SI8910630A - Process for obtaining novel alkanophenones - Google Patents

Abstract

Substituted alkanophenones of the general formula I wherein R1 is optionally fluorinated lower alkyl, R2 represents hydrogen, optionally fluorinated lower alkyl or lower alkenyl, X means lower alkylene, oxy, thio but directly bond, alk represents lower alkylene, n stands for 1 or 2, R 3 is unsubstituted or optionally substituted fluorinated lower alkyl, etched or sharpened hydroxy, optionally lower alkylated amino and / or optionally esterified or amidated carboxy substituted phenyl or optionally fluorinated or with v optionally esterified or amidated carboxy substituted lower alkyl, R 4 represents as appropriate esterified or amidated carboxy or 5-tetrazolyl and R5 stands for hydrogen or lower alkyl, have antagonistic properties against leukotrienes and can be used as active substances for anti-allergic medicines. Procedure for their preparation is characterized in that the epoxide s formula II, wherein R1, R2, X, alk, n and R3 have the meanings given above, is reacted with a thiol of formula III, in which R 4 and R 5 have the above meanings, or salt, and optionally a compound which may be obtained in a sense the process is converted to another compound of formula I, a mixture of stereoisomers which can be obtained in a sense process, separated into components, and / or free compound, which can be obtained in terms of process is converted into salt or salt, which may be obtained in the sense of process, into free compound or to another salt.

Description

CIBA-GEIGY AG

Process for the preparation of new alkanophenones

The invention relates to a process for the preparation of new substituted alkanophenones of the general formula 2 in which optionally fluorinated lower alkyl represents hydrogen, optionally fluorinated lower alkyl or lower alkenyl, X means lower alkylene, oxy, thio or a direct bond , alk represents lower alkylene, n stands for 1 or 2, R4 represents unsubstituted or optionally fluorinated lower alkyl, esterified or esterified hydroxy, optionally lower alkylated amino and / or optionally esterified or amidated carboxy substituted phenyl, or in optionally fluorinated or in the case of esterified or amidated carboxy substituted lower alkyl, R1 represents optionally esterified or amidated carboxy or 5-tetrazolyl and R4 stands for hydrogen or lower alkyl, and their salts, for processes for the preparation of pharmaceutical preparations, containing these compounds as an active ingredient and their use as active ingredients for medicaments.

The spatial representation in Formula I above is to be understood for preferred compounds in which the hydroxyl acid atom 0 and the S atom are in a relative trans configuration such that the symbols of the first row lie above and the symbols of the third row then below the display plane (or vice versa), corresponding to the formula shown opposite to the kunfiguration, (RS) - (SR), after

Kahn-Ingold-Prologue Convention on a carbon atom bound by a sulfur atom (C-S-) and a carbon atom carrying a hydroxyl group (C-OH). In this case, when n is for 2, the enantiomers with S (CS-), R (C-OH) -configuration are particularly preferred, and if n is for 1, the enantiomers with R (CS-), S (C-OH) -configuration. In vinyl or. the buta-1,3-dienylene residue represented by the - 3 symbol - (CH = CH4-n, lies the double bond or double bond of the butadienylene residue derived from the C atom attached to the alk moiety, preferably, but not necessarily, in the cis configuration, usually denoted by (Z) wherein the second double bond is then preferred, but also not necessarily the ^ trans configuration, usually denoted by (E) In the given case, fluorinated lower alkyl is lower alkyl or mono-, di- or polyfluoro-lower alkyl.

Zaetren oz. esterified hydroxy is e.g. lower alkoxy or. halogen. In the given case, the lower alkylated amino is e.g. amino, lower alkylamino or, in particular, lower alkylamino. Optionally, esterified or amidated carboxy is carboxy, esterified carboxy, such as lower alkoxycarbonyl, or amidated carboxy, such as carbamyl or N-mono- or N, N-lower-alkylcarbamoyl, or preferably in the phenyl moiety, optionally lower alkyl, lower alkoxy and / or halogen substituted N- (benzolsulfonyl) carbamoyl. In the phenyl moiety, optionally substituted N- (benzolsulfonyl) -carbamoyl, e.g. unsubstituted or monosubstituted, preferably in the ortho position. As in the present case, the esterified or amidated carboxy substituent in R1 is particularly preferred carboxy and, as the R4 esterified carboxy, in particular lower alkoxycarbonyl.

Forward and forwards are meant by " lower " residues and compounds e.g. those who are no more than 7 and, if

not otherwise stated, preferably not more than 4 carbon atoms (C atoms). The following applies:

Lower alkyl is e.g. C1-C4-alkyl, in particular unbranched C1-C4-alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or secondary butyl, but may also be branched C1-C4-alkyl, such as isobutyl or tertiary butyl, or pentyl , hexyl or heptyl residue. Lower alkyl R1, R4 or. as a phenyl substituent or N- (benzolsulfonyl) carbamoyl Preferably C 1 -C 4 -alkyl, e.g. methyl, lower alkyl R 2 preferably C 2 -C 4 -alkyl, e.g. propyl, and lower alkyl R ^ preferably C prednost-C prednost-alkyl, e.g. propyl, butyl or pentyl.

Mono-, di- or polyfluoro and lower alkyl have e.g. to and crucial 5 fluorine atoms and is e.g. mono-, di- or trifluoro-C1-C3-alkyl, in particular tu-fluoro- or t-fluoro-trifluoro-C1-C6-alkyl, such as trifluoromethyl, 2,2,2-trifluoroethyl or 3,3,3 -trifluoropropyl. Fluorinated lower alkyl R1 as well as such a phenyl substituent R1 is in particular trifluoromethyl and fluorinated lower alkyl R1 preferably u- >, oU, o ' -trifluoro-C2-C1-6 alkyl, e.g. 3,3,3-Trifluoropropyl.

The lower alkenyl R2 is e.g. C8-C4-alkenyl, such as vinyl, prop-1-enyl or in particular prop-2-enyl (allyl).

Lower alkylene is e.g. unbranched C 1 -C 4 -alkylene, in the case of X in particular C 1 -C 4 -alkylene, such as methylene or ethylene, and in the case of alk, in particular C 2 -C 8 -alkylene, such as ethylene, 1,3-propylene, 1,4-butylene, hereinafter 1,5-pentylene or 1,6-hexylene.

The lower alkoxy is e.g. C1-C4-alkoxy, such as methoxy.

Lower alkoxycarbonyl is e.g. (C 1 -C 4 -alkoxycarbonyl, - 5 - as methoxy-, ethoxy-, propyloxy- or butyloxycarbonyl.

The lower alkylamino is e.g. C1-C4-alkylamino, such as methyl-, ethyl-, propyl- or isopropylamino.

The dicycloalkylamino is e.g. di-C 1 -C 4 -alkylamino, such as dimethylamino, diethylamino or N-ethyl-N-methyl-amino. N-mono- or Ν, Ν-dihydroalkylcarbamoyl is e.g. N-C 1 -C 4 -alkyl- or N, N-di-C 1 -C 4 -alkylcarbamyl, such as N-methyl-, N-ethyl- or N, N-dimethylcarbamyl.

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

Most of the compounds of formula I may also be present in the form of salts by their individual character. Those having sufficient acidity, such as those with carboxyl, tetrazolyl or sulfamoyl groups, may form salts with bases, such as inorganic bases, preferably salts of alkali metals, in particular sodium and potassium salts. Ammonium salts with ammonia or physiologically tolerable organic amines, such as mono-, di- or trisulfonylamines, e.g. diethylamine, mono-, di- or tri (hydroxyalkyl) amines, such as tris (hydroxymethyl) methyl-amine, or D-glucosamine.

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

Thus, they inhibit e.g. in vitro in a concentration range of about 0.001 to 1.0 pmol / l with leukotriene— (LTD ^) induced 6 smooth muscle contraction. This so-called LTDjj antagonism is found experimentally e.g. as follows: In segments taken from ileum of 300-400 g of heavy guinea pig and incubated in an organ bath in Tyrode's solution at 38 ° C and fumigated with a mixture of 95% oxygen and 5% carbon dioxide under load 1 g, is triggered by synthetic leukotriene (as potassium salt) contractions and isotonically registered. The extent of inhibition with the test substance is determined after a 2-minute preincubation and evaluated as IC ^ Q, that is, a concentration that reduces the test contraction by 50%. The compounds of formula I are also in vivo exquisitely effective. In addition, they show a specific and therapeutically very important advantage of the relatively long duration of the effect. Thus, we were able to demonstrate in the standard in vivo guinea pig bronchocone-striking assay by aerosol administration of a solution containing 0.0001 to 1 wt% of the test substance, a distinct antagonistic effect against LTD ^. (A description of the test method is provided in the appendix by example).

Surprisingly, many compounds of Formula I also have a pronounced inhibitory effect on other physiologically relevant enzyme systems. Thus, inhibition of phospholipase A ^ from human leukocytes was observed in the tested concentration range of about 0.5 to 50 pmol / l. (The experimental layout for this determination is described in more detail in the Appendix by example). Inhibition of phospholipase C from human platelets was also observed in the tested concentration range of about 1 to 100 pmol / l. - 7 -

Due to these valuable pharmacological properties, the compounds of formula I of the invention can be therapeutically used wherever the leukotrienes effect the disease states, which can be alleviated or eliminated. Therefore, they can be used e.g. for the treatment of allergic conditions and diseases, in particular asthma, as well as hay fever as well as obstructive pulmonary diseases, including cystic fibrosis. Also, due to their anti-inflammatory efficacy, they are suitable as anti-inflammatory agents, especially as external (topical) skin phlogistatics for the treatment of inflammatory dermatoses of any origin, as for light skin irritations, contact dermatitis, exanthema and burns, as well as phlogostatics for mucous membranes for the treatment of mucosal inflammation, e.g. eyes, nose, lips, mouth and genital respectively. anal regions. They can then be used as sunscreens. The high inhibitory potency for various blood factors also indicates the potential for therapeutic use of the compounds of Formula I in the indication range of thrombosis and blood clotting.

The invention relates primarily to the preparation of compounds of formula I, in which R1 is lower alkyl or mono-, di- or polyfluoro-lower alkyl, 1 * 2 represents hydrogen, lower alkyl, lower alkenyl or mono-, di- or polyfluoro-lower alkyl, X represents lower alkylene, oxy or thio, alk means lower alkylene, unsubstituted or with lower alkyl, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl, amino, N-mono- or Ν, d-dibenzylalkylamino, carbamyl, N-mono- or Ν, d-dihydroalkyl-carbamyl and / or trifluoromethyl substituted phenyl, lower - 8 - alkyl, mono-, di- or trifluoro-loweralkyl, carboxymethylalkyl, loweralkyloxycarbonylalkyl, or carbamylalkylalkyl or arylalkyl or N-monylcarbonyl, alkoxycarbonyl, 5-tetrazolyl, carbamyl, N-mono- or Ν, d-dihydroalkylcarbamyl or optionally substituted N- (benzolsulfonyl) carbamoyl in the phenyl moiety with lower alkyl, lower alkoxy, halogen and / or trifluoromethyl and a is hydrogen or lower alkyl, and salts thereof, in particular pharmaceutically useful salts.

The invention relates primarily to e.g. for the preparation of such compounds of formula I wherein R1 is lower alkyl, R1 represents optionally fluorinated lower alkyl or lower alkenyl and X, R4, and 85 have the above meanings, and salts thereof, especially pharmaceutically useful salts.

Preferably, the group X is attached to the group R ^ -C (= O) in the para position, i.e., the compounds have the formula »

Ri X v > \

I II (la),

/ \ / \ 9H HO N · X-alk — fCH = CH -) - CH-CH-R3 A * Ί

\ / \ A R 5 - + wherein R 2, R 8, X * alkyl, n, R 4, R 4 and R 4 have the meanings indicated, but R 4 is preferably lower alkyl, R 2 being optionally fluorinated lower alkyl or lower alkenyl and / or phenyl is R ^ but preferably substituted, 9 as indicated.

The invention relates in particular to the preparation of compounds of formula I or. Ia, in which R1 is C1-C4-alkyl, such as methyl, or here, uo »uu-trifluoro-C1-C4-alkyl, such as trifluoromethyl, R2 represents C1-C6-alkyl, such as propyl, C2-C1J -alkenyl, such as allyl, u, N, -trifluoro-C 1 -C 4 -alkyl, such as 3,3,3-trifluoropropyl, or other hydrogen, X represents C 1 -C 4 -alkylene, such as methylene, oxy or thio, alk represents unbranched C 2 -C 8 alkylene ethylene, 1,3-ppopylene or 1,4-butylene, n is 1 or 2, R 4 is unsubstituted or C 1 -C 6 alkyl, such as methyl, C 1 -C 4 alkoxy , such as methoxy, halogen having an atomic number up to and including 35, such as chlorine or bromine, trifluoromethyl, carboxy and / or C 1 -C 6 alkoxycarbonyl, such as methoxycarbonyl, substituted phenyl, C 1 -C 6 alkyl, such as propyl or butyl, LU, uu , uu-trifluoro-C2-C4-alkyl, such as 3,3,3-trifluoropropyl or 4,4,4-trifluorobutyl, carboxy-C2-C4-alkyl, such as 3-carboxypropyl or 4-carboxybutyl, or C1- C 1 -alkoxycarbonyl-C 2 -C 4 -alkyl, such as 3-methoxycarbonyl-propyl or 4-methoxycarbonylbutyl, R 4 represents carboxy or N- (benzolsulfonyl) carbamyl, and R ^ stands for hydrogen, where, if n stands for 1, the chain atom C attached to the sulfur atom has the (R) configuration and the chain atom C attached to the hydroxy group preferably (S) - configure, respectively. having n for 2 has a chain C atom attached to the sulfur atom, preferably a (S) -configuration, and a chain C atom bearing a hydroxy group, preferably a (R) -configuration, and having a double bond attached to the alk the bond is preferably 10 in the cis-configuration, and optionally present an additional double bond, preferably in the trans-configuration, preferably those in which C 1 -C 4 -alkyl and R2, X, R 4, R 4 and R 1 have the meanings indicated ^ and salts thereof, in particular pharmaceutically useful salts.

The invention relates in particular to e.g. for the preparation of compounds of formula I or Ia, in which R 1 is C 1 -C 4 -alkyl, such as methyl, R 2 represents C 1 -C 6 -alkyl, such as propyl, C 2 -C 1 -alkenyl, such as allyl, or uj, oj, ul / -trifluoro-C 1 C N -alkyl, such as 3,3,3-trifluoro-propyl, X represents C 1 -C 4 -alkylene, such as methylene, oxy or thio, alk represents unbranched C 2 -C 8 -alkylene, such as ethylene, 1,4-butene or 1 , 6-hexylene, n stands for 1 or 2, R 4 represents a group of formula -AR 2, in which -A- represents C 1 -C 4 -alkylene, phenylene or a direct bond, and R 4 represents C 1 -C 4 - alkyl, such as methyl, trifluoromethyl, carboxy or C 1 -C 4 -alkoxycarbonyl, such as methoxycarbonyl, R 1 represents carboxy or N- (benzenesulfonyl) carbamyl and R 1. stands for hydrogen, where, if n is for 1, the chain C atom attached to the sulfur atom has the (R) -configuration preferred and the hydroxy group attached to the chain C atom has the (S) -configuration or preference. if n stands for 2, the sulfur atom C is attached to the bonded C atom preferably (S) -configuration and the chain atom C, which bears the hydroxy group, preferably the (R) -configuration, and has a double bond preferably attached to the cis residue -configuration and optionally an additional double bond, preferably in the trans-configuration, and salts thereof, in particular pharmaceutically useful salts.

The invention relates in particular to the preparation of compounds of formula Ia wherein C 1 -C 4 -alkyl is methyl, R 2 is C 1 -C 4 -alkyl, propyl, X is oxy, alk is C 2 -C 8 -alkylene, such as ethylene. 1,3-propylene or 1,4-butylene, n is 1 or preferably 2, R 4 is -C 1 -alkyl, such as methyl, C 1 -C 4 -alkoxy, such as methoxy, halogen having an atomic number up to and including 35, such as chlorine, trifluoromethyl or C 1 -C 6 alkoxycarbonyl, such as methoxycarbonyl, substituted phenyl, C 2 -C 8 -, in particular C 1 -C 6 alkyl, such as propyl or butyl, Ου, υυ, tu-trifluoro-C ^ -C N-alkyl, such as 3,3,3-trifluoropropyl or 4,4,4-trifluorobutyl, or C 1 -C 4 -alkoxycarbonyl-C 1 -C 6 -alkyl, such as 3-methoxycarbonylpropyl or 4-methoxycarbonylbutyl, R 4 represents carboxy and R 4 is hydrogen , wherein if n is 1, the sulfur atom C-linked chain has the (R) -configuration priority and the hydroxy group the C-chain attached preference (S) -configuration pz. if n is 2, the sulfur atom is linked by a chain atom, the C atom is preferably a (S) -configuration, and the hydroxy group-bearing chain C is a (R) -configuration and the double bond is preferably attached in the cis-configuration, and optionally present, an additional double bond, preferably in the trans-configuration, and salts thereof, especially pharmaceutically useful salts.

The invention preferably relates to the preparation of compounds of formula Ia, in which R1 is C1-C4-alkyl, such as methyl, R2 is C1-C4-alkyl, such as propyl, X is oxy, alk is C2-C8-alkylene, such as ethylene or 1,4-butylene, n stands for 1 or 12, preferably 2, R 4 represents a group of the formula -AR 2 in which -A-C 1 -C 4 -alkylene represents ethylene, or phenylene, in particular m-phenylene, and R 4 represents C 1 -C 4 -alkyl, such as methyl, trifluoromethyl or C 1 -C 4 -alkoxycarbonyl, such as raetoxycarbonyl, R 1 represents carboxy or N- (benzenesulfonyl) carbamoyl, and R 4 is hydrogen, having, if n is 1, an atom sulfur-linked chain C atom preferred (R) -configuration and hydroxy group-linked chain C atom preferred (S) -configuration or. if n is 2, the sulfur atom C-linked chain has a preferred (S) -configuration and a hydroxy group-bearing chain C, preferably the (R) -configuration, and a double bond is preferably attached in the cis- configuration and, optionally, an additional double bond present preferably in the trans configuration, and salts thereof, especially pharmaceutically useful salts.

The invention relates first and foremost to the preparation of compounds of formula Ia, in which R 1 is C 1 -C 4 -alkyl, such as methyl, r 2 represents C 1 -C 6 -alkyl, as propyl, X stands for oxy, and alk represents C 2 -C 4 - alkylene, such as ethylene, 1,3-propylene or 1, M-butylene, n stands for 2, means C1-C4-alkyl, such as methyl, trifluoromethyloxy or C1-C4-alkoxycarbonyl, such as methoxycarbonyl, especially in the meta position substituted phenyl, C1-C4-alkyl, such as propyl or butyl, uu, uu, u-trifluoro-C1-C4-alkyl, such as 3,3,3-trifluoropropyl or k, H, M-trifluorobutyl, or C1-C4-alkoxycarbonyl-C1-C4-alkyl, such as 3-methoxycarbonylpropyl or N-methoxycarbonylbutyl, R4 represents carboxy and R4 is hydrogen, with the sulfur atom having a bonded C atom preferably (S) - the configuration and the C chain atom bearing the hydroxy group, preferably the (R) -configuration and the residual alk bonded double bond, preferably in the cis-configuration and other additional double bond, preferably in the trans-configuration and their salts, in particular pharmaceutical o usable salts.

The invention relates in particular to the preparation in the cases of said compounds of formula I and their salts, in particular pharmaceutically acceptable salts.

The process of the invention for the preparation of compounds of formula I and their salts is based on methods known per se and characterized in that the epoxide of formula (II),

r / x / \ A 1 ί. -H-Χ-alkf CH '= CH) -CH-CH-R 3

HO

Aa in which R ^, R2, X, alk, n and R ^ have the above meanings, metabolizes a thiol of the formula " V \ A / '(III), R5— + · II II • v * · · V \ / ΰ in which R ^ and the above meanings, or with the salt thereof, and optionally the compound which can be obtained in the sense of the process, are converted to another compound of formula I, the mixture of stereoisomers which can be obtained in the sense of the process is separated into components ^ 14 and / or the free compound that can be obtained in the sense of the process is converted into a salt, or the salt that can be obtained in the sense of the process is converted into the free compound or another salt.

The metabolism of epoxides II by thiols III is carried out by changing the configuration on the thio atom that binds to the thio group and while maintaining the configuration on the hydroxy group bearing the C atom.

Therefore, to obtain preferred compounds of the opposite configuration on both of these C atoms, we therefore proceed preferably from the corresponding trans epoxides II. This is obtained from the R, R-epoxy-II, Compound I with the S (C-S-), R (C-OH) -configuration, respectively. . starting from S, S-epoxides II, compound I with R (C-S), S (C-OH) -configuration. The metabolism is carried out under known conditions, at temperatures from about -20 ° C to about +50 ° C, preferably at room temperature, i.e. 18 ° C to 25 ° C, and in particular in a basic environment, e.g. in the presence of an amine, in particular a tertiary aliphatic, arylaliphatic or saturated heterocyclic amine, such as trialkylamine (e.g. triethylamine or ethyl-diisopropylamine), dialkyl-benzylamine (e.g., Ν, Ν-dimethylbenzylamine), Ν, dial-dialkylaniline (e.g. , Ν-dimethylaniline) resp. N-methyl-or N-ethyl-piperidine or N, N-dimethylpiperazine. Usually, the reaction is carried out in an indifferent organic solvent, such as lower alkanol, e.g. methanol or ethanol. In a preferred embodiment, we begin with components II and III in which the carboxy or tetrazolyl is esterified and R1 has the indicated meaning and means e.g. esterified carboxy, or optionally fluorinated lower alkyl, hydrolyses R4 (selectively in the 15th day) into carboxy and optionally converted to amidated carboxy.

The starting materials for the process of the invention are either inherently known or can be obtained by known analogous procedures in a manner known per se.

As the starting material, the epoxide of formula (II) defined above can be prepared in particular by the same procedures as used for the synthesis of leukotrienes. For a typical general synthesis route for compounds II in which n stands for 1, e.g. from an aldehyde of formula 0 = CH-R3 (iv) in which A and the above meanings, wherein optionally present a free carboxyl group R ^ in the form protected as an ester, e.g. as the lower alkyl ester. This compound is condensed with formylmethylenetrophenylphosphorane (or equivalent reagent) to form the corresponding trans-3-R 1 -prop-2-enal of formula

0 = CH

(V).

This compound is then epoxidized with aqueous hydrogen peroxide in a manner known per se, preferably under weakly alkaline conditions (e.g., in the presence of alkali carbonates), to produce trans, i.e. 2 (RS), 3 (RS) -Epoxy-3-Rg-pr * opanal of formula (vi). 16 -

Epoxydehyde VI can then be condensed with phosphonium halide

VII (VII) in which R2 and alk have the meanings given and Hal represents a halogen atom, preferably bromine, and with a base, e.g. sodium amide, is reacted in tetrahydrofuran to the corresponding epoxide II, in which R1 is esterified carboxy and n is 1.

Compounds VII are prepared in particular by metabolizing the corresponding compound of formula

4t-X-alkyl-CH2-Hal * (VIII) with triphenylphosphine in the usual way. Compounds VIII, in which X is oxy or thio, are obtained e.g. by making the corresponding compounds of formulas

We condense each other in the usual way.

- 17 - Another method for the preparation of compounds of trans-3-Rg-prop-2-enol of the formula HOCH2v, CH II is that (XI) in which R4 has the above meaning but is a free carboxy as a substituent in R preferably protected in the form of an ester, epoxides e.g. with tertiary butylhydroperoxide in the presence of titanium tetraisopropanolate and alkali ester D-oz. L-tartaric acids, thereby obtaining predominantly 2R, 3R-epoxy-3-Rg-propanol XIIa'oz using the D-tartaric ester. when using L-tartaric acid ester predominantly the corresponding 2S, SS-epoxy-S-R ^ -propanol XIIb (XIIb).

HOCH2. A > H HOCH2v .0. , H / - (XIIa) OZ. - < H \ 3

This is then oxidized, e.g. by treatment with oxalyl chloride / dimethylsulfoxide and then with triethylamine, into the corresponding epoxy dialdehyde VI, which can then be converted by the corresponding phosphonium salt VII to the corresponding epoxide II, in which R1 is esterified carboxy and n is 1.

This mainly results in epoxides II, in which the double bond prefers cis-stereotaxy. When used with the D-tartaric acid ester, as mentioned above, the compounds II, in which the epoxy group has the R, R-configuration, or, respectively, are obtained. S, S-enantiomers if the reaction is carried out in the presence of L-tartaric acid esters. - 18 -

For the preparation of epoxies II in which n is 2, we translate e.g. epoxy alcohol XIIa or. XIIb first by treatment with N, N′-dicyclohexylcarbodiimide and dimethylsulfoxide in the presence of trifluoroacetic acid and pyridine and then with triphenylphosphoranylideneacetaldehyde first in the corresponding 4R, 5R- or 4S, 5S-4,5-epoxy-5-R2-pent-2-enal of the formulas XIIIa or. XIIIb

0 = HC-CH = CH 0 H 0 = HC-CH = CH 0 H; c-c '(ΧΙΙϋ) 0X. c— < (XXIIb) H R3 h '\ 3 which are then further metabolised by phosphonium halide VII to the corresponding epoxide II, in which n is n by 2. Preferably, those in which the residual alk has the double bond cis-stereotaxis and oxiran ring bound double bond trans-stereotaxy.

Compounds which can be obtained in terms of the process can optionally be converted to other compounds of formula I.

E.g. the esterified or amidated carboxy groups may be hydrolyzed to free hydroxy, preferably under basic conditions, e.g. in the presence of sodium hydroxide, and preferably in an organic water miscible solvent such as tetrahydrofuran, dioxane or lower alkanol, such as methanol or ethanol. Starting from compounds I in which esterified carboxy, such as lower alkoxycarbonyl, and containing such as substituent, hydrolysis can be conducted by selectively hydrolyzing only R1 or both R4 as well as lower alkoxycarbonyl 19 substituent v into carboxy. If equimolecular sodium lye is used and mild reaction conditions are selected, e.g. For 0.5 to 2 hours stirring at room temperature, virtually only alkoxycarbonyl R4 is hydrolyzed, while under drastic conditions, e.g. at prolonged reaction times or when heated, hydroxycarbonyl hydrolyzes both carboxy and carboxycarbonyl to carboxy.

Conversely, the carboxy R ^ as well as the carboxy substituent in R ^ can be esterified in the usual way.

The free or esterified carboxy R ^ and such as the substituent in R ^ can be further amidlated in the usual way, e.g. by treatment with ammonia or mono- or di-alkylamine. For example, the carboxy can be R4 in the usual way, e.g. in the presence of a carbodiimide salt, e.g. N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride and 4-dimethylaminopyridine, optionally substituted benzolsulfonamide, are converted into the corresponding N-benzolsulfamidoylcarbamyl groups.

Of course, the resulting mixtures of diastereomers, based on the different physical properties of the components, can also be separated into individual components, and / or the resulting enantiomer mixtures can be separated by conventional procedures for separating racemates into individual enantiomers. If individual diastereomers are desired, the individual diastereomer of the starting material or of the starting material, which is in the form of a diastereomer, can be advantageously used at any stage, preferably forming diastereomers, 20 or racemic mixtures of diastereomers with physical separators with stereoselective reaction conditions or optically active reagents. methods, optionally using optically active auxiliaries, are separated into individual diastereomers. In stereochemistry, however, both / condensation according to the invention of components II and III as well as the preparation of starting materials are carried out, in particular by always using stereotactically uniform starting materials each time, preferably carrying out reactions in a stereoselective manner, e.g. using stereotactically uniform, optically active reagents and / or excipients, and isolated from the reaction mixtures directly after the reaction, stereotactically 'single products. So e.g. in the preparation of unsaturated starting materials, the cis- and trans-isomers formed in the given case are immediately separated from one another, for which conventional physical separation methods, such as chromatography, are appropriate. In the main reaction, the stereomeric epoxide II with the terminal substance is preferably used in the stereo-toxia of double (double) bonds, in racemic form (as is often formed in the variant of the epoxidation of compound V with hydrogen peroxide) or preferably as an individual diastereomer with configuration; on the oxiran atom C bonding to the S atom, which is opposite to the configuration on the (C-S) -C atom, which is preferred in the final substance I.

Also salts obtained, e.g. by treatment with acid, it is converted into free acids or. of the free acid obtained by treatment with a base in salt.

Due to the close connection between the new compounds in the free form and in the form of their salts, the corresponding salts or the corresponding salts are reasonably foreseen in the foregoing and in the continuation with the free compounds or their salts. free compounds. 21

The invention also relates to those embodiments of the process by which a compound can be obtained at any stage of the process as an intermediate, and the missing steps are carried out, or a starting material is used in the form of a salt or formed under the reaction conditions.

In the processes according to the invention and their precursors, emerging new starting materials and intermediates also form the object of the invention.

Preferably, such starting materials are used and the reaction conditions are chosen in such a way that they come to the fore as particularly preferred compounds.

The compounds which can be obtained in terms of the process are used in the preparation of pharmaceutical preparations and medicaments. Pharmaceutical preparations containing as active ingredient the compounds of the invention are particularly intended for topical administration and especially for administration by inhalation, e.g. in the form of an aerosol, a micro-powder or a fine-dispersed solution, to a mammal, in particular to humans, and containing the active substance alone or together with a pharmaceutically useful carrier material.

Pharmaceutical preparations for topical and topical use are e.g. for the treatment of the skin lotions and creams containing liquid or semi-solid oil-in-water or water-in-oil emulsion and ointments (containing a preferred preservative). Eye drops containing the active compound in aqueous or oily solution and eye ointments, preferably in sterile 22 form, are suitable for eye treatment. For the treatment of the nose, aerosols and sprays (similar to those described below for the treatment of respiratory tracts), coarse powders which are administered by rapid inhalation through the nostrils, and especially nasal drops containing the active compound in aqueous or oily solution are suitable; for local treatment of the oral cavity, lollipops containing the active ingredient in the mass, prepared generally from sugar and gum arabic or tragacanth to which flavoring agents may be added, as well as lozenges containing the active substance in the inert mass, are also suitable , e.g. from gelatin and glycerin or sugar and gum arabicum.

As pharmaceutical preparations for administration in the form of aerosols or sprays, e.g. solutions, suspensions or emulsions of the active ingredients of formula I according to the invention with a suitable pharmaceutically acceptable solvent, such as ethanol and water in particular, or a mixture of such solvents. They may, if necessary, contain other pharmaceutical auxiliaries, such as non-ionic or anionic surfactants, emulsifiers and stabilizers, as well as active substances of another kind, and are especially preferably mixed with propellant, as inert gas under high pressure, or in particular with a volatile liquid. preferably boiling under normal atmospheric pressure below normal ambient temperature (e.g., between about -30 and +10 ° C), such as with at least partially fluorinated polyhalogenated lower alkanes, or a mixture of such liquids. Such pharmaceutical preparations, which are used predominantly as intermediates or stock mixtures for the preparation of suitable pharmaceuticals in finished form, contain the active ingredients typically in a concentration of from about 0.1 to about 10, in particular from - 23 - about 0.3 to about 3 mA3. %. For the ready-to-use preparation of the pharmaceutical formulation, the pharmaceutical formulation is filled into suitable containers, such as brushed inhalation bottles and pressurized bottles, equipped with a spray dispenser or dispenser. valves suitable for such purposes. The valve is preferably designed as a metering valve that delivers a predetermined amount of fluid, corresponding to a predetermined dose of the active ingredient, when pressed. In the preparation of ready-made forms of medicines, it is also possible to work by pouring into the containers particularly suitable quantities of a pharmaceutical preparation, which is present as a stock solution, and propellants which are mixed only in the container. The dosage of the active ingredient of Formula I to be administered} and the frequency of administration depend on the respective efficacy and / or efficacy. the length of effect of each of these compounds, the severity of the disease to be treated or its symptoms, as well as the sex, age, weight and individual response of the mammal to be treated. On average, a daily dose of a compound of the invention of formula I in a 75 kg heavy mammal (especially human) in the range of from about 10 to about 500, preferably between about 25 to about 250 mg, would be recommended, where appropriate administration may be performed as needed in multiple doses daily.

The invention also relates to the use of the active ingredients of the invention of formula I for the alleviation or elimination of conditions and / or symptoms of the mammalian body, in particular human, which can be attributed to the action of leukotrienes and which occur - 24 especially in asthma. This use or. the appropriate method of treatment is indicated by the treatment of the affected body or. body work with an anti-allergic effective amount of a compound of formula I alone or in the form of a medicament, in particular a pharmaceutical preparation intended for inhalation. By the term " anti-allergic effective amount " is meant an amount of the active ingredient that is sufficient to significantly prevent leukotriene contractions.

The following examples further illustrate the present invention without limiting its scope. All temperatures are in degrees Celsius. - 25 - EXAMPLE 1:

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

Solution 0.93 g (1R, 2R) -1,2-epoxy-1- (3-trifluoromethyl-phenyl) -8- (4-acetyl-3 ** hydroxy-2-propyl-phenoxy) -octa-3 ( E), 5 (Z) dienes in 25 ml of methanol were stirred under argon with 0.80 g of triethylamine and 0.62 g of 7-mercapto-2-carboxylic acid methyl ester for 20 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate and filtered through silica gel. The filtrate was washed once with 2 n hydrochloric acid and 3 times with brine, dried over magnesium sulfate and evaporated. Purification of the residue by chromatography on silica gel with hexane / ethyl acetate (1: 1) gave the title compound from the ground. 62-63 °; / < X / ^ (methanol, 0.135%) = 103 + 7.4 ° UV (methanol): / | (e) = 216 (50Ό00), 235 / sh, 271 (27 * 940), 285 / sh; 325

ula X (12 ^ 900).

The starting material is prepared e.g. as follows: a) (2R, 3R) -2,3-epoxyl-3- (3-trifluoromethylphenyl) -propanol

Under absolutely anhydrous conditions and argon atmosphere, cool a solution of 4.62 ml of tetraisopropyl orthotitanate in 100 ml of methylene chloride to -70 ° and add 3.2 rmlL $ IU $ of D (-) tartaric acid ester and 5.45 g of 3- (3- trifluoromethylphenyl) -prop-2 (E) -enol in a little of methylene chloride. After stirring at -70 ° for 10 minutes, 21.5 ml of 3-molar solution of tertiary butylhydro 26 peroxide in toluene was added, increasing the temperature to -60 ° C. Allow the temperature to rise to 0 ° for 2 hours, slowly pour the resulting yellow solution into a solution of 14.5 g of ferrous sulphate II and 5.8 g of L (+) -tartaric acid in 60 ml of water (cooling, exothermic) and stir 30 minutes at 5 to 10 °. The aqueous phase was separated and extracted with ether. The combined organic extracts were dried over sodium sulfate and evaporated. The residue was dissolved in 90 ml of ether, cooled to 0 to 5 °, a suspension of 2.32 g of sodium hydroxide in 60 ml of brine was added and stirred for 1 hour at 0 to 5 °. The aqueous phase was separated and extracted with ether. The combined ether phases were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with hexane / ethyl acetate (3: 2). The title compound is obtained as a colorless oil; IR (Ci ^ Clg): 3550, 3430, 2950, 2880, 2830, 1310, 1150, 1110, 1050 cm < -1 > X / {^ (methanol, 0.175%) = 42.3 + 5.7 °; Rf = 0.30 (hexane / ethyl acetate 3: 2). b) (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal

A solution of 4.5 g (2R, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanol in 105 ml of dimethylsulfoxide was stirred under argon with 1.7 ml of pyridine, 0.77 ml of trifluoroacetic acid and 12.75 g of N, N-dicyclohexylcarbodiimide for 6 hours at room temperature. After the addition of 8.25 g of formylmethylenetrophenylphosphorane, the mixture was stirred for another 20 hours at room temperature # 320 ml of ethyl acetate were added and poured into 320 ml of brine after 10 minutes. The resulting suspension was stirred for 5 minutes and filtered. In the filtrate, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases were washed 27 times with brine, dried over sodium sulfate and evaporated. The residue was filtered with ether / hexane = (4: 1) over silica gel. The filtrate was evaporated and the residue was purified by chromatography on silica gel with hexane / ethyl acetate (3: 1). The title compound is obtained as a light yellow oil; IR (CH2 Cl2): 2780, 2695, 1670, 1620, 1305, 1145, 1105 cm < -1 >; R f = 0.31 (hexane / ethyl acetate 3: 1) / m / z 0 (chloroform, 0.245%) = 144.5 + 4.1 °. c) 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl-triphenylphosphonium bromide

A solution of 27 g of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propyl bromide in 50 ml of toluene was heated with 21.85 g of triphenylphosphine for 20 hours to reflux. The resulting suspension was cooled to room temperature, 200 ml of ether was added and stirred for 1 hour. The colorless precipitate was filtered off with suction, washed with ether and dried. The title compound has melt. 211 to 212 °. d) (1R, 2R) -1,2-epoxy-1- (3 ~ trifluoromethylphenyl) -8- (4 ~ acetyl-3 ~ hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dien

A suspension of 5.55 g of 3- (4-acetyl-3-hydroxy-2-propylphenoxy) -propylphenylphosphonium bromide in 80 ml of tetrahydrofuran is mixed with 0.78 g of NaNH2 and 60 mg of potassium tertiary butanol under argon for 1 hour at room temperature, cooled to 0-5 °, 1.7 g (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal in 20 tetrahydrofuran was added over 5 minutes and then added stirred for 2 hours at room temperature. The resulting suspension was poured onto phosphate buffer (pH 7) and extracted with ether. The combined ether extracts were washed with phosphate buffer pH 7, dried over sodium sulfate and evaporated. The residue was taken up in hexane / ethyl acetate / triethylamine (24: 71: 5) and filtered through a silica gel, which was previously washed with this solvent mixture. The filtrate was evaporated to give the title compound as a pale yellow oil; Rf = 0.75 (hexane / ethyl acetate 3: 2). EXAMPLE 2:

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8-4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene-2 -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid 0.7 g methyl (1R, 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-1-benzopyran-2-carboxylic acid is dissolved under of argon in 20 ml of tetrahydrofuran, 5.1 ml of 0.2 n sodium hydroxide was added and stirred for 1 hour at room temperature. Evaporation and chromatographic purification of the residue on a column of ® silica gel " Reversed Phase " (e.g. Merck Lichroprep " RP-8) with methanol / water (3: 1) to give the title compound, m.p. 207-209 °, / oO / ^ 0 (0.54%, methanol) = 96.3 + 1.9 ° UV (methanol): Xmov (ε ·) = 220 (488840), 235 / sh, 267 (25940) ), 285 (22900), 324 / sh. EXAMPLE 3:

(1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene-2 methyl ester -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1) from (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3--29-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene; m.p. 68-69 °. The starting material is prepared e.g. also: a) (2S, 3S) -2,3-epoxy-3- (3-trifluoromethylphenyl-propanol)

The title compound was prepared as described in Example 1a) but using L (+) tartaric acid diethyl ester; colorless oil; IR (CH2 Cl2): 3590, 3480, 2920, 2870, 1330, 1165, 1125, 1070 cm "1; / ot // J ^ O (methanol, 0.175%) - -41.7 + 5.7 °; Rf = 0.34 (hexane / ethyl acetate 1: 1). b) (4S, 5S) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b) of epoxy alcohol according to a); light yellow oil; IR (Cl ^ Clg): 2780, 2695, 1670, 1620, 1305, 1145, 1110 cm "1; / * lt / j * ° (chloroform, 0.15%) = -158.0 + 6.7 °; Rf = 0.4 (hexane / ethyl acetate 4: 1). c) (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dien

The title compound was prepared analogously to Example Id) of epoxydehyde according to b); light brown oil; Rf 0.61 (hexane / ethyl acetate 3: 2). EXAMPLE 4:

Sodium salt of (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3 ~ hydroxy-2-propylphenoxy) -octa-3 (E), S ^ -diene ^ - il - ^ - thio ^ -oxo ^ H1-benzopyran ^ -carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 3; m.p. 210-212 °, / cUJ / p ° - 30 - (MeOH, 0.18%) = -86.1 + 5.6 ° UV (MeOH): Λ max (£,) = 220 (42820); 235 / sh; 267 (26660); 285 (23760); 320 (15800). EXAMPLE 5:

Methylater (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxyl-2-propylphenoxy) -hex8-3 (Z) -en-2-yl-7 " Thio-4-oxo-: 4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethyl-phenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ena; light yellow thick oil; IcM / 1 ° (MeOH, 0.115%) = 57.4 + 8.7 °; UV (MeOH): Λ max (£) = 220 / sh; 271 (5280); 285 / sh; 320 (2800).

The starting material is prepared e.g. also: a) (2S, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanal

A solution of 1.1 g of oxalyl chloride in 15 ml of methylene chloride is cooled under argon to -65-70 ° and 1.5 g of dimethyl sulfoxide in 5 ml of methylenedichloride are added over 2 minutes. After stirring at -65-70 ° for 10 minutes, 1.7 g (2R, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanol in 15 ml of methylene chloride are added dropwise. After stirring for a further 30 minutes, 4 g of triethylamine were added dropwise, increasing the temperature to -40 °. The temperature was allowed to rise to 0 ° and the reaction mixture was poured onto phosphate buffer (pH 8). The organic phase was separated and the aqueous phase was extracted with methylene chloride. The combined organic extracts were washed twice with brine, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with hexane / ethyl-31 acetate (7: 3) gave the title compound as a colorless oil: IR (methylene chloride): 2820, 1730, 1330, 1165, 1125, 1070 cm ”1.

Rf = 0.36 (hexane / ethyl acetate 3: 2). / ^ ° (chloroform, 0.20%) = 17.5 + 5 °. b) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -6- (4'-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en

The title compound was prepared analogously to Example 1d) of epoxydehyde according to a); light yellow oil; Rf 0.69 (hexane / ethyl acetate 3: 2). EXAMPLE 6:

(1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex3-3 (Z) -en-2-yl-7 sodium salt -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 5; m.p. 222-224 °; // J ^ (MeOH, 0.135%) = 62.2 + 7.4 °. UV (MeOH): Λ) = 267 (22060); 285 (21140); 318 / sh. EXAMPLE 7:

Methylester (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex3-3 (Z) -en-2-yl-7 " thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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 dust from the ground. 69-71 °. - 32 -

The starting material is prepared e.g. also: a) (2R, 3S) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanal

The title compound was prepared analogously to Example 5a) from (2S, 3S) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanol.

Light yellow liquid; IR (CH 2 Cl 2): 2820, 1730 * 1330, 1165, 1130, 1070 cm-1; JU / ^ ° (chloroform, 0.20%) = 0.0 + 5; * *. , 20 ppm // 365 (chloroform, 0.20%) with 475.0 + 5.0 °; Rf = 0, 14 (hexane / ethyl acetate 7: 3). b) (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en

The title compound was prepared analogously to Example 1d) from the corresponding epoxydehyde according to a). Light yellow oil; Rf = 0.43 (hexane / ethyl acetate 3: 2). EXAMPLE 8;

(1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7 sodium salt -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 7; m.p. 239-241 °; / < Jj / 1 ° (methanol, 0.15%) = -60.7 + 6.7 °; UV (methanol): Λ u - max (t) = 216 (44080); 268 (22520); 285 (21640) 320 / sh. 33 - EXAMPLE 9:

(1R, 2S) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene-2 methyl ester -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E ), 5 (Z) -diene; light yellow powder from the ground. 71-72 °; Δ J / l ° = 81.7 + 8.7 ° (MeOH, 0.115%); UV (MeOH): X Ct > = 217 (53680); 235 / sh; 271 (29120); 285 / sh; 325 (13200).

The starting material is prepared e.g. also: a) (2R, 3R) -2,3-epoxy-3- (3-methylphenyl) -propanol

The title compound was prepared analogously to Example 1a) from 3- (3-methylphenyl) -prop-2 (E) -enol; colorless thick oil; IR (CH2Cl2): 3560, 3410, 2880, 2830, 1590, 1050 cm "1; Rf = 0.39 (hexane / ethyl acetate 1: 1); / oW ^ 0 = 38.9 + 5.3 ° (chloroform, 0.19%). b) (4R, 5R) -4,5-epoxy-5- (3-methylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b) of epoxy alcohol according to a); light yellow powder, m.p. 60-61 °; IR (CH2Cl2): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1130 cm "1; Rf = 0.34 (hexane / ethyl acetate 4: 1). c) (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dien

The title compound is prepared analogously to Example Id) from the corresponding epoxydehyde according to a); light yellow oil; Rf = 0.63 (hexane / ethyl acetate 3: 2). - 34 - EXAMPLE TO:

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 9; beige powder from the ground. 217 (dec.); Δ / J / p ° (methanol, 0.15%) = 71.3 + 6.7 °; UV (methanol); λ max (^) = 219 (51520) »234 / sh; 267 (26460); 284 (23280); 322 / sh. EXAMPLE 11:

Methyl ester (1S, 2R) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene-2 -yl-7-thio-4-oxo 4H-1 ~ benzopyran-1-2-carboxylic acid

The title compound was 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; / 20 (MeOH, 0.148%) = -75.7 + 6.8 °; UV (MeOH): Λ max (£) = 217 (51760); 240 / sh; 271 (27860); 290 / sh; 328 (12600).

The starting material is prepared e.g. also: a) (2S, 3S) -2,3-epoxy-3- (3-methylphenyl) -propanol

The title compound was prepared analogously to Example 1a) from 3- (3-methylphenyl) -prop-2 (E) -enol, but using the L (+) tartaric acid diethyl ester; colorless oil; IR (CHpCl?): 3550, 3470, 2940, 2880, 2830, 1590, 1050 cm < -1 > Rf =? * 31 (hexane / ethyl acetate 3: 2). - 35 - b) (4S, 5S) -4,5-epoxy-5- (3-roethylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b) of epoxy alcohol according to a); light yellow oil; IR (CH2 Cl2): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1130, 1085 cm -1. Rf = 0.29 (hexane / ethyl acetate 4: 1). c) (1S, 2S) -1,2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dien

The title compound was prepared analogously to example 1d) of epoxydehyde according to b); light yellow oil; Rf 0.51 (hexane / ethyl acetate 7: 3). EXAMPLE 12:

Sodium salt of (1S, 2R) -1-hydroxyl-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from the corresponding methyl ester of Example 11; m.p. 197-198 °; / cM β / 20 (0.14% methanol) = -72.1 + 7.1 °, UV (MeOH): / max (£) = 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- methyl ester thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was obtained 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 dust from the ground. 136-138 ° / aU / p ° = - 36 - 28.1 + 7.4 ° (methanol, 0.135%) UV (methanol): λ (') = 271 * ”roax ^ (26020; 282 / sh; 323 (13700).

The starting material is prepared e.g. as follows: a) (2S, 3R) -2,3-epoxy-3- (3-flulethylphenyl) -propanal

The title compound was prepared analogously to Example 5a) from (2R, 3R) -2,3-epoxy-3- (3-raethylphenyl) -propanol; light yellow oil; IR (methylene chloride): 2920, 2820, 1730, 1610, 1140, 1070 cnT1; Rj, r 0.49 (hexane / ethyl acetate 3: 2). b) (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en

The title compound was prepared analogously to Example Id) from the corresponding epoxydehyde according to a); light yellow oil; R 4 O 4 (hexane / ethyl acetate 3: 2). EXAMPLE 14:

(1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) - »en-2-yl- sodium salt 7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 13, beige powder from the ground. 238-240 °; fj / 20 (methanol, 0.135%) = 31.1 + 7.4 °; UV (methanol) Λ max (-) = 268 (2ΐ8οο) ϊ 285 (20860); 322 / sh. EXAMPLE 15:

(1R, 2S) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene-2 methyl ester -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid 20-37

The title compound was prepared analogously to Example 1 from (1R, 2R) -1,2-epoxy-1- (3 ~ methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E). 5 (Z) -diene; // β (methanol, 0.14%) = 27.9 + 7.1 °; UV (methanol): X max (£) = 221 (53560); 234 / sh; 270 (28980); 285 / sh; 326 (13860).

The starting material is prepared e.g. as follows: a) (2R, 3R) -2,3-epoxy-3- (3-nitroxycarbonylphenyl) -propanol

The title compound was prepared analogously to Example 1a) from (E) -3-methoxycarbonyl cinnamon alcohol; slightly yellowish oil; Rf = 0.3 (hexane / ethyl acetate 1: 1). b) (4R, 5R) -4,5-epoxy-5- (3-methoxycarbonylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b) from the corresponding epoxy alcohol; light yellow oil; Rf = 0.35 (hexane / ethyl acetate 3: 2). c) (1R, 2R) -1,2-epoxy-1- (3-acetoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dlen

The title compound was prepared analogously to Example 1d) from the corresponding epoxydehyde according to b); thick yellow oil; Rf = 0.50 (hexane / ethyl acetate 3: 2). EXAMPLE 16:

(1R, 2S) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -1-octa-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from - 38 - methyl ester (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid according to Example 15; light brown dust from the ground. 181 (dec.); / < * £ > / p (methanol, 0.15%) = 32.0 + 6.7 °; UV (methanol): λ K) = 222 (51600); ^ 'IuaX ^ 232 / sh; 267 (24160); 284 (22940); 320 / sh; 400 / sh. EXAMPLE 17:

Methyl ester (1S, 2R) -1-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene-2 -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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 ° (colorless powder) / o ^ / p ° (methanol, 0.15%) = -52.7 + 6.7 °; UV (methanol): Λ max (£) = 221 (57420); 235 / sh; 271 (29980); 288 / sh; 326 (14320).

The starting material is prepared e.g. as follows: a) (2S, 3S) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propanol

The title compound was prepared analogously to Example 1a) from (E) -3-methoxycarbonyl cinnamic alcohol, but using the L (+) tartaric acid diethyl ester; colorless oil; Rf = 0.48 (hexane / ethyl acetate 1: 1). b) (4S, 5S) -4,5-epoxy-5- (3-methoxycarbonylphenyl) -pent-2- (E) -enal

The title compound was prepared analogously to Example Ib) from - 39 - the corresponding epoxy alcohol; colorless oil; IR (methylene chloride) · 3050, 2990, 29 ^ 5, 2820, 2730, 1725, 1695, 1640, 1290, 1255 cm < -1 >; Rf = 0.34 (hexane / ethyl acetate 3: 2). c) (1S, 2S) -1t2-epoxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene

The title compound was prepared analogously to Example 1d) from the corresponding epoxydehyde according to b); light yellow oil; Rf = 0.54 (hexane / ethyl acetate 3: 2). EXAMPLE 18

Sodium salt of (1S, 2R) -1-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 17; beige powder from the ground. 174-176 °; (methanol, 0.155%) = -80.6 + 6.5 °; UV (methanol): (fe) = 223 (59300); 235 sh; 267 (27300); 284 (24800); 321

^ / IUclX (16200). 40 - EXAMPLE 19

(1R, 2S) -1-Hydroxy-1- (3-iPethoxycarbonylphenyl) -6- '(4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7 methyl ester -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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; (B / h) = (methanol, 0.11%) = 24.5 + 9.1 °; UV (methanol): /) mav (£) - 270 (22400); 322 (12000).

The starting material is prepared e.g. like this:

a) (2S, 3R) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propane

The title compound was prepared analogously to Example 5a) from (2R, 3R) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propanol; light yellow oil; IR (methylene chloride): 2950, 2820, 1725, 1610 1590, 1430, 1290, 1255 cm -1; Rf = 0.33 (hexane / ethyl acetate 3: 2) b) (1R, 2R) -i, 2-epoxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hek3-3 (Z) -en

The title compound was prepared analogously to Example 1d)

from epoxydehyde according to a); light yellow oil Rf = 0.39 (hexane / ethyl acetate 3: 2). EXAMPLE 20

(1R, 2S) -1-Hydroxy-1- (3-nitroxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7 sodium salt -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid (A) and disodium salt of (1R, 2S) -1-hydroxy-1- (3-carboxyphenyl) -6- (4-acetyl-3- hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid (B)

A solution of 0.5 g of (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2 methyl ester -il-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid according to Example 19 in 20 ml of tetrahydrofuran was stirred under argon for 40 hours with 7.5 ml of 0.2 n sodium hydroxide at room temperature and then evaporated . The residue was purified by chromatography on Lichroprep''0 'RP-8, Merck, with methanol / water (3: 1) to afford the title compound B in fractions 2-5; m.p. 262-264 °; N - (+) (methanol, 0.105%) = 17.1 + 9.5 °; UV (methanol): Λ (&) = 268 (19680), 284 (19060); 325 / sh; and in fractions 8-12 the title compound A; m.p. 155 (dec.); / < ^ / ^ ° (methanol, 0.12%) = 22.5 + 8.3 °; UV methanol): A (6-) = 268 (26200); 286 (29220); 325 / sh. max EXAMPLE 21

(1S, 2R) -1-Hydroxy-1- (3-niethoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7- methyl ester thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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 42 solidifies in the refrigerator, m.p. 90-91 °; A > W20 = -41.5 + 7.7 ° (0.13% methanol); UV (methanol): / \ (f) = 271 (25120); 322 (13280).

The starting material is prepared e.g. as follows: a) (2R, 3S) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propanal

The title compound was 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 / ethyl acetate 3: 2). b) (1S, 2S) -1,2-epoxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en

The title compound was prepared analogously to Example 1d) from the corresponding epoxydehyde according to a); colorless oil, not further characterized. EXAMPLE 22

(1S, 2R) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7 sodium salt -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 21; beige powder from the ground. 208-210 ° / (methanol, 0.12%) = -41.7 + 8.3 °, UV (methanol): ^ max = 268 (21 ° 6 °); 285 (21540); 325 / sh. EXAMPLE 23

Methyl ester (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -uneca-6 (E), 8 (Z) -diene-5 -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1) from

(4R, 5R) -4,5-epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -uneca-6 (E), 8 (Z) -diene; beige powder from the ground. 64-66 °, / e ^ / j · 0 (methanol, 0.15%) = 147.3 + 6.7 °. UV (methanol): λ (t) = 220 (48960); 270 (28500); 283 / sh; 325 (13400).

/ (Yes X

The starting material is prepared e.g. as follows: a) (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanol

The title compound was prepared analogously to Example 1a) of 20 6,6,6-trifluoro-hex-2 (E) -enol; colorless oil; ΔJ / β (chloroform, 0.17%) = 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 title compound was prepared analogously to example ib) from the corresponding epoxy alcohol according to a); light yellow oil; IR (CH2Cl2) 3050, 2980, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm "1; Rf = 0.41 (hexane / ethyl acetate = 3: 2). c) (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) - dien

The title compound was prepared analogously to Example 1d) from epoxy aldehyde according to b); light yellow oil; Rf = 0.48 (hexane / ethyl acetate 3: 2). EXAMPLE 24

Sodium salt of (4R, 5S) -1,1,1-trifluoro-4-hydroxy-n- (4-acetyl-3-hydroxy-2-propylphenoxy) -uneca-6 (E), 8 (Z) -diene- 5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 23; beige powder from the ground. 198-200 °, / J / p ° (methanol, 0.15%) = 127.3 + 6.7 °; UV (methanol): - 44 - > max) ~ 221 (4882 °); 230 / sh; 267 (25440); 285 (23080); 322 / sh. EXAMPLE 25

Methylester (4S, 5R) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -uneca-6 (E), 8 (Z) -diene-5 -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (4S, 5S) -4,5-epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undek-6 (E). 8 (Z) -diene; colorless dust from the ground. 69-71 °; [?] = -153.3 + 6.7 ° (methanol, 0.15%). UV (methanol) A max (£} = 220 (49560); 235 / sh; 270 (29220); 285 / sh; 325 (12990).

The starting material is prepared e.g. as follows: a) (2S, 3S) -2,3-epoxy-6,6,6-trifluoro-hexanol

The title compound was prepared analogously to Example 1a) from 6,6,6-trifluorohex-2 (E) -enol but using the diethyl 20 ester of L (+) tartaric acid; colorless oil; / p (chloroform 0.17%) = -25.9 + 5.9 °; IR (methylene chloride): 3550, 3430, 2940, 2880, 2830, 1125 cnf1. b) (4S, 5S) -4,5-epoxy ~ 8,8,8-trifluoro-oct-2 (E) -enal

The title compound was prepared analogously to Example 1b) from the corresponding epoxy alcohol according to a); light yellow oil; IR (methylene chloride): 3050, 2990, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cnT1; Rf = 0.36 (hexane / ethyl acetate 3: 2). c) (4S, 5S) -4,5-epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) - palm -'45'-

The title compound was prepared analogously to Example 1d) from the corresponding epoxydehyde according to b); light yellow oil. EXAMPLE 26

Sodium salt of (4S, 5R) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propyphenoxy) -uneca-6 (E), 8 (Z) -diene- 5-yl-7-soil-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 25; beige powder from the ground. 201-203 ° (methanol), 0.15%) = -117.3 + 6.7 ° UV (methanol): λπ, αν (£) = 222 (^ 8320); 233 / sh .; 267 (26440); 285 (24440); 330 / sh. EXAMPLE 27

(4R, 5S) -1,1,1-Trifluoro-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxyl) -non-6 (Z) -en-5-yl-7- methyl ester thio-4-oxo-4H-1-benzoplrane-2-carboxylic acid

The title compound was 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) -ene; colorless, thick oil; IR (methylene chloride): 3530, 2920, 2890, 2820, 1720, 1640, 1605, 1585 cm < -1 >.

The starting material is prepared e.g. as a) (2S, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanal

The title compound was prepared analogously to Example 5a) from (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanol; colorless liquid with boiling water. 80-8l ° / 26 mbar: / oO / ^ ° (chloroform, 0.15%) = -10.7 + 6.7 °. b) (4R, 5R) -4,5-epoxy-1,1, 1-trifluoro-9- (4-acetyl-3-hydroxyl-2-propylphenoxy) -non-6 (Z) -en

The title compound was prepared analogously to Example 1d) of epoxydehyde according to a); light yellow oil. EXAMPLE 28

Sodium salt of (4R, 5S) -1,1,1-trifluoro-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

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 27; light yellow powder from the ground. 204-206 °; Go / p ° (methanol, 0.15%) = 42.7 + 6.7 °, UV (methanol):

Amov (ί) = 218 (36920); 268 (20280); 285 (20180); 325 / sh.

DlaX EXAMPLE 29

(5R, 6S) -5 ~ Hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -methyl ester c-7 (Z) -en-6-yl-7-thio-4-oxo- 4H-1-Benzo-pyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) - dodec-7- (Z) -ene; light yellow oil; Rf 0.37 (hexane / ethyl acetate 1: 1).

The starting material is prepared e.g. like this. a) 5- (4-Acetyl-3-hydroxy-2-propylphenoxy) pentyl-triphenyl-phosphonium bromide

The title compound was prepared as in Example 1c) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyl bromide; colorless crystals from the ground. 82-85 °. b) (2S, 3R) -2,3-epoxy-heptanal

The title compound was prepared analogously to Example 5a) ~ -47-'- from (2R, 3R) -2,3-epoxyheptanol; / Jj = -99.4 + 0.1 °. c) (5R, 6R) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodefe-7- (Z) -en

The title compound was prepared analogously to Example Id) of epoxydehyde according to a); light yellow oil. EXAMPLE 30

(5R, 6S) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7 (Z) -en-6-yl-7-soil-4-oxo-4H sodium salt -1-Benzo-pyran-2-carboxylic acids

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 29; m.p. 192-194 °; (m / z) (methanol, 0.125%) - + 5.6 + 8.0 °; UV (methanol): \ (£) = 218 (38000); 268 (22040); 285 (21120); 325 sh. EXAMPLE 31

Methyl ester (5S, 6R) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy)-dodo-7 (Z) -en-6-11-7-thio-4-oxo-4H- 1-Benzo-plran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7- (Z) -ene; light yellow oil; Rf = 0.41 (hexane / ethyl aoetate 1: 1).

The starting material is prepared as follows. a) (2R, 3S) -2,3-epoxy-heptanal

The title compound was prepared analogously to Example 5a) from (2S, 3S) -2,3-epoxy-heptanol; / oO = +104.3 + 0.4 °. b) (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-bidroxy-2-propylphenoxy)-dodec-7 (Z) -en 48

The title compound was prepared analogously to example ld) of epoxydehyde according to a); light yellow oil; Rf = 0.42 (hexane / ethyl acetate 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-4 sodium salt -1-Benzo-pyran-2-carboxylic acids

The title compound was prepared analogously to Example 2 from the corresponding methyl ester according to Example 31. 192-194 °; / c ^ // ^ 0 (methanol, 0.145%) = 0 + 6.9 °; UV (methanol): A (S) = 218 (37060); 268 (21760); 286 (20520); 325 sh. EXAMPLE 33

Methyl ester (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undec-6 (Z) -en-5-yl-7- thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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) - one, light yellow oil; Rf = 0.47 (hexane / ethyl acetate 1: 1).

The starting material is prepared e.g. analogous to Example 1 d) from (2S, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanal; light yellow oil. EXAMPLE 34

(4R, 5S) -1,1,1-Trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undec-6 (Z) -en-5-yl-7 sodium salt -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 33; m.p. 193-195 °; - 49 - / ^ / 2 ° (methanol, 0.135%) = +16.3 + 7.4 °; UV (MeOH): A max (£) = 218 (37380), 267 (21380); 286 (21020); 325 / sh. EXAMPLE 35

Methyl ester (5R, 6S) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dec-7 (Z) -en-6-yl-7-thio-4-oxo- 4H-1-Benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -20 dec-7 (Z) -ene; light yellow oil; / «0 (methanol, 0.135%) = +48.9 + 7.4 °, UV (methanol): X (?) Z 216 (38140); 271 (24040; 285 sh, 322 (12700).

The starting material is prepared e.g. analogous to Example 1d) of (2S, 3R) -2,3-epoxy-heptanal; light yellow oil; Rf = 0.45 (hexane / ethyl acetate 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 title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 35 and converted with hydrochloric acid to free acid; m.p. 58-60 °; Ισ & (methanol, 0.130%) = +36.2 + 7.7 °; UV (methanol): ^ fflax (£) = 218 (35240); 269 (20760); 283 (19800); 330 sh. EXAMPLE 37

Methyl ester (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 50

The title compound was prepared analogously to Example 1 of (5S, 6S) -5,6-epoxy-10 (4-acetyl-3-hydroxy-2-propylphenoxy) - dec-7 (Z) -ene, light yellow oil; / Jj (methanol, 0.115%) = -50.4 + 8.7 °; UV (MeOH): Λ max Φ = 217 (38000), 271 (24100) 285 sh, 321 (12800).

The starting material was prepared analogously to Example 1d) from (2R, 3S) -2,3-epoxy-heptanal; light brown oil; Rf = 0.52 (hexane / ethyl acetate 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-4 sodium salt -1-Benzopyran-2-carboxylic acids

The title compound was prepared analogously to Example 2 from the corresponding methyl ester of Example 37; mp.224-226 °, / o < 7 > 0 (methanol, 0.145%) = -29.0 + 6.9 °; UV (methanol); Λ (< L) = 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-benzene-sulfonamidyl) carboxamide

A solution of 0.20 g (5S, 6R) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dec-7 (Z) -en-6-yl-7-thio- 4-Oxo-4H-1-benzopyran-2-carboxylic acid in 10 ml of methylene chloride was stirred under argon with 60 mg of benzolsulfonamide, 44 mg of 4-dimethyl-aminopyridine and 70 mg of N-ethyl-N, N-diraethylaminopropyl) carbodiimide hydrochloride 24 hours at room temperature. The resulting solution was diluted with 30 ml of methylene chloride, washed twice with 1 n hydrochloric acid and twice with brine, dried over magnesium 51 sulfate and evaporated. Chromatography of the residue on silica gel with methylene chloride / methanol (9: 1) gave the title compound from m.p. 140-142 °. EXAMPLE 40

Methyl ester (4RS, 5SR) -1-methoxycarbonyl-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

The title compound was prepared analogously to Example 1 from (4RS, 5RS) -4,5-epoxy-1-methoxycarbonyl-9- (4-acetyl-3-hydroxy 20 2- propylphenoxy) -non-6 (Z) -ene; colorless oil; lob I ^ (methanol, 0.125%) - 0.0 + 8.0 °, UV (methanol): \ fflax (£) = 270 (24000); 340 (13200).

The starting material is prepared e.g. analogous to Example 1d) of 5,6-epoxy-6-formylhexanoic acid methyl ester; light yellow oil; Rf = 0.35 (hexane / ethyl acetate 3: 2). EXAMPLE 41

Disodium salt of (4RS, 5SR) -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 0.24 g of methyl ester according to Example 40 was dissolved under argon in 15 ml of tetrahydrofuran, 3.8 acre of 0.2 n sodium hydroxide was added and stirred for 20 hours at room temperature. Pairing and cro-mat cleaning of the residue on a quartz gel column " Reversed Phase " (e.g. Merck Lichroprep® '* RP-8) with methanol / water (7: 3) to give the title compound from m.p. 248-250 ° (dec); UV (methanol): λ mQV φ = 218 (33900); 268 (18580); 284 (18240);

DlaX 330 sh. 52 EXAMPLE 42

Methyl ester (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -1-deca-3 (E), 5 (Z) -diene-2 -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -1Q- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E). 5 (Z) -diene; light yellow oil. / cP / ^ ° (CHCl3, 0.363%) = 46.6 + 2.8 ° UV (CHCl3): X in W = 270 (26500); 285 (24240); 322 (15200).

The starting material is prepared e.g. thus, a) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z ) -diene. The title compound was prepared analogously to Example 1d) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyltriphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- (3- trifluoromethylphenyl) - pn pent-2 (E) -enal (Example Ib); light brown oil; / g /// * (CHCl 2, 0.224%) = 70.8 + 10 °, Rf = 0.50 (hexane / ethyl acetate = 1: 1), IR (CH 2 Cl 2): 2960, 2930, 2865, 1735, 1625 , 1330, 1125 cm " 1. EXAMPLE 43

(1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3- (E), 5 (Z) - sodium salt diene-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 of

the corresponding methyl ester (Example 42); m.p. 217-219 °; / o0 (MeOH 0.160%) = 145.6 + 6.3 °, UV (MeOH): λ mav (£) = 220 (50480), 230 (sh), 267 (26240), 284 (23000), 320 ( sh). - 53 - EXAMPLE 44

(1R, 2S) -1-hydroxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene-2 methyl ester -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (IR, 2R) -1,2-epoxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene; m.p. 59-60 °; (B / w) (CHCl3, 0.163%) = 31.9 + 6.1 °; UV (CHC13): Λ max (D = 241 (31420); 286 (23060).

The starting material is prepared e.g. like this. a) (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - dien.

The title compound was prepared analogously to Example 1d) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentylphenylphenyl-phosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- (3- oethylphenyl) -pent-2 (E) -enal (Example 9b); light yellow oil; (CHCl3, 0.273%) = 118.7 ° + 3.7, Rf = 0.62 (hexane / ethyl acetate = 3: 2). EXAMPLE 45

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 44); m.p. 208-210 °; ! < & (MeOH, 0.30%) = 50.7 + 3.3 °. UV (MeOH): \ fflax (f) = 219 (52420), 230 (sh), 267 (26620), 285 (23520), 325 (sh). - 54 - EXAMPLE 46

(1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3 ~ hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -dlen-2 methyl ester -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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 mass; Rf = 0.48 (1: 1 hexane / ethyl acetate).

The starting material is prepared e.g. like this. a) (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - dien.

The title compound was prepared analogously to Example 1d of 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyltriphenylphosphonium bromide (Example 29a) and (4S, 5S) -4,5-epoxy-5- (3-tri - fluoromethylphenyl) -pent-2 (E) -enal (Example 3b); light yellow oil; / o0 / p ° (chloroform, 0.454% = -86.8 + 2.2 °; Rf = 0.46 (hexane / ethyl acetate = 1: 1). IR (methylene chloride): 2960, 2930 * 1730, 1625, 1330 , 1130 cm ”EXAMPLE 47

Sodium salt of (1S, 2R) -1-hydroxy-1- (3-trifluoroethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 of

the corresponding methyl ester (Example 46); m.p. 168-170 °; % (methanol, 0.150%) = -66.7 + 6.7 °; UV (MeOH): X max (£.) = 220 (49640), 230 (sh), 266 (25640), 285 (22140), 320 (sh). 55 EXAMPLE 48

(1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3 > 3 > 3-trifluoropropyl) -phenoxy] -octa-3 methyl ester (E ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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; light yellow oil; Rf = 0.34 (hexane / ethyl acetate = 1: 1). The starting material is prepared e.g. like this. a) (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

The title compound was prepared analogously to Example 1d of 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); light yellow oil; / ob / d ° (chloroform, 0.406%) = -58.6 + 2.5 °; Rf = 0.45 (hexane / ethyl acetate = 7: 3). IR (methylene chloride: 2945, 1670, 1610, 1310, 1055 cm < -1 > b) 3- [4-acetyl-3-hydroxy-2- (3,3 ' -trifluoropropyl) -phenoxy] -propyl-triphenylphosphonium bromide.

The title compound was prepared analogously to Example 1c of 3- (4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy) -propyl bromide. Tal. 184-185 °.

EXAMPLE 49

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -octa-3 ( E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 48); m.p. 238-240 °; (methanol, 0.150%) = 208 + 6.6 °; UV (MeOH): ^ fflax (< ^) = 216 (50040), 230 (sh), 267 (28960), 280 (sh), 320 (16020). EXAMPLE 50

(1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -octa-3 methyl ester (E ), 5 (Z) -diene-2-yl-7-thio-4-oxo-4H-1-benzoprene-2-carboxylic acid

The title compound was 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; light 20 yellow thick oil; R ^. = 0.41 (hexane / ethyl acetate = 1: 1). hk (chloroform, 0.155%) = 32.3 + 6.5 °. UV (chloroform): \ max (£) 271 (32320), 318 (16100).

The starting material is prepared e.g. like this. a) (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

The title compound was prepared analogously to Example 1d of 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), light yellow oil; R ^. = 0.38 (hexane / ethyl acetate = 3: 2). - 57 EXAMPLE 51

(1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3 > 3-trifluoropropyl) -phenoxy] -octa-3 salt ( E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 50); m.p. 233-235 °; (I) (methanol, 0.195%) = 69.7 + 5.1 °; UV (MeOH): λ maY (£) = 218 (52320), 230 (sh), 267 (29040), 280 (sh), 320 (16000). EXAMPLE 52

Methyl ester (1R, 2S) -1-hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dlen -2-11-7-thio-4-ok30-4H-1-benzopyran-2-carboxylic acid

The title compound was 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 °,

Rf = 0.23 (hexane / ethyl acetate = 3: 2). iJj ^ (methanol, 0.150%) = 22.0 + 6.7 °; UV (MeOH): Λ (£) = 216 (50000), 238 (sh), 271 (27860), 285 (sh), 324 (13900).

The starting material is prepared e.g. such, a) (1R, 2R) -1,2-epoxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy N-propyltriphenyl-phosphonium bromide (Example 1c) and (4R, 5R) -4,5-epoxy-5- ( 2-Trifluoromethylphenyl) -pent-2 (E) -enal; light brown oil; (chloroform, 0.207%) = -5.8 + 4.8 °; Rf = 0.25 (hexane / ethyl acetate = 4: 1). - 58 '- b) (4R, 5R) -4,5-epoxy-5- (2-trifluoromethylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b of (2R, 3R) ~ 2,3-epoxy-3- (2-trifluoromethylphenyl) -propanol; yellow 20 crystals; Rf = 0.36 (hexane / ethyl acetate = 4: 1). / o < // D (methanol, 0.165%) = 23.0 + 6.1; UV (MeOH): A max (£) = 216 (14400), 235 (17240). c) (2R, 3R) -2,3-epoxy-3- (2-trifluoromethylphenyl) -propanol

The title compound was prepared analogously to Example 1a from 3- (2-trifluoromethylphenyl) -prop-2 (E) -enol; colorless crystals.

Rj, = 0.38 (hexane / ethyl acetate 3: 2); IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm ”1. EXAMPLE 53

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

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 52); m.p. 155-157 °; (methanol, 0.180%) = 12.8 + 5.6 °; UV (MeOH): λ max (£,) = 219 (48400), 230 (sh), 266 (25480), 284 (22540), 325 (sh). EXAMPLE 54

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

The title compound was prepared analogously to Example 1 from (IS, 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 °

Rf = 0.25 (hexane / ethyl acetate = 3: 2). / ^ /// ^ ° (methanol, 0.170% = 59 -27.1 ± 5.9 °; UV (MeOH): Amax (£) = 216 (51040), 235 (ah), 271 (28140), 285 (sh), 324 (13500).

The starting material is prepared e.g. like this. a) (1S, 2S) -1,2-epoxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -diene.

The title compound was prepared analogously to Example Id of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenyl-phosphonium bromide (Example 1c) and (4S, 5S) -4,5-epoxy-5- ( 2-

PD trifluoromethylphenyl) -pent-2 (E) -enal; reddish oil; / o (// p (chloroform, 0.207%) = 5.4 + 4.8 °; Rf = 0.29 (hexane / ethyl acetate = 4: 1). b) (4S, 5S) -4 , 5-epoxy-5- (2-trifluoromethylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b of (2S, 3S) -2,3-epoxy-3- (2-trifluoromethylphenyl) -propanol; yellow 20 crystals; Rf = 0.38 (4: 1 hexane / ethyl acetate); / p (methanol, 0.180%) = -25.0 + 5.6 °; UV (MeOH): X fflax (£) = 215 (13960), 236 (17060). c) (2S, 3S) -2,3-epoxy-3- (2-trifluoromethylphenyl) -propanol

The title compound was prepared analogously to Example 1a from 3- (2-trifluoromethylphenyl) -prop-2 (E) -enol; colorless crystals = 0.35 (hexane / ethyl acetate = 3: 2). IR (methylene chloride: 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm-1. EXAMPLE 55

(1S, 2R) -1-Hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (2) - dlen-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 of 60 - the corresponding methyl ester (Example 54); m.p. 182-184 °; 0 (methanol, 0.205%) = -16.6 + 4.9 °; UV (MeOH): / i (t) = 219

* “* IQ3X (47680), 235 (sh), 266 (24960), 284 (22100), 330 (sh). EXAMPLE 56

(1R, 2S) -1-Hydroxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene methyl ester -2-yl-7-thio-4-ox3Q-4H-1-benzopyran-2-carboxylic acid

The title compound was 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?

Rf = 0.16 (hexane / ethyl acetate = 3: 2). (% methanol, 0.155%) 110.3 + 6.5 °; UV (MeOH): Λ fflax (£) = 217 (52880), 236 (sh), 270 (28880), 285 (sh), 326 (13700).

The starting material is prepared e.g. like this. a) (1R, 2R) -1,2-epoxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propyl-triphenylphosphonium bromide (Example 1c) and (4R, 5R) -4,5-epoxy-5- (4-tri-fluoromethylphenyl) -pent-2 (E) -enal; yellow oil; / pi // ^ (chloroform, 0.220%) = 6.5 + 4.5 °; Rf = 0.35 (hexane / ethyl acetate = 4: 1). b) (4R, 5R) -4,5-epoxy-5- (4-trifluoromethylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b of (2R, 3R) -2,3-epoxy-3- (4-trifluoromethylphenyl) -propanol; yellow crystals; m.p. 67-70 °. Rf = 0.24 (hexane / ethyl acetate = 4: 1). / JJ / p ° (methanol, 0.150%) = 171.3 + 6.7 °; UV (MeOH): Λ max < £ > 237 (19660). 61 c) (2R, 3R) -2,3-epoxy-3- (4-trifluoromethylphenyl) -propanol

The title compound was prepared analogously to Example 1a from 3- (4-trifluoromethylphenyl) -prop-2 (E) -enol; colorless crystal}

Rf = 0.25 (hexane / ethyl acetate = 3: 2). IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm " 1. EXAMPLE 57

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

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 56); m.p. 229-231 °; (c) methanol, 0.160% = 118.8 + 6.3 °; UV (MeOH): Λ max (£) = 220 (53060), 235 (sh), 267 (27280), 284 (23880), 320 (16300). EXAMPLE 58

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

The title compound was 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? or \

Rj, = 0.13 (hexane / ethyl acetate = 3: 2). (methanol; 0.155%) = -109.7 + 6.5 °; UV (MeOH): A max (£) = 217 (52640), 235 (sh), 270 (28660), 285 (sh), 326 (13680).

The starting material is prepared e.g. such, a) (1S, 2S) -1,2-epoxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium 62 bromide (Example 1c) and (4S, 5S) -4,5-epoxy-5- (4 -trifluoromethyl-phenyl) -pent-2 (E) -enal; reddish oil; / o /// ^ (chloroform, 0.199%) = -5.4 + 5.0 °; R ^. = 0.23 (hexane / ethyl acetate = 4: 1). b) (4S, 5S) -4,5-epoxy-5- (4-trifluoromethylphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b of (2S, 3S) -2,3-epoxy-3- (4-trifluoromethylphenyl) -propanol; yellow crystals; m.p. 67-69 °. Rf = 0.18 (hexane / ethyl acetate = 4: 1), (J) / p ° (raetandl, 0.150%) = -180.0 + 6.7 °; UV (MeOH): / max (£) 236 (19740). c) (2S, 3S) -2,3-epoxy-3- (4-trifluoromethylphenyl) -propanol

The title compound was prepared analogously to Example 1a from 3- (4-trifluoromethylphenyl) -prop-2 (E) -enol; colorless crystals; Rf = 0.23 (hexane / ethyl acetate = 3: 2. IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm-1. EXAMPLE 59

(1S, 2R) -1-Hydroxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa salt (3 (E), 5 (Z) - dlen-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 58); m.p. 228-230 °; / (methanol, 0.175%) = -99.4 + 5.7 °; UV (MeOH): λ mav (D = 220 (49800), 235 (sh), 267 (25320), 284 (22200), 320 (15600). EXAMPLE 60

(1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (Z) -en-2-ylmethyl ester 7-Thio-4-oxo-4H-1-benzoprene-2-carboxylic acid - 63 -

The title compound was prepared analogously to Example 1 from (IR, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (Z ) -ena; colorless oil; R ^. = 0.41 (hexane / ethyl acetate = 1: 1). / cC / j ^ 0 (chloroform, 0.150%) = 46.7 - * · 6.7 °; UV (MeOH): Λ (£) = 271 (22760), 288 (20060), 270 (28880), 324 (14460).

The starting material was prepared as follows: a) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (Z ) -en

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (2S, 3R) -2,3-epoxy-3- ( 3-Trifluoromethylphenyl) -propanal (Example 5a); light yellow oil; / o (chloroform, 0.221%) = 25.3 + 4.5 °; Rf = 0.56 (hexane / ethyl acetate = 3 *. 2). EXAMPLE 61

(1R, 2S) -1-Hydroxyl-1- (3-trifluoromethylphenyl) -8- (4-aoethyl-3-hydroxyl-2-propyl-phenoxy) -octa-3 (Z) -en-2-yl sodium salt -7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 60); m.p. 231-233 °; / o (/ (methanol, 0.190%) = 51.1 + 5.3 °; UV (MeOH): λ maY (E) with 215 (42320), 267 (22220), 286 (20800), 320 (sh EXAMPLE 62

(1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -9- (N-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene-2 methyl ester -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid - 64 -

The title compound was 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; light yellow thick oil; / o < / > (chloroform, 0.155%) = 44.5 6.5 °; Rf = 0.50 (hexane / ethyl acetate = 1: 1); UV (CHCl,: (£) = 270 (26800), 284 (23100), 323 (14480).

The starting material is prepared e.g. like this. a) 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) butyl-triphenyl-phosphonium bromide

The title compound was prepared analogously to Example 1c of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) butyl bromide.

Tal. 167-169 °. b) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona- (3 (E), 5 (Z) -dien

The title compound was prepared analogously to Example 1d of 5_ (4_acetyl-3-hydroxy-2-propylphenoxy) butyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) - 20 pent-2 (E) -enal (Example Ib); light yellow oil; / < X / ^ (chloroform, 0.308%) = 40.7 + 3.2 °; R f = 0.70 (hexane / ethyl acetate = 3: 2); IR (methylene chloride): 2950, 2860, 1625, 1325, 1120 cm 1. EXAMPLE 63

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 of the ΛO Λ of the corresponding methyl ester (Example 62); m.p. 204-206; / CX (chloroform, 0.289%) = 8.0 + _ 3.5 °; / = 55.5 + 6.5 ° (methanol,

0.155%); UV (methanol): Amax ^) = 219 (49320), 232 (sh), 266 (25800), 285 (22060), 330 (sh). EXAMPLE 64

Methylester (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) -diene-2 -yl-7-soil-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E). 5 (Z) -diene, light yellow thick oil; / < * / ^ ° (chloroform, 0.160%) = 48.1 + 6.3 °; Rf = 0.50 (hexane / ethyl acetate = 1: 1). UV (CHClO: λ (£) = 270 (27120), 286 (23300), 323 (14740).

The starting material is prepared e.g. like this. a) 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) hexyl-triphenylphosphonium bromide

The title compound was prepared analogously to Example 1c of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) hexyl bromide; the compound crystallizes very slowly. b) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) - dien

The title compound was prepared analogously to Example 1d of 5- (4-acetyl-3-hydroxy-2-propylphenoxy) hexyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) - 20 pent-2 (E) -enal (Example 1b); light yellow oil; / p (/ D (chloroform, 0.450%) = 41.1 + 2.2 °; Rf = 0.66 (hexane / ethyl acetate = 3: 2); IR methylene chloride): 2960, 2860, 1625, 1325. 1120 cm " 1. - 66- EXAMPLE 65

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -uneca-3 (E), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 64); m.p. 216-218 °; / (chloroform, 0.258%) - 34.9 + 3.9 °; Δ X / p ° = 73.8 + 6.3 ° (methanol, 0.160%); UV (methanol): v (£) = 219 (50140), 232 (sh), 266 (26120), 286 (22460), 320 (15600). EXAMPLE 66

Methylester (1R, 2S) -1-hydroxy-1-phenyl-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

The title compound was prepared analogously to Example 1 from (1R, 2R) -1,2-epoxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 ( Z) -diene; light yellow foam; Rf = 0.41 (hexane / ethyl acetate = 1: 1); = 47.3 + 2.6 ° (chloroform, 0.385%).

The starting material is prepared e.g. such, a) (1R, 2R) -1,2-epoxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) - dien

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3 "hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1c) and (4R, 5R) -4,5-epoxy-5-phenyl -pent-2 (E) -enal; light yellow oil; R f = 0.60 (hexane / ethyl acetate = 3: 2). h) (4R, 5R) -4,5-epoxy-5-phenyl-pent-2 (E) -enal

The title compound was prepared analogously to Example 1b of - 67 - (2R, 3R) -2,3-epoxy-3-phenyl-propanol; yellow oil which, if left standing, crystallizes; Rf = 0.38 (hexane / ethyl acetate = 3: 2) / C < / RTI > = 185 + 5.0 °, (chloroform, 0.200%). g) (2R, 3R) ~ 2,3-epoxy-3-phenyl-propanol

The title compound was prepared analogously to Example 1a from 3-phenyl-prop-2 (E) -enol; a colorless oil which crystallizes in cold. R ^. = 0.49 (hexane / ethyl acetate = 1: 1); IR (methylene chloride) 3590, 3040, 2980, 2920, 2870, 1605, 1080, 1070 cm @ -1. / o C / * (chloroform, 0.279%) = 47.7 + 3.6 °. EXAMPLE 67

Sodium salt of (1R, 2S) -1-hydroxy-1-phenyl-8- (4-acetyl-3-hydroxy 2-propyl-phenoxy) -octa-3 (E), 5 (Z 1 -diene-1-yl) -thio - ^ - oxo ^ H1-benzopyran ^ -carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 66); m.p. 219-221 °; / 0 (/ ^ ® (chloroform, 0.160%) = 103.1 + 6.3 °; UV (methanol): λ (£) = 221 (51180), 232 (sh), 267 (27040), 284 (23840) ), 321 (16200); UV (chloroform: A mav (s) = 274 (26080), 286 (sh), 330 (sh).

Ul0A

EXAMPLE 68

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

The title compound was 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 prepared e.g. also: a) 3- (3-acetyl-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 methylethylketone 6.2 g of potassium carbonate and 0.5 g of potassium iodide are added. The reaction mixture was heated to reflux for 24 hours. It is then poured onto 300 ml of ice water, acidified with hydrochloric acid and extracted with dichloromethane (3 x 150 ml). The combined extracts were washed with 50 ml of water and dried over sodium sulfate. After filtration and evaporation in vacuo, the residue is chromatographed on dichloro-methane on 400 g of silica gel. In the first fraction, the title compound is obtained, which is obtained after evaporation in the form of light yellow crystals from the ground. 69 to 70 °. b) 3- (3-acetyl-4-hydroxy-5-propyl-phenoxy) propyl-triphenyl-phosphonium bromide

The title compound was prepared analogously to Example 1c) from 3- (3-acetyl-4-hydroxy-5-propyl-phenoxy) propyl bromide and triphenylphosphine; m.p. 103 to 105 °. 69 - c) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene

The title compound was prepared analogously to Example 1d) from 3 < 3-acetyl-4-hydroxy-5-propyl-phenoxy) propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal; Rf = 0.54 (hexane / ethyl acetate, 2: 1). EXAMPLE 69:

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

The title compound was prepared analogously to Example 2 from methyl (1R, ZSJ-1-hydroxy-1-S-trifluoromethylphenyl-N- acetyl-hydroxy-S-propyl-phenoxy-octa-SiE), 5 (Z) -diene- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; yellow foam; 1 H-NMR (CD 3 OD): δ = 7.91, 7.76-7.56, 7.50, 7.36, 7.05, 6.82, 6.41, 6.00, 5.75, 5 , 47, 5.12, 4.45, 3.78, 2.65-2.35, 1.88, 1, 58, 0.94 ppm. EXAMPLE 70:

(1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene methyl ester -2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (1R, 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 °; / o < L / p0 (chloroform, 0.215%) - 51.2 + 4.7 °; UV (chloroform): max (^ *) = 271 (28160), 285 (sh), 321 (15380). 70 -

The starting material is prepared e.g. also: a) (1R, 2R) -1,2-epoxy-1- (3-chlorophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E) , 5 (Z) -diene.

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1c) and (4R, 5R) -4,5-epoxy-5- ( 3-chlorine-

p A phenyl) -pent-2 (E) -enal; light yellow oil; / a ^ / * (chloroform, 0.541%) = 63.9 + 1.8 °. b) (4R, 5R) -4,5-epoxy-5- (3-chlorophenyl) -pent-2 (E) -enal.

The title compound was prepared analogously to Example 1b of (2R, 3R) -2,3-epoxy-3- (3-chlorophenyl) -propanol; dark yellow 20 oil; Rf = 0.23 (hexane / ethyl acetate = 4: 1). / oC / p (chloroform, 0.30%) = 184.7 + 3.3. c) (2R, 3R) -2,3-epoxy-3- (3-chlorophenyl) -propanol.

The title compound was prepared analogously to Example 1a of 3- (3-chlorophenyl) -prop-2 (E) -enol; light yellow oil; R ^. = 0.22 (hexane / ethyl acetate = 7: 3). IR (methylene chloride): 3580, 3040, 2980, 2910, 2860, 1600, 1570, 1070 cm < -1 >, o & p0 (chloroform, 0.334%) = 47.3 + 3.0 °. EXAMPLE 71:

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -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

The title compound was prepared analogously to Example 2 of

p Q of the corresponding methyl ester (Example 70); m.p. 217-9 °; δ / p * 71 (methanol, 0.160%) = 107.5 + 6.3 °; UV (methanol): ^ max (£) = 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-phenoxyl) -deca-3 (E), 5 (Z) -diene methyl ester -2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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 °. (chloroform, 0.170%) = 52.9 + 5.9 °; UV (chloroform): X max (f) = 271 (27120), 286 (24800), 322 (15400).

The starting material is prepared e.g. also: a) (1R, 2R) -1,2-epoxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E) , 5 (Z) -diene

The title compound was prepared analogously to Example Id of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- ( 3-chloro-phenyl) -pent-2 (E) -enal (Example 70b); light yellow oil; / c * / p0 (chloroform, 0.391%) = 61.4 + 2.5 °. EXAMPLE 73:

Sodium salt of (1R, 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

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 72); m.p. 204-206 °; (B / c) 72 - (methanol, 0.205%) = 58.5 + 4.9 °; UV (MeOH): / max (£) = 218 (27940), 267 (13140), 285 (11600), 320 (sh). EXAMPLE 74:

(1R, 2S) -1-Hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxyl) -octa-3 (E), 5 (Z) -diene methyl ester -2-yl-7-thio-4-ox3Q-4H -1? Benzopyran-2-carboxylic acid

The title compound was 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 °, UV (chloroform: λ m (f) = 271 (30360), 285 (sh), 323 (16600).

The starting material is prepared e.g. also: a) (1R, 2R) -1,2-epoxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy 2-propyl-phenoxy) -octa-3 (E). 5 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1c) and (4R, 5R) -4,5-epoxy-5- ( 3-meto-

Of \ xiphenyl) -pent-2 (E) -enal; light yellow oil; M / z (chloroform, 0.315%) = 78.4 + 3.2. b) (4R, 5R) -4,5-epoxy-5- (3-methoxyphenyl) -pent-2 (E) -enal

The title compound was prepared analogously to Example 1b of (2R, 3R) -2,3-epoxy-3- (3-methoxyphenyl) -propanol; yellow 20 oil; Rf = 0.41 (hexane / ethyl acetate = 3: 2); (chloroform, 0.567%) = 168.9 + 1.8 °. c) (2R, 3R) -2,3-epoxy-3- (3-n-ethoxyphenyl) -propanol

The title compound was prepared analogously to Example 1a of 3- (3-methoxyphenyl) -prop-2 (E) -enol; light yellow oil; Rf = 73 - 0.31 (hexane / ethyl acetate = 3: 2). IR (methylene chloride): 3550, 2890, 1580, 1565, 1465, 1445, 1130 cm “1. EXAMPLE 75:

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

The title compound was prepared analogously to Example 2 from Λ Pfi of the corresponding methyl ester (Example 74); m.p. 206-208; / oC / p (methanol, 0.293%) = 99.7 + 3.4 °; UV (methanol): X Μχ ({) = 221 (57840), 235 (sh), 268 (29360), 282 (26400), 320 (16800). EXAMPLE 76: 1

Methylester (IR, 2S) -1-hydroxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxyl-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -diene -2-yl-7-soil-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (1R, 2R) -1,2-epoxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxy-74-oil; / ο (/ 2ΌΌ (chloroform) , 0.375%) = 72.5 + 2.7 EXAMPLE 77:

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-fluoxyphenyl) -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

The title compound was prepared analogously to Example 2 from rt pn of the corresponding methyl ester (Example 76); m.p. 187-8; (methanol, 0.150%) = 72.0 + 6.7 °; UV (methanol): ^ max (f) = 222 (55780), 268 (27820), 282 (25200), 321 (16200). EXAMPLE 7 &:

(1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluorooethyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) -dien-2-methyl methyl ester -7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoro-acetyl-3-hydroxy-phenoxy) -octa-3 (E). 5 (Z) -diene; Rf = 0.23 (hexane / ethyl acetate 3: 2).

The starting material is prepared e.g. also: a) 3- (4-Trifluoroacetyl-3-hydroxy-phenoxy) propyl bromide

The title 3 compound was prepared analogously to Example 68a from 2,4-dihydroxytrifluoroacetophenone and obtained as a light yellow oil; IR (dichloromethane): 3150, 2940, 1645, 1625, 1380, 1210, 1150, 1125, 1020, 940 cm " 1. b) 3- (4-Trifluoroacetyl-3-hydroxy-phenoxy) propyl-triphenyl-phosphonium bromide - 75 -

The title compound was prepared analogously to Example 1c of 3- (4-Trifluoroacetyl-3-hydroxy-phenoxy) propyl bromide and triphenylphosphine; m.p. 125-130 ° C. o) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoro-acetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) - dien

The title compound was prepared analogously to Example 1d of 3- (4-trifluoroacetyl-3-hydroxy-phenoxy) propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal; Rf = 0.56 (hexane / ethyl acetate 2: 1). EXAMPLE 79:

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) -dlen-2- il-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid To a solution of 708 mg of methyl ester of the title compound (cf. Example 78) in 25 ml of tetrahydrofuran cooled to 10 ° C was added 10 ml of 0.1 N of aqueous sodium hydroxide. The reaction mixture was stirred for 24 h at room temperature, the solvent removed in vacuo and the residue taken up in water. After clear filtration, the solution was lyophilized. The title compound is obtained as an olive green, amorphous powder. 1 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:

(1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) -1-octa-3 (E), 5 (Z) -diene methyl ester -2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid - 76 -

The title compound was 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 / ethyl acetate 5: 1).

The starting material is prepared e.g. also: a) 3- (4-Trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) propyl bromide

The title compound was prepared analogously to Example 68a from 2,4-dihydroxy-3-propyl-trifluoroacetophenone and obtained 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 title compound was prepared analogously to Example 1c from 3_ (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) propyl bromide and triphenylphosphine; m.p. 170-190 ° C. c) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoro-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoro- methylphenyl) -pent-2 (E) -enal; Rf = 0.55 (hexane / ethyl acetate 2: 1). EXAMPLE 81:

Sodium salt of (1R, 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-carboxylic acid - 77 - To a solution of 500 mg methyl ester of the title compound (compare Example 80) in 20 ml of tetrahydrofuran, cooled to 10 ° C , 6.6 ml of 0.1 N aqueous sodium hydroxide solution is added. The reaction mixture was stirred for 1 h at 10 ° C, tetrahydrofuran was removed in vacuo and the remaining solution lyophilized. The title compound is obtained as a yellow-green, amorphous powder; 1 H-NMR (CD 2 OD): S = 7.93, 7.77-7.60, 7.50, 7.36, 6.92, 6.43, 6.04, 5.73, 5. 47, 5.13, 4.47, 4.00, 2.50, 2.38, 0.72 ppm. EXAMPLE 82:

(1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E), 5 (Z) -diene methyl ester -2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared 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 / ethyl acetate 3: 2).

The starting material is prepared e.g. also: a) 3- (4-acetyl-3-hydroxy-2-propyl-phenylthio) propyl bromide

The title compound was prepared analogously to Example 68a from 2-hydroxy-4-mercaptoacetophenone: light yellow oil. b) 3- (4-acetyl-3-hydroxy-2-propyl-phenylthio) propyl-triphenyl-phosphonium bromide

The title compound was prepared analogously to Example 1 from 3- (4-acetyl-3-hydroxy-2-propyl-phenylthio) propyl bromide and triphenylphosphine.

c) (1R, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E), 5 (Z ) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenylthio) propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) - pent-2 (E) -enal. EXAMPLE 83:

Sodium salt of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E) t 5 (Z) - dien-2-yl-7-soil-4-oxo-4H-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 82). EXAMPLE 84:

Methyl ester (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -deca-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo-4H-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (1R, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -deca-3 (E ), 5 (Z) -diene; R ^. = 0.17 (hexane / ethyl acetate 3: 2).

The starting material can be prepared e.g. also: a) 5- (4-acetyl-3-hydroxy-2-propyl-phenylthio) pentyl bromide

The title compound was prepared analogously to Example 68a from 2-hydroxy * 4-mercapto-acetophenone; light yellow oil. --7Ϋ b) 5- (4-Acetyl-3-hydroxy-2-propyl-phenylthio) pentyl-triphenyl-phosphonium bromide

The title compound was prepared analogously to Example 1 from 5- (4-acetyl-3-hydroxy-2-propyl-phenylthio) pentyl bromide and triphenylphosphine. c) (1R, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -deca-3 (E), 5 (Z ) -diene

The title compound was prepared analogously to Example 1d of 5- (4-acetyl-3-hydroxy-2-propyl-phenylthio) pentyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) - pent-2- (E) -enol. EXAMPLE 85:

(1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenylthio-deca-3 (E), 5 (Z) -diene sodium salt -2-yl-7-thio-4-oxo-4H-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 84). EXAMPLE 86:

Methyl ester (5R, 6S) -1,1,1-trifluoro-5-hydroxy-12- (4-acetyl-3-hydroxyl-2-propyl-phenoxy) -deca-7 (E), 9 (Z) -diene -6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E ), 9 (Z) -diene; light yellow foam;

Rf = 0.24 (hexane / ethyl acetate = 3: 2).

The starting material is prepared e.g. so-le: ...... -: se -'- ------ a) (2R, 3R) -2,3-epoxy-7,7,7-trifluoro-heptanol

The title compound was prepared analogously to Example 1a of 7,7,7-trifluoro-hept-2 (E) -enol; light yellow oil; Rf = pn 0.38 (hexane / ethyl acetate = 3: 2). / < * / £ (chloroform, 0.490%) = 15.3 + 2.0 °. IR (methylene chloride): 3550, 3430, 2900, 1180, 1125 cm-1. b) (4R, 5R) -4, 5-epoxy-9,9,9, -trifluoro-non-2 (E) enal

The title compound was prepared analogously to Example 1b from (2R, 3R) -2,3-epoxy-7,7,7-trifluoro-heptanol; oil which crystallizes in the refrigerator. Rf = 0.63 (hexane / ethyl acetate = 1: 1). / c < / > (chloroform, 0.210%) r 19.5 + 4.8 °. c) (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E), 9 (Z ) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyltriphenyl-phosphoene bromide (Example 1c) and (4R, 5R) -4,5-epoxy-9,9 , 9-tri-fluoro-non-2 (E) -enal; yellow oil; R f = 0.56 (hexane / ethyl acetate = 3: 2). EXAMPLE 87:

(5R, 6S) -1,1,1-Trifluoro-5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) - sodium salt dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 86); m.p. 190-191 °; / «F / p (methanol, 0.268% = 105.2 + 3.7 °; UV (methanol): -λ __„ (£) = 222 (48800), 235 (sh), 267 (25920), 285 ( 22920), 320 (16000).

EXAMPLE 88:

(4R, 5S) -1,1,1-Trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -trideca-6 (E), 8 (Z) -diene methyl ester -5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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 prepared e.g. also: a) (4R, 5R) -4,5-epoxy-8,8,8-trifluoro-oct-2 (E) -enal

The title compound was prepared analogously to Example 1b of (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanol; a light yellow oil which crystallizes in the refrigerator; R f = 0.53 (hexane / ethyl acetate = 3: 2). / o C / 0 (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 title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-8,8 , 8-trifluoro-oct-2 (E) -enal; yellow oil; Rf = 0.69 (hexane / ethyl acetate = 3: 2). EXAMPLE 89:

(4R, 5R) -1,1,1-Trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E), 8 (Z) -dlen- sodium salt 5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid ...... -'32 '-

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 88); m.p. 150-152; / 0 (/ £ (methanol, 0.265%) = 72.5 + 3.8 °; UV (methanol): λΒβχ (£) = 221 (44680), 231 (sh), 266 (22560), 285 (20560) , 330 (sh). EXAMPLE 90:

Methyl ester (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-6 (E), 8 (Z) -diene -5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-6 (E ), 8 (Z) -diene; yellow oil; Rf = 0.31 (hexane / ethyl acetate = 3: 2).

The starting material is prepared e.g. also: a) (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-6 (E) , 8 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) butyl-triphenylphosphonium bromide (Example 62b) and (4R, 5R) -4,5-epoxy-8,8 , 8-trifluoro-oct-2 (E) -enal (Example 88a); yellow oil; Rf = 0.64 (3: 2 hexane / ethyl acetate). EXAMPLE 91:

(4R, 5S) -1,1,1-Trifluoro-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E), 8 (Z) - sodium salt dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 90); m.p. 180-182 °; - - ·, sy- ------ / o ^ / § ° (methanol, 0.292) = 77.1 + 3.4 °; UV (Methanol): λΜχ (£) = 222 (47480), 231 (sh), 267 (24840), 285 (22120), 321 (15800). EXAMPLE 92:

Methyl ester (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E), 9 (Z) -dien-5-yl-7-thio -4-Oxo-4H-1-benzo-pyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E), 9 (Z) -diene ; light yellow foam; Rf = 0.43 (hexane / ethyl acetate = 1: 1); (oC / C (methanol), 0.150%) - 22.0 + 6.7 °; IR (methylene chloride): 3580, 2950, 1745, 1655, 1625, 1600 cm “1. The starting material is prepared e.g. also: a) (4R, 5R) -4,5-epoxy-non-2- (E) -enal

The title compound was prepared analogously to Example 1b from (2R, 3R) -2,3-epoxyheptanol; yellow oil; R ^. = 0.29 (hexane / ethyl acetate = 4: 1); / o < / (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-propyl-phenoxy) -deca-7 (E), 9 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1c) and (4R, 5R) -4,5-epoxy-non-2 ( E) - 20 equals; light yellow oil; / oO ^ (chloroform, 0.650%) = 23.7 EXAMPLE 93:

Sodium salt of (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E), 9 (Z) -dien-6-yl-7- thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 92); m.p. 205-207 °; nol, 0.278%) = 115.1 + 3.6 °; UV (methanol): j \ (£) - 222 (50960), 232 (sh), 267 (27400), 285 (24000), 321 (16400). EXAMPLE 94;

(5R, 6S) -5-Bidroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E), 9 (Z) -dien-6-yl-7-thiomethyl ester -4-Oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) - 20 dodeca-7 (E), 9 (Z) - diena; colorless foam; / PC / D (methanol, 0.260%) = 136.2 + 3.8 °; UV (methanol): λ (9) = 221 (48040), 271 (28320), 327 (13200).

The starting material is prepared e.g. also: a) (4s, 5S) -4,5-epoxy-non-2 (E) -enal

The title compound was prepared analogously to Example 1b from (2S, 3S) -2,3-epoxy-heptanol; yellow oil; R ^. = 0.27 (hexane / ethyl acetate = 5: 1; N or N (° chloroform, 0.325%) = 23.1 + 3.0 °. B) (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E), 9 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyltriphenylphosphonium ...... - '85' - 'bromide (Example 1c) and ( 4S, 5S) -4,5-epoxy-non-2 (E) -en-1a; light yellow oil; (chloroform, 0.600%) = 24.8 + 1.6 °. EXAMPLE 95:

Sodium salt of (5S, 6R) -5-hydroxy-12- (4-acetyl-3'-hydroxy-2-pyrrol-phenoxy) -deca-7 (E), 9 (Z) -dien-6-yl -7-Thio-4-oxo-4H-1-benzo-pyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 94); m.p. 204-206 °; / < X / p ° (methanol, 0.570%) = 121.1 + 1.8 °; UV (methanol): λ (£) = 22 2 (51240), 235 (sh), 267 (27360), 284 (21400), 320 (16400). EXAMPLE 96:

Methylester (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-benzo-pyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) - 20

tetradeca-7 (E), 9 (Z) -diene; light yellow thick oil; / eC / D (chloroform, 0.424%) = 66.5 + 2.4 °; UV (chloroform); λ (£) = - max 270 (28560), 288 (sh), 325 (15240).

The starting material is prepared e.g. also: a) (5R, 6R) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-non-2 (E) - " - 8ο - en π ala nala (Example 92a) light yellow oil; (chloroform, 0.441%) = 20.6 + 2.3 °. EXAMPLE 97:

Sodium salt of (5R, 6S) -5-hydroxy-1- (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

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 96); m.p. 193-195 °; (methanol, 0.284%) = 71.1 + 3.5 °. UV (methanol): X (f) = 222 (49320), 232 (sh), 267 (25520), 286 (22680), 321 (16000). EXAMPLE 98:

Methyl ester (5S, 6R) -5-hydroxy-1-4- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7-thio -4-Oxo-4H-1-benzo-pyran-2-carboxylic acid

The title compound was prepared analogously to Example 1 from (5S, 6S) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene ; light yellow tough mass; / te / and ° (chloroform, 0.463%) = 79.0 + 2.2 °. UV (chloroform): av mav. (^) = 270 (27120), 288 (sh), 326 (14960).

The starting material is prepared e.g. also: a) (5S, 6S) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4S, 5S) -4,5-epoxy-non-2 (E) - 20 ...... '--87- - ----- enala (Example 94a); light yellow oil; (chloroform, 0.472%) = 18.8 + 2.1 °. EXAMPLE 99;

(5S, 6R) -5-Hydroxy-1- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7- sodium salt thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 98); m.p. 193-195 °; (meta nol, 0.296%) = 65.9 + 3.4 °. UV (methanol): λ mav (£) = 222 (49760), 232 (sh), 267 (25800), 285 (22520), 320 (16000). EXAMPLE 100:

Methyl ester (5R, 6S) -1,1,1-trifluoro-5-hydroxy-14- (4-aoethyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene -6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid

The title compound was 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; light yellow oil; Rf = 0.32 (hexane / ethyl acetate = 3: 2).

The starting material is prepared e.g. also: a) (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-1- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E) , 9 (Z) -diene

The title compound was prepared analogously to Example 1d of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-9,9 , 9-tri-fluoro-non-2 (E) -enal (Example 86b); yellow oil; Rf = 0.72 (hexane / ethyl acetate = 3: 2). EXAMPLE 101:

Sodium salt of (5R, 6S) -1t1t1-trifluoro-5-hydroxy-1-4- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene-6- yl-7-thio-4-oxo-4H-1-benzopyran-2- "carboxylic acid

The title compound was prepared analogously to Example 2 from the corresponding methyl ester (Example 100); UV (methanol); = 222 (48800), 235 (sh), 267 (25920), 285 (22920), 320 (16000). EXAMPLE 102:

The (1R, 2S) -1-hydroxy-1-phenyl-11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) sodium salt can be further prepared in an analogous manner as described in Examples 1 to 77 ) -undeca-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-Hydroxy-1-phenyl-10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -diene-2- sodium salt yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1-phenyl-9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z) -diene-2- sodium salt yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) nona-3 (E) t5 (, z) - sodium salt dien-2-yl-7-oxo-4H-1-benzopyran-2-carboxylic acid; • -89- Sodium salt of (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -undek-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-Hydroxy-1- (3-fluorophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (3-fluorophenyl) -9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (3-fluorophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; sodium salt of (1R, 2S) -1-hydroxy-1- (3-fluorophenyl) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -undeca-3 (E), 5 (Z) - dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-Hydroxy-1- (3-methoxyphenyl) -9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-Hydroxy-1- (3-methoxyphenyl) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -unedeca-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; -'90- ·· - di-sodium salt of (1R, 2S) -1-hydroxy-1- (3-carboxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; di-sodium salt of (1Rf2S) -1-hydroxy-1- (3-carboxyphenyl) -9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z) - diene-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; di-sodium salt of (1R, 2S) -1-hydroxy-1- (3-carboxyphenyl) 7-10- (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; di-sodium salt of (1R, 2S) -1-hydroxy-1- (3-carboxyphenyl) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -undek-3 (E), 5 (Z ) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (3-ethoxycarbonylphenyl) -9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z) sodium salt -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (3-ethoxycarbonylphenyl) -10 (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-Hydroxy-1- (3-Ethoxycarbonylphenyl) -11 (4-acetyl-3-hydroxy-2-propyl-phenoxy) -unedek-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; - 9-1 Sodium salt of (1R, 2S) -1-hydroxy-1- (3,4-dichlorophenyl) -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; (1R, 2S) -1-Hydroxy-1- (2,4-dichlorophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) sodium salt ) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (3,4-dimethoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) sodium salt ) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (2,4-dimethoxyphenyl) -10- (4-acetyl-3-bidroxy-2-propyl-phenoxy) -deca-3 (E) sodium salt, 5 (Z ) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; sodium salt of (1R, 2S) -1-hydroxy-1- (2,4-dimethylphenyl) -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; (1R, 2S) -1-hydroxy-1- (3-dimethylaminophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid, - 92 - EXAMPLE 103:

In an analogous manner as described in Examples 1 to 101; the following compounds can be further prepared: (1R, 2S) -1-hydroxy-1- (3-bromophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E) sodium salt , 5 (Z) -Dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-hydroxy-1- (3-bromophenyl) -9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-Hydroxy-1- (3-bromophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (1R, 2S) -1-Hydroxy-1- (3-bromophenyl) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -unedeca-3 (E), 5 (Z) - sodium salt dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (5R, 6S) -1,1,1-Trifluoro-5-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-7 (E), 9 (Z) -diene- sodium salt 6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (5R, 6S) -1,1,1-Trifluoro-N-5-hydroxy-15- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentadeca-7 (E), 9 (Z) -diene sodium salt -6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; - 93 - Sodium salt of (5R, 6S) -5-hydroxy-13 ~ (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-7 (E), 9 (Z) -dien-6-yl-7 -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (5R, 6s) -5-hydroxy-15- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentadeca-7 (E) sodium salt, N, N -dien-B-yl ^ -thio-oxo-H1 -benzopyran - ^ - carboxylic acids; (4Rf5S) -1-carboxy-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) di-sodium salt undeca-6 (E), 8 (Z) -dien-6-yl- 7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (4R, 5S) -1-Carboxy-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -disodium salt-dodeca-6 (E), 8 (Z) -diene-5- yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (4Rf5S) -1-Carboxy-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E), 8 (Z) -dien-5-yl- di-sodium salt 7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid; (4R, 5S) -1-carboxy-4-hydroxy-1- (4-acetyl-3-hydroxy-2-propylphenoxy) -tetradeca-6 (E), 8 (Z) -diene-5- di-sodium salt yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid, - 94'-

Examples of pharmaceutical preparations and suitable pharmaceutical forms With " active ingredient " the compound of formula I of the invention should be further understood, in particular as described in Claims 1 to 9, as e.g. (1R, 2S) sodium salt * 1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), SiZ ^ diene- N -yl-T-thio - N - oxo N-benzopyran-N-carboxylic acid. EXAMPLE A:

Inhalation suspension containing propellant forming an aerosol of solids containing 0.1% by weight of active substance

Composition: wt% active ingredient, micronized_0,1

Sorbitantrioleate 0.5

Propellant A (trichlorotrifluoroethane) 4.4

Propellant B (dichlorodifluoromethane and 15.0 1,2-dichlorotetrafluoroethane) 80,0

Preparation: Suspend the active ingredient with the exclusion of moisture by means of a conventional homogenizer with the addition of sorbitantioleate in trichlorotrifluoroethane, and fill the suspension in an aerosol container equipped with a metering valve, which is closed and filled under pressure with propellant B.

EXAMPLE B:

Suitable for inhalation is about 2% aqueous solution of the active substance in the form of its sodium or potassium salt.

Composition 2000 mg 10 mg 10 mg 100 ml Active ingredient (K or Na salt) Disodium salt of ethylenediamine-tetraacetic acid BenzalkoniumVi chloride Water, freshly distilled ad

Preparation; The active substance is dissolved in about 60 ml of freshly distilled water and a stabilizer (disodium salt of ethylenediaminotetra acetic acid) and a preservative (benzalkonium chloride) are added. After complete dissolution of all components, make up to 100 ml of the solution obtained, fill it in pressure bottles and seal them tightly. The propellant is added, if necessary, in a gaseous state under pressure or in liquid form.

APPENDIX - PHARMACOLOGICAL TEST METHODS

Test for bronchoconstriction in guinea pigs (and vlvo, aerosol): 400 to 700 g of heavy guinea pigs are anesthetized intraperitoneally with 1.4 g / kg of urethane and a polyethylene cannula is introduced into the jugularis. The second cannula is introduced into the trachea. With the cannula introduced into the esophagus, which is connected to the Stathara pressure transducer, the esophageal pressure is recorded. Place the animal in an airtight, sealed Plexi glass chamber connected to Fleisch tube no. 000 and Validyne-Transducer MP 45-1. This arrangement measures the flow.

After surgical preparation of the experimental animals, we wait for some time for the pulmonary functions to stabilize. The test compound is then administered according to the following protocol. The test animals are exposed for 1 minute to a 1% aerosol solution of the test compound (w / v) or distilled water (for control purposes). For all test compounds administered by inhalation, a Monaghan ultrasonic sprayer (Models 670) is used, with a particle size between 1 and 8 pm with a major fraction of 3 pm.

The aqueous solutions are prepared fresh each time and introduced into the spray chamber with " on-stream another vial ". The spray mist produced is administered to the test animals via a 65 ml glass chamber connected to the trachea by a cannula.

After the treatment time has elapsed, it is administered via a second Monaghan ultrasonic sprayer (Models 670) and via the same glass chamber for 2 minutes LTD ^ (0.3 pg / ml).

We read reduction • 'Compliance " at 3 minutes after application of 97 LTDjj, compare the mean of three animals with the mean of three control animals and calculate the percentage inhibition of compliance according to the following formula: (100 - Compliance). 100% inhibition = 100 - (100 - Compliance controls) When investigating different concentrations of the substance, record the percentage inhibition for each concentration by applying the log concentration to the abscissa against its percent inhibition on the ordinate. Ι0 ^ 0 is then determined by linear regression analysis.

An in vitro assay for the determination of phospholipase inhibition by human leukocytes

Neutrophilic polymorphic nuclei of human leukocytes are isolated by multistage fractionated sedimentation, starting from " Buffy coats ", and deep freezing. Phospholipo z A? Was extracted from the cell suspension by homogenization with the addition of freezing 0.36 N and ^ SOjj in 2N NaCl, and the supernatant obtained after centrifugation at 10000 x g was dialyzed against sodium acetate buffer pH 4.5.

To determine the enzyme activity, the enzyme (10-30 / µg protein) was incubated in 0.1 M tris / HCl buffer pH 7, supplemented with 14 1 mM CaCl2 and a substrate consisting of blosynthetic C-oleic acid radiolabelled phospholipids (2 µM) Escherichia coli at 37 ° C were incubated for 1 hour. The reaction was quenched by the addition of Dole reagent (isopropanol / heptane / 1N HgSOn - 9t 40: 10: 1, v / v) and extracted with <RTI ID = 0.0> C-oleic </RTI> acid selectively released by phospholipase Ag. The extractable substrate was completely removed by filtration of the extract through a silica gel column. The determination of C-oleic acid in the eluate is done by radiometry.

To determine the inhibitory effect of the test substances on phospholipase A2, they are added to the incubation line as solutions in water, dimethyl sulfoxide (final concentration below 5%, v / v) or ethanol (final concentration below 2.5%, v / v). The effect strength of the test substances is expressed by IC ^ 0, i.e. concentration that causes a 50% inhibition of control activity. IC, -0 is determined graphically by applying percentage inhibition to ordinate against log concentration (μΜ) on the abscissa.

Under the described conditions, the experiment inhibits Mepacrine phospholipase A2 with IC5Q 1600 μΜ.

In vitro assay for the determination of phospholipase C inhibition by human platelets Human platelets are obtained from &quot; Buffy coats &quot; by fractional centrifugation and then deep-frozen. Phospholipase C is released by ultrasonic treatment of the cell suspension and is located after solubilization after ultracentrifugation (150000 x g for 1 hour) in soluble form.

To determine enzyme activity, we incubate the enzyme (20 to 100 µg protein) in 0.025 M tris / maleate buffer pH 6 with the addition of 0.2 M CaCl0 and 0.02 mM radiolabelled substrate, phosphatidyl-

9 d &quot; V: -9S— 1 it o / C / -inositol, at 37 5 minutes. The reaction was quenched by shaking with CHClg / CHgOH 2: 1 (v / v). In doing so, the unused substrate is extracted into the organic phase, while the reaction product 1 N -inositol phosphate remains in the aqueous phase and is measured by aliquot radiometry.

To determine the inhibitory effect of the test substances on phospholase-C, they are added to the incubation line as solutions in water, dimethylsulfoxide (final concentration below 5%, v / v) or ethanol (final concentration below 2.5%, v / v ). The effect strength of the test substances is expressed by IC ^ 0, i.e. concentration that causes a 50% inhibition of control activity. IC ^ q is determined graphically by applying percentage inhibition to the ordinate against log concentration (μΜ) on the abscissa.

Under the described conditions, Mepacrine phospholipase C with IC50 was inhibited by 20 μΜ.

Claims (124)

100. PATENT APPLICATIONS 1. A process for the preparation of novel substituted alkano-phenones of the general formula R m m Ri R5-I- HH \ / \ / '8 tv which means optionally fluorinated lower alkyl, R ^ represents hydrogen, optionally fluorinated lower alkyl or lower alkenyl, X means lower alkylene, oxy, thio or a direct bond, alk represents lower alkylene, n stands for 1 or 2, R4 represents unsubstituted or optionally fluorinated lower alkyl, esterified or esterified hydroxy, optionally lower alkylated amino and / or optionally esterified or amidated carboxy substituted phenyl, or optionally fluorinated or optionally esterified or amidated carboxy substituted lower alkyl, R1 represents optionally esterified or amidated carboxy or 5-tetrazolyl and R1 stands for hydrogen or lower alkyl, and salts thereof, 101 characterized in that the epoxide of formula (II) in which R2, X, alk, n and R4 have the meanings above, is reacted with a thiol of the formula R5- +. nm • v · · ^ / \ / (III), ft in which R ^ and R ^ have the above meanings, or a salt thereof, and optionally the compound which may be obtained in the sense of the process is converted to another compound of formula I. a mixture of stereoisomers obtainable in the process sense is separated into components and / or a free compound obtainable in the process sense, converted into a salt or salt obtainable in the process sense, into a free compound or another salt. A process according to claim 1 for the preparation of compounds of formula I, wherein R 1 represents lower alkyl and R 2 optionally fluorinated lower alkyl or lower alkenyl, and salts thereof. The process of claim 1 for the preparation of compounds of formula -. 102 I in which R1 represents lower alkyl or mono-, di- or polyfluoro-lower alkyl, R2 represents hydrogen, lower alkyl, lower alkenyl or mono-, di- or polyfluoro-lower alkyl, X represents lower alkylene, oxy or thio, alk means lower alkylene, R4 is unsubstituted or with lower alkyl, lower alkoxy, halogen, I carboxy, lower alkoxycarbonyl, amino, N-mono- or Ν, d-dihydroalkylamino, carbamyl, N-mono- or N, N-di-dialkylcarbamyl, and / or trifluoromethyl substituted phenyl, lower alkyl, mono-, di- or trifluornižjialkil, karboksinižjialkil, nižjialkoksikarbonilnižjialkil, karbamilnižjialkil or N-mono- or N, N-Diniz j ialkilkarbatni lniž jialkil, R represents a carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamyl, N-mono- or N, N-dihydroalkylcarbamyl, or optionally substituted phenyl with lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, N- (benzolsulfonyl) carbamoyl and R, - stands for hydrogen or lower alkyl, and theirs h of salt, · D A process according to claim 3 for the preparation of compounds of formula I in which lower alkyl is? and salts thereof. A process according to claim 1 for the preparation of compounds of formula I in which R 1 is C 1 -C 4 -alkyl or t-trifluoro-C 1 -C 6 -alkyl, R 2 represents hydrogen, C 1 -C 4 -alkyl , C1-C4-alkylene or C1-C10-trifluoro-C1-C6-alkyl, X represents C1-C4-alkylene, oxy or thio, alk represents unbranched C1-C8-alkylene, n is 1 or 2, R 3 means unsubstituted or C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen having an atomic number up to and including 35, trifluoromethyl, carboxy and / or 103-C 1 -C 4 -alkoxycarbonyl substituted phenyl, C 1 -C 8 -alkyl, a), 60, O-trifluoro-C 2 -C 6 -alkyl carboxy-C 1 -C 4 -alkyl or C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl means carboxy or n- (benzenesulfonyl) carbamyl , and stands for hydrogen, and their salts. A process according to claim 5 for the preparation of compounds of formula I in which R 1 is C 1 -C 4 -alkyl, and salts thereof. A process according to any one of claims 1, 3 and 5 for the preparation of compounds of formula I in which group X is attached to the group R 1 -C (= O) in the vapor position, and salts thereof. A process according to any one of claims 2, 4 and 6 for the preparation of compounds of formula I in which the group X is attached to the group R 1 -C (= O) in the vapor position, and salts thereof. The process of claim 1 for the preparation of compounds of formula ^ / \ / • · (la) in which R1 is C1-C4-alkyl, R4 represents C1-C4-alkyl, C8-C6-alkenyl or υυ, υυ »LU-trifluoro-C--Cy- alkyl, X represents C1-C4-alkylene, oxy or thio, alk represents unbranched C2 "^ 6" allcylene &gt; n is 1 or 2, R 4 represents a group of the formula -AR 2, in which -A- represents C 1 -C 4 -alkylene, phenylene or a direct bond, and R 4 represents C 1 -C 4 -alkyl, trifluoromethyl, carboxy or C1-C4-alkoxycarbonyl, R4 represents carboxy or 104 N- (benzenesulfonyl) -carbamyl and stands for hydrogen and their salts. The process of claim 1 for the preparation of compounds of formula R 1 · R 5 't is R 1 is C 1 -C 6 -alkyl, R 2 is O, -C 1 -alkyl, X is oxy, alk is C 2 -C 8 -alkylene, n is 1 or 2, R 4 is C 1 -C 4 -alkyl, C1-C4-alkoxy, halogen having an atomic number up to and including 35, trifluoromethyl or C1-C4-alkoxycarbonyl, substituted phenyl, C2-C8-alkyl, UL /, OJ, LU-trifluoro-C8-C5-alkyl or C 1 -C 4 -alkoxycarbonyl-C 1 -C 6 -alkyl, R 1 represents carboxy and R 5 is hydrogen, and salts thereof. A process according to claim 9 for the preparation of compounds of formula Ia in which R 1 is C 1 -C 4 -alkyl, R 2 represents C 1 -C 5 -alkyl, X stands for oxy, alk represents C 2 -C 8 alkylene, n stands for for 1 or 2, R 8 represents a group of the formula -AR 2, in which -A- is C 1 -C 1 -alkylene or phenylene, and R 4 represents C 1 -C 4 -alkyl, trifluoromethyl or C 1 -C 4 -alkoxycarbonyl, R4 represents carboxy or N- (benzolsulfonyl) carbamyl, and R4 is hydrogen and their salts. The process of claim 10 for the preparation of compounds of formula Ia; wherein R 1 is C 1 -C 4 -alkyl, R 2 represents C 1 -C 5 -alkyl, X stands for oxy, alk stands for C 2 -C 5 -alkylene, 105 n stands for 2, R 4 stands for C 1 -C 5 -alkyl, trifluoromethyl or C 1 -C 1 -alkoxycarbonyl substituted phenyl, C 1 -C 4 -alkyl, uJ, uu, tU-trifluoro-C 2 -C (j-alkyl, or C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkyl, R 4 represents carboxy and R4 is hydrogen, and salts thereof. A process according to any one of claims 1, 3, 5 and 7 for the preparation of compounds of formula I in which X stands for oxy ^ and their salts. A process according to any one of claims 2, 4, 6, 8 and 10 for the preparation of compounds of formula I or. Ia, in which X stands for oxy, and their salts. A process according to any one of claims 9 and 11 for the preparation of compounds of formula I or. Ia in which X stands for oxy; and * their salts. A process according to any one of claims 1, 3, 5, 7 and 13 for the preparation of compounds of formula I in which n is 2 and their salts. A process according to any one of claims 2, 4, 6, 8, 10 and 14 for the preparation of compounds of formula I or. Ia, in which n stands for 2, and their salts. A process according to any one of claims 1, 9 and 15 for the preparation of compounds of formula I or. Ia, in which n stands for 2, and their salts. A process according to any one of claims 1, 3, 5, 7, 13 and 16 for the preparation of compounds of formula I in which R 1 is C 1 -C 4 -alkylphenyl or m-trifluoromethylphenyl, R 6 carboxy and R 4 hydrogen, and their salts. 106 - A process according to any one of claims 2, 4, 6, 8, 10, 12, 14 and 17 for the preparation of compounds of formula I or. Ia, in which R 1 is C 1 -C 1 -C 6 -alkylphenyl or m-trifluoromethylphenyl, R 6 carboxy and R 4 hydrogen, and salts thereof. 21. A process according to any one of claims 1, 9, 15 and 18 for the preparation of compounds of formula I or. Ia, in which R 1 is C 1 -C 4 -alkylphenyl or m-trifluoromethylphenyl, R 6 carboxy and R 4 hydrogen, and salts thereof. A process according to any one of claims 1, 3, 5, 7, 13, 16 and 19 for the preparation of compounds of formula I in which the closest double bond of the residue - (CH = CH) n - v (Z) - , ie cis-configuration, and optionally present an additional double bond of the residue - (CH = CH) n in (E) -, i.e. trans-configuration, and salts thereof. A process according to any one of claims 2, 4, 6, 8, 10, 12, 14, 17 and 20 for the preparation of compounds of formula I or. Ia, in which the closest double bond of the residue - (CH = CH) n-v (Z) -, i.e. cis-configuration, and optionally present an additional double bond of the residue - (CHsCH) n in (E) -, i.e. trans-configurations, and salts thereof. A process according to any one of claims 1, 9, 15, 18 and 21 for the preparation of compounds of formula I or. Ia, in which the closest double bond of the residue - (CH = CH) n - to (Z) - is located in the alk residue, i.e. cis-configuration, and optionally present an additional double bond of the residue - (CHsCH) n in (E) -, i.e. trane-configuration, 107 and their salts. A process according to any one of claims 1, 3, 5, 7, 13, 16, 19 and 22 for the preparation of compounds of formula I in which the chain atom C, which is attached to the sulfur atom, has (S) configuration and chain a C atom bearing the hydroxy group, (R) configuration, and salts thereof. 26. A process according to any one of claims 2, 4, 6, 8, 10, 12, 14, 17, 20 and 23 for the preparation of compounds of formula I or. Ia, in which the chain atom C, which is attached to the sulfur atom, has the (S) -configuration and the chain atom C, which carries the hydroxy group, (R) -configuration, and their salts. A process according to any one of claims 1, 9, 15, 18, 21 and 24 for the preparation of compounds of formula I or. Ia, in which the chain atom C, which is attached to the sulfur atom, has (S) -configurations and a chain atom C bearing a hydroxy group, (R) -configuration, and salts thereof. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 29- The process of claim 1 for the preparation of (1R, 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-1-benzopyran-2-carboxylic acid. 30. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-108 4-oxo-4H-1-benzopyran-2-carboxylic acid. 31. The process of claim 1 for the preparation of (1S, 2R) -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-1-benzopyran-2-carboxylic acid. 32. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) methyl ester -en-2-yl-7-thio-4-oxo-4H-1-benzo-pyranecarboxylic acid. 33. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -hex-3 (Z) -en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 34. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) methyl ester -en-2-yl-7-thio-4-oxo-4H-1-benzo-pyranecarboxylic acid. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) hex-3 (Z) -en- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. A process according to claim 1 for the preparation of (1Rf2S) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-109 3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 39. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-phenlethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 40. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) methyl ester - en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 41. The process of claim 1 for the preparation of (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. 42. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 43. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -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. 110 44. The process of claim 1 for the preparation of the (1S, 2R) -1-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) raethyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy 1- (3-methoxycarbonylphenyl) -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. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) methyl ester - en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. The process of claim 1 for the preparation of (1R 12 S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -hex-3 (Z) -en -2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy 1- (3-carboxyphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid or its disodium salt. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) methyl ester - en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. A process according to claim 1 for the preparation of (1S, 2R) -1-hydroxy 1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -hex-3 (Z) - en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2- 111 111 carboxylic acid 51. A process according to claim 1 for the preparation of (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) methyl-ester methyl ester-6 (E) f8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 52. The process of claim 1 for the preparation of (4R, 5S) -1,1,1-tri-fluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -unde-6 ( E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 53. The process of claim 1 for the preparation of (4S, 5R) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) methyl-ester methyl ester-6 (E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 54. The process of claim 1 for the preparation of (4S, 5R) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undek-6 (E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 55. The process of claim 1 for the preparation of (4r, 5S) -1,1,1-trifluoro-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z) methyl ester - en-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 56t The process of claim 1 for the preparation of (4R, 5S) -1,1,1-tri-fluoro-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. 57. The process of claim 1 for the preparation of (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy)-dodec-7 (Z) -en-6-yl-112 7- thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 58. The process of claim 1 for the preparation of (5R, 6S) -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. 59. The process of claim 1 for the preparation of (5S, 6R) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) methyl ester-dodec-7- (Z) -en-6-yl-7 -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 60. The process of claim 1 for the preparation of (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. 61. The process of claim 1 for the preparation of (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undec-6 (Z) methyl ester - en-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 62. The process of claim 1 for the preparation of (4r, 5S) -1,1,1-tri-fluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undec-6 (Z) -en-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 63. The process of claim 1 for the preparation of (5R, 6S) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7- methyl ester thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 64. The process of claim 1 for the preparation of (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. 113 - 65. The process of claim 1 for the preparation of (5S, 6R) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7- methyl ester thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 66. The process of claim 1 for the preparation 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. 67. The process of claim 1 for the preparation of (5S, 6R) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) dec-1 H-en-b-yl - N -thio 4 - oxo N-H-benzopyran-2- (N-benzolsulfonamidyl) carboxamide. * 68. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propylphenoxy) -octa-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 69. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7- * thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. The process of claim 1 for the preparation of (4RS, 5SR) -1-methoxy-carbonyl-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. 71. The process of claim 1 for the preparation of (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 or its disodium salt. 72. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 73. The process of claim 1 for the preparation of (1R, 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. 74. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 75. The process of claim 1 for the preparation of (1R, 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. 76. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 77. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -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. 78. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) methyl ester - phenoxy / -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 115 79. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy / -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1 benzopyran-2-carboxylic acid. A process according to claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-roethylphenyl) -8- (4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 81. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -8- [4-acetyl] -3-hydroxy-2- (3,3,3-trifluoropropyl) - phenoxy / -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 82. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E) methyl ester ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 83. The process of claim 1 for the preparation of (1R, 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-benzo-pyran-2-carboxylic acid. 84. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 methyl ester (E) * 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 85. The process of claim 1 for the preparation of (1S, 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-benzopyran-2-carboxylic acid. 86. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E) methyl ester ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1 · -benzopyran-2-carboxylic acid. 87. The process of claim 1 for the preparation of (1R, 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. 88. The process of claim 1 for the preparation of (1S, 2R) -1-hydroxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-3-propyl-phenoxy) -octa-3 methyl ester (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 89. The process of claim 1 for the preparation of (1S, 2R) -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. 90. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 methyl ester (Z) -en-2-yl-7-thio-4-oxo-4H-1-benzo-pyran-2-carboxylic acid. 91. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (Z) -en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 92. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy "" 2-propylphenoxy) -nona-3 (E) methyl ester , 5 (Z) -Dien-2-yl-7-thio-4- -1 117-oxo-4H-1-benzopyran-2-carboxylic acid. 93. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoroethyl) phenyl) -9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E) , SiZj-dien ^ -yl ^ -thio ^ -oxo ^ H1-benzopyran-P-carboxylic acid. 94. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undek-3 (E) methyl ester, 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 95. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -uneca-3 (E) , 5 (Z) -Dien-2-yl-7-thio-4-oxo-4H-1-benzo-pyran-2-carboxylic acid. 96. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E) methyl ester, 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzo-pyran-2-carboxylic acid. 97. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1-phenyl-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. 98. The process of claim 1 for the preparation of the methyl ester of (1R-, 2S) -1-hydroxy-1- (3-chloro-phenyl) -8- (4-acyl-3-hydroxy-2-propyl-phenoxy) -octa -3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 99. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -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. 118 100. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E (methyl) ester ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 101. The process of claim 1 for the preparation of (1R, 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. 102. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E) methyl ester ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 103. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy 1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 104. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E (methyl) ester ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 105. The process of claim 1 for the preparation of (1R, 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. 106. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl 3-hydroxy-2-propyl-phenoxy) -octa-3 (E) methyl ester , 5 (Z) -Dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 119 107. The process of claim 1 for the preparation of (IR, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl 3-hydroxy-phenoxy) -octa-3 (E) methyl ester, SiZ 2 -diene N -yl-thio-oxo-N-benzopyran-carboxylic acid. 108. The process of claim 1 for the preparation of (1R, 2S) -1-hydroxy 1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzo-pyran-2-carboxylic acid. 109. The process of claim 1 for the preparation of (1R, 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-carboxylic acid. 110. The process according to claim 1 for the preparation of (5R, 6S) -1,1,1-trifluoro-5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -7-dodeca-7 (E ), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 111. The process of claim 1 for the preparation of (5R, 6S) -1,1,1-tri-fluoro-5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 ( E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 112. The process of claim 1 for the preparation of (4R, 5S) -1,1,1-trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -trideca-6 (E) methyl ester ), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-benzopyran-2-carboxylic acid. 113. The process of claim 1 for the preparation of (4R, 5R) -1,1,1-tri-fluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E) , 8 (Z) -Dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. -'120 '-' - 114. The process of claim 1 for the preparation of (4R, 5S) -1,1,1-trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 methyl ester (E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 115. The process of claim 1 for the preparation of (4R, 5S) -1,1,1-tri-fluoro-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-6 ( E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 116. The process of claim 1 for the preparation of (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -ester (7) (E), 9 (Z) -diene methyl ester -5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 117. The process of claim 1 for the preparation of (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-7 (E), 9 (Z) -diene- 6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 118. The process of claim 1 for the preparation of (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) - (methyl) ester - dodeca-7 (E) 9 (Z) - dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 119. The process of claim 1 for the preparation of (5S, 6R) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-7 (E), 9 (Z) -diene-6- yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 120. The process of claim 1 for the preparation of (5R, 6S) -5-H hydroxy-1- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) - methyl ester dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 121. The process of claim 1 for the preparation of (5R, 6S) -5-hydroxy-4_ (4-acetyl-3 "hydroxy-2-propyl-phenoxy) -tetradec-7 (E), 9 (Z) - 121 diene- 6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 122. The process of claim 1 for the preparation of (5S, 6R) -5-hydroxy-1- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene methyl ester -6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 123. The process of claim 1 for the preparation of (5S, 6R) -5-hydroxy-1- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene- 6-yl-7-thio-4-oxo-4B-1-benzopyran-2-carboxylic acid. 124. The process of claim 1 for the preparation of (5R, 6S) -1,1,1-trifluoro-5-hydroxy-1- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradecyl ester methyl 7 (E ), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 125.1. The process of claim 1 for the preparation of (5R, 6S) -1,1,1-tri-fluoro-S-hydroxy-N-acetyl-S-hydroxy-propyl-phenoxy-tetradeca-7 (E) , 9 (Z) -Dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 126. The process according to any one of claims 1 to 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 50, 52, 54, 56, 58, 60, 62, 64, 66, 69 , 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 108, 109, 111, 113, 115, 117, 119, 121 , 123 and 125, characterized in that the sodium salt of the compound of formula I is prepared. Ia that can be obtained in terms of procedure. For CIBA-GEIGY AG: 20710-III-89 / LZ, AK, MD Procedure for the preparation of new alkanophenones Summary Substituted alkanophenones of the general formula ff / \ A? HH-R3 (I), HO '/ V hn \ / \ / U \ Rs-4 5 r *' vN / in which, where appropriate, fluorinated lower alkyl represents hydrogen, optionally fluorinated lower alkyl or lower alkenyl, X represents lower alkylene, oxy, thio or a direct bond, alk represents lower alkylene, n is 1 or 2, R 6 is unsubstituted or optionally fluorinated lower alkyl, ethereal or esterified hydroxy, optionally lower alkylated amino and / or optionally esterified or amidated carboxy substituted phenyl or optionally fluorinated or optionally esterified or amidated carboxy substituted lower alkyl, R1 represents optionally esterified or amidated carboxy or 5-tetrazolyl and Rg stands for hydrogen or lower alkyl having antagonistic properties against leukotrienes and make them lightweight o used as active ingredients for anti-allergic medicines. The process for their preparation is characterized in that the epoxide of the formula R 1/4 / o o 4 - X-alk-fCH = CH) -d 1 - CH-R 2 • T 1 HO '/ V ta (II) in which they have R ^, R ^, X, alk, n, and R ^ of the above meanings are reacted with a thiol of the formula &quot; \ AA / '(III), Rs ~ + II II • · · V 8 in which R ^ and R ^ of the above meanings, or a salt thereof, and optionally a compound which may be obtained in the sense of the process, is converted to another compound of formula I, and the mixture of stereoisomers which may be obtained in the sense of the process is separated into components, and / or a free compound which it can be obtained in the sense of a process, converted into a salt or salt which can be obtained in the sense of a process, into a free compound or into another salt.