^ (chloro5 form, 0.490 %) = 15.3 ± 2.0°. IR (methylene chloride): 3550, 3430, 2900, 1180, 1125 cm-1. b) (4R.5R)-4.5-epoxv-9,9,9-trifluoro-non-2(Ξ)-enal The title compound is prepared analogously to Example lb) from (2R,3R)-2,3-epoxy-7,7,7-trifluoro-heptanol; oil, which crystallises in the refrigerator. Rf = 0.63 ο n (hexane/ethyl acetate = 1:1). [a]θ (chloroform, 0.210 %) = 19.5 ± 4.8°. c) (5R,6R)-5.6-epoxv-l,1.l-trifluoro-l2-(4-acetvl-3hydroxv-2~oropylphenoxy)-dodeca-7(E). 9 (Z)-diene The title compound is prepared analogously to Example Id) from 3-(4-acetvl-3~hydroxy-2-propylphenoxy)-propyltriphenylphosphonium bromide (Example lc) and (4R,5R)-4,5epoxy-9,9,9-trifluoro~non-2(E)-enal; yellow oil; Rf = 0.56 (hexane/ethyl acetate = 3:2).

Example 87: Sodium salt of (5R.6S1-1.1.l-trifluoro-5hydroxy-12-f 4-acetvl3hvdroxv°2-propylphenoxy)-dodeca-7(Ξ)„9f Z)-dien-6-yl~7-thio4-OXO-4H-1-benzoovrane--2-carboxvlic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 86); 0 m.p. 190-191°; [a]D (methanol, 0.268 %) = 105.2 ± 3.7°; UV (methanol): Λ max(£) = 222 (48800), 235 (sh), 267 (25920), 285 (22920), 320 (16000).

Example 88: ( 4R, 5S)-1,1, l-trif luoro-4-hydroxv--13-( 4acetyl~3-hydroxy-2-propvlphenoxy)-trideca~ 6(E) .8('Z)-dien-5-vl-7thio-4-oxo-4Hlbanzopyrane-2-carboxvlic acid methyl ester The title compound is prepared analogously to Example 1 from (4R,5R)-4,5-epoxv-l,1,l~trifluoro-T3~(4-acetyl-3hydroxy-2-propylphenoxy)-trideca-6(E) ,8(Z)-diene; yellow oil.

The starting material is prepared, for example, as follows: a) (4R, 5R)-4.5-epoxv-8 a 8.8-trif luoro—oct-2 (Ej-.snsl The title compound is prepared analogously to Example lb) from (2R,3R)-2,3-epoxy-6,6,δ-trifluoro-hexanol; lightyellow oil which crystallises in the refrigerator; Rf = 0,53 (hexane/ethyl acetate = 3:2). [α]θ (chloroform, 0.290 %) = 21.7 ± 3.4°. XR (methylene chloride): 3050, 2980, 2930, 2810, 2730, 1690, 1640, 1145 cm"1. b) (4R.5R)-4„5-epoxy-l.l.l-trifluoro-13-(4-acetyl-3hydroxy-2-propylphenoxy)-trideca-6(E) ,8(Z)-diene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentyl—triphenylphosphonium bromide (Example 29a) and (4R,5R)-4,5epoxy-8,8,8-trifluoro-oct-2(E)-enal; yellow oil; Rf = 0.69 (hexane/ethyl acetate = 3:2).

Exajaple_89: Sodium salt of (4R, 5R)-1 l-trifluoro-4r hydroxy-13-(4-acetyl-3-hydroxv°2-oropylT phenoxy)-trideca~6(E),8(Z)-dien°5-yl-7-thio° 4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 88); m.p. 150-152°; [α]θ (methanol, 0.255 %) = 72.5 ± 3.8°; UV (methanol): A max( £) = 221 (44680), 231 (sh), 266 (22560), 285 (20560), 330 (sh).

Example 90: (4R.5S)-1.1.1-trifluoro-4-hydroxy-l2-(4acetyl~3-hydroxy-2-propylphenox_y.L-dodeca6 (E1.8 (Z) -dien-5-vl-7-thio-4~oxo-4H-lrbenzppyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (4R,5R)-4,5-epoxy-1,1,l-trifluoro-12-(4-acetyl-3hydroxy-2-propylphenoxy)-dodeca-6(E),8(Z)-diene; yellow oil; Rf = 0.31 (hexane/ethyl acetate = 3:2).

The starting material is prepared, for example, as follows: a) j 4R„ 5R.L~4_p 5-epoxy-.ll.„J.-trif luoro-12-( 4-acetyl τ_3ρ hydroxy-2-propylphenoxy) -dodeca-6 (Ε),8(Zj -diene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy-2-propy 1 phenoxy) -butyl-triphenylphosphonium bromide (Example 62b) and (4R,5R)-4,5epoxy-8,8,8-trifluoro-oct-2(E)-enal (Example 88a); yellow oil; Rf - 0.64 (hexane/ethyl acetate = 3:2).

Example 91: Sodium salt of (4R.5S)-1,,1.1-trif luoro^hydroxyrl2-(4re)cety,l-3^.hizd.Eoxy-2rPropylr phenoxy)-dodeca-6(E).8(Z)-dien-5-yl-7-thio4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 90); m.p. 180-182°; [a](methanol, 0.292 %) = 77.1 ± 3.4°; UV (methanol): Λraax(£) = 222 (47480), 231 (sh), 267 (24840), 285 (22120), 321 (15800).

Example 92: (5R? 6S)-5-hvdroxy-l2-( 4-acetyl-3-hyd.roxy-2propylphenoxy )jidpdeca-_7.Lg U-gJf.Z) -dienr 5,-ylr_7thio-4-oxo-4H-l-benzooyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (5R,6R)-5,6-eppxy-12-(4-acetyl-3-hydroxy-2-propylphenpxy)-dodeca-7(E),9(Z)-diene; light-yellow foam; Rf = 0.43 (hexane/ethyl acetate = 1:1); [α]θ (methanol, 0.150 %) = 22.0 ± 6.7°; IR (methylene chloride): 3580, 2950, 1745, 1655, 1625, 1600 cm-1.

The starting material is prepared, for example, as follows: a) (4R,5R)-4,5-epoxv-non-2(Ξ)-enal The title compound is prepared analogously to Example lb) from (2R,3R)~2,3-epoxy-heptanol; yellow oil; Rf = 0.29 20 (hexane/ethyl acetate = 4:1); [α]θ (chloroform, 0.390 %) = 21.3 ± 2.6°; IR (methylene chloride): 2950, 2920, 2860, 1690, 1640, 1100, 970 cm-1. b) (5R.6R)-5,6-epoxy~l2-(4-acetyl~3-hydroxy-2-propylphenoxv)-Tdodeca-7(E), 9 (Z_)-diene The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl-triphenylphosphonium bromide (Example lc) and (4R,5R)-4,520 epoxy-non-2(E)-enal; light-yellow oil; [e]Q (chloroform, 0.650 %) = 23.7 ± 1.5*.

Example 93; Sodium salt of (5R.6S)-5-hydroxy-12-(4acety1-3-hydroxy-2-propylphenoxy)-dodeca7(E),9(Z)-dien-0-yl°7-thio-4~oxo-4H-lbenzopvrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 92); m.p. 205-207°; [α]θ° (methanol, 0.278 %) = 115.1 ± 3.5°; UV (methanol): Λmax(e) = 222 (50960), 232 (sh), 267 (27400), 285 (24000), 321 (16400).

Example 94: (5R,, 6S) - 5~hvdroxy~12 - (4-acetyl^3-h.ydrox_y_^2propylphenoxy)-dodeca-7(Ξ),9(Z)-dien-6-yl-7thio-4-oxo~4Hl-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (5S,6S)~5,6-epoxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodeca-7(E),9(Z)-diene; colourless foam; o [α]θ (methanol, 0.260 %) = 136.2 ± 3.8 ; UV (methanol): Amax(£) = 221 (48040), 271 (28320), 327 (13200).

The starting material is prepared, for example, as follows: a) (4S,5S)-4,5-epoxy-non~2(Ξ)-enal The title compound is prepared analogously to Example lb) from (2S,3S)-2,3-epoxv-heptanol; yellow oil; Rf = 0.27 20 (hexane/ethyl acetate = 5:1); [^]θ (chloroform, 0.325 %) = 23.1 ± 3.0°. b) (5S „ 6S)-5,6-epoxy-12-(4-acetyl-3-hydroxy-2-propvlphenoxy)-dodeca-7(B),9(Z)-diene The title compound is prepared analogously to Example Id) from 3-(4-acetv1-3-hydroxy-2-propylphenoxy)-propy1tri30 phenylphosphonium bromide (Example Ic) and (4S,5S)-4,5- 82 20 epoxy-non-2(E)-enal; light-yellow oil; [α]θ (chloroform, 0.600 %) = 24.8 ± 1.6°.

Example 95: Sodium salt of (5S,5R)-5-hydroxv-12-(4acetyl-3-hvdroxy-2-propvlphenoxy)-dodeca5 7(E) ,9(Z)-dien-6-yl-7-thio-4-oxo-4H-lbenzopvrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 94); m.p, 204-206°; [α]θ° (methanol, 0.570 %) = 121.1 ± 1.8°; UV (methanol): λ max(e) = 222 (51240), 235 (sh), 267 (27360), 284 (21400), 320 (16400).

Example 96: (5R,6S)-5-hydroxv-14-(4-acetvl-3~hvdroxy-2propyIphenoxy)-tetradeca-7(E) , 9 (Z)-dien-6vl-7-thio~4-oxo-4H-l-benzopyrane-2-carbox1 5 ylic acid methvl ester The title compound is prepared analogously to Example 1 from (5R,6R)-5,6-epoxy-14-(4~acetyl-3-hydroxy-2-propylphenoxy)-tetradeca-7(E),9(Z)-diene; light-yellow viscous oil; [β]ρ° (chloroform, 0.424 %) = 66.5 ± 2.4°; UV (chloroform) : -λ saax(e) = 270 (28560), 288 (sh), 325 (15240).

The starting material is prepared, for example, as follows: a) (5R,6R)-5,6-epoxy-14°(4-acetvl-3-hydroxy-2-propyl25 Phenoxv)-tetradeca-7(E) , 9 (Z)-diene The title compound is prepared analogously to Example Id) from 3-(4-acetvl-3-hydroxy~2-propyIphenoxy)-pentyl-triphenylphosphoniura bromide (Example 29a) and (4R,5R)-4,5epoxy-non-2(E)-enal (Example 92a); light-yellow oil; [α]θ (chloroform, 0.441 %) = 20.6 ± 2.3°.

Example 97: Sodium salt of (5R,6S)-5-hydrpxy-l^-(4acetvl-3rhydroxy-2PrQpylphenoxy)-tefcradeca7(E).9 f Z )~dien-6-yl-7rthio-4-oxo-4H-l-benzo5 pyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 96); m.p. 193-195°; [e]^° (methanol, 0.284 %) = 71.1 ± 3.5°.

UV (methanol): A max(£) = 222 (49320), 232 (sh), 267 TO (25520), 286 (22680), 321 (16000).

Example 98: (55Α6Β)^5ζΛΐνάΓθχν-14-(4-acetyl.-3rh.ydrpxyr.2r proovlphenoxv)-tetradeca-7(Ξ),9(Z)-dien-6vl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxvlic acid .methyl ester T5 The title compound is prepared analogously to Example 1 from (53,65)-5,6-epoxy-14-(4-acetyl-3-hydroxy-2-propylphenoxy)-tetradeca-7(E),9(Z)-diene; light-yellow viscous 20 mass; [g]d (chloroform, 0.463 %) = 79.0 ± 2.2°; UV (chloroform): Aroax(£) = 270 (27120), 288 (sh), 326 (14960).

The starting material is prepared, for example, as follows: a) j5Sa6Sjr5,6-epoxy-14-(4-acetyl-3-hydgoxy-2-propylr phenoxy)-tetradeca-7(E),9(Z)~diene 25 The title compound is prepared analogously to Example Id) from 3-(4-acetyl-3~hydroxy-2-propylphenoxy)-pentyl-triphenylphosphoniu.ro bromide (Example 29a) and (4S,55)-4,5epoxy-non-2(E)-enal (Example 94a); light-yellow oil; [α]θ° (chloroform, 0.472 %) = 18.8 ± 2.1°.

Example 99: Sodium salt of (5S,6R)-5-hydroxv-14-(4acetyl-3~hvdroxy~2-propylphenoxy)tetradeca7(E),9(Z)-dien-6-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 98); m.p. 193-195°; [G]20 (methanol, 0.296 %) = 65.9 ± 3.4°.

UV (methanol): A max(£) = 222 (49760), 232 (sh), 267 (25800), 285 (22520), 320 (16000).

Example 100: (5R,6S)-1,1,1-trifluorp-5-hydroxy-14°(4acetyl-3°hydroxy~2-propylphenoxy)-tetradeca7 (E) , 9 (Z)-dien~6-yl-7-thio°4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester The title compound is prepared analogously to Example 1 from (5R,6R)-5,6-epoxy-1,1,1-trifluorol4(4-acacyl™3 hydroxy-2-propylphenoxy)-tetradeca-7(E),9(Z)-diene; light-yellow oil; Rf = 0.32 (hexane/ethyl acetate = 3:2).

The starting material is prepared, for example, as follows: a) (5R,6R)-5,6-epoxy-l,1,1-trifluoro-14-(4-acetvl-3hydroxy-2-propylphenoxy)-tetradeca-7(E) , 9 (Z)-diene The title compound is prepared analogously to Example Id) from 3-(4-acety1-3-hydroxy-2-propy1phenoxy)-penty1-triphenylphosphonium bromide (Example 29a) and (4R,5R)-4,5epoxy-9,9,9-trifluoro-non-2(E)-enal (Example 86b); yellow oil; Rf = 0.72 (hexane/ethyl acetate = 3:2).

Example 101: Sodium salt of f5R,6S)-1,1,l-trifluoro-5hydroxv-14-( 4--acetvl-3-hvdroxv-2-prooy_lphenoxy)-tetradeca-7(E),9(Z)~dien~5-yl-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 100); UV (methanol): λ ,η&κ(ε) = 222 (48800), 235 (sh), 267 (25920), 285 (22920), 320 (16000). 0 Example 102: In a manner analogous to that described in Examples 1 to 77 it is also possible to prepare: the sodium salt of (lR,2S)-l-hydroxy-l~phenyl-ll-(4acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z)-dien15 2-yl~7-thio-4-oxo-4H~l-benzopyrane-2-carboxylic acid; the sodium salt of (IR,2S)-l~hydroxy-l-phenyl-10-(4~ acetvl-3-hydroxy-2-propylphenoxy)-deca-3(E),5(Z)-dien-2yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (IR,2S)-1-hydroxy-1-phenyl-9-(420 acetyl-3-hydroxy-2-propylphenoxy)-nona-3(E) ,5(Z)-dien-2yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (IR,2S)-l-hydroxv-l~(3-chlorophenyl)9- (4-acety 1- 3-hydroxy-2-propy lphenoxy) -nona-3 (E),5(Z)dien-2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (IR,2S)-l-hydroxy-1-(3-chlorophenyl)11-( 4-acety 1-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) dien-2-yl-7-thio~4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (lR,2S)-l~hydroxy-l-(3-fluorophenyl)8- (4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E),5(Z)dien-2-yl-7~thio-4-oxo-4H-l-benzopyrane-2-carhoxylic acid; the sodium salt of (IR,2S)-l-hydroxy-l~(3-fluorophenyl)9- (4-acetyl-3~hydroxy-2-propylphenoxy)-nona~3(E),5(Z)dien-2-yl-7-thio-4-oxo~4H-l^benzopyrane-2~carboxylic acid; the sodium salt of (lR,2S)-l-hydroxy-l-(3-fluorophenyl)~ - (4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E),5(Z)dien-2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (IR,2S)-l-hydroxv-l-(3-fluorophenyl)11- (4-acetyl-3-hydroxy"2-propylphenoxy)-undeca-3 (E),5(Z)dien-2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (lR,2S)-l-hydroxy-i-(3-methoxyphenyl)9-(4-acetyl-3-hydroxy-2-propylphenoxy)-nona-3(E),5(2)dien-2-yl"7-thio-4"Oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (IR,2S)-1-hydroxy-1-(3-methoxypheny1)11-(4-acetyl-3~hydroxy-2~propylphenoxy)-undeca-3 (£),5(2)dien-2~yl-7-thio-4-oxo-4H~i-benzopyrane~2-carboxylic acid; the disodium salt of (lR,2S)-l-hydroxv-l-(3-carboxyphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa87 3(Ε),5(Ζ)-dien-2-vl-7-thio-4-oxo-4H-l-benzopyrane-2carboxylic acid; the disodium salt of (IR,2S)-1-hydroxy-1-(3-carboxyphenyl)-9-(4-acetyl-3-hvdroxy-2-propylphenoxy)-nona3(E),5(Z)-dien~2~yl-7-thio-4~oxo-4H-l-benzopyrane-2carboxylic acid; the disodium salt of (1R,2S)-1-hydroxy-1-(3-carboxyphenyl )-10-(4-acetyl-3-hydroxy-2-propylphenoxv)-deca3(E),5(Z)-dien-2~yl-7-thio-4~oxo-4H-l~benzopyrane~2carboxylic acid; the disodium salt of (IR,2S)-l-hydroxy-l~(3-carboxyphenyl )-11-(4-acetyl~3"hydroxv-2~propylphenoxy)-undeca3(E),5(Z)~dien-2-yl-7-thio-4--oxo-4H-l-benzopyrane-2carboxylic acid; the sodium salt of (IR,2S)-l-hydroxy-l-(3-methoxycarbonylphenyl)-9-(4-acetyl-3-hydroxy-2-propvlphenoxy)nona-3(E),5(Z)-dien-2-yl-7-thio-4-oxo-4H~l-foenzopyrane-2 carboxylic acid; the sodium salt of (IR,2S)-1-hydroxv-l-(3-methoxycarbonylphenyl)-10-(4-acetyl-3-hydroxy-2-propvlphenoxy)deca-3(E),5(Z)-dien-2"yl-7-thio-4-oxo-4H"l"benzopyrane-2 carboxylic acid; the sodium salt of (IR,2S)-l-hvdroxy-l-(3-methoxycarbonylphenyl )-11-(4-acetyl-3-hydroxy~2-propylphenoxv)undeca-3(E),5(Z)-dien-2-yl-7~thio-4-oxo-4H-l-benzopyrane 2-carboxylic acid; the sodium salt of (IR,2S)-l-hydroxy-l-(3,4-dichloro88 phenyl )-10- (4-acetyl-3-hydroxy-2-propy lphenoxy) -deca3 (Ε),5(Z) -dien-2-yl~7~thio-4-oxo-4H-l-benzopyrane-2carboxylic acid; the sodium salt of (lR,2S)-l-hydroxy-l-(2,4-dichloro5 phenyl )-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca3 (Ε),5(Z)-dien-2~yl-7-thio~4-oxo-4H-l-benzopyrane-2carboxylic acid; the sodium salt of (IR,2S)-1-hydroxy-l-(3,4-dimethoxyphenyl) -10-( 4-acetyl-3-hydroxy-2-propy lphenoxy )-deca10 3(E),5(Z)-dien-2-yl-7-thio-4-oxo-4H=l-benzopyrane-2carboxylic acid; the sodium salt of (IR,2S)-1-hydroxy-1-(2,4-dimethoxyphenyl )-10-( 4 -acetyl - 3-hydroxy- 2-propy 1 phenoxy) -deca3 (Ξ), 5(Σ)-dien-2-yl-7-thio-4-oxo~4«~l-benzopyrane-215 carboxylic acid; the sodium salt of (lR,2S)-l-hydroxy-l-(2,4-dimethylphenyl)-10-( 4-acetvl~3-hydroxy-2-propylphenoxy )-deca~ 3(E),5(Z)-dien-2~yl-7~thio-4-oxo-4H-l-benzopyrane-2carboxylic acid; the sodium salt of (IR,2S)-l-hydroxy-l-(3-dimethylaminophenyl )-10-( 4~acetyl-3-hydroxy~2~propylphenoxy)-deca~ 3(Ε),5(S)~dien-2-yl~7-thio~4-oxo-4H-l-benzopyrane-2~ carboxylic acid.

Example 103: In a manner analogous to that described in Examples 1 to 101 it is also possible to prepare the following compounds: the sodium salt of (lR,2S)-l-hvdroxy-l-(3-bromophenyl)-8 - 89 (4-acetyl-3-hydroxy-2-propyIphenoxy)-octa-3(E),5(Z)-dien 2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (IR,2S)-1-hydroxy-1-(3-bromophenyl)-9 (4-acetyl-3-hvdroxy-2-propyIphenoxy)-nona-3(E),5(Z)-dien 2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (lR,2S)-l-hydroxy-l-(3-bromophenyl)~ - (4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E),5(Z)dien-2-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (lR,2S)-l-hydroxy-l-(3-bromophenyl)11- (4-acetyl-3-hydroxy-2-propyIphenoxy)-undeca-3(E),5(Z) dien-2-yl-7-thio-4-oxo-4H~l-benzopyrane-2-carhoxylic acid; the sodium salt of (5R,6S)-1,1,1-trifluoro-5-hydroxy-131 5 (4-acetyl-3-hydroxy-2-propvIphenoxy)-trideca-7(E),9(Z)dien-6~yl-7-thio-4~oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (5R,6S)-1,1,1-trifluoro-5~hydroxy-15(4-acetyl-3-hvdroxy-2-propyIphenoxy)-pentadeca-7(E),9(Z) dien-6-yl-7-thio~4-Oxo-4H-l-ben2opyrane-2-carboxylic acid; the sodium salt of (5R,6S)-5-hydroxy-13-(4-acatyl-3hydroxy-2-propylphenoxy)-trideca-7(S),9(Z)-dien-5-yl-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the sodium salt of (5R,6S)-5~hydroxy-15-(4-acetyl~3hydroxy-2-propylphenoxy)-pentadeca-7(E),9(Z)-dien-6-y1-7 thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; - 90 the disodium salt of (4R,5S)-l-carboxy-4-hydroxy-ll-(4acetyl-3-hydroxy-2"propylphenoxy)-undeca-6(E),8(Z)-dien6-yl~7-thio-4-oxo-4H~l~benzopyrane~2~carboxylic acid; the disodium salt of (4R,5S)-l-carboxy-4-hydroxy-12-(45 acetyl-3-hydroxy-2-propylphenoxy)-dodeca-6(E),8(Z)-dien5-yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; the disodium salt of (4R,5S)-l-carboxy-4-hydroxy~13~(4~ acetyl-3~hydroxy~2~propylphenoxy)-trideca-6(E),8(Z)-dien -yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid; TO the disodium salt of (4R,5S)-l-carboxv-4-hydroxy-14-(4acetyl-3~hydroxy-2"Propylphenoxy)-tetradeca-6(E),8(Z)dien-5-yl-7-thio-4-oxo-4H~l-benzopyrane-2-carboxylic acid.

Examples of pharmaceutical preparations T5 and corresponding finished medicament forms In the following the term active ingredient" is to be understood as being a compound of formula I according to the invention, especially a compound described as a product in Examples 1 to 9, for example the sodium salt of (IR,2S)-l-hydroxv-l-(3-trifluoromethylphenyl)-8-(4acetvl-3-hydroxy~2-propylphenoxv)-octa-3(E),5(Z)-dien-2yl-7-thio-4-oxo-4H-l-benzopyrane-2~carboxylic acid.

Example Ai An inhalation suspension, comprising propellant and forming a solid aerosol, comprising 0.1 % by weight active ingredient Composition: active ingredient, micronised sorbitan trioleate Propellant A (trichlorotrifluoroethane) Propellant B (dichlorodifluoromethane and 1,2-dichlorotetrafluoroethane) % by weight 0.1 0.5 4.4 .0 80.0 Preparation: In the absence of moisture, the active ingredient is suspended in trichlorotrifluoroethane using a customary homogeniser and with the addition of the sorbitan trioleate, the suspension is introduced into an aerosol container provided with a metering valve; the container is sealed and filled up with propellant B under pressure.

Example B: An approximately 2 % aqueous solution, suitable for inhalation, of an active ingredient in the form of its sodium or potassium salt.

Composition: active ingredient (K or Na salt) 2000 mg disodium salt of ethylenediaminetetraacetic acid 10 mg benzalkonium chloride 10 mg water, freshly distilled ad 100 ml Preparation: The active ingredient is dissolved in approximately 60 ml of freshly distilled water, and the stabiliser (disodium salt of ethylenediaminetetraacetic acid) and the preservative (benzalkonium chloride) are added. When all the components have completely dissolved, the resulting solution is made up to 100 ml and introduced into small pressurised bottles which are then sealed in gas-tight manner. The propellant is added, as required, in gaseous form under pressure or in liquid form.

APPENDIX - PHARMACOLOGICAL TEST METHODS Bronchoconstriction test on guinea pigs (in vivo, aerosol): Male guinea pigs weighing 400-700 g are anaesthetised intraperitoneally with 1.4 g/kg of urethane and a polyethylene cannula is inserted into the jugular vein. A second polyethylene cannula is inserted into the trachea. The pressure in the oesophagus is recorded by means of a cannula that is inserted into the oesophagus and that is connected to a Statham pressure transducer. The animal is placed in an airtight plexiglass chamber which is connected to a Fleisch's tube No. 000 and a Validyne transducer MP 45-1. This arrangement is used to measure the flow.

After the surgical preparation of the test animals, a certain period of time is allowed to elapse to enable the pulmonary functions to stabilise. The test compound is then administered in accordance with the following procedure: The test animals are exposed for one minute to a 1 % aerosol solution of the test compound (weight/volume) or to distilled water (for control purposes). For all the test compounds that are administered by inhalation, a Monaghan ultrasound spray apparatus (model 670) of which the particle size varies between 1 and 8 microns, the majority being 3 microns, is used.

Aqueous solutions are freshly prepared each time and are introduced into the chamber of the spray device using an On-stream drug vial. The spray mist produced is administered to the experimental animals via a glass chamber of 65 ml capacity which is connected to the trachea by a cannula. When the treatment period has elapsed, LTD4 (0.3 /xg/ml) is administered over a period of 2 minutes using a second Monaghan ultrasound spray device (model 670) and via a similar glass chamber.

The reduction in compliance in the third minute after the LTD4 administration is read off and the average value of three animals is compared with the average value of three control animals and the percentage inhibition of compliance is calculated in accordance with the following formula: (100 - compliance preparation) x 100 % inhibition = 100 --(100 - compliance control) If different concentrations of active ingredient are tested, the percentage inhibition for each concentration is recorded, the log concentration on the abscissa being plotted against the percentage inhibition on the ordinate. The IC5Q is then determined by linear regression analysis.

In vitro test to determine the inhibition of phospholipase Ao obtained from human leucocytes Neutrophilic polymorpho-nuclear human leucocytes are isolated from ’Buffy coats by multi-step fractional sedimentation and are deep-frozen. The phospholipase A2 is extracted from the cell suspension by homogenisation with the addition of ice-cold 0.36N H2SO4 in 2N NaCl and the supernatant obtained after centrifugation at 10,000 x g is dialysed against sodium acetate buffer pH 4.5.

In order to determine the enzyme activity, enzyme (10-30 pg of protein) is incubated at 37° for 1 hour in O.IM tris/HCl buffer pH 7 with the addition of 1 mmol of CaCl2 and substrate consisting of phospholipids (2 Mm) of Escherichia coli radioactively labelled biosynthetically with 14C-oleic acid. The reaction is stopped by the addition of Dole reagent (isopropanol/heptane/lN H2SO4 40:10:1, v/v) and the 14C~oleic acid freed selectively by phospholipase A2 is extracted. Substrate extracted therewith is completely removed by filtration of the extract through a column of silica gel. The determination of -^C-oleic acid in the eluate is effected by radiometrv.

In order to detect an inhibitory action of test substances on phospholipase A2, the test substances are added to the incubation mixture in the form of solutions in water, dimethyl sulfoxide (final concentration in the batch up to 5 %, v/v) or ethanol (final concentration in the batch up to 2.5 %, v/v). The degree of action of the test substances is expressed by the IC50, that is to say the concentration which effects inhibition of 50 % of the control activity. The IC50 is determined graphically by plotting the percentage inhibition on the ordinate against the log of the concentration (mki) on the abscissa.

Under the described test conditions mepacrin inhibits phospholipase A2 ^ith an IC5Q of 1600 μιη.

In vitro test to determine the inhibition of phospholipase C obtained from human thrombocytes Human thrombocytes are obtained from 5Buffy coats55 by fractional centrifugation and are then deep-frozen. The phospholipase C is freed by ultrasound treatment of the cell suspension and after ultracentrifugation (150,000 x g for 1 hour) is present in soluble form in the supernatant.

In order to determine the enzyme activity, enzyme (20100 pg of protein) is incubated at 37° for 5 minutes in 0.025M tris/maleate buffer pH 6 with the addition of 0.2 mmol of CaCl2 and 0.02 mmol of radioactively labelled substrate, phosphatidyl-[14C]-inositol. The reaction is stopped by shaking with CHCI3/CH3OH 2:1 (v/v), in the course of which unused substrate is extracted into the organic phase, while the reaction product, 14C-inositol phosphate, remains in the aqueous phase and can be measured by radiometry of an aliquot.

In order to detect an inhibitory action of test substances on phospholipase C, the test substances are added to the incubation mixture in the form of solutions in water, dimethyl sulfoxide (final concentration in the batch up to 5 %, v/v) or ethanol (final concentration in the batch up to 2.5 %, v/v). The degree of action of the test substances is expressed by the IC5Q, that is to say the concentration which effects inhibition of 50 % of the control activity. The IC5Q is determined graphically by plotting the percentage inhibition on the ordinate against the log of the concentration (μπι) on the abscissa.

Under the described test conditions mepacrin inhibits phospholipase C with an IC50 of 20 μτη.

Claims (33)

1. Patent claims

1. A compound of formula I O R X-alk-(CH=CH)j^-CH— CH- R 3 OH O (I) in which R^ is lower alkyl or mono-, di- or poly-fluorolower alkyl, R 2 is hydrogen, lower alkyl, lower alkenyl or mono-, di- or poly-fluoro-lower alkyl, X is Cf-Cjalkylene, oxy or thio, alk is lower alkylene, n is 1 or 2, R 3 is phenyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl, amino, N-mono- or N,N-di-lower alkylamino, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl and/or by trifluoromethyl, or is lower alkyl, mono-, dior tri-fluoro-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl or Nmono- or N,N-di-lower alkylcarbamoyl-lower alkyl, R 4 is carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, or N-(benzenesulfonyl)-carbamoyl that is unsubstituted or is substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or by trifluoromethvl, and R 5 is hydrogen or lower alkyl; radicals designated lower having not more than 7 carbon atoms; or a salt thereof.

2. A compound according to claim 1, of formula I, in which R} is C 1 -C 4 alkyl or fu, ¢0 , co-trifluoro-C 1 -C 4 alkyl, R 2 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or trifluoro-C 1 -C 4 alkyl, X is C 1 -C 3 alkylene, oxy or thio, - 98 alk is straight-chain C 2 -Cgalkylene, n is 1 or 2, R 3 is phenyl that is unsubstituted or is substituted by Cf-C^alkyl, Cj_-C 4 alkoxy, halogen having an atomic number of up to and including 35, trifluoromethyl, carboxy 5 and/or by Cj-C 4 alkoxycarbonyl, or is Ci-C 7 alkyl, ,6J trifluoro-C2“C5alkyl, carboxy-C 2 -C 5 alkyl or C 1 -C 4 alkoxycarbonyl-C 2 -C 5 alkyl, R 4 is carboxy or N-(benzenesulfonyl)-carbamoyl, and R s is hydrogen, or a salt thereof.

3. A compound according to either claim 1 or claim 2, of 10 formula I, in which Ηχ is Ci-C 4 alkyl or GJ, 6J , 6J-trifluoro-C 1 -C 4 alkyl, R 2 is Cx-C 4 alkyl, C 2 -C 4 alkenyl or (H, a) , 60-trifluoro-Ci -C 4 alkvl, and the group X is bonded in the para-position with respect to the 1^-(3(=0) group, or a salt thereof. 15

4. A compound of formula la in which R 3 is C 3 -C 4 alkyl, R 2 is C],-C 4 alkyl, C 2 -C 4 alkenyl or A?, , -triiluoro-Cx-C 4 alkvl, X is C 3 -C 3 alkylene, oxy or thio, alk is straight-chain C 2 -Cg20 alkylene, n is 1 or 2, R 3 is a group of formula -A-R 3 ' in which -A- is Cx-C 4 alkylene, phenylene or a direct bond and R 3 ' is Cx-C 4 alkyl, trifluoromethyl, carboxy or Cx-C 4 alkoxvcarbonyl, R 4 is carboxy or N-(benzenesulfonvl)-carbamoyl, and R 5 is hydrogen, or a salt thereof.

5. A compound according to claim 4, of formula la, in which Ri is C 1 -C 4 alkyl, R 2 is Cj-C 4 alkyl, X is oxy, alk is C 2 -Cgalkylene, n is 1 or 2, Rg is phenyl substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxv, halogen having an atomic 5 number of up to and including 35, trifluoromethyl or by Cj-C 4 alkoxycarbonyl, or is C 2 -Cgalkyl, 6J, ίύ ,6J -trifluoro Cg-Cgalkvl or Ci-C 4 alkoxycarbonyl-C 1 -C 4 alkyl, R 4 is carboxy, and Rg is hydrogen, or a salt thereof.

6. A compound according to claim 4, of formula Ia, in 10 which R^ is C 1 -C 4 alkyl, R 2 is C 1 -C 4 alkvl, X is oxy, alk is C 2 -Cgalkylene, n is 2, Rg is a group of formula -A-Rg' in which -A- is C 1 -C 4 alkylene or phenylene, and Rg' is C 1 -C 4 alkvl, trifluoromethyl or C 1 -C 4 alkoxycarbonyl, R 4 is carboxy or N-(benzenesulfonyl)-carbamoyl 15 and R 5 is hydrogen, or a salt thereof.

7. A compound according to any one of claims 1 to 4, of formula I or la, in which X is oxy, or a salt thereof.

8. A compound according to any one of claims 1 to 5, of formula I or la, in which n is 2, or a salt thereof. 20

9. A compound according to any one of claims 1 to 8, of formula I or la, in which Rg is m-C^-C 4 alkylphenyl or mtrifluoromethylphenyl, R 4 is carboxy and Rg is hydrogen, or a salt thereof.

10. A compound according to any one of claims 1 to 9, of 25 formula I or la, in which in the radical -(CH=CH) n the double bond adjacent to the radical alk is in the (Z)-, that is to say the cis-configuration. and the additional double bond which may be present in the radical -(CH=CH) n - is in the (E)-, that is to say the 30 trans-configuration, or a salt thereof. 100

11. A compound according to any one of claims l to 10, of formula I or la, in which the chain carbon atom bonded to the sulfur atom has the (S)-configuration and the chain carbon atom carrying the hydroxy group has the (R) — configuration, or a salt thereof.

12. (IR,2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E),5(Z)-dien-2yl-7-thio-4-oxo-4H-l-ben2opyrane-2-carboxylic acid or the sodium salt thereof.

13. (IR,2S)-1-hydroxy-1-(3-methylphenyl)-8-(4-acetyl-3hydroxy-2-propylphenoxy)-octa-3(E),5(Z)-dien-2-yl-7-thio4-oxo-4H-l-benzopyrane-2-carboxylic acid or the sodium salt thereof.

14. (IR,2S)-1-hydroxv-l-pheny1-10-(4-acetyl-3-hydroxy-2propylphenoxy)-deca-3(E),5(Z)-dien-2-yl-7-thio-4-oxo-4Hl-benzopyrane-2-carboxylic acid or the sodium salt thereof.

15. (4R,5S)-1,1,l-trifluoro-4-hydroxy-ll-(4-acetyl-3hvdroxy-2-propylphenoxy)-undeca-6(E),8(Z)-dien-5-yl-7thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid or the sodium salt thereof.

16. (IR,2S)-1-hydroxv-l- (3-fluorophenvl)-10-(4-acetyl-3hydroxv-2-propylphenoxy)-deca-3(E),5(Z)-dien-2-yl-7-thio4-oxo-4H-l-benzopyrane-2-carboxylic acid or the sodium salt thereof.

17. (lR,2S)-l-hydroxy-l-(3-bromophenyl)-10-(4-acetvl-3hydroxy-2-propylphenoxy)-deca-3(E),5(Z)-dien-2-yl-7-thio4-OXO-4H-1-benzopyrane-2-carboxylic acid or the sodium salt thereof. 101 1Θ . (IR,2S)-1-hydroxy-l-(3-trifluoromethylphenyl)-10-(4acetvl-3-hydroxy-2-propylphenoxy)-deca-3(E),5(2)-dien-2yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid or the sodium salt thereof. 5 19. (IR,2S)-l-hydroxv-l-(3-methylphenyl)-10-(4-acetyl-3hydroxy-2-propylphenoxy)-deca-3(Ξ),5(2)-dien-2-yl-7-thio4-oxo-4H-l-benzopyrane-2-carboxylic acid or the sodium salt thereof.

18. 20. (IR,2S)-1-hydroxy-l-(3-trifluoromethylphenyl)-9-(41 0 acetyl-3-hydroxy-2-propylphenoxy)-nona-3(E), 5(Z)-dien-2yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxylic acid or the sodium salt thereof.

19. 21. (IR,2S)-1-hydroxy-l-(3-trifluoromethylphenyl)-11-(4acetvl-3-hydroxy-2-propylphenoxy)-undeca-3(E),5(2)-dien15 2-yl-7-thio-4-oxo-4H-l-benzopvrane-2-carboxylic acid or the sodium salt thereof.

20. 22. (IR,2S)-1-hydroxy-1-(3-chlorophenyl )-10-(4-acetyl-3hydroxy-2-propylphenoxv)-deca-3(E),5(2)-dien-2-vl-7-thio4-oxo-4H-l-benzopvrane-2-carboxylic acid or the sodium 20 salt thereof.

21. 23. (IR,2S) -1-hydroxy-l-(3-methoxyphenyl )-10-(4-acetyl3-hydroxy-2-propylphenoxy)-deca-3(E),5(Z)-dien-2-yl-7thio-4-oxo-4H-l-benzopyrane-2-carboxvlic acid or the sodium salt thereof.

22. 25 24. (IR,2S)-1-hydroxy-l-(3-methoxycarbonylphenyl)-10-(4acetyl-3-hydroxy-2-propy lphenoxy)-deca-3(E),5(Z)-aien-2yl-7-thio-4-oxo-4H-l-benzopyrane-2-carboxvlic acid or the sodium salt thereof. 25. A compound according to any one of claims 1 to 24 - 102 for use in a method for the therapeutic treatment of the human or animal body.

23. 26. A pharmaceutical composition comprising a compound according to any one of claims l to 24 and at least one 5 pharmaceutically acceptable carrier.

24. 27. A pharmaceutical composition comprising a compound according to claim 14 and at least one pharmaceutically acceptable carrier.

25. 28. A pharmaceutical composition comprising a compound 10 according to claim 18 and at least one pharmaceutically acceptable carrier.

26. 29. A process for the preparation of a compound of formula I according to claim l, or a salt thereof, which process comprises reacting an epoxide of formula II in which Rj , R 2 , X, alk, n and R 3 are as defined for formula I, with a thiol of formula III in which R 4 and R 5 are as defined for formula I, or with a salt thereof, and, if desired, converting a compound obtainable in accordance with the process into a different compound of formula I, separating a stereoisomeric mixture obtainable in accordance with the 103 process into the components and/or converting a free compound obtainable in accordance with the process into a salt, or converting a salt obtainable in accordance with the process into the free compound or into a different . 5 salt.

27. 30. The use of a compound according to any one of claims 1 to 24 for the preparation of a pharmaceutical composition.

28. 31. The use of a compound according to any one of claims 10 1 to 24 for the preparation of an anti-allergic medicament .

29. 32. A compound of formula (ϊ) given and defined in claim 1, or a salt thereof, substantially as hereinbefore described and exemplified. 15

30. 33. A pharmaceutical composition according to claim 26, substantially as hereinbefore described and exemplified.

31. 34. A process for the preparation of a compound of formula (I) given and defined in claim 1, or a salt thereof, substantially as hereinbefore described and exemplified. 20

32. 35. A compound of formula (I) given and defined in claim 1, or a salt thereof, whenever prepared by a process claimed in a preceding claim.

33. 36. Use according to claim 30, substantially as hereinbefore described.