NO171555B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW, THERAPEUTIC-ACTIVE, SUBSTITUTED ALKANPHENONES - 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

The present invention relates to the preparation of therapeutically active, substituted alkanephenones with the general formula

wherein R 1 means C 1 -C 4 alkyl or fluorinated C 1 -C 4 alkyl,

I?2 means hydrogen, C₁-C₁-alkyl or fluorinated C₁-C₁alkyl,

X means oxy or thio, alk means C^-Cy alkylene, n means 1 or 2, R 3 means phenyl, which is unsubstituted or substituted by C 1-C 4 alkyl, fluorinated C 1-C 4 alkyl, C 1-C 4 alkoxy . -C4-Alkoxycarbonyl-C1-C4-Alkyl,

and R 4 means carboxy, C 1 -C 4 alkoxycarbonyl or N-(benzenesulfonyl)carbamoyl, and salts thereof.

The spatial arrangement of the above formula I is, for the preferred compounds, in which the O atom of the hydroxyl group is in relative trans configuration with the S atom, so as to understand that the symbols of the first line lie above, the third line below the plane of the paper (or vice versa), which for the given formula corresponds to the opposite configuration, (RS)-(SR), according to the Kahn-Ingold-Prelog convention for the sulfur atom attached to the carbon atom (C-S-), and for the carbon atom bearing the hydroxy group (C-OH). Thereby, when n stands for 2, the enantiomers with the S(C-S-), R(C-OH) configuration are particularly preferred and, when n stands for 1, the enantiomers with R(C-S-), S(C-OH) -configuration particularly preferred. In the vinyl indicated with the symbol -(CH=CH)n - or the buta-1,3-dienylene residue has the double bond or the double bond of the butadienyl residue originating from the C atom connected to the residue alk is preferably, but not necessarily, in cis configuration, usually denoted by (Z), whereby the other double bonds then preferably, but also not necessarily, have trans configuration, usually denoted with (E).

The compound of formula I and their salts exhibit advantageous pharmacological properties, in particular a pronounced leukotriene antagonism.

Consequently, they inhibit e.g. in vitro in the concentration range from 0.001 to 1.0 jjmol/1 that of leukotriene-D4 (LTD4) induced the contraction of a smooth muscle. This so-called LTD4 antagonism is determined experimentally, e.g. in the following manner: In segments taken from the ileum of a guinea pig weighing 300-400 g and incubated in an organ bath in "Tyrode" solution at 38° C under gas treatment with a mixture of 95% oxygen and 5% carbon dioxide in an amount of 1 g, contractions are triggered with synthetic leukotriene D4 (as potassium salt) and recorded isotonically. The degree of inhibition achieved by the test substance is determined after a pre-incubation of 2 minutes and is given as IC50, i.e. the concentration at which the test contraction is reduced by 5056. The compound of formula I also shows in vivo excellent activity. Accordingly, in the in vivo bronchoconstriction standard test on guinea pigs, by aerosol administration of a solution containing 0.0001 to 1 wt-# of the substance to be investigated, a clear LTD4 antagonizing effect could be demonstrated.

(The description of the experimental procedure can be found in the appendix after the experiments).

Surprisingly, many compounds of formula I also exhibit a pronounced inhibitory effect on other physiologically important enzyme systems. Consequently, inhibition of phospholipase A from human leukocytes was observed in the investigated concentration range of approx. 0.5-50 pmol/l. (The experimental procedure for this determination is described in more detail in Appendix 1 after the examples). Furthermore, inhibition of phospholipase C from human platelets was observed in the examined concentration range of 1-100 pmol/1.

Because of these valuable pharmacological properties, the compounds of formula I produced according to the invention can find therapeutic application wherever the action of leukotrienes leads to disease states, and mitigate or abolish them. Consequently, they can, for example, be used for the treatment of allergic conditions and diseases, such as asthma in particular, but also hay fever and obstructive lung diseases including cystic fibrosis. Furthermore, due to their anti-inflammatory activity, they are suitable as anti-inflammatory agents, especially as external (topical) skin phlogistics for the treatment of inflamed dermatoses of any genesis, such as in light skin irritations, contact dermatitis, exanthems and burns, as well as mucosal phlogistics for the treatment of mucosal inflammations, e.g. in the eyes, nose, lips, mouth and genital or anal area. Furthermore, they can be used as a sun protection agent. The high inhibitory activity on various blood factors further points to the possibility of therapeutic application of the compound of formula I within the indication area of thrombosis and regulation of the fluidity of blood.

The group X is preferably attached in the para-position to the R^-C(=0) group, that is to say the compounds of the formula in which R}, R 2 , X, alk, n, R 3 and R 4 have the indicated meanings.

It is particularly preferred that the chain C atom connected to the sulfur atom preferably has (S) and the hydroxy group-bearing chain C atom preferably has (R) configuration, and the double bond connected to the residue alk is preferably in cis-configuration and the second additional double bond preferably in trans-configuration, and salts thereof, especially pharmaceutically usable salts.

The process according to the invention for the production of compounds of formula I and their salts is based on methods known per se and is characterized by reacting an epoxide of the formula

wherein R 1 , R 2 , X, alk, n and R 3 have the above meanings, with a thiol of the formula

in which R4 has the meanings given above, or a salt thereof, and if desired, a compound obtained according to the method is converted into another compound of formula I, a stereoisomer mixture obtained by the method is divided into its components and/or a free compound obtained by the method is transferred to a salt or a by the procedure

the salt obtained is transferred to the free compound or to another salt.

The reaction of epoxides II with thiols III takes place during configuration conversion at the bond with the C atom that forms part of the thio group and during configuration maintenance at the C atom that carries the hydroxy group. In order to arrive at the preferred compounds with the opposite configuration at these two C atoms, one therefore preferably starts from the corresponding trans-epoxides II. Thereby, starting from R,R-epoxides II, compounds with S(C-OH), R(C-OH) configuration are obtained, resp. starting from S,S-epoxides II compound I with R(C-S), S(C-OH) configuration. The reaction takes place under known conditions at temperatures from -20°C to +50°C, preferably at room temperature, i.e. 18°C to 25°C, and primarily in a basic environment, for example in the presence of a amine, especially a tertiary aliphatic, arylaliphatic or saturated heterocyclic amine, such as trialkylamine (e.g. triethylamine, or ethyl diisopropylamine), dialkylbenzylamine (e.g. N,N-dimethylbenzylamine), N,N-dialkylaniline (e.g. N,N-dimethylaniline) or N-methyl or N-ethylpiperidine or N,N'-dimethylpiperazine Usually the reaction is carried out in an indifferent organic solvent, such as a lower alkanol, e.g. methanol or ethanol.

The epoxide of the above-mentioned formula II used as starting material can in particular be produced by the same method as is used in the synthesis of leukotrienes. In a typical general synthesis method for compound II, where n stands for 1, one goes, e.g. from an aldehyde of the formula

in which A and R 3 have the above-mentioned meanings, whereby an optionally present free carboxyl group R 3 exists in a protected form as an ester, e.g. as lower alkyl esters. This compound is condensed with formylmethylenetriphenylphosphorane (or an equivalent reagent), whereby the corresponding trans-3-R3~<p>ro<p->2-enal compound of the formula is formed. This compound is then epoxidized in a manner known per se, preferably under slightly alkaline conditions (e.g. in the presence of alkali carbonates) with aqueous hydrogen peroxide, whereby a trans. i.e. 2(RS),3-(RS)-epoxy-3-R3~propanal of the formula The epoxy aldehyde VI can then be reacted by condensation with a phosphonium halide

in which R 1 , R 2 and alk have the indicated meanings and Hal constitutes a halogen atom, preferably bromine, and a base, e.g. sodium amide, in tetrahydrofuran to the corresponding epoxide II, in which R4 means esterified carboxy and n stands for 1.

Compounds VII are prepared in particular by reacting a corresponding compound of the formula with triphenylphosphine in the usual way. Compound VIII, in which X means oxy or thio, is obtained, for example, by condensing corresponding compounds of the formula

and Hal-alk-CH2-Hal (X),

in the usual way with each other.

Another method for preparing compound II consists in epoxidizing trans-3-R3-2-enol of the formula

in which R 3 has the above meaning, free carboxy as a substituent for R 3 is preferably protected in an ester form, for example by means of tertiary butyl hydroperoxide in the presence of titanium tetraisopropanolate and a D- or L-tartaric acid dilave alkyl ester, by using a D-tartaric acid ester, one thereby obtains predominantly 2R,3R-epoxy-3-R3~propanol XIIa, respectively. by the use of an L-tartaric acid ester predominantly the corresponding 2S,3S-epoxy-3-R3-propanol Xllb.

These are then oxidized, for example by treatment with oxalyl chloride/dimethylsulfoxide and then with triethylamine, to the corresponding epoxide aldehyde VI, which can then be reacted with the corresponding phosphonium salt VII to the corresponding epoxide II, in which R3 means esterified carboxy and n stands for 1.

Thereby, one mainly obtains epoxide II, in which the double bond has the preferred cis-stereotaxy. If you use a D-tartaric acid ester, you obtain, as mentioned, predominantly compound II, in which the epoxy group exhibits R,R configuration, resp. S,S-enantiomers when the reaction is carried out in the presence of L-tartaric acid esters.

In the production of the epoxide II, where n stands for 2, the epoxy alcohol Xlla or Xllb first by treatment with N,N'-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of trifluoroacetic acid and pyridine and then with triphenylphosphoranylidene acetaldehyde first to the corresponding 4R,5R- or The 4S,5S-4,5-epoxy-5-R3-pent-2-enal compounds of the formulas XHIa or XHIb

which is then further reacted with phosphonium halide VII to the corresponding epoxide II, in which n stands for 2. This preferably results in such compounds in which the residue alk

linked double bond exhibits cis-stereotaxis and the double bond linked to the oxirane ring exhibits trans-stereotaxis.

Compounds obtained by the method can, if desired, be transferred to other compounds of formula I.

For example, esterified or amidated carboxy groups can be hydrolysed to free hydroxy, preferably under basic conditions, e.g. in the presence of caustic soda, 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 R 3 means esterified carboxy, such as lower alkoxycarbonyl, and R 3 contains such as substituents, the hydrolysis can be controlled in such a way that selectively only R 3 or both R 4 and also the lower alkoxy carbonyl substituent of R 3 are hydrolyzed to carboxy. If you use an equimolar sodium hydroxide solution and choose mild reaction conditions, e.g. 0.5 to 2 hours of stirring at room temperature, practically only the alkoxycarbonyl R4 is hydrolysed, while under more drastic conditions, e.g. with longer reaction times or during heating, both R4 and also the alkoxycarbonyl group in R3 are hydrolyzed to carboxy.

Conversely, carboxy R4 and a carboxy substituent for R3 can be esterified in the usual way.

Free or esterified carboxy R4 and such as a substituent for R3 can further be amidated in the usual way, for example by treatment with ammonia or a mono- or dilave alkyl amine. For example, carboxy R4 can be transferred in the usual way, e.g. in the presence of a carbodiimide salt, e.g. of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 4-. dimethylaminopyridine, with an optionally substituted benzenesulfonamide to the corresponding N-benzenesulfamidoylcarbamyl group.

Naturally, one can also divide obtained diastereomer mixtures on the basis of different physical properties of the components into the individual components, and/or divide obtained enantiomeric mixtures by usual racemate separation procedures into the individual enantiomers.

When individual diastereomers are desired, then advantageously at any stage, an individual diastereomer of a starting material can be used, or formed from a starting material present in the form of a diastereomer by stereoselective reaction conditions or optically active reagents, preferably a diastereomer, or racemic diastereomer mixtures can be separated by physical separation methods, possibly using optically active auxiliaries, into the individual diastereomers.

In a stereochemical sense, however, both the condensation of components II and III, as well as the preparation of the starting materials, are mainly carried out in such a way that stereotactically uniform starting materials are always used, if possible the reactions are carried out stereoselectively, e.g. by using stereotactically uniform, optically active reagents and/or auxiliaries, and isolates stereotactically uniform products from the reaction mixtures immediately after the reaction. Consequently, e.g. in the preparation of the unsaturated starting materials, it possibly formed cis- and trans-isomers immediately from each other, whereby the usual physical separation methods, such as chromatography in particular, are suitable. In the main reaction, the stereomeric epoxide II is preferably used with the stereotaxy preferred in the final product for the double bond(s) and also in racemic form (which is often formed by the variant with epoxidation of the compound V with hydrogen peroxide) or preferably as an individual diastereomer with the final the substance In the preferred configuration at the (C-S-)-C atom of the opposite configuration at the bond that the S atom enters into with the oxirane C atom.

Furthermore, salts obtained, for example by acid treatment, can be transferred to the free acids or obtained free acids by base treatment to salts.

Due to the close relationship between the new compounds in free form and in the form of salts, in the above and subsequently under free compound or salts thereof shall also be understood the corresponding salts or free connections.

The following examples illustrate the present invention in more detail.

Example 1: ( IR . 2S )-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The solution of 0.93 g of (1R,2R)-1,2-epoxy-1-(3-trifluoromethyl-phenyl)-8-(4-acetyl-3-hydroxy-2-propyl-1-phenoxy)-octa-3 The (E),5(Z)-diene in 25 ml of methanol is stirred under argon with 0.80 g of triethylamine and 0.62 g of 7-mercaptochromone-2-carboxylic acid methyl ester for 20 hours at room temperature and evaporated. The residue is dissolved in vinegar and filtered over silica gel. The filtrate is washed 1 time with 2n-hydrochloric acid and 3 times with sol, dried over magnesium sulphate and evaporated. Purification of the residue by chromatography over silica gel with hexane/ethyl acetate (1:1) gave the title compound of mp 62-63°C;

[a]D2<0> (methanol, 0, 135%) = 103 ± 7.4° UV (methanol): Xmax (<c>) = 216 (50'000), 235/sh, 271 (27'940 ), 285/sh; 325 (12900).

The starting material is produced e.g. as follows:

a) ( 2R. 3R)- 2. 3- epoxy- 3-( 3- trifluoromethylphenyl)- propanol Under absolutely anhydrous conditions and an argon atmosphere, the solution of 4.62 ml of tetraisopropyl orthotitanate in 100 ml of methylene chloride cooled to -70°C is mixed, with 3.2 ml of D(-) tartaric diethyl ester and 5.45 g of 3-(3-trifluoromethylphenyl)-prop-2(E)-enol in a little methylene chloride. After 10 minutes of stirring at -70°C, 21.5 ml of 3 molar tertiary butyl hydroperoxide solution in toluene is added, whereby the temperature rises to -60°C. The temperature is allowed to rise slowly to 0°C over the course of 2 hours, the resulting yellow solution is poured slowly into a solution of 14.5 g of iron(II) sulfate and 5.8 g of L(+)-tartaric acid in 60 ml of water (cooling! exothermic) and it is stirred for 30 minutes at 5-10°C. The aqueous phase is separated and extracted with ether. The combined organic extracts are dried over sodium sulfate and evaporated. The residue is dissolved in 90 ml of ether, cooled to 0-5°C, mixed with a suspension of 2.32 g of sodium hydroxide in 60 ml of sol and stirred for 1 hour at 0-5°C. The aqueous phase is separated and extracted with ether. The combined ether phases are dried over sodium sulphate and evaporated. The residue is purified chromatographically on silica gel with hexane/acetic acid (3:2). The compounds in the title are thus obtained as colorless oil; IR (CH2Cl2): 3550, 3430, 2950, 2880, 2830, 1310, 1150, 1110, 1050 cm-1; [α]D2<0> (methanol, 0.17556) = 42.3 ± 5.7°; Rf = 0.30 (hexane/acetic ester 3:2). b) (4R.5R)-4.5-epoxy-5-(3-trifluoromethylphenyl)-pent-2(ET-enal) The solution of 4.5 g of (2R,3R)-2,3-epoxy-3-( 3-trifluoromethylphenyl)-propanol in 105 ml of dimethylsulfoxide 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 adding 8.25 g of formylmethylenetriphenylphosphorane, stir for a further 20 hours at room temperature, mixed with 320 ml of acetic acid and poured after 10 minutes into 320 ml of sol. The resulting suspension is stirred for 5 minutes and filtered. In the filtrate, the aqueous phase is extracted 2 times with acetic acid. The combined organic phases are washed 3 times with sol, dried over sodium sulfate and evaporated. The residue is filtered with ether/hexane (4:1) over silica gel. The filtrate is evaporated and the residue is purified by chromatography on silica gel with hexane/acetic ester (3:1). The title compound is obtained on this manner as clear, yellow oil; IR (CH2C12): 2780, 2695, 1670, 1620, 1305, 1145, 1105 cm-<1>; Rf = 0.31 (hexane/acetic ester 3:1) [α]D<20> (chloroform, 0.245#) - 144.5 ± 4.1°.

c) 3-( 4- acetyl- 3- h. hydroxy- 2- propylphenoxy) propyl- triphenyl- phosphonium bromide

The solution of 27 g of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide in 50 ml of toluene is heated with 21.85 g of triphenylphosphone for 20 hours to reflux. The resulting suspension is cooled to room temperature, mixed with 200 ml of ether and stirred for 1 hour. The colorless precipitate is filtered off with suction, washed with ether and dried. The compound in the title shows a melting point of 211-212°C.

d) (IR. 2R)-1.2-epoxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E). 5(Z)- diene

The suspension of 5.55 g of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl-triphenylphosphonium bromide in 80 ml of tetrahydrofuran is stirred with 0.78 g of NaNH2 and 60 mg of potassium tert.butanolate under argon for 1 hour at room temperature , cooled to 0-5°C, mixed during 5 minutes with 1.7 g of (4R,5R)-4,5-epoxy-5-(3-trifluoromethylphenyl)-pent-2(E)-enal in 20 ml of tetrahydrofuran and then 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 pE 7, dried over sodium sulphate and evaporated. The residue is taken up in hexane/acetic ester/triethylamine (24:71:5) and filtered over silica gel which has previously been washed with this solvent mixture. The filtrate is evaporated to give the title compound as a clear, yellow oil; Rf = 0.75 (hexane/acetic ester 3:2).

Example 2: ( IR . 2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E). 5( Z )-dien-2-yl-7-thio-4-oxo-4H-" benzopyran-2-carboxylic acid e- sodium salt

0.7 g (IR,2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E),5(Z)- dien-2-yl-7-1io-4-oxo-4H-1-benzopyran-2-carboxylic acids ethyl ester is dissolved under argon in 20 ml of tetrahydrofuran, mixed with 5.1 ml of 0.2n-sodium hydroxide solution and stirred in 1 hour at room temperature. Evaporation and chromatographic purification of the residue on a "Reversed Phase" silica gel column (eg Merck "Lichroprep RP-8") with methanol/water (3:1) gives the title compound, mp 207-209°C, [a ]D<20> (0.5456, methanol) = 96.3 ± 1.9°

UV (methanol): Xmax (c) = 220 (488840), 235/sh, 267 (25940), 285 (22900), 324/sh.

Example 3: ( IS . 2R )- 1- hydroxy- 1-( 3- trl fluoromethvulfenyl )- 8-( 4- acetyl- 3-h. vdroxy- 2- propylphenoxy )- octa- 3( E) . 5 ( Z )-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1) from (1S,2S)-1,2-epoxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E ),5(Z)-diene; m.p. 68-69°C.

The starting material is produced e.g. as follows:

a) ( 2S, 3S)- 2. 3- epoxy- 3-( 3- trifluoromethylphenyl)- propanol

The compound in the heading is produced as described in

example la), but using L(+)-tartaric acid diethyl ester; colorless oil; IR (CH 2 Cl 2 ): 3590, 3480, 2920, 2870, 1330, 1165, 1125, 1070 cm-<1>; [α]D 2 O (methanol, 0.17556) = -41.7 ± 5.7°; Rf = 0.34 (hexane/acetic ester 1:1).

b) ( 4S. 5S1- 4. 5- epoxyv- 5-( 3- trifluoromethylphenyl1- pent- 2( É 1- enal) The compound in the title is prepared analogously to example lb)

from the epoxy alcohol prepared according to a); clear, yellow oil; IR(CH 2 Cl 2 ): 2780, 2695, 1670, 1620, 1305, 1145, 1110 cm-<1>; [α]D<20> (chloroform, 0.1556) = -158.0 ± 6.7°; Rf = 0.4 (hexane/acetic acid 4:1).

c) (1S.2S1-1.2-epoxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E).5(Z)-diene

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde prepared according to b); light brown oil; Rf = 0.61 (hexane/acetic ester 3:2).

Example 4: ( IS . 2R1- 1- hydroxyz-(3- trifluoromethylphenyl)-8-( 4- acetyl- 3-hydroxyz- 2- propylphenoxyz)- octa- 3( E ). 5( Z )- diene- 2- vl- 7- thio- 4-oxo- 4H- l- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester prepared according to example 3; m.p. 210-212°C, [α]D<20> (MeOH, 0.1856) = -86.1 <+> 5.6° UV (MeOH): Xmax (c) = 220 (42820); 235/sh; 267 (26660); 285

(23760); 320 (15800).

Example 5: ( IR . 2S 1 - 1-hydroxyl- ( 3-trifluoromethylphenyl )- 6-( 4- acetyl- 3-hydroxy sv- 2- propylphenoxy)- hex- 3( Z )- en- 2- yl- 7- thio- 4- oxo- 4H-1- benzopvran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (IR,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z) -one; clear, yellow viscous oil; [α]D2<O> (MeOH, 0.11556) = 57.4 ± 8.7°; UV (MeOH): Xmax (c) = 220/sh; 271 (5280); 285/sh; 320 (2800).

The starting material is produced e.g. as follows:

a) ( 2S. 3R )- 2 . 3- er>oxv- 3-( 3- trifluoromethylphenyl )- propanol The solution of 1.1 g of oxalyl chloride in 15 ml of methylene chloride

cooled under argon to -65 to -70°C and mixed during 2 minutes with 1.5 g of dimethylsulfoxide in 5 ml of methylene chloride. After stirring for 10 minutes at -65 to -70°C, 1.7 g of (2R,3R)-2,3-epoxy-3-(3-trifluoromethylphenyl)-propanol in 15 ml of methylene chloride is added dropwise. After a further 30 minutes of stirring, 4 g of triethylamine are added dropwise, whereby the temperature rises to -40°C. The temperature is allowed to rise to 0°C, and the reaction mixture is poured onto phosphate buffer (pH 8). The organic phase is separated, and the aqueous phase is extracted with methylene chloride. The combined organic extracts are washed twice with sol, dried over sodium sulphate and evaporated. Chromatography of the residue on silica gel with hexane/ethyl acetate (7:3) gives the title compound as a colorless oil;

IR (methylene chloride): 2820, 1730, 1330, 1165, 1125, 1070 cm-<1>. Rf = 0.36 (hexane/acetic ester 3:2). [a]])<20> (chloroform, 0.20$) = 17.5 ± 5°.

b) (IR. 2R)-1.2-epoxy-1-(3-trifluoromethylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z)-ene

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde prepared according to a); clear, yellow oil; Rf = 0.69 (hexane/acetic ester 3:2).

Example 6: ( IR . 2S )-1-hydroxy-1-(3-trifluoromethylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z)-ene- 2- yl- 7- thio- 4- oxo- 4H-1- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 5; m.p. 222-224°C; [oc]D<20> (MeOH, 0.13556) = 62.2 ± 7.4°. UV (MeOH): <x>max (c) = 267 (22060); 285 (21140); 318/sh.

Example 7: ( IS . 2R )-1-hydroxyl- (3-trifluoromethylphenyl)-6-(4-acetl-3-hydroxy-2-propylphenoxy-hex-3(Z)-ene-2- yl- 7- thio- 4- oxo- 4H- 1-benzopyran- 2- carboxyl ester

The compound in the title is prepared analogously to example 1 from (1S,2S)-1,2-epoxy-1-(3-trifluoromethylphenyl)-6-(4-acetyl-3~hydroxy-2-propylphenoxy)-hex-3(Z) -one; colorless powder of melting point 69-71°C.

The starting material is produced e.g. as follows:

a) (2R.3S)-2.3-epoxy-3-(3-trifluoromethylphenyl)-propanol The compound in the title is prepared analogously to example 5a)

from (2S,3S)-2,3-epoxy-3-(3-trifluoromethylphenyl)-propanol. Clear, yellow liquid; IR (CH 2 Cl 2 ): 2820, 1730, 1330, 1165, 1130, 1070 cm-<1>; [a]D<20> (chloroform, 0 .205é) = 0.0 ± 5; [a]20365 (chloroform, 0 .2056) = 475.0 + 5.0°; Rf = 0.44 (hexane/acetic acid 7:3).

b) (IS. 2S)-1.2-epoxy-1-(3-trifluoromethylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z)-ene

The compound in the title is prepared analogously to example ld) from the corresponding epoxy aldehyde prepared according to a). Clear, yellow oil; Rf = 0.43 (hexane/acetic ester 3:2).

Example 8: (IS. 2R)-1-hydroxy-1-(3-trifluoromethylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z)-ene- 2- yl- 7- thio- 4- oxo- 4H-1- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 7; m.p. 239-241°C; [α]D<20> (methanol, 0.1556) = -60.7 ± 6.7°; UV(methanol): xmax (c) = 216 (44080); 268 (22520); 285 (21640) 320/sh. Example 9: (1R.2S)-1-hydroxy-1-(3-methylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E). 5 (Z)-diene-2-vl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid nrethyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-methylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E) ,5(Z)-diene; clear, yellow powder of m.p. 71-72°C; [α]D<20> = 81.7 ± 8.7° (MeOH, 0.11556); UV(MeOH): X max (c) = 217 (53680); 235/sh; 271 (29120); 285/sh; 325 (13200).

The starting material is produced e.g. as follows:

a) ( 2R. 3R)- 2. 3- epoxy- 3-( 3- methylphenyl)- propanol

The compound in the heading is prepared analogously to example la)

from 3-(3-methylphenyl)-prop-2(E)-enol; colorless, viscous oil; IR (CH 2 Cl 2 ): 3560, 3410, 2880, 2830, 1590, 1050 cm-<1>; Rf = 0.39 (hexane/acetic ester 1:1); [oc]D<20> = 38.9 ± 5.3° (chloroform, 0.19$).

b) ( 4R. 5R)- 4. 5- epoxy- 5-( 3- methylphenyl)- pent- 2( E)- enal

The compound in the heading is prepared analogously to example lb)

from the epoxy alcohol prepared according to a); clear, yellow powder, m.p. 60-61°C; IR (CH 2 Cl 2 ): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1130 cm-<1>; Rf = 0.34 (hexane/acetic ester 4:1).

c) ( IR. 2R )- 1. 2- epoxy- 1-( 3- methylphenyl)- 8-( 4- acetyl- 3-hydroxy- 2- propyl- phenoxy)- octa- 3( E). 5(Z)- diene

The compound in the title is prepared analogously to example ld) from the corresponding epoxy aldehyde according to a); clear, yellow oil; Rf = 0.63 (hexane/acetic ester 3:2).

Example 10: (1R.2S)-1-hydroxy-1-f3-methylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E). 5 ( Z )-diene-2-vl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 9; beige powder of m.p. 217°C (decomposition); [ot]j)<2>° (methanol, 0.1556) - 71.3 ± 6.7°; UV (methanol): Xmax (<c>) = 219 (51520); 234/sh; 267 (26460); 284 (23280); 322/sh.

Example 11: (IS. 2R)-1-hydroxy-1-(3-methylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E). 5 ( Z )-dien-2-vl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

r

The compound in the title is prepared analogously to example 1 from (1S,2S)-1,2-epoxy-1-(m-tolyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E) ,5(Z)-diene; [cx]D<20> (MeOH, 0.14856) — 75.7 ± 6.8°; UV (MeOH): <X>max (c) = 217 (51760); 240/sh; 271

(27860); 290/sh; 328 (12600).

The starting material is produced e.g. as follows:

a) ( 2S. 3S)- 2. 3- epoxy- 3-( 3- methylphenyl)- propanol

The compound in the heading is prepared analogously to example la)

from 3-(3-methylphenyl)-prop-2(E)-enol, but using L(+) tartaric acid diethyl ester; colorless oil; IR (CH 2 Cl 2 ): 3550, 3470, 2940, 2880, 2830, 1590, 1050 cm-<1>; Rf = 0.31 (hexane/-acetic ester 3:2).

b) (4S.5S)-4.5-epoxy-5-(3-methylphenyl)-pent-2(E)-enal The compound in the title is prepared analogously to example lb)

from the epoxy alcohol according to a); clear, yellow oil; IR (CH 2 Cl 2 ): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1120, 1085 cm-<1>; Rf = 0.29 (hexane/acetic ester 4:1).

c) (1S.2S)-1.2-epoxy-1-(3-methylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5( the Z1 die

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde according to b); clear, yellow oil; Rf = 0.51 (hexane/acetic acid 7:3).

Example 12: (1S. 2R)-1-hydroxy-1-(3-methylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E). 5 ( Z )-dien-2-yl-7-tlo-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 1 from the corresponding methyl ester prepared according to example 11; m.p. 197-198°C; [α]D<20> (0.1456 methanol) 72.1 ± 7.1°, UV (MeOH): Xmax (c) = 218 (50700); 235/sh; 267 (25780), 285

(22600); 321 (15000).

Example 13: (1R.2S)-1-hydroxy-1-(3-methylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z)-en-2-yl - 7- thio- 4- oxo- 4H- 1- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-tolyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z) -one; colorless powder of m.p. 136-138°C; [a]D<20> = 28.1 ± 7.4° (methanol, 0 .13556) UV (methanol): *max (c) = 271 (26020); 282/sh; 323 (13700).

The starting material is produced e.g. as follows:

a) ( 2S. 3R)- 2. 3- epoxyv- 3-( 3- methylphenyl)- propanol The compound in the title is prepared analogously to example 5a)

from (2R,3R)-2,3-epoxy-3-(3-methylphenyl)-propanol; clear, yellow oil. IR (methylene chloride): 2920, 2820, 1730, 1610, 1140, 1070 cm-<1>; Rf = 0.49 (hexane/acetic acid 3:2).

b) ( IR . 2R ) - 1. 2- epoxyv- 1-( 3- methylphenyl)- 6-( 4- acetvl- 3-hydroxy- 2- propyl- phenoxy)- hex- 3( Z)- one

The compound in the title is prepared analogously to example ld) from the corresponding epoxy aldehyde according to a); clear, yellow oil; Rf = 0.73 (hexane/acetic ester 3:2).

Example 14: (1R.2S)-1-hydroxy-1-(3-methylphenyl)-6-(4-acetyl-3-hydroxy-2-prop.ylphenoxy)-hex-3(Z)-ene-2- yl- 7- thio- 4- oxo- 4H- l- benzopvran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 13; beige powder of m.p. 238-240°C; [α]D<20> (methanol, 0.13556) = 31.1 ± 7.4°; UV (Methanol): Xmax (c) = 268 (21800); 285 (20860); 322/sh.

Example 15: ( IR . 2S )-1-hydroxyl-1-(3-methoxycarbonylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E). 5( Z )-diene- 2- vl- 7- thio- 4-oxo- 4E- l- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-methoxycarbonylphenyl)-8-(4-acety 1-3-hydroxy-2-propylphenoxy) -octa-3(E),5(Z)-diene; [α]D 2 O (methanol, 0.1456) = 27.9 ± 7.1°; UV (methanol): Xmax (c) - 221 (53560); 234/sh; 270 (28980): 285/sh; 326 (13860).

The starting material is produced e.g. as follows:

a) ( 2R. 3R)- 2. 3- epoxy- 3-( 3- methoxycarbonylphenyl)- propanol The compound in the title is prepared analogously to example la)

from (E)-3-methoxycarbonylcinnamon alcohol; slightly yellow colored oil; Rf = 0.3 (hexane/acetic acid 1:1).

b ) ( 4R . 5R) - 4 . 5-epoxy-5-f 3-methoxycarbonylphenyl)-pent-2(E)-enal

The compound in the title is prepared analogously to example 1b) from the corresponding epoxy alcohol; clear, yellow oil, Rf = 0.35 (hexane/acetic ester 3:2).

c) ( IR. 2R )- 1. 2- epoxy- 1-( 3- methoxycarbonylphenyl)- 8-( 4- acetyl-3- hydroxy- 2- propylphenoxy)- octa- 3( E). 5(Z)- diene

The compound in the title is prepared analogously to example ld) from the corresponding epoxy aldehyde according to b); tough yellow oil; Rf = 0.50 (hexane/acetic ester 3:2).

Example 16: ( IR. 2S )-1-hydroxyl-1-(3-methoxycarbonylphenyl)-8-(4-acetyl-3-hvdroxy-2-pr opvl f enoxy )-octa-3( E) . 5( Z)-diene- 2- vl- 7- thio- 4-oxo- 4H- l- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from (IR,2S)-1-hydroxy-1-(3-methoxycarbonylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E),5 (Z)-dien-2-yl-7-1 in o-4-oxo-4H-1-benzopyran-2-carboxylic acids ethyl ester prepared according to example 15; light brown powder of m.p. 181°C (decomposition); [α]D<20> (methanol, 0.1556) = 32.0 ± 6.7°; UV (methanol): Xmax (c) = 222 (51600); 232/sh; 267 (24160), 284

(22940); 320/sh; 400/sh.

Example 17: ( IS . 2R )-1-hydroxy-1-(3-methoxycarbonylphenyl)-8-(4-acetvl-3-hydroxy-2-propylphenoxy)-octa-3( E). 5 ( Z )-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1S,2S)-1,2-epoxy-1-(3-methoxycarbonylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E) ,5(Z)-diene; m.p. 77-78°C (colorless powder); [α]D<20> (methanol, 0.1556) - -52.7 ± 6.7°; UV (methanol): Xmax (c) = 221 (57420); 235/sh; 271

(29980); 288/sh; 326 (14320).

The starting material is produced e.g. as follows:

a) ( 2S. 3S)- 2. 3- epoxy- 3-( 3- methoxycarbonylphenyl)- propanol The compound in the title is prepared analogously to example la)

from (E)-3-methoxycarbonylcinnamic alcohol, but using L(+) tartaric acid diethyl ester; colorless oil; Rf = 0.48 (hexane/acetic ester 1:1).

b) ( 4S. 5S)- 4 . 5- epoxy- 5-( 3- methoxycarbonylphenyl)- pent- 2-( E )-enal

The compound in the title is prepared analogously to example 1b from the corresponding epoxy alcohol; colorless oil; IR (methylene chloride): 3050, 2990, 2945, 2820, 2730, 1725, 1695, 1640, 1290, 1255 cm-<1>; Rf = 0.34 (hexane/acetic ester 3:2).

c) ( IS. 2S )- 1. 2- epoxy- 1-( 3- methoxycarbonylphenyl)- 8-( 4- acetyl-3- hydroxy- 2- propylphenoxy)- octa- 3( E). 5(Z)- diene

The compound in the title is prepared analogously to example ld) from the corresponding epoxy aldehyde according to b); clear, yellow oil; Rf = 0.54 (hexane/acetic ester 3:2).

Example 18: ( IS . 2R )-1-hydroxy-1-(3-methoxycarbonylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3( E). 5( Z)-diene- 2- vl- 7- thio- 4-oxo- 4H- 1- benzopvran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 17; beige powder of m.p. 174-176°C; [α]D<20> (methanol, 0.15556) = -80.6 ± 6.5°; UV (methanol): Xmax (c) = 223 (59300); 235 shs; 267

(27300); 284 (24800); 321 (16200).

Example 19: ( IR . 2S )- 1-hydroxy- 1-( 3- methoxycarbonylphenyl)- 6-( 4- acetvl- 3-hvdr ok sv- 2- propylphenoxy)- hex- 3( Z)-ene- 2 - yl- 7- thio- 4- oxo- 4H-1- benzopyran- 2- carboxylic acid nrethyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-methoxycarbonylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z) -one; colorless oil: [oc]D20 = (methanol, 0.1156) - 24.5 ± 9.1°; UV (methanol): xmax (c) " 270 (22400); 322 (12000).

The starting material is produced e.g. as follows:

a) ( 2S. 3R)- 2. 3- epoxy- 3-( 3- methoxycarbonylphenyl)- propanol The compound in the title is prepared analogously to example 5a)

from (2R,3R)-2,3-epoxy-3-(3-methoxycarbonylphenyl)-propanol; clear, yellow oil; IR (methylene chloride): 2950, 2820, 1725, 1610, 1590, 1430, 1290, 1255 cm-<1>; Rf = 0.33 (hexane/acetic acid 3:2).

b) ( IR. 2R )- 1. 2- epoxy- 1-( 3- methoxycarbonylphenyl)- 6-( 4- acetyl-3- hydroxy- 2- propylphenoxy)- hex- 3( Z )- one

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde according to a); clear, yellow oil; Rf = 0.39 (hexane/acetic ester 3:2).

Example 20: ( IR . 2S )-1-hydroxy-1-(3-methoxycarbonylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z)-en-2-yl - 7- thio- 4- oxo- 4H-1- benzopyran- 2- carboxylic acid sodium salt ( A), and

( IR. 2S )- l- hydroxy- l-( 3- carboxyphenyl )- 6-( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- hex- 3( Z)- en- 2- vl- 7- thio- 4- oxo- 4H-l- benzopyran- 2- carboxylic acid disodium salt ( B)

The solution of 0.5 g of (1R,2S)-1-hydroxy-1-(3-methoxycarbonylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3( Z )-ene-2 -yl-7-1io-4-oxo-4H-1-benzopyran-2-carboxylic acid 1-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 caustic soda at room temperature and evaporated thereafter. The residue is purified by chromatography on "Lichroprep RP-8", Merck with methanol/water (3:1), and gives in fractions 2-5 the compound B in the title; m.p. 262-264C0;[α]D2<0> (methanol, 0.10556) = 17.1 ± 9.5°; UV (methanol): Xmax (c) = 268 (19680); 284 (19060); 325/sh; and in fractions 8-12 the compound Å in the heading; m.p. 155°C (decomposition); [cx]])<20> (methanol, 0.12$) = 22.5 ± 8.3°; UV (methanol): Xmax (c) = 268 (26200); 286 (29220); 325/sh.

Example 21: ( IS . 2R )-1-hydroxy-1-(3-methoxycarbonylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z)-ene-2-y1- 7- thio- 4- oxo- 4H-1- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1S,2S)-1,2-epoxy-1-(3-carboxymethylphenyl)-6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hex-3(Z) -one; colorless oil, which solidifies in a refrigerator, m.p. gO-<g>i^C; [a]])<20> = -41.5 ± 7.7°

(0.1356 methanol); UV (methanol): Xmax (c) = 271 (25120); 322

(13280).

The starting material is produced e.g. as follows:

a) ( 2R. 3S)- 2 . 3-epoxy-3-(3-methoxycarbonylphenyl)propanol The compound in the title is prepared analogously to example 5

from (2S,3S)-2,3-epoxy-3-(3-methoxycarbonylphenyl)-propanol; colorless oil; IR (methylene chloride): 2910, 2780, 1705, 1590, 1570, 1415, 1270, 1235 cm-<1>; Rf = 0.36 (hexane/acetic ester 3:2).

b) f IS. 2S) - 1. 2- epoxy- 1-(3- methoxycarbonylphenyl)- 6-( 4- acetyl-3- hydroxy- 2- propylphenoxy)- hex- 3( Z)- ene

The compound in the title is prepared analogously to example ld) from the corresponding epoxy aldehyde according to a); colorless oil, not further characterized.

Example 22: ( IS. 2R )-1-hydroxy-1-(3-methoxycarbonylphenyl)-6-(4-acetvl-3-hydroxy-2-propylphenoxy)-hex-3( Z ^en^-vl^-thio ^- oxo^ H-l- benzopyran^- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 21; beige powder of m.p. 208-210°C; [a]D<20> (methanol, 0.1256) = -41.7 ± 8.3°, UV (methanol): Xmax (c) = 268 (21060); 285 (21540); 325/sh.

Example 23: (4R.5S)-1.1.1-trifluoro-4-hydroxy-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6(E). 8( Z )-diene- 5- vl- 7- thio- 4- oxo- 4H- 1-benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1) from (4R,5R)-4,5-epoxy-1,1,1-trifluoro-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6. E) ,8(Z)-diene; beige powder of m.p. 64-66°C, [a]D<20> (methanol, 0 .1556) = 147.3 <+> 6.7". UV (methanol): Xmax (c) = 220 (48960); 270 (28500) ); 283/sh; 325

(13400).

The starting material is produced e.g. as follows:

a) ( 2R. 3R)- 2 . 3- epoxy- 6. 6. 6- trifluorohexanol The compound in the title is prepared analogously to example la)

from 6,6,6-trifluorohex-2(E)-enol; colorless oil; [oc]d<20 >(chloroform, 0.1756) = 35.9 ± 5.9°; IR (methylene chloride): 3550, 3420, 2950, 2890, 2830, 1125 cm-<1>.

b) ( 4R. 5R)- 4. 5- epoxy- 8. 8. 8- trifluoro- oct- 2( E)- enal The compound in the title is prepared analogously to example lb)

from the corresponding epoxy alcohol according to a); clear, yellow oil; IR (CE2C12): 3050, 2980, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm-<1>; Rf = 0.41 (hexane/acetic ester = 3:2).

c) (4R.5R)-4.5-epoxy-1.1.1-trifluoro-II-f4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6(E),8(Z)-diene

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde according to b); clear, yellow oil; Rf = 0.48 (hexane/acetic acid 3:2).

Example 24: (4R.5S)-1.1.1-trifluoro-4-hydroxy-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6(E). 8(Z)-dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 23; beige powder of m.p. 198-20CC; [α]D<20> (methanol, 0.1556) = 127.3 ± 6.7°; UV (methanol): Xmax (c) = 221 (48820); 230/sh; 267

(25400), 285 (23080); 322/sh.

Example 25: ( 4S . 5R )- l . 1. 1-trifluoro-4-hydroxy-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6(E). 8(Z)-diene-5-vl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (4S,5S)-4,5-epoxy-1,1,1-trifluoro-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6(E) ,8(Z)-diene; colorless powder of m.p. 69-71°C; [α]D<20> -153.3 ± 67° (methanol, 0.1556). UV (methanol): Xmax (c) = 220 (49560); 235/sh; 270 (29220); 285/sh; 325 (12990).

The starting material is produced e.g. as follows:

a) ( 2S. 3S)- 2. 3- epoxyv- 6. 6. 6- trifluorohexanol

The compound in the heading is prepared analogously to example la)

from 6,6,6-trifluorohex-2(E)-enol, but using L(+) tartaric diethyl ester; colorless oil; [cOd<20> (chloroform,

0.1756) = -25.9 ± 5.9°; IR (methylene chloride): 3550, 3430, 2940, 2880, 2830, 1125 cm-<1>.

b) ( 4S. 5S1- 4. 5- epoxy- 8. 8. 8- trifluoro- oct- 2( E)- enal The compound in the upper shift is prepared analogously to example lb)

from the corresponding epoxy alcohol according to a), clear, yellow oil; IR (methylene chloride): 3050, 2990, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm-<1>; Rf = 0.36 (hexane/acetic ester 3:2).

c) (4S.5S)-4.5-epoxy-1.1.1-trifluoro-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6(E). 8(Z)- diene

The compound in the title is prepared analogously to example ld) from the corresponding epoxy aldehyde according to b); clear, yellow oil.

Example 26: (4S.5R)-1.1.1-trifluoro-4-hydroxy-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-6(E). 8( Z)-diene- 5- vl- 7- thio- 4- oxo- 4H- 1-benzopyran- 2- carboxyl vrene- sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 25; beige powder of m.p. 201-203°C; [α]D<20> (methanol, 0.1556) = -117.3 ± 6.7°; UV (methanol): Xmax (c) = 222 (48320); 233/sh; 267

(26440); 285 (24440); 330/sh.

Example 27: (4R.5S1-1.1.1-trifluoro-4-hydroxy-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-non-6-(Z)-ene-5- yl- 7- thio- 4- oxo- 4H- 1- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (4R,5R)-4,5-epoxy-1,1,1-trifluoro-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-non-6(Z) -one; colorless, viscous oil; IR (methylene chloride): 3530, 2920, 2890, 2820, 1720, 1640, 1605, 1585 cm-1.

The starting material is produced e.g. as follows:

a) ( 2S. 3R)- 2. 3- epoxy- 6. 6. 6- trifluorohexanol The compound in the title is prepared analogously to example 5a)

from (2R,3R)-2,3-epoxy-6,6,6-trifluorohexanol; colorless liquid of boiling point 80-81°C/26 mbar. ; [a]j)<20> (chloroform, 0.1556) 10.7 <+> 6.7° .

b) (4R.5R)-4.5-epoxy-1.1.1-trifluoro-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-non-6(Z)-ene

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde according to a); clear, yellow oil.

Example 28: ( 4R . 5S )- l. 1 . 1- trifluoro- 4- hydroxy- 9-( 4- acetvl- 3- hydroxy- 2- propylphenoxy)- non- 6( Z)- en- 5- y1- 7- thio- 4- oxo- 4H- l- benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 27; clear, yellow powder of m.p. 204-206°C; [a]D<20> (methanol, 0.1556) = 42.7 ± 6.7°, UV (methanol): Xmax (c) = 218 (36920); 268 (20280); 285 (20180); 325/sh.

Example 29: (5R.6S)-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7(Z)-en-6-yl-7-thio-4-oxo- 4E-l-benzopyran-2-carboxyl ester

The compound in the title is prepared analogously to example 1 from (5R,6R)-5,6-epoxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7-(Z)-ene; clear, yellow oil; Rf = 0.37 (hexane/acetic acid 1:1).

The starting material is produced e.g. as follows:

a) 5-(4-acetyl-3-hydroxy-2-propylphenoxyIpentyl-triphenylphosphonium bromide

The compound in the title is prepared as in example lc) from 5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl bromide; colorless crystals of m.p. 82-85°C.

b) ( 2S. 3R)- 2. 3- epoxyv-heptanal

The compound in the heading is prepared analogously to example 5a)

from (2R,3R)-2,3-epoxyheptanol; [a]D<20> = -99.4 ± 0.1°.

c) ( 5R . 6R) - 5 . 6- epoxy- 12-( 4- acetyl- 3- hydroxy- 2- propylphenoxy )- dodec- 7-( Z)- ene

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde according to a), clear, yellow oil.

Example 30: (5R.6S)-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7(Z)-en-6-yl-7-thio-4-oxo- 4H-l-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to 29; m.p. 192-194°C; [oc]d<20> (methanol, 0.12556) = +5.6 ± 8.0°; UV (methanol): Xmax (c) = 218 (218 (38000); 268 (22040); 285 (21120); 325 sh.

Example 31: (5S.6R1-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7(Z)-en-6-yl-7-thio-4-oxo-4H - l- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (5S,6S)-5,6-epoxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7-(Z)-ene; clear, yellow oil; Rf = 0.41 (hexane/acetic acid 1:1).

The starting material is produced e.g. as follows:

a) ( 2R. 3S)- 2 . 3- epoxyv-heptanal

The compound in the heading is prepared analogously to example 5a)

from (2S,3S)-2,3-epoxyheptanol; [a]D<20> = +104.3 ± 0.4°.

b) (5S. 6S)-5. 6- epoxy- 12-( 4- acetyl- 3- hydroxy- 2- propylphen-oxv)- dodec- 7( Z)- ene

The compound in the title is prepared analogously to example ld) from the epoxy aldehyde according to a); clear, yellow oil, Rf = 0.42 (hexane/acetic ester 3:2).

Example 32: (5S.6R)-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7(Z)-en-6-yl-7-thio-4-oxo- 4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 31; m.p. 192-194°C; [oc]D<20> (methanol, 0 .14556) = 0 ± 6.9°; UV (methanol): *max (£) " 218 (37060); 268 (21760); 286 (20520); 325 sh.

Example 33: ( 4R . 5S 1- 1. 1. 1- trifluoro- 4- hydroxy- ll-( 4- acetvl- 3- hydroxy- 2- propylphenoxy )- undec- 6( Z ) - en- 5- yl - 7- thio- 4- oxo- 4H- 1- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (4R,5R)-4,5-epoxy-1,1,1-trifluoro-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undec-6(Z) -a, clear, yellow oil; Rf = 0.47 (hexane/acetic ester 1:1).

The starting material is produced e.g. analogous example 1d) from (2S,3R)-2,3-epoxy-6,6,6-trifluorohexanal; clear, yellow oil. Example 34: (4R.5S)-1.1.1-trifluoro-4-hydroxy-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undec-6(Z)-ene-5- vi- 7- thio- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 33; m.p. 193-195°C; [α]D<20> (methanol, 0.135*) = +16.3 ± 7.4°; UV (MeOH): X max (e) = 218 (37380); 267 (21380); 286 (21020), 325/sh.

Example 35: (5R.6S)-5-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z)-en-6-yl-7-oxo-4H-1- benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (5R,6R)-5,6-epoxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z)-ene, clear, yellow oil; [oc]D<20> (methanol, 0.135$) = +48.9 ± 7.4°, UV (methanol): <X>max (c) = 216 (38140); 271

(24040); 285/sh, 322 (12700).

The starting material is produced e.g. analogous example 1d) from (2S,3R)-2,3-epoxy-heptanal; clear, yellow oil. Rf = 0.45 (hexane/acetic acid 7:3).

Example - 36: (5R.6S)-5-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z)-en-6-yl-7-thio-4-oxo - 4H-1-benzopyran-2-carboxylic acid

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 35 and is converted with hydrochloric acid to free acid, m.p. 58-60°C; [α]p<20 >(methanol, 0.13056) = +36.2 ± 7.7°; UV (methanol): Xmax (<c>) = 218 (35240); 269 (20760); 283 (19800); 330 shs.

Example 37: (5S.6R)-5-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z)-en-6-yl-7-thio-4-oxo- 4H-1-benzopyran-2-carboxylic acid methyl ester The compound in the title is prepared analogously to example 1 from (5S,6S)-5,6-epoxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z )-en, clear, yellow oil; [cx]j)20 (methanol, 0.115$) = -50.4 ± 8.7°; UV (MeOH): Xmax (c) = 217 (38000); 271 (24100); 285 sh, 321 (12800).

The starting material is produced e.g. analogous example 1d) from (2R,3S)-2,3-epoxy-heptanal; light brown oil; Rf = 0.52 (hexane/acetic acid 7:3).

Example 38: (5S.6R)-5-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z)-en-6-yl-7-thio-4-oxo - 4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester according to example 37; m.p. 224-226°C; [α]D<20> (methanol, 0.145$) = -29.0 ± 6.9°; UV (methanol): Xmax (c) = 219 (38760); 268 (21880); 285 (21260); 325 sh.

Example 39: (5S.6R)-5-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z)-en-6-yl-7-thio-4-oxo- 4H-1-benzopyran-2-(N-benzenesulfonamyl)carboxamide

The solution of 0.20 g of (5S,6R)-5-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-dec-7(Z)-en-6-yl-7-thio-4 -oxo-4H-1-benzopyran-2-carboxylic acid in 10 ml of methylene chloride is stirred under argon with 60 mg of benzenesulfonamide, 44 mg of 4-dimethylaminopyridine and 70 mg of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride for 24 hours at room temperature. The resulting solution is diluted with 30 ml of methylene chloride, washed twice with 1N hydrochloric acid and twice with sols, dried over magnesium sulphate and evaporated. Chromatography of the residue on silica gel with methylene chloride/methanol (9:1) gives the title compound of m.p. 140-142°C.

Example 40: (4RS.5SR)-1-methoxycarbonyl-4-hydroxy-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-non-6(Z)-ene-5-y1-7-thio- 4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (4RS,5RS)-4,5-epoxy-1-methoxycarbonyl-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-non-6(Z)-ene; colorless oil; [a]jj<20 >(methanol, 0.125$) = 0.0 ± 8.0°, UV (methanol): Xmax (<c>) <=> 270

(24000); 340 (13200).

The starting material is produced e.g. analogous example ld) from 5,6-epoxy-6-formylhexanoic acid methyl ester; clear, yellow oil; Rf = 0.35 (hexane/acetic ester 3:2).

Example 41: (4RS.5SR)-1-carboxy-4-hydroxy-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-non-6(Z)-en-5-yl-7-thio- 4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt

0.24 g of the methyl ester according to example 40 is dissolved under argon in 15 ml of tetrahydrofuran, mixed with 3.8 ml of 0.2 n sodium hydroxide solution and stirred for 20 hours at room temperature. Evaporation and chromatographic purification of the residue on a "Reversed Phase" silica gel column (eg Merck "Lichroprep RP-8") with methanol/water (7:3) gives the title compound of m.p. 248-250°C (decomposition); UV (methanol): Xmax (c) = 218

(33900); 268 (18580); 284 (18240); 330 shs.

Example 42: ( IR . 2S ) - 1- hydroxy sv- 1- ( 3- trifluoromethylphenvl )- 10-( 4- acetvl- 3- hydroxy v- 2- pr op vi f phenoxy )- deca- 3( E) . 5( Z )-diene-2-vl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E) ,5(Z)-diene; clear, yellow oil. [α]D<20> (CHC13, 0.363$) = 46.5 ± 2.8°; UV (CHCl 3 ): <X>max (c) - 270 (26500); 285 (24240); 322 (15200).

The starting material is produced e.g. as follows:

a) ( IR . 2R )- l . 2-epoxy-1-f3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentyltriphenyl-phosphonium bromide (example 29a) and (4R,5R)-4,5-epoxy-5-(3- trifluoromethylphenyl)-pent-2(E)-enal (Example 1b); clear, yellow oil; [α]D 2 O (CHC 13 , 0.224$) = 70.8 10°, Rf = 0.50 (hexane/acetic ester = 1:1); IR (CH 2 Cl 2 ): 2960, 2930, 2865, 1735, 1625, 1330, 1125 cm-<1>.

Example 43: (IR, 2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E). 5( Z)- en- 2- vl- 7- thio- 4-oxo- 4H- 1- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 42); m.p. 217-219°C; [a]D<20> (MeOH; 0.160$) = 145.6 ± 6.3° UV (MeOH): Xmax (c) = 220 (50480); 230 (sh); 267 (26240); 284 (23000); 320 (sh).

Example 44: ( IR . 2S )-1-hydroxy-1-(3-methylphenyl-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3( E), 5( )-diene-2 - yl- 7- thio- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-methylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E) ,5(Z)-diene; m.p. 59-60°C; [α]D2<0> (CEC13, 0.163$) = 31.9 ± 6.1°; UV (CHCl 3 ): X max (c) = 241 (31420); 286 (23060).

The starting material is produced e.g. as follows:

a) (1R.2R)-1.2-epoxy-1-(3-methylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentylyl in phenyl-phosphonium bromide (example 29a) and (4R,5R)-4,5-epoxy-5-( 3-methylphenyl)-pent-2(E)-enal (Example 9b); clear, yellow oil; [α]D2<0> (CHCl3, 0.273$) = 118.7° ± 3.7. Rf = 0.62 (hexane/acetic acid = 3:2).

Example 45: (IR, 2S)-1-hydroxy-1-(3-methylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E). 5 ( Z )-dien-2-yl-7-thio-4-6xo-4H-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 44); m.p. 208-210°C; [oOd<20> (MeOH, 0.30$) = 50.7 ± 3.3°. UV (MeOH): Xmax (c) = 219 (52420); 230 (sh), 267 (26620); 285 (23520); 325 (sh).

Example 46;

( IS . 2R )- l- hvdroxv- 1- ( 3- trifluoromethylphenvl )- 10-( 4- acetvl- 3- hvdroxy- 2- pr op vi f enoxy )- deca- 3( E) . 5 (2)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1S,2S)-1,2-epoxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E) ,5(Z)-diene; tough pulp; Rf = 0.48 (hexane/acetic ester = 1:1).

The starting material is produced e.g. as follows:

a) ( IS . 2S ) - 1 . 2-epoxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentyltriphenyl-phosphonium bromide (example 29a) and (4S,5S)-4,5-epoxy-5-(3- trifluoromethylphenyl)-pent-2(E)-enal (Example 3b); clear, yellow oil; [ot]D<20> (chloroform, 0.454$) = -86.8 ± 2.2°; Rf = 0.46 (hexane/acetic ester = 1:1). IR (methylene chloride): 2960, 2930, 1730, 1625, 1330, 1130 cm-<1>.

Example 47: ( IS . 2R)-1-hydroxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E). 5( Z )-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 46); m.p. 168-170°C; [cx]d<20> (methanol, 0.150$) = -66.7 ± 6.7°; UV (MeOH): *max (c) = 220 (49640), 230 (sh); 266 (25640); 285 (22140); 320 (sh).

Example 48: ( IR . 2S 1- 1 - hydroxy- 1-( 3- trifluoromethylphenyl )- 8- r4- acetyl- 3-hydroxy- 2-( 3. 3. 3- trifluoropropyl 1- phenoxy"!- octa- 3( E 1. 5( Zl-diene- 2- vi- 7- thio- 4- oxo- l- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-8-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl) )-phenoxy]-octa-3(E),5(Z)-diene; clear, yellow oil; Rf = 0.34 (hexane/acetic ester = 1:1).

The starting material is produced e.g. as follows:

a) (1R.2R)-1.2-epoxy-1-(3-trifluoromethylphenyl)-8-r4-acetyl-3-hydroxy-2-(3.3.3- trifluoropropyl)-phenoxyl- octa-3( E). 5 ( 2 1-dien

The compound in the title is prepared analogously to example ld) from 3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyltriphenylphosphonium bromide and (4R,5R)-4,5-epoxy-5 -(3-trifluoromethylphenyl)-pent-2(E)-enal (Example 1b); clear, yellow oil; [oGd<20> (chloroform, 0.406$) = -58.6 <+> 2.5°; Rf - 0.45 (hexane/acetic ester = 7:3). IR (methylene chloride): 2945, 1670, 1610, 1310, 1055 cm-<1>.

b) 3- f 4 - acetyl- 3- hydroxy- 2-( 3. 3. 3- trifluoropropyl)- phenoxyl-propyl- triphenylphosphonium bromide

The compound in the title is prepared analogously to example 1c) from 3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl bromide. Temp. 184-185'C.

Example 49: ( IR . 2S 1- 1- hydroxy- 1- ( 3- trifluoromethylphenyl)- 8- T 4- acetyl- 3- hydroxy- 2-( 3 . 3 . 3- trifluoropropyl 1- phenoxyl- octa- 3( E 1. 5( Zl-d in en- 2- vi - 7- t io- 4- oxo- 4E- l- benzopyran- 2- carboxylic acid-sodium salt t.

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 48); m.p. 238-240°C; [α]D<20> (methanol, 0.150$) = 208 ± 6.6°; UV (MeOH): Xmax (c) = 216 (50040); 230 (sh); 267 (28960); 280 (sh); 320

(16020).

Example 50: (1R.2S)-1-hydroxyl-(3-methylphenyl)-8-r4-acetyl-3-hydroxy-2-(3.3.3-trifluoropropyl)-phenoxyl-octa-3 (E). 5 ( Z )-diene- 2- vl- 7-t i o- 4- oxo- 4H- l- T3enzopvran- 2 - carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-methylphenyl)-8-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl) )-phenoxy]-octa-3(E),5(Z)-diene; clear, yellow viscous oil; Rf = 0.41 (hexane/acetic ester = 1:1). [a]D<20> (chloroform, 0.155$) - 32.3 ± 6.5°; UV (chloroform): <X>max (c) = 271 (32320); 318 (16100).

The starting material is produced e.g. as follows:

a) (1R.2R)-1.2-epoxyl-1-(3-methylphenyl)-8-r4-acetvl-3-hydroxyl-2-(3.3.3- trifluoropropyl)-phenoxyl- octa-3( E). 5( Z )-diene

The compound in the title is prepared analogously to example ld) from 3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyltriphenylphosphonium bromide (example 48b) and (4R,5R)-4,5 -epoxy-5-(3-methylphenyl)-pent-2(E)-enal (Example 9b), clear yellow oil; Rf = 0.38 (hexane/acetic ester = 3:2).

Example 51: (IR. 2S')-1-hydroxy-1-(3-methylphenyl)-8-r4-acetvl-3-hydroxy-2-(3.3.3-trifluoropropyl)-phenoxyl-octa- 3(E). 5 ( Z )-diene- 2- vl- 7-thio- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 50); m.p. 233-235°C; [α]D<20> (methanol, 0.195$) = 69.7 ± 5.1°; UV (MeOH): <x>max (c) = 218 (52320); 230 (sh); 267 (29040); 280 (sh); 320

(16000).

Example 52: ( IR . 2S)-1-hydroxy-1-(2-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5( Z )-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(2-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E) ,5(Z)-diene; m.p. 66-68°C; Rf = 0.23 (hexane/acetic ester = 3:2). [α]D<20> (methanol, 0.150$) = 22.0 ± 6.7°; UV (MeOH): Xmax (c) = 216 (50000); 238 (sh); 271 (27860); 285 (sh); 324 (13900).

The starting material is produced e.g. as follows:

a) ( 1R. 2R1- 1. 2- epoxy- 1-( 2- trifluoromethylphenyl)- 8-( 4- acetvl- 3- hydroxy- 2- propyl- phenoxy)- octa- 3( E). 5( Z) - the day

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyltriphenyl-phosphonium bromide (example 1c) and (4R,5R)-4,5-epoxy-5-( 2-trifluoromethylphenyl)-pent-2(E)-enal; light brown oil; [a]])<20 >(chloroform, 0.207$) = -5.8 <+> 4.8°; Rf = 0.25 (hexane/acetic ester = 4:1).

b) (4R.5R)-4.5-epoxy-5-(2-trifluoromethylphenyl)-pent-2(E)-enal The compound in the title is prepared analogously to example lb)

from (2R,3R)-2,3-epoxy-3-(2-trifluoromethylphenyl)-propanol; yellow crystals; Rf = 0.36 (hexane/acetic ester = 4:1).

[α]D2<0> (methanol, 0.165$) = 23.0 ± 6.1°; UV (MeOH): Xmax (c) = 216 (14400); 235 (17240).

c) ( 2R. 3R)- 2. 3- epoxyv- 3-( 2- trifluoromethylphenyl)- propanol The compound in the title is prepared analogously to example la)

from 3-(2-trifluoromethylphenyl)-prop-2(E)-enol; colorless crystals; Rf = 0.38 (hexane/acetic ester = 3:2); IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm-<1>.

Example 53: ( IR . 2S )-1-hydroxy-1-(2-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E), 5 ( Z )- dien- 2- yl- 7- thio- 4-oxo- 4H- 1- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 52); m.p. 155-157°C; [α]D<20> (methanol, 0.180$) = 12.8 <+> 5.6°; UV (MeOH): <x>max (c) " 219 (48400); 230 (sh); 266 (25480); 284 (22540); 325 (sh).

Example 54: ( IS . 2R )-1-hydroxyl-1-(2-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1S,2S)-1,2-epoxy-1-(2-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E),5(Z)-diene; m.p. 71-73°C; Rf = 0.25 (hexane/acetic ester = 3:2). [α]D<20> (methanol, 0.170$) = -27.1 ± 5.9°; UV (MeOH): Xmax (c) = 216 (51040); 235 (sh); 271 (28140); 285 (sh); 324 (13500).

The starting material is produced e.g. as follows:

a) ( IS. 2S)- 1. 2- epoxyv- 1-( 2- trifluoromethylphenyl)- 8-( 4- acetyl- 3- hydroxy- 2- propyl- phenoxy)- octa- 3( E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propyl-triphenyl-phosphonium bromide (example 1c) and (4S,5S)-4,5-epoxy-5- (2-trifluoromethylphenyl)-pent-2(E)-enal; reddish oil; [c<]d<20 >(chloroform, 0.207$) = 5.4 ± 4.8°; Rf = 0.29 (hexane/acetic ester = 4:1).

b) (4S.5S 1-4.5-epoxy-5-(2-trifluoromethylphenyl)-pent-2(E)-enal

The compound in the title is prepared analogously to example 1b) from (2S,3S)-2,3-epoxy-3-(2-trifluoromethylphenyl)-propanol; yellow crystals; Rf = 0.38 (hexane/acetic ester = 4:1); [a]D<20 >(methanol, 0.180$) = -25.0 <+> 5.6°; UV (MeOH): Xmax (c) = 215

(13960); 236 (17060).

c) (2S.3S)-2.3-epoxy-3-(2-trifluoromethylphenyl)-propanol The compound in the title is prepared analogously to example la)

from 3-(2-trifluoromethylphenyl)-prop-2(E)-enol; colorless crystals; Rf = 0.35 (hexane/acetic ester = 3:2). IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm-<1>.

Example 55: ( IS . 2R )-1-hydroxy-1-(2-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E), 5( Z)- dien- 2- yl- 7- thio- 4-oxo- 4H- 1- benzopvran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 54); m.p. 182-184°C; Md 20 (methanol, 0.205$) = -16.6 ± 4.9°; UV (MeOH): x max (c) = 219 (47680); 235 (sh); 266 (24960); 284 (22100); 330 (sh).

Example 56: f IR . 2S )-1-hydroxy-1-(4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E),5(Z)-diene; m.p. 68-70°C; Rf = 0.16 (hexane/acetic ester = 3:2). [α]D<20> (methanol, 0.155$) = 110.3 ± 6.5°; UV (MeOH): <X>max (c) = 217 (52880); 236 (sh); 270 (28880), 285 (sh); 326 (13700).

The starting material is produced e.g. as follows:

a) f IR. 2R)- 1.2-epoxy-1-(4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyl-triphenyl-phosphonium bromide (example 1c) and (4R,5R)-4,5-epoxy-5 -(4-trifluoromethylphenyl)-pent-2(E)-enal; yellow oil; [oc]d<20 >(chloroform, 0.220$) = 6.5 ± 4.5°; Rf = 0.35 (hexane/acetic ester = 4:1).

b) (4R.5R)-4.5-epoxy-5-(4-trifluoromethylphenyl)-pent-2(E)-enal The compound in the title is prepared analogously to example lb)

from (2R,3R)-2,3-epoxy-3-(4-trifluoromethylphenyl)-propanol; yellow crystals; m.p. 67-70°C; Rf = 0.24 (hexane/acetic ester = 4:1). [cx]d<20> (methanol, 0.150$) = 171.3 ± 6.7°; UV (MeOH): <x>max (O - 237 (19660).

c) (2R.3R)-2.3-epoxy-3-(4-trifluoromethylphenyl)-propano! The compound in the heading is prepared analogously to example la)

from 3-(4-trifluoromethylphenyl)-prop-2(E)-enol; colorless crystals; Rf = 0.25 (hexane/acetic ester = 3:2). IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm-<1>.

Example 57: ( IR . 2S )-1-hydroxy-1-(4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5 (Z)-dien-2-yl-7-thio-4-oxo-4E-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 56); m.p. 229-231°C; [cx]])20 (methanol, 0.160$) = 118.8 <+> 6.3°; UV (MeOH); <X>max (c) = 220 (53060); 235 (sh), 267 (27280); 284 (23880), 320 (16300).

Example 58;

( IS . 2R )- 1- hydroxy- 1- ( 4- trifluoromethylphenyl )- 8-( 4- acetyl- 3-hydroxy- 3- propyl- phenoxy )- octa- 3( E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1S,2S)-1,2-epoxy-1-(4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E),5(Z)-diene; m.p. 67-69°C; Rf 0.13 (hexane/acetic ester = 3:2). [o<]d<20> (methanol, 0.155$) = -109.7 ± 6.5°; UV (MeOH): X max (c) = 217 (52640); 235 (sh); 270 (28660); 285 (sh); 326 (13680).

The starting material is produced e.g. as follows:

a) (1S.2S)-1.2-epoxy-1-(4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5(Z)- part

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyl-triphenyl-phosphonium bromide (example 1c) and (4S,5S)-4,5-epoxy-5 -(84-trifluoromethylphenyl)-pent-2(E)-enal; reddish oil; [a]])<20 >(chloroform, 0.199$) = -5.4 ± 5.0°; Rf = 0.23 (hexane/acetic ester = 4:1).

b) (4S.5S)-4.5-epoxy-5-(4-trifluoromethylphenyl)-pent-2(E)- enal The compound in the title is prepared analogously to example lb)

from (2S,3S)-2,3-epoxy-3-(4-trifluoromethylphenyl)-propanol; yellow crystals; m.p. 67-69°C; Rf = 0.18 (hexane/acetic ester = 4:1). [α]D<20> (methanol, 0.150$) = -180.0 ± 6.7°; UV (MeOH): <x>max (O - 236 (19740).

c) (2S.3S)-2.3-epoxy-3-(4-trifluoromethylphenyl)-propanol The compound in the title is prepared analogously to example la)

from 3-(4-trifluoromethylphenyl)-prop-2(E)-enol; colorless crystals; Rf = 0.23 (hexane/acetic ester = 3:2). IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm"<1>.

Example 59: ( IS . 2R 1-1-hydroxy-1-f 4-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 58); m.p. 228-230°C; [α]D<20> (methanol, 0.175$) = -99.4 ± 5.7°; UV (MeOH): xmax (c) = 220 (49800); 235 (sh); 267 (25320); 284 (22200); 320 (15600).

Example 60: (IR.2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(Z)-ene- 2- vl- 7- thio- 4- oxo- 4H-l- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( the Z) one; colorless oil; Rf = 0.41 (hexane/acetic ester = 1:1). [α]D<20> (chloroform, 0.150$) = 46.7 ± 6.7°; UV (MeOH): <X>max (c) = 271 (22760); 288

(20060); 270 (28880); 324 (14460).

The starting material is produced e.g. as follows:

a) (1R.2R1-1.2-epoxy-1-(3-trifluoromethylphenyl1-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(Z)-ene)

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-pentyl-triphenyl-phosphonium bromide (example 29a) and (2S,3R)-2,3-epoxy-3 -(3-trifluoromethylphenyl)-propanol (Example 5a); clear, yellow oil; [α]D<20> (chloroform, 0.221$) = 25.3 ± 4.5°; Rf = 0.56 (hexane/acetic ester = 3:2).

Example 61: ( IR . 2S 1 - 1 - hydroxy- 1-( 3- trifluoromethylphenyl )- 8-( 4- acetyl- 3-hydroxy- 2- propyl-phenoxy)- octa- 3(Z)-ene - 2- yl- 7- thio- 4- oxo- 4H-l- benzopvran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 60); m.p. 231-233°C; [odn<20> (methanol, 0.190$) = 51.1 ± 5.3°; UV (MeOH): <x>max (c) = 215 (42320); 267 (22220); 286 (20800); 320 (sh).

Example 62: ( IR . 2S 1- 1- hydroxy- 1-( 3- trifluoromethylphenyl )- 9-( 4- acetvl- 3- hydroxy- 2- propyl phenoxy )- nona- 3( E ) . 5( Z )- diene- 2- vl- 7- thio- 4-oxo- 4H- 1- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-nona-3(E) ,5(Z)-diene; clear, yellow viscous oil; [oc]D<20> (chloroform, 0.155$) = 44.5 ± 6.5°; Rf = 0.50 (hexane/acetic ester = 1:1); UV (CHC13): <X>max (c) = 270

(26800); 284 (23100); 323 (14480).

The starting material is produced e.g. as follows:

a) 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-butyl-triphenyl-phosphonium bromide

The compound in the title is prepared analogously to example 1c from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-butyl bromide. Temp. 167-169°C.

b) (1R.2R1-1.2-epoxy-1-(3-trifluoromethylphenyl)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-nona-3(E).5(Z1-diene

The compound in the title is prepared analogously to example ld) from 5-(4-acetyl-3-hydroxy-2-propylphenoxy)-butyl-triphenyl-phosphonium bromide and (4R,5R)-4,5-epoxy-5-(3-trifluoromethylphenyl) -pent-2(E)-enal (Example 1b); clear, yellow oil; [α]jj20 (chloroform, 0.308$) = 40.7 ± 3.2°; Rf = 0.70 (hexane/acetic ester = 3:2); IR (methylene chloride): 2950, 2860, 1625, 1325, 1120 cm-1.

Example 63: (IR. 2S 1-1-hydroxy-1-(3-trifluoromethylphenyl)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-nona-3(E).5(Z) - dien- 2- yl- 7- thio- 4-oxo- 4H- 1- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 62); m.p. 204-206°C; [ot]]}20 (chloroform, 0.289$) = 8.0 ± 3.5'; [α]D<20> = 55.5 ± 6.5° (methanol, 0.155$); UV (methanol): Xmax (c) = 219

(49320); 232 (sh); 266 (25800); 285 (22060); 330 (sh).

Example 64: (IR.2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-II-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-3(E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (IR,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-3(E) ,5(Z)-diene, clear yellow viscous oil; [oc]D<20> (chloroform, 0.160$) = 48.1 ± 6.3°; Rf = 0.50 (hexane/acetic ester =1:1). UV (CHC13): Xmax (c) = 270

(27120); 286 (23300); 323 (14740).

The starting material is produced e.g. as follows:

a) 3 - ( 4- acetyl- 3- hydroxy- 2- propyl- phenoxy ) hexyl- triphenyl- phosphonium bromide

The compound in the title is prepared analogously to example 1 from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)hexyl bromide; the compound crystallizes very slowly.

b) ( IR . 2R )- l . 2-epoxy-1-(3-trifluoromethylphenyl)-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-3(E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 5-(4-acetyl-3-hydroxy-2-propylphenoxy)hexyl-triphenyl-phosphonium bromide and (4R,5R)-4,5-epoxy-5-(3-trifluoromethylphenyl)- pent-2(E)-enal (Example 1b); clear, yellow oil; [ot]])<20 >(chloroform, 0.450$) - 41.1 ± 2.2°; Rf = 0.66 (hexane/acetic ester = 3:2); IR (methylene chloride): 2960, 2860, 1625, 1325, 1120 cm-1.

Example 65: ( IR . 2S )-1-hydroxy-1-(3-trifluoromethylphenyl)-11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undeca-3(E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 64); m.p. 216-218°C; [α]D<20> (chloroform, 0.258$) = 34.9 ± 3.9°; [a]D<20> = 7.38 ± 6.3° (methanol, 0.160$): UV (methanol): Xmax (<c>) - 219

(50140); 232 (sh); 266 (26120); 286 (22460); 320 (15600).

Example 66: ( IR . 2S )-1-hydroxy-1-phenoxy 1-8-(4-acetvi-3-hydroxy-2-propyl-phenoxy)-octa-3( E ) . 5 ( Z )-diene- 2- vl- 7- thio- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (IR, 2R)-1,2-epoxy-1-phenyl-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E),5 (Z)-diene; clear, yellow foam; Rf = 0.41 (hexane/acetic ester = 1:1); [a]D<20> = 47.3 2.6°

(chloroform, 0.385$).

The starting material is produced e.g. as follows:

a) ( IR . 2R ) - 1 . 2- epoksv-l- phenvl-8- f 4- acetvl- 3- hvdroksv- 2-propvl- phenoxv' l- octa- 3( E) . 5(Z)- diene

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyl-triphenyl-phosphonium bromide (example lc) and (4R,5R)-4,5-epoxy- 5-phenyl-pent-2(E)-enal; clear, yellow oil; Rf = 0.60 (hexane/acetic ester = 3:2).

b) ( 4R. 5R1- 4, 5- epoxy- 5- phenyl- pent- 2( E)-enal

The compound in the heading is prepared analogously to example lb)

from (2R,3R)-2,3-epoxy-3-phenyl-propanol; yellow oil; which crystallizes on standing; Rf = 0.38 (hexane/acetic ester = 3:2); [cx]D20 = 185 ± 5.0° (chloroform, $0.200).

c) ( 2R. 3R)- 2. 3- epoxyv- 3- phenyl- propanol

The compound in the heading is prepared analogously to example la)

from 3-phenyl-prop-2(E)-enol; colorless oil, which crystallizes in the cold state. Rf = 0.49 (hexane/acetic ester = 1:1); IR (methylene chloride): 3590, 3040, 2980, 2920, 2870, 1605, 1080, 1070 cm-<1>. [cx]d<20> (chloroform, 0.279$) = 47.7 <+> 3.6°.

Example 67: ( IR . 2S )-1-hydroxy-1-phenyl-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3( E ). 5 ( Z )-diene- 2- vl- 7- thio- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 66); m.p. 219-221°C; [α]D<20> (chloroform, 0.160$) = 103.1 ± 6.3°; UV (methanol): Xmax (c) = 221 (51180); 232 (sh); 267 (27040); 284

(23840); 321 (16200); UV (chloroform): Xmax (c) = 274 (26080); 286 (sh); 330 (sh). Example 68: ( IR . 2S 1- 1- hydroxy- 1- ( 3- trifluoromethylphenyl )- 8-( 3- acetvl- 4- hydroxy- 5- propyl- phenoxy 1- octa- 3( E ") . 5 ( Z )-diene- 2- vl- 7- thio- 4-oxo- 4H- l- henzopyran- 2- carboxylic acid esters

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-8-(3-acetyl-4-hydroxy-5-propyl-phenoxy)-octa-3( E),5(Z)-diene; Rf = 0.21 (hexane/ethyl acetate = 3:2).

"The starting material is produced, for example, as follows:

a) 3-( 3- acetvi- 3- 4- hydroxy- 5- propyl- phenoxy)- propyl bromide

To a solution of 5.8 g of 2,5-dihydroxy-3-propyl-acetophenone

and 6.1 ml of 1,3-dibromopropane in 60 ml of methyl ethyl ketone, 6.2 g of potassium carbonate and 0.5 g of potassium iodide are added. The reaction mixture is heated to reflux for 24 hours. It is then poured into 300 ml of ice water, acidified 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 sulphate. After filtration and evaporation in a vacuum, the residue is chromatographed on 400 g of silica gel with dichloromethane. In the first fraction, the title compound is eluted, which after evaporation is obtained in the form of clear, yellow crystals of m.p. 69-70°C.

b) 3-(3-acetyl-3-hydroxy-5-propyl-phenoxy)-propyl-triphenyl-phosphonium bromide

The compound in the title is prepared analogously to example lc) from 3-(3-acetyl-4-hydroxy-5-propyl-phenoxy)propyl bromide and triphenylphosphine; m.p. 103-105'C.

c) ( IR. 2R)- 1. 2- epoxy- 1- f 3- trifluoromethylphenyl)- 8-( 3- acetvl- 3-hydroxy- 5- propyl- phenoxy)- octa- 3( E). 5(Z)- diene

The compound in the title is prepared analogously to example ld) from 3-(3-acetyl-4-hydroxy-5-propyl-phenoxy)-propyl-triphenyl-phosphonium bromide and (4R,5R)-4,5-epoxy-5-(3- trifluoromethylphenyl)-pent-2(E)-enal; Rf = 0.54 (hexane/acetic ester = 2:1).

Example 69: ( IR . 2S )-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(3-acetyl-4-hydroxy-5-propyl-phenoxy)-octa-3(E). 5( Z)-diene- 2- yl- 7- thio- 4-oxo- 4H- 1- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from (IR, 2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(3-acetyl-4-hydroxy-5-propyl-phenoxy)-octa-3(E) ,5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester, yellow foam; 1H-NMR (CD30D): S = 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: ( IR . 2S )-1-hydroxy-1-(3-chlorophenyl)-8-β-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E ). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid enretviester

The compound in the title is prepared analogously to example 1 from (IR,2R)-1,2-epoxy-1-(3-chlorophenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E),5(Z)-diene; m.p. 76-77°C; [cx]D 2 O (chloroform, 0.215$) = 51.2 ± 4.7°; UV (chloroform): <x>max (c) - 271 (28160); 285 (sh).

The starting material is produced e.g. as follows:

a) (1R.2R1-1.2-epoxy-1-(3-chlorophenyl)-8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octa-3(E).5(Z)-diene

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyl-triphenyl-phosphonium bromide (example 1c) and (4R,5R)-4,5-epoxy-5 -(3-chlorophenyl)-pent-2(E)-enal; clear, yellow oil; [cx]])<20> (chloroform, 0.541$) = 63.9 ± 1.8°.

b) (4R.5R)-4.5-epoxy-5-(3-chlorophenyl)-pent-2(E)- enal The compound in the title is prepared analogously to example lb)

from (2R,3R)-2,3-epoxy-3-(3-chlorophenyl)-propanol; dark yellow oil; Rf = 0.23 (hexane/acetic ester = 4:1). [ot]D<20> (chloroform, 0.30$) - 184.7 ± 3.3.

c) (2R.3R)-2.3-epoxy-3-(3-chlorophenyl)-propanol

The compound in the heading is prepared analogously to example la)

from 3-(3-chlorophenyl)-prop-2(E)-enol; clear, yellow oil; Rf = 0.22 (hexane/acetic ester = 7:3). IR (methylene chloride): 3580, 3040, 2980, 2910, 2860, 1600, 1570, 1070 cm-<1>. [oc]D<20> (chloroform, 0.334$) = 47.3 ± 3.0°.

Example 71:

( IR . 2S )- 1-hydroxy- ( 3- chlorophenoxy )- 8-( 4- acetyl- 3- hydroxy- 2-propyl- phenoxy)- octa- 3( E) . 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 70); m.p. 217-219°C; [oc]D<20>= (methanol, 0.160$) = 107.5 ± 6.3°; UV (methanol): Xmax (c) = 219 (55060); 235 (sh); 267 (27340); 284

(23920); 320 (16500).

Example 72: (1R.2S)-1-hydroxy-1-(3-chlorophenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-deca-3(E). 5(Z)-diene-2-vl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-chlorophenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-deca-3( E),5(Z)-diene; m.p. 61-62°C; [α]D2<0> (chloroform, 0.170$) = 52.9 ± 5.9°; UV (chloroform): <X>max (c) = 271 (27120); 286 (24800); 322 (15400).

The starting material is produced e.g. as follows:

a) ( IR. 2R)- l . 2-epoxyl-1-(3-chlorophenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-deca-3(E). 5( Z )- diene

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)pentyl-triphenyl-phosphonium bromide (example 29a) and (4R,5R)-4,5-epoxy-5- (3-Chlorophenyl)-pent-2(E)-enal (Example 70b); clear, yellow oil; [oc]D<20> (chloroform, 0.391$) = 61.4 <+> 2.5°.

Example 73;

( IR. 2S )- 1- hydroxy- 1-( 3- chlorophenyl)- 10-( 4- acetyl- 3- hydroxy- 2-propyl- phenoxy)- deca- 3( E). 5( Z )-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 72); m.p. 204-206°C; [α]D<20> (methanol, 0.205$) = 58.5 ± 4.9°; UV (MeOH): x max (c) = 218 (27940); 267 (13141); 285 (11600); 320 (sh).

Example 74: (1R.2S)-1-hydroxy-1-(3-methoxyphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-methoxyphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3( E),5(Z)-diene; m.p. 65-67°C; UV (chloroform): Xmax (c) = 271 (30360); 285 (sh); 323

(16600).

The starting material is produced e.g. as follows:

a) ( IR . 2R ) - 1 . 2- epoxyv-l - (3- methoxyvf envl )- 8-( 4- acetyl- 3-hydroxyv- 2- propyl- phenoxy)- octa- 3( E). 5(Z)- diene

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propyl-triphenyl-phosphonium bromide (example lc) and (4R,5R)-4,5-epoxy-5- (3-me toxy phenyl )-pent-2(E)-enal; clear, yellow oil; [oc]d<20> (chloroform, 0.315$) = 78.4 ± 3.2.

b) ( 4R. 5R)- 4. 5- epoxy- 5-( 3- methoxyphenvl)- pent- 2( E)-enal The compound in the title is prepared analogously to example lb)

from (2R,3R)-2,3-epoxy-3-(3-methoxyphenyl)-propanol; yellow oil; Rf = 0.42 (hexane/acetic ester = 3:2); [α]D<20> (chloroform, 0.567$) = 168.9 ± 1.8°.

c) (2R.3R)-2.3-epoxy-3-(3-methoxyphenyl)-propanol The compound in the title is prepared analogously to example la) from 3-(3-methoxyphenyl)-prop-2(E)-enol; clear, yellow oil; Rf = 0.31 (hexane/acetic ester = 3:2). IR (methylene chloride): 3550, 2890, 1580, 1565, 1465, 1445, 1130 cm-<1>.

Example 75: (IR. 2S)-1-hydroxy-1-(3-methoxyphenoxy)-8-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 74); m.p. 206-208°C; [oc]D<20> (methanol, 0.293$) = 99.7 ± 3.4°; UV (methanol): <X>max (c) = 221 (57840); 235 (sh); 268 (29360); 282 (26400); 320 (16800).

Example 76: (IR. 2S)-1-hydroxy-1-(3-methoxyphenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-deca-3(E). 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (IR,2R)-1,2-epoxy-1-(3-methoxyphenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-deca-3( E),5(Z)-diene; m.p. 53°C (sublimes partially); UV (chloroform): Xmax (c) = 272 (29920); 285 (sh); 323 (15540); [oc]D<20> (chloroform, 0.180$) = 44.4 5.6° .

The starting material is produced e.g. as follows:

a) ( IR . 2R)- l . 2-epoxy-1-f3-methoxyphenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-deca-3( E) . 5( Z )- diene

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)pentyl-triphenyl-phosphonium bromide (example 29a) and (4R,5R)-4,5-epoxy-5- (3-Methoxyphenyl)-pent-2(E)-enal (Example 74b); clear, yellow oil; [a]D 2 O (chloroform, 0.375$) = 72.5 ± 2.7.

Example 77: (IR. 2S)-1-hydroxy-1-(3-methoxyphenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-deca-3(E). 5( Z )-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 76); m.p. 187-188°C; [α]D<20> (methanol, 0.150$) = 72.0 ± 6.7°; UV (methanol): xmax (c) = 222 (55780); 268 (27820); 282 (25200); 321

(16200).

Example 78: (IR. 2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4-trifluoroacetyl-3-hydroxy-phenoxy)-octa-3(E). 5 ( Z )-diene-2-vl-7-thio-4-oxo-4E-l- benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (IR,2R)-1,2-eoxy-1-(3-trifluoromethylphenyl)-8-(4-trifluoroacetyl-3-hydroxy-phenoxy)-octa-3(E),5 (Z)-diene; Rf 0.23 (hexane/acetic ester = 3:2).

The starting material is produced e.g. as follows:

a) 3-(4-trifluoroacetyl-3-hydroxyphenoxy)propyl bromide The compound in the title is prepared analogously to example 68a)

from 2,4-dihydroxy-trifluoroacetophenone and occurs as clear yellow

oil; IR (chloromethane): 3150, 2940, 1645, 1625, 1380, 1210, 1150, 1125, 1020, 940 cm-<1>.

b) 3-(4-trifluoroacetyl-3-hydroxy-phenoxy)propyl-triphenylphosphonium bromide

The compound in the title is prepared analogously to example lc) from 3-(4-trifluoroacetyl-3-hydroxy-phenoxy)propyl bromide and triphenylphosphone; m.p. 125-130°C.

c) ( IR . 2R )- 1. 2- epoxy- 1-( 3- trifluoromethylphenyl)- 8-( 4- trifluoroacetyl- 3- hydroxyphenoxy)- octa- 3( E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 3-(4-trifluoroacetyl-3-hydroxy-phenoxy)propyl-triphenyl-phosphonium bromide and (4R,5R)-4,5-epoxy-5-(3-trifluoromethylphenyl)-pent- 2(E)-enal; Rf = 0.56 (hexane/acetic ester 2:1).

Example 79: (IR. 2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4-trifluoroacetyl-3-hydroxyphenoxy)-octa-3(E). 5( Z )-dien-2-vl-7-thio-4-oxo- 4H- 1- benzopyran- 2- carboxylic acid sodium salt

To a cooled to 10°C solution of 708 mg of the methyl ester of the compound in the title (cf. Example 78) in 25 ml of tetrahydrofuran is added 10 ml of 0.1 N aqueous sodium hydroxide solution. The reaction mixture is stirred for 24 hours at room temperature, freed of solvent in vacuo and the residue taken up in water. After filtering until clear, the solution is lyophilized. The title compound is obtained as an olive green, amorphous powder;

<i>H-NMR (CD 3 OD): δ = 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-trifluoromethylphenyl)-8-(4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E). 5( Z )- dien- 2- yl- 7-thio- 4- oxo- 4H- 1-" benzopyran- 2- carboxyl methyl ester

The compound in the title is prepared analogously to example 1 from (1R,2R)-1,2-epoxy-1-(3-trifluoromethylphenyl)-8-(4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy)- octa-3(E),5(Z)-diene; Rf = 0.18 (toluene/acetic ester 5:1).

The starting material is produced e.g. as follows:

a) 3 - (4-trifluoroethyl-3-hydroxy-2-propvl- f enoxy)- propyl bromide

The compound in the title is prepared analogously to example 68a) from 2,4-dihydroxy-3-propyl-trifluoroacetophenone and occurs as a yellow oil; IR (dichloromethane): 3150, 2950, 2860, 1640, 1620, 1500, 1295, 1210, 1150, 1120, 1070 cm-<1>.

b) 3-(4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy)propyl-triphenylphosphonium bromide

The compound in the title is prepared analogously to example lc) from 3-(4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy)propyl bromide and triphenylphosphine; m.p. 170-190°C.

c) (IR.2R)-1.2-epoxy-1-(3-trifluoromethylphenyl)-8-(4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy)-octa-3(E) . 5( Z )-diene

The compound in the title is prepared analogously to example ld) from 3-(4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy)propyl-triphenylphosphonium bromide and (4R,5R)-4,5-epoxy-5-(3-trifluoromethylphenyl)- pent-2(E)-enal; Rf = 0.55 (hexane/acetic ester 2:1).

Example 81: (IR. 2S)-1-hydroxy-1-(3-trifluoromethylphenyl)-8-(4-trifluoroacetvi-3-hydroxy-1-propyl-phenoxy)-octa-3(E). 5( Z)-diene- 2- vl- 7-thio- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid sodium salt

To a cooled to 10°C solution of 500 mg of the methyl ester of the compound in the title (cf. example 80) in 20 ml of tetrahydrofuran is added 6.6 ml of 0.1 N aqueous sodium hydroxide solution. The reaction mixture is stirred for 1 hour at 10°C, freed from tetrahydrofuran in vacuo, and the remaining solution is lyophilized. The title compound is obtained as yellow-green, amorphous powder; 3 H NMR (CD 3 OD): S = 7.93, 7.77-7.60, 7.50, 7.36, 6.92, 6.43, 6.04, 5.73, 5.47 , 4.47, 4.00, 2.50, 2.38, 0.72 ppm.

Example 82: ( IR . 2S )- 1- hydroxy- 1-( 3- trifluoromethylphenyl 1- 8-( 4- acetvl- 3- hydroxy- 2- propyl- phenylthio)- octa- 3( E). 5( Z l- dlen^- yl^- thio^-oxo^ H- l- benzopyran^- carboxylic acid methyl ester

The compound in the title is obtained analogously to example 1 from (1R,2S)-1,2-epoxy-1-(3-trifluoromethylphenyl)-8-(4-acetyl-3-hydroxy-2-propyl-phenylthio)-octa-3 (E),5(Z)-diene; Rf = 0.19 (hexane/acetic ester 3:2).

The starting material is produced e.g. as follows:

a) 3-(4-acetyl-3-hydroxy-2-propyl-phenylthiopropyl bromide The compound in the title is prepared analogously to example 68a)

from 2-hydroxy-4-mercapto-acetophenone; clear, yellow oil.

b) 3-(4-acetyl-3-hydroxy-2-propyl-phenylthio)propyl-triphenyl-phosphonium bromide

The compound in the title is prepared analogously to example 1 from 3-(4-acetyl-3-hydroxy-2-propyl-phentylthio)propyl bromide and triphenylphosphine.

c) ( IR. 2S1- 1. 2- epoxy- 1-( 3- trifluoromethylphenyl1-8-( 4- acetvl- 3- hydroxy- 2- propyl- phenylthio)- octa- 3( E). 5( Z)- the day

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenylthio)propyl-triphenyl-phosphonium bromide and (4R,5R)-4,5-epoxy-5-(3-trifluoromethylphenyl) )-pent-2(E)-enal.

Example 83: ( IR . 2S1 - 1- hydroxy- 1-( 3- trifluoromethylphenyl )- 8-( 4- acetvl- 3- hydroxy- 2- propyl- phenylthiol- octa- 3( El. 5( Z)- dlene - 2- vl- 7- thio- 4-oxo- 4H- benzopyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 82).

Example 84: ( IR . 2S 1- 1- hydroxy- 1- O- trifluoromethylphenyl 1- 10-( 4-acetvl- 3-hydroxy- 2- propyl- phenylthiol- deca- 3( E). 5( Z)-diene - 2- vl- 7- thio- 4-oxo- 4H- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (IR,2S)-1,2-epoxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenylthio)-deca-3( E),5(Z)-diene; Rf = 0.17 (hexane/acetic ester 3:2).

The starting material can e.g. produced as follows:

a) 5-(4-acetyl-3-hydroxy-2-propyl-phenylthioIpentyl bromide The compound in the title is prepared analogously to example 68a)

from 2-hydroxy-4-mercapto-acetophenone; clear, yellow oil.

b ) 5 -( 4- acetyl - 3- hydroxy- propyl- phenylthio 1- pentyl- triphenyl- phosphonium bromide

The compound in the title is prepared analogously to example 1 from 5-(4-acetyl-3-hydroxy-2-propyl-phenylthio)pentyl bromide and triphenylphosphine.

c) (IR.2S)-1.2-epoxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propyl-phenylthio)-deca-3(E). 5(Z)- diene

The compound in the title is prepared analogously to example 1d) from 5-(4-acetyl-3-hydroxy-2-propyl-phenylthio)pentyl-triphenyl-phosphonium bromide and (4R,5R)-4,5-epoxy-5-(3-trifluoromethyl) -phenyl)-pent-2(E)-enol.

Example 85: ( IR . 2S)- 1- hydroxy- 1-( 3- trifluoromethylphenyl )- 10-( 4- acetvl- 3- hydroxy- 2- propyl- phenylthio- deca- 3( E), 5( Z)- dien- 2- yl- 7- thio- 4-oxo- 4H- ben20pyran- 2- carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 84).

Example 86;

( 5R . 6S )- l. 1. 1- trifluoro- 5- hydroxy- 12-( 4- acetyl- 3- hydroxy- 3- hydroxy- 2- propyl- phenoxy)- dodeca- 7( E). 9( Z)-dien- 6- yl- 7- thio-4- oxo- 4H- 1- benzopyran- 2- carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (5R,6R)-5,6-epoxy-1,1,1-trifluoro-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-7( E),9(Z)-diene; clear, yellow foam; Rf = 0.24 (hexane/acetic ester = 3:2).

The starting material is produced e.g. as follows:

a) ( 2R. 3R)- 2. 3- epoxyv- 7. 7. 7- trifluoro-heptanol

The compound in the heading is prepared analogously to example la)

from 7,7,7-trifluoro-hept-2(E)-enol; clear, yellow oil; Rf = 0.38 (hexane/acetic ester = 3:2). [oc]d<20> (chloroform, 0.490$) = 15.3 2.0°. IR (methylene chloride): 3550, 3430, 2900, 1180, 1125.

b) ( 4R. 5R)- 4. 5- epoxyv- 9. 9. 9- trifluoro- non- 2( E)- enal The compound in the title is prepared analogously to example lb)

from (2R,3R)-2,3-epoxy-7,7-7-trifluoroheptanol; oil, which

crystallizes in a refrigerator. Rf = 0.63 (hexane/acetic ester = 1:1). [a]D<20> (chloroform, 0.210$) = 19.5 <+> 4.8°.

c) (5R.6R)-5.6-epoxy-1.1.1-trifluoro-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-7(E). 9(Z)- diene

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propyltriphenyl-phosphonium bromide (example lc) and (4R,5R)-4,5-epoxy-9,9, 9-trifluoro-non-2(E)-enal; yellow oil; Rf = 0.56 (hexane/acetic ester = 3:2).

Example 87: (5R.6S)-1.1.1-trifluoro-5-hydroxy-12-f4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-7(E). 9(Z)-dien-6-yl-7-thio-4-oxo-4E-l-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 86); m.p. 190-191°C; [α]D<20> (methanol, 0.268$) = 105.2 <+> 3.7°; UV (methanol): Xmax (c) = 222 (48800); 235 (sh); 267 (25920); 285 (22920); 320 (16000).

Example 88: ( 4R . 5S )- l . 1. 1-trifluoro-4-hydroxy-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-trideca-6(E). 8( Z)-diene- 5- vl- 7- thio- 4- oxo-4H- 1- benzopyran- 2- carboxylic acid metviester

The compound in the title is prepared analogously to example 1 from (4R,5R)-4,5-epoxy-1,1,1-trifluoro-13-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-trideca-6( E),8(Z)-diene; yellow oil.

The starting material is produced e.g. as follows:

a) ( 4R. 5R)- 4. 5- epoxyv- 8. 8. 8- trifluoro- oct- 2( E)- enal The compound in the title is prepared analogously to example lb)

from (2R,3R)-2,3-epoxy-6,6,6-trifluorohexanol; clear, yellow oil, which crystallizes in a refrigerator; R f = 0.53

(hexane/acetic acid = 3:2). [α]D<20> (chloroform, 0.290$) = 21.7 ± 3.4°. IR (methylene chloride): 3050, 2980, 2930, 2810, 2730, 1690, 1640, 1145 cm-<1>.

b) (4R.5R)-4.5-epoxy-1♦ 1.1-trifluoro-13-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-trideca-6(E). 8(Z)- diene

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)pentyl-triphenyl-1-phosphonium bromide (example 29a) and (4R,5R)-4,5-epoxy-8, 8,8-trifluoro-oct-2(E)-enal; yellow oil; Rf = 0.69 (hexane/acetic ester = 3:2).

Example 89: (4R.5R)-l.1.l-trifluoro-4-hydroxyl-13-f4-acetvl-3-hydroxl-2-propvlf enoxl)-tr in deca- 6 (E) . 8( Z )-diene- 5- vl- 7- thio- 4- oxo- 4H- benzopyran- 2- carboxyl disulfide sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 88); m.p. 150-152°C; [α]D<20> (methanol, 0.265$) = 72.5 ± 3.8°; UV (methanol): Xmax (c) = 221 (44680); 231 (sh); 266 (22560); 285 (20560); 330 (sh).

Example 90: ( 4R . 5S )- l . 1. 1-trifluoro-4-hydroxy-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-6(E). 8(Z)-diene-5-vl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (4R,5R)-4,5-epoxy-1,1,1-trifluoro-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-6( E),8(Z)-diene; yellow oil; Rf = 0.31 (hexane/acetic ester = 3:2).

The starting material is produced e.g. as follows:

a) ( 4R. 5R)- 4. 5- epoxyv- l. 1. l- trifluoro- 12-( 4- acetyl- 3- hydroxy-2- propyl- phenoxy)- dodeca- 6( E). 8(Z)- diene

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)butyl-triphenyl-phosphonium bromide (example 62b) and (4R,5R)-4, 5-epoxy-8, 8,8-trifluoro-oct-2(E)-enal (Example 86b); yellow oil; Rf = 0.64 (hexane/acetic ester = 3:2).

Example 91: (4R.5S)-1.1.1-trifluoro-4-hydroxy-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-6(E). 8(Z)-dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 90); m.p. 180-182°C; [α]D<20> (methanol 0.292$) = 77.1 ± 3.4°; UV (methanol): xmax (c) " 222 (47480), 231 (sh); 267 (24840); 285 (22120); 321 (15800).

Example 92: (5R.6S)-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-7( E ) . 9( Z )-dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (5R,6R)-5,6-epoxy-12-(4-acetyl-3-hydroxy-2-propylphenoxy)-dodeca-7(E),9(Z)-diene; clear, yellow foam; Rf = 0.43 (hexane/acetic ester = 1:1); [α]j)20 (methanol, 0.150$) = 22.0 ± 6.7°; IR (methylene chloride): 3580, 2950, 1745, 1655, 1625, 1600 cm-1.

The starting material is produced e.g. as follows:

a) ( 4R. 5R)- 4. 5- epoxy- non- 2( E)-enal

The compound in the heading is prepared analogously to example lb)

from (2R,3R)-2,3-epoxyheptanol; yellow oil; Rf = 0.29 (hexane/acetic ester = 4:1); [a]D<20> (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- 12-( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- dodeca- 7( E). 9(Z)- part

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy-propyl-triphenyl-phosphonium bromide (example 1c) and (4R,5R)-4,5-epoxy-non-2( E)-enal; clear, yellow oil; [a]D<20> (chloroform, $0.650) = 23.7 1.5° .

Example 93: (5R.6S)-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-7(E). 9( Z )-diene- 6- yl- 7- thio- 4- oxo- 4H- 1- benzopyran- 2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 92); m.p. 205-207°C; [α]D<20> (methanol, 0.278$) = 115.1 ± 3.6°; UV (methanol): Xffiax (c) = 222 (50960); 232 (sh); 267 (27400); 285 (24000); 321 (16400).

Example 94: (5R.6S)-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-7( E ). 9( Z )-diene- 6- yl- 7- thio- 4- oxo- 4H- 1- benzopyran- 2-carboxylic acid methyl ester

The compound in the title 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; colorless foam; [α]D<20 >(methanol, 0.260$) = 136.2 ± 3.8°; UV (methanol): Xmax (c) = 221 (48040); 271 (28320); 327 (13200).

The starting material is produced e.g. as follows:

a) ( 4S. 5S)- 4. 5- epoxy- non- 2( E)- enal

The compound in the heading is prepared analogously to example lb)

from (2S,3S)-2,3-epoxyheptanol; yellow oil; Ef = 0.27 (hexane/acetic ester =5:1); [a]j)<20> (chloroform, 0.325$) = 23.1 3.0° .

b) ( 5S. 6S )- 5 . 6- epoxy- 12-( 4- acetyl- 3- hydroxy- 2- propyl-phenoxy)- dodeca- 7( E). 9(Z)- diene

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propyltriphenyl-phosphonium bromide (example 1c) and (4S,5S)-4,5-epoxy-non-2( E)-enal; clear, yellow oil; [oc]D 2 O (chloroform, 0.600$) = 24.8 ± 1.6° .

Example 95: (5S.6R)-5-hydroxy-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-dodeca-7(E). 9( Z )-dien- 6- yl- 7- thio- 4- oxo- 4H- 1- benzopyran- 2-carboxylase- sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 94); m.p. 204-206°C; [α]D<20> (methanol, 0.570$) = 121.1 ± 1.8°; UV (methanol): Xffiax (c) = 222 (51240); 235 (sh); 267 (27360); 284 (21400); 320 (16400).

Example 96: (5R.6S)-5-hydroxy-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-tetradeca-7(E). 9(Z)-dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title 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; clear, yellow viscous oil; [α]D2<0> (chloroform, 0.424$) = 66.5 ± 2.4°; UV (chloroform): <x>max (c) - 270 (28560); 288 (sh); 325 (15240).

The starting material is produced e.g. as follows:

a) ( 5 R , 6 R ) - 5 . 6- epoxy- 14-( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- tetradeca- 7( E). 9(Z)- diene

The title compound 1 is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxyJpentyl-triphenyl-phosphonium bromide (Example 29a) and (4R,5R)-4,5-epoxy-non-2 (E)-enal (Example 92a); clear, yellow oil; [α]D<20> (chloroform, 0.441$) = 20.6 ± 2.3°.

Example 97: (5R.6S)-5-hydroxy-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-tetradeca-7(E). 9( Z )- dien- 6- yl- 7- tlo- 4- oxo- 4H- 1- benzopyran- 2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 96); m.p. 193-195°C; [α]D<20> (methanol, 0.284$) = 71.1 ± 3.5°. UV (methanol): xmax (c) = 222 (49320), 232 (sh); 267 (25520), 286 (22680);

321 (16000).

Example 98: (5S.6R)-5-hydroxy-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-tetradeca-7(E),9(Z)-dien-6-yl-7 - thio- 4- oxo- 4H- 1- benzopyran- 2-carboxylic acid ethyl ester

The compound in the title is prepared analogously to example 1 from (5S,6S)-5,6-epoxy-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-tetradeca-7(E),9(Z)- dien; clear, yellow chewy pulp; [cx]d<20 >(chloroform, 0.463$) = 79.0 ± 2.2°. UV (chloroform): Xmax (<c>) = 270 (27120); 288 (sh); 326 (14960).

The starting material is produced e.g. as follows:

a) ( 5S , 6S )- 5 . 6- epoxy- 14-( 4- acetyl- 3- hydroxy- 2- propyl-phenoxy)- tetradeca- 7( E). 9(Z)- diene

The compound in the title is prepared analogously to example 1d) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)pentyl-triphenyl-phosphonium bromide (example 29a) and (4S,5S)-4,5-epoxy-non- 2(E)-enal (Example 94a); clear, yellow oil; [a]])20 (chloroform, 0.472$) = 18.8 ± 2.1°.

Example 99: (5S.6R)-5-hydroxy-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-tetradeca-7( E). 9( Z )-diene- 6- vl- 7- thio- 4- oxo- 4H- l- benzopyran- 2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 98); m.p. 193-195°C; [α]D<20> (methanol, 0.296$) = 65.9 ± 3.4°. UV (methanol): xmax (c) = 222 (49760); 232 (sh); 267 (25800); 285 (22520); 320 (16000).

Example 100: ( 5R . 6S)- 1 . 1. 1-trifluoro-5-hydroxy-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-tetradeca-7(E). 9( Z )-dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The compound in the title is prepared analogously to example 1 from (5R,6R)-5,6-epoxy-1,1,1-trifluoro-14-(4-acetyl-3-hydroxy-2-propylphenoxy)-tetradeca-7(E) ,9(Z)-diene; clear, yellow oil; Rf = 0.32 (hexane/acetic ester = 3:2).

The starting material is produced e.g. as follows:

a) ( 5R. 6R1- 5. 6- epoxy- l. 1. 1- trifluoro- 14-( 4- acetyl- 3- hydroxy-2- propyl- phenoxy)- tetradeca- 7( E). 9( Z) - the day

The compound in the title is prepared analogously to example ld) from 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)pentyl-triphenyl-phosphonium bromide (example 29a) and (4R,5R)-4,5-epoxy-9, 9,9-trifluoro-non-2(E)-enal (Example 86b); yellow oil; Rf = 0.72 (hexane/acetic ester = 3:2).

Example 101: (5R.6S)-1.1.1-trifluoro-5-hydroxy-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-tetradeca-7(E). 9( Z )-dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The compound in the title is prepared analogously to example 2 from the corresponding methyl ester (example 100); TJV (methanol): Xmax (c) = 222 (48000); 235 (sh); 267 (25920); 285

(22920); 320 (16000).

APPENDIX - PHARMACOLOGICAL EXPERIMENTAL PROCEDURES

Guinea pig - bronchoconstriction. lon experiments (in vivo. aerosol)

Male guinea pigs weighing 400-700 g are anesthetized intraperitoneally with 1.4 g/kg urethane and a polyethylene cannula is inserted into the vena jugularis. A second polyethylene cannula is inserted into the trachea. Using a cannula inserted into the esophagus, which is connected to a Statham pressure transducer, the pressure in the esophagus is recorded. The animal is placed in an airtight plexiglass chamber which is connected by a Fleisch'er tube No. 000 to a "Validyne transducer MP 45-1". With this device the flow is measured .

After the surgical preparation of the experimental animals, a certain time is waited for the pulmonary function to stabilise. The compound to be examined is then administered according to the following protocol. The experimental animals are exposed for 1 minute to a 1% aerosol solution of the compound to be investigated (weight/volume) or distilled water (for control purposes). For all test compounds administered by inhalation, a Monoghan ultrasonic nebulizer (model 670) is used whose particle size ranges between 1 and 8 µm, with a major proportion of 3 µm.

Aqueous solutions are freshly prepared and introduced with an "On-stream" drug bottle into the chamber of the spray apparatus. The produced spray mist is administered to the test animals via a glass chamber with a content of 65 ml which is connected to the trachea with a needle. After the expiration of the treatment time, administer with a second Monoghan ultrasonic spray device (model 670) and via a corresponding glass chamber LTD 4 (0.3 pg/ml) within 2 minutes.

The reduction in Compliance is read in the 3rd minute after LTD4 administration and the mean value for 3 animals is compared with the mean value for 3 control animals, and the percentage inhibition of Compliance is calculated according to the following formula:

If different concentrations of active substance are examined, the percentage inhibition is recorded for each concentration, and the log concentration is plotted on the abscissa against the percentage inhibition on the ordinate. The Ic50 is then estimated by linear regression analysis.

In vitro test for determining the inhibition of phospholipase Ao from human leukocytes.

Neutrophil polymorph-nucleated human leukocytes are isolated starting from "Buffy coats" by multi-step fractional sedimentation and deep frozen. Phospholipase A2 is extracted from the cell suspension by homogenization with the addition of ice-cold 0.36 N H2SO4 in 2N NaCl, and the supernatant obtained after centrifugation at 10,000 x g is dialyzed against sodium acetate buffer, pE 4.5.

For the determination of the enzyme activity, enzyme is incubated (10-30

>jg protein) in 0.1 M Tris/HCl-buf f is pH 7 with the addition of 1 mM CaCl2 and substrate, consisting of biosynthetically with ^<4>C-oleic acid radioactively labeled phospholipids (2 jjM) of Escherichia coli at 37 °C for 1 hour. The reaction is stopped by the addition of Dole reagent (Isopropanol/heptane/lN H2SC"4 40:10:1, v/v) and the <14>C-oleic acid selectively released by phospholipase A2 is extracted. Any co-extracted substrate is completely removed by filtering the extract through a column of silica gel The determination of the <*4>C-oleic acid in the eluate takes place by radiometry.

To determine an inhibitory effect of the substances being investigated on phospholipase A2, these are added as solutions in water, dimethylsulfoxide (final concentration in mixture up to 5%, v/v) or ethanol (final concentration in mixture up to 2.5% v/v) to the incubation mixture. The potency of the substances under investigation is expressed by the IC50, i.e. the concentration which causes an inhibition of 50% of the control activity. IC5Q is determined graphically by plotting the percentage inhibition of the ordinate as a function of log of the concentration (jjM) on the abscissa.

Under the indicated experimental conditions, mepacrine inhibits phospholipase A2 with an IC50 of 1600 µM.

In vitro assay for determining the inhibition of phospholipase C from human platelets

Human platelets are recovered as "Buffy coats" by fractional centrifugation and then deep frozen. Phospholipase C is set free by ultrasound treatment of the cell suspension, and is found after ultracentrifugation (150,000 x g for 1 hour) in soluble form in the supernatant.

To determine the enzyme activity, enzyme (20-100 pg protein) is incubated in 0.025 M Tris/Maleate buffer, pH 6, with the addition of 0.2 mM CaCl2 and 0.02 mM radioactively labeled substrate, phosphatidyl-[<14>C] -inositol, at 37°C for 5 minutes. The reaction is stopped by shaking out with CHCI3/CH3OH 2:1 (v/v). Thereby, unused substrate is extracted in the organic phase, while the reaction product <14>C-inositol phosphate remains in the aqueous phase and can be measured by radiometry of a portion.

To determine an inhibitory effect of the substances being investigated on phospholipase C, these are added as solutions in water, dimethylsulfoxide (final concentration in mixture up to 5$, v/v) or ethanol (final concentration in mixture up to 2.5$, v/v) to the incubation mixture. The potency of the substances under investigation is expressed by IC5Q, i.e. the concentration which causes an 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 (jjM) on the abscissa.

Under the stated experimental conditions, mepacrine inhibits phospholipase C with an IC50 of 20 pM.

Claims (3)

1. Analogous process for the preparation of therapeutically active substituted alkanophenones of general formula I wherein Ri means C1-C4 alkyl or fluorinated C1-C4 alkyl, P*2 means hydrogen, C-^-C^-alkyl or fluorinated C1-C4-alkyl, X means oxy or thio, alk means C 1 -C y alkylene, n means 1 or 2, R 3 means phenyl, which is unsubstituted or substituted by C 1 -C 4 alkyl, fluorinated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, carboxy, C1-C4-alkoxycarbonyl and/or halogen, or R3 means C1-Cy-alkyl, co,co,10-trifluoro-C1-Cyalkyl, carboxy-C1-C4-alkyl or C1-C4-alkoxycarbonyl-Ci- C4-alkyl, and R4 means carboxy, C1-C4-alkoxycarbonyl or N-(benzenesulfonyl)-carbamoyl, and salts thereof, characterized by reacting an epoxide of formula II where R 1 , R 2 , X, alk, n and R 3 have the above meanings, with a thiol of formula III in which R4 has the above-mentioned meaning, or a salt thereof, and if desired, a compound obtained by a method is converted into another compound of formula I, or a stereoisomeric mixture obtained by the method is divided into its components and/or a free compound obtained by the method or a salt obtained by the process is transferred to the free compound or to another salt. 2. Analogous process according to claim 1 for the preparation of (IR , 2S )-1-hydroxy-1-(3-trifluoromethylphenyl)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E ), 5(Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid or its sodium salt, characterized by using correspondingly substituted starting materials. 3. Analogous process according to claim 1 for the preparation of (IR ,2S )-1-hydroxy-1-(3-methylphenyl )-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-deca-3(E) ,5( Z)-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid or its sodium salt, characterized by using correspondingly substituted starting materials. 3. Analogous method according to claim 1 for the production of (IR , 2S )-1-hydroxy-1-phenyl )-10 - (4-acety 1-3-hydroxy-2-propyl phenoxy )-deca-3(E ) , 5 (Z )-dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid or its sodium salt, characterized by using correspondingly substituted starting materials.