DD283617A5 - PROCESS FOR THE PREPARATION OF NEW ALKANOPHENONE - Google Patents

Abstract

The invention relates to a process for the preparation of novel substituted alkanophenones of the general formula wherein the substituents have the meaning given in the description, which have leukotriene-antagonistic properties and can be used as anti-allergic pharmaceutical active ingredients. The process for their preparation is characterized in that an epoxide of the formula * in which R1, R2, X, alk, n and R3 have the above meanings, with a thiol of the formula (III) in which R4 and R5 have the above meanings, or reacting a salt thereof and, if desired, converting a compound obtainable according to the process into another compound of the formula I, separating a mixture of stereoisomers obtained in the process into the components and / or a free compound obtained by process into a salt or a salt obtained according to the method into the free compound or into a free compound other salt is transferred. Formulas (I) to (III) {Production process; Alkanophenone; substituted; New; favorable pharmacological properties}

Description

Process for the preparation of new substituted alkanophenones Field of application of the invention

The invention relates to a process for the preparation of novel substituted alkanophenones and their salts, to processes for preparing these compounds as active ingredient-containing pharmaceutical preparations and to their use as active pharmaceutical ingredients.

Characteristic of the known state of the art . At present no such compounds are known. Object of the invention

The invention provides a process for the preparation of novel substituted alkanophenones and their salts which have advantageous pharmacological properties, in particular a pronounced leukotriene antagonism.

Explanation of the essence of the invention

The object of the invention is to provide processes for the preparation of novel compounds which possess valuable pharmacological properties.

According to the invention, new substituted alkanophenones of the general formula

i '. OH

^Ä 1 j -HX-alk- (CH =CH) _n -CH-GH-β ₅ (I),

HS ₅ -I; Ϊ! ⁴ ^,; UL1H89 * 609'i3l o

2B36 1

wherein R ,. optionally fluorinated lower alkyl, E _{2 is} hydrogen, optionally fluorinated Niederalkyl.oder lower alkenyl, X is lower alkylene, oxy, thio or a direct bond, alk is lower alkylene, η is 1 or 2, E, unsubstituted or by optionally fluorinated lower alkyl etherified or esterified hydroxy, optionally nxederalkyliertes amino and / or optionally esterified or amidated carboxy-substituted phenyl or optionally fluorinated or substituted by optionally esterified or amidated carboxy lower alkyl means, E ^ optionally esterified or amidated carboxy or 5-tetrazolyl and R, - represents hydrogen or Lower alkyl is prepared, and their salts.

The space representation in formula I above is for the preferred compounds in which the O atom of the hydroxyl group with the S atom in the relative trans configuration to be understood, that the symbols of the first line above that of the third line then lie below the representation plane (or vice versa), which is for the depicted formula

2 83 6 ί γ

of the opposite configuration, (RS) - (SR), according to the Kahn-Ingoldr ^ elog convention on the iP.it associated with the sulfur atom carbon atom, (CS-), and the hydroxyl group bearing carbon atom, (C-OH) , Dabe? when η is 2, the enantiomers having an S (CS), R (C-OH) configuration and, when η is 1, the enantiomers with R (CS-), S (C-OH) - Confguration particularly preferred. The double bond or the double bond of the butadienylene radical starting from the C atom attached to the radical alk is preferred, but not necessarily, in the vinylene or buta-1,3-dienyl radical which is represented by the symbol - (CH =CH-) - in cis configuration, usually designated (Z), wherein the other double bond is then preferential, but also not necessarily trans, usually designated (E).

Optionally fluorinated lower alkyl is lower alkyl or mono-, di- or Polyfluorniederalkyl.

Etherified or esterified hydroxy is, for example, lower alkoxy or

Optionally lower alkylated amino is, for example, amino, lower alkylamino or especially di-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 Ν, Ν-di-lower alkylcarbamoyl, or as R 3, preferably in the phenyl moiety optionally substituted by lower alkyl, lower alkoxy and / or halogen-substituted N- (benzenesulphonyl) carbamoyl. In the phenyl moiety optionally substituted as indicated, substituted N- (benzenesulphonyl) -carbr.moyl is, for example, unsubstituted or monosubstituted, preferably in ortho-addition. As optionally esterified or amidated carboxy substituent of R3 is carboxy and as Ri esterified carboxy, especially NiederalKoxycarbonyl, particularly preferred.

nau'i]

'. "· . 2 836 ί

  - 3 - ·

Above and below, "lower" radicals and compounds are, for example, those which have not more than 7 and, unless stated otherwise, preferably not more than A carbon atoms (C atoms). Furthermore:

Lower alkyl is, for example, C 1 -C 7 -alkyl, especially straight-chain C 1 -C 4 -alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or secondary butyl, but may also be a branched C 1 -C 4 -alkyl, such as isobutyl or tert-butyl or pentyl - be hexyl or heptyl. Lower. Ri, Rs or as a substituent of phenyl or N- (benzenesulphonyl) carbamoyl is preferably Ci-Ci, alkyl, for example methyl, lower alkyl R2 preferably C2-Cs-alkyl, for example propyl, and lower alkyl R _3, preferably C ₃ -C7 -Alkyl, for example propyl, butyl or pentyl.

Mono-, di- or polyfluoro-lower alkyl has, for example, up to and with 5 fluorine atoms and is, for example, mono-, di- or trifluoro-C 1 -C 7 -alkyl, especially ω-fluoro- or ω, ω, ω-trifluoro-C 1 -C 4, alkyl, such as trifluoromethyl, 2,2,2-trifluoroethyl or 3,3,3-trifluoropropyl. Fluorinated lower alkyl Ri and also as a substituent of phenyl R ₃ is in particular trifluoromethyl and fluorinated lower alkyl R _{3 is} preferably ω, ω, ω-trifluoro-Cz-Cu-alkyl, for example 3,3,3-trifluoropropyl.

Lower alkenyl R 2 is, for example, C 2 -C -alkenyl, such as vinyl, prop-1-enyl or, in particular, prop-2-enyl (allyl).

Lower alkylene is, for example, straight-chain C 1 -C 7 -alkylene, in the case of X in particular C 1 -C 8 -alkylene, such as methylene or ethylene, and in the case of alk, in particular C 2 -C 6 -alkylene, such as ethylene, 1,3-propylene, 1,4 Butylene, also 1,5-pentylene or 1,6-hexylene.

Lower alkoxy is, for example, Ci-Ci, -Alkoxy, such as methoxy.

Lower alkoxycarbonyl is, for example, C 1 -C 4 -alkoxycarbonyl, such as methoxy, ethoxy, propyloxy or butyloxycarbonyl.

    , ; 2 33 6

• _ 4 -

Niederalkylamd.no is, for example, Ci-Cu-alkylamino, such as methyl, ethyl, propyl or isopropylamino.

Diniederalkylamino is, for example, di-Ci-Ci * alkylamino, such as dimethylamine, diethylamino or N-ethyl-N-methyl-amino.

N-Mono- or Ν, Ν-di-lower alkylcarbamoyl is, for example, N-Ci-Cii-alkyl or N, N-di-Ci-Ctt-alkylcarbamyl, such as N-methyl-r, N-ethyl or N, N-dimethylcarbamyl.

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

Most compounds of the formula I can, according to their individual character, also be present in the form of salts. Those which have a sufficient acidity, in particular those with carboxyl, tetrazolyl or sulphamoyl groups, can form salts with bases, in particular inorganic bases, preferably physiologically compatible alkali metal salts, especially sodium and potassium salts. However, ammonium salts with ammonia or physiologically compatible organic amines, such as mono-, di- or tri-lower alkylamines, e.g. Diethylamine, mono-, di- or tri (hydroxyalkyl) amines, such as tris (hydroxymethyl) methylamine, or D-glucosamine.

The compounds of the formula I and their salts have advantageous pharmacological properties, in particular a pronounced leukotriene antagonism.

For example, they inhibit in vitro in the concentration range of about 0.001-1.0 μΜοΙ / l by the leukotriene-Di * (LTDi,) induced contraction of a smooth muscle. This so-called LTDi ₁ antagonism is determined experimentally, for example as follows: In segments taken from the ileum of a guinea pig weighing 300-400 g and in an organ bath in Tyrode solution at 38 ° C. and gassed with a mixture of 95% oxygen and 5% carbon dioxide were incubated at a load of 1 g, are mixed with synthetic leukotriene Di, (as potassium salt)

, . 2 83 6

• - 5 - ·

Contractions triggered and isotonic. The extent of inhibition by the test substance is determined after a preincubation of 2 minutes and evaluated as IC50, ie the concentration which reduces the test contraction by 50%. The compounds of formula I are also excellently active in vivo. They also have the specific and therapeutically very significant advantage of a relatively long duration of action. Thus, in the standard in vivo bronchoconstriction standard guinea pig test, a marked LTDi-antagonizing effect could be detected by aerosol administration of a solution containing 0.0001 to 1% by weight of the test substance. (The description of the test method can be found in the appendix to the examples).

Surprisingly, many compounds of formula I also exert a pronounced inhibitory effect on other physiologically important enzyme systems. Thus, the inhibition of phospholipase A2 from human leukocytes was observed in the tested concentration range of about 0.5-50 μΜοΙ / l. (The experimental setup for this determination is described in more detail in the appendix to the examples.) Also, the inhibition of phospholipase C from human platelets in the concentration range tested of about 1-100 μΜοΙ / l was observed.

Thanks to these valuable pharmacological properties, the compounds of the formula I according to the invention can find therapeutic use wherever the action of the leukotrienes leads to morbid conditions and ameliorates or eliminates them. Accordingly, they can be used, for example, for the treatment of allergic conditions and diseases, such as, in particular, asthma, but also hay fever and obstructive pulmonary diseases, including cystic fibrosis. Also, thanks to their anti-inflammatory efficacy, they are anti-inflammatory agents, particularly as external (topical) skin phlogistatics for the treatment of inflammatory dermatoses of any genesis, such as mild skin irritations, contact dermatitis, rashes and burns, and as mucosal phlogostatics for the treatment of mucosal inflammation, e.g. the eyes, nose, lips, mouth and genital or anal region. Further, they can be used as a sunscreen. The high inhibitory activity on various blood

Factors also indicates the possibility of therapeutic use of the compounds of formula I in the indications thrombosis and blood coagulation.

The invention relates primarily to the preparation of compounds of formula I wherein Ri is lower alkyl or mono-, di- or Polyfluorniederalkyl, R2 is hydrogen, lower alkyl, lower alkenyl or mono-, di- or Polyfluorniederalkyl, X is lower alkylene, oxy or thio , alk lower alkylene, R3 is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl, amino, N-mono- or Ν, Ν-di-lower alkylamino, carbamyl, N-mono- or N, N-di-lower alkylcarbamyl and / or trifluoromethyl-substituted phenyl , Lower alkyl, mono-, di- or trifluoroloweralkyl, carboxy-lower alkyl, lower-alkoxycarbonyl-lower alkyl, carbamyl-lower alkyl or N-mono- or N, N-di-lower alkylcarbamyl-lower alkyl, Ri, carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamyl, N-mono- or Ν, Ν- Diniederalkylcarbamyl or optionally substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl substituted N- (benzenesulphonyl) carbamoyl tet and R5 is hydrogen or lower alkyl, and their salts, especially pharmaceutically acceptable salts.

The invention relates primarily to e.g. the preparation of those compounds of the formula I in which R 1 is lower alkyl, R 2 is optionally fluorinated lower alkyl or lower alkenyl and X, R 3, R 1 and R 5 have the meanings given above, and their salts, in particular pharmaceutically acceptable salts.

In this case, the group X is preferably bonded in the para- position to the R 1 -C (= O) group, ie the compounds have the formula

¹ J OH

* ^N X-aik-fCH = CH> -CH-CH-R3

"U

• ·

2 330

(Ia)

in which R 1, R 2, X, alk, n, R 3, R 2 and R 5 have the meanings indicated, but R 1 preferably represents lower alkyl, R 2 optionally denotes fluorinated lower alkyl or lower alkenyl and / or phenyl R 3 is preferably substituted as indicated, and their salts, especially pharmaceutically acceptable salts.

The invention relates in particular to compounds of the formula I or Ia in which R 1 is C 1 -C 4 -alkyl, such as methyl, or ω, ω, ω-trifluoro-C 1 -C 4 -alkyl, such as trifluoromethyl, R 2 is C 1 -C 4 Alkyl, such as propropyl, C 2 -C 18 -alkenyl, such as allyl, tert-butyl-trifluoro-C 1 -C 6 -alkyl, such as 3,3,3-trifluoropropyl, or secondarily alkylated 'X represents C ₁ -C ₃ -alkylene, such as methylene / oxy • or thio, alk denotes straight-chain C 1 -C 5 -alkylene, such as ethylene, 1,3-propylene or 1,4-butylene, represents η for 1 or 2 R3 is unsubstituted or substituted by Ci-Ci, -Alkyl, such as methyl, Ci-Ct, -Akoxy, such as methoxy, halogen of the atomic only to ier and 35, such as chlorine or bromine, trifluoromethyl, carboxy and / or Ci-Ci, -Alkoxycarbonyl, such as methoxycarbonyl, substituted phenyl, Ci-Ca-alkyl, such as propyl or butyl, ü), ü), iü-trifluoro ~ C2-C5-alkyl, such as 3,3,3-trifluoropropyl or 4 , 4,4-trifluorobutyl, carboxy-C2-Cs-alkyl, such as 3-carboxypropyl or 4-carboxybutyl, or Ci-Ci, -alkoxycarbonyl-C2-Cs-alkyl, such as 3-methoxycarbonyl propyl or 4-Muthoxycarbonylbutyl, means Ri, carboxy or N- (benzenesulphonyl) -carbi. yl, and R5 is hydrogen, wherein when η is 1, the chain C atom attached to the sulfur atom preferably has (R) - and the chain C atom attached to the hydroxy group preferably has (S) configuration or, when η is 2, the chain C atom attached to the sulfur atom is preferably (S) - and the hydroxy group bearing chain v. atom has preferably (R) configuration and the double bond connected to the alk radical preferably in cis configuration

and the optionally present additional double bond is preferably present in trans configuration, preferably those in which Ri is Ci-Ci-alkyl and Rz, X, R3, Ri ₁ and R5 have the meanings indicated and their salts, especially pharmaceutically acceptable salts ,

The Erfirdung relates * -jr particular example, compounds of formula I or Ia wherein Ri Ci-Ci alkyl, such as methyl, Rz Ci-Cij-alkyl, such as propyl, ζ C -C, alkenyl, ν: '.a allyl, or ω, ω, ω-trifluoro-Ci-C ^ alkyl, such as 3,3,3-trifluoropropyl, X is Ci-C3-alkylene, such as methylene, oxy or thio darstell alk straight-chain Cz -Cβ-alkylene, such as ethylene, 1,4-butylene or 1,6-hexylene, represents η is 1 or 2, R3 represents a group of the formula -A-R3 'in which -A- Ci-C ^ - Alkylene, phenylene or a direct bond and R3 'is Ci-Ct, alkyl, such as methyl, trifluoromethyl, carboxy or Ci-Ci ₁ alkoxycarbonyl, such as methoxycarbonyl, Ri _{1 is} carboxy or N- (benzenesulphonyl) carbamyl, and R5 is hydrogen, where, when η is 1, the chain C atom connected to the sulfur atom preferably has (R) - and the chain-C atom linked to the hydroxy group preferably has (S) -configuration or 'when η is 2, which with the sulfur atom v linked chain C atom preferably (S) - and having the hydroxy group-bearing chain C atom preferably (R) configuration and the double bond connected to the radical alk preferably in cis configuration and the optional additional double bond preferably in trans Configuration, and their salts, especially pharmaceutically acceptable salts.

The invention relates in particular to compounds of the formula Ia in which R 1 is C 1 -C -alkyl, such as methyl, R z is C 1 -C 4 -alkyl, such as propyl, X is oxy, C 1 -C 6 -alkylene, such as ethylene, Is 1,3-propylene or 1,4-butylene, η is 1 or preferably 2, R 3 is by v ..- Ci, alkyl, such as methyl, Ci-Ci ₁ -alkoxy, such as methoxy, halogen of Atomnumrer to and including 35, such as chlorine, trifluoromethyl or C 1-C ₁ alkoxycarbonyl, such as methoxycarbonyl, substituted phenyl, C2-C8, in particular C3-Cs-alkyl, such as propyl or butyl, ω, ω, ω-trifluoro-C3- Cs-alkyl, such as 3,3,3-trifluoropropyl or 4,4,4-trifluorobutyl, or Ci-C ^ alkoxycarbonyl-Ci-Cu-alkyl, such as 3-methoxycarbonylpropyl or 4-methoxycarbonyl

233 6

wherein, when η is 1, the chain C atom attached to the sulfur atom is preferably (R) - and the chain C atom attached to the hydroxy group is preferably (S) -configuration or, if η is Preferably, the chain-C atom connected to the sulfur atom preferably has (S) - and the hydroxy group-bearing chain C-atom preferably has (R) configuration and the double bond connected to the radical alk preferably in cis configuration and optionally existing additional double bond is preferably present in trans configuration, and their salts, especially pharmaceutically acceptable salts. ,

The invention preferably relates to the preparation of compounds of the formula Ia in which R _{1 is} C ₁ -C 4 -alkyl, such as methyl, R _{2 is} C ₁ -C ₁ -alkyl, such as propyl, X is oxy, C 2 -C 6 -alkylene such as ethylene or 1,4-butylene, η is 1 or preferably 2, R3 is a group of the formula -A-R3 ', in which -A- Ci-Ci, -Alkylen, such as ethylene, or phenylene, in particular m-phenylene, and R3 'is Ci-Ci, alkyl, such as methyl, trifluoromethyl or Ci-Cu-alkoxycarbonyl, such as methoxycarbonyl, Rt, carboxy or N- (benzenesulphonyl) carbamoyl, and R5 is hydrogen, wherein when η is 1, the chain C atom attached to the sulfur atom is preferably (R) - and the chain C atom connected to the hydroxy group is preferably (S) -configuration or, when η is 2, the Preferably, the chain-C atom linked to the sulfur atom has (S) - and the chain-C atom carrying the hydroxy group preferably has the (R) -configuration and which is bonded to the R est alk connected double bond preferably in cis configuration and the optionally present additional double bond is preferably present in trans configuration, and their salts, especially pharmaceutically acceptable salts.

The invention relates in the first place to the preparation of compounds of the formula Ia in which R 1 is C 1 -C 4 -alkyl, such as methyl, R _{2 is} C ₁ -C 4 -alkyl, such as propyl, X is oxy, alk C ₂ - C ₅ -alkylene, such as ethylene, 1,3-propylene or 1,4-butylene, η is, R 3 is C 1 -C 4 -alkyl, such as methyl, trifluoromethyl or C 1 -C 1, alkoxycarbonyl, such as methoxycarbonyl, in particular meta-substituted phenyl, C3-Cs-alkyl, such as propyl or butyl, ω, ω, ω-tri-

, 0 · U. x \ L. i ^ i - ^

2 8 3 6 ί

Propyl or butyl, ω, ω, ω-trifluoro-Cs-Cs-alkyl, such as 3,3,3-trifluoropropyl or 4,4,4-trifluorobutyl, or Ci-Ci, alkoxycarbonyl-Cz-Cw-alkyl, as 3-methoxycarbonylpropyl or 4-methoxycarbonylbutyl, Ru means carboxy, and Rs is hydrogen, where the chain C atom attached to the sulfur atom is preferably (S) - and the chain C atom bearing the hydroxy group is preferably (R) - Configuration and the double alk bond bonded to the radical alk is preferably in the cis configuration and the other additional double bond is preferably in the trans configuration, and their salts, especially pharmaceutically acceptable salts.

The invention relates in particular to the compounds of the formula I mentioned in the examples and their salts, in particular pharmaceutically usable salts. · _ --- '

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

¹ I -HX-alk - (- CH =CH) -CH-CH-R ₃ (II),

March

wherein Ri, R2, X, alk, η and R3 have the above meanings, with a thiol of the formula

R ₅ - + - II N (III),

wherein Ri ₁ and R5 have the above meanings, or a salt thereof and if desired converts a compound obtainable according to the method into another compound of the formula I, a mixture of stereoisomers obtainable by the method is separated into the components and / or one

CQ ^for M -OQQ * · ~ C ^ ~ ', °

2 336 (7

• - π -

according to the process obtainable free compound in a salt or a salt obtainable according to the method in the free compound or converted into another salt. ·

The conversion of epoxides II with thiols III is carried out under configuration reversal on the C-atom entering the bond with the thio group and with retention of the configuration on the carbon atom carrying the hydroxyl group. Therefore, in order to arrive at the preferred compounds of opposite configuration at these two C-atoms, it is preferable to start from the corresponding trans-epoxides II. Starting from R, R epoxides II, compounds I are obtained with S (CS-), R (C-OH) -configuration or, starting from S, S-epoxides II, compounds I with R (CS), S (C-) OH) configuration. The reaction is known per se unter.an conditions at temperatures of about -20 ⁰ C to about +50 ⁰ C, preferably at room temperature, ie 18 ° C to 25 ⁰ C, and especially in a basic medium, for example in the presence of an amine, in particular a tertiary aliphatic, arylaliphatic or saturated heterocyclic amine, such as trialkylamine (eg triethylamine, or ethyl-diisopropylamine), dialkylbenzylamine (eg N, N-dimethylbenzylamine), N, N-dialkylaniline (eg N, N-dimethylaniline) or N-methyl- or N-ethylpiperidine or N, N ¹ -Dimethylpiperazin. Ueblicherwiese, the reaction in an inert organic solvent, such as a lower alkanol, for example, methanol or ethanol, performed.

In a preferred embodiment starting from components II and III wherein Ru is esterified carboxy or tetrazolyl and R3 has the meaning given and for example represents esterified carboxy or optionally fluorinated lower alkyl, Ri ₄ hydrolyzes (optionally selectively) to carboxy and converts this, if desired, into amidated carboxy.

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

2 3 3 * 17

  - 12 -

The epoxide of the above-defined formula II used as the starting material can be prepared mainly by the same methods which are also used in the synthesis of leukotrienes. In a typical general synthetic route for compounds II wherein η is 1, e.g. from an aldehyde of the formula

O = CH-R ₃ (IV)

where A and R3 have the meanings given above, wherein an optionally present free carboxyl group R ₃ in a protected form as an ester, for example as a lower alkyl ester, is present. This compound is condensed with formylmethylenetriphenylphosphorane (or an equivalent reagent) to give the corresponding trans -3-R3-prop-2-enal of the formula

^{0 = CH}

CW Tl

CW

Tl ₃

is formed. This compound is then epoxidized in a conventional manner, preferably under weakly alkaline conditions (eg in the presence of alkali metal carbonates) with aqueous hydrogen peroxide, resulting in a trans , ie 2 (RS), 3 (RS) -epoxy-3-R ₃ propanal the formula -CH 0 η

) c - c '(VI)

H Tl ₃

results. The epoxy aldehyde VI may then be condensed with a phosphonium halide

^{R 1} i 4f ^-X -alk-CH 2 -P (C ₆ Hs) ₃ Hal (VII)

2 3 36 \

• - 13 - ·

wherein Ri, R2 and alk have the meanings given and Hai is a halogen atom, preferably bromine, and a base, e.g. Sodium amide, in tetrahydrofuran to the corresponding epoxide II, wherein Ri is esterified carboxy and η is 1, are reacted.

Compounds VII are in particular by reacting a corresponding compound of formula

j -H-X-alk-CHz-Hal (VIII)

R ₂

j Hc / Υ

prepared with triphenylphosphine in the usual manner. Compounds VIII wherein X is oxy or thio are obtained, for example, by adding corresponding compounds of the formulas

4-XH (IX) and Hal-alk-CH ₂ -Hal (X)

condensed together in the usual way.

Another method for the preparation of compounds II is that trans -3-R3-prop-2-enol of the formula

wherein R3 has the above meaning, free carboxy substituent of R3 but preferably protected in an ester form, for example by Tertiarbutylhydroperoxid in the presence of Titantetraisopropanolat and a D- and L-tartaric acid lower alkyl ester epoxidized, using a D-tartaric acid ester is obtained predominantly 2R , 3R-epoxy-3-R3 ~ propanol XIIa or when using an L-tartaric acid ester predominantly the corresponding 2S, 3S-epoxy-3-R3-propanol XIIb

90 P.ji -ioqg

O.- J · in · · .. I * J '= » ti

jgjjwjja ^ ^ is YFO ^ ffi ^

HIGH _2n (XIIa) or. HIGH ₂ H * 0 ^ H H* Sl ₃ s A · * \ ₃

- <(XIIb).

This is then, for example, by treatment with oxalyl chloride / dimethyl sulfoxide and then with triethylamine, oxidized to the corresponding epoxy aldehyde VI, which then with the corresponding phosphonium salt VII in the corresponding epoxide II, wherein R3 is esterified carboxy and η is 1, can be reacted.

In this case, predominantly epoxides II, wherein the double bond has the preferred cis stereotaxy. When a D-tartaric acid ester is used, as mentioned, predominantly compounds II in which the epoxy group has R, R configuration or S, S-enantiomers are obtained when the reaction is carried out in the presence of L-tartaric acid esters.

The preparation of epoxides II in which η is 2, for example, the epoxy alcohol XIIa or XIIb first by treatment with N, N'-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence γοη trifluoroacetic acid and pyridine and then with Triphenylphosphoranylidenacetaldehyd first in the corresponding 4R.5R- or 4S, 5S-4,5-epoxy-5-R3-pent-2-enal of the formulas XIIIa or XIIIb

O = HC-CH = Oi 0, .HO = HC-CH = CH 0 β

\ r - c ' (XIIa) or ^ CC ^ (XIIb)

Π Λ3 Π Κ3

then converted with the phosphonium halide VII to the corresponding epoxide II, wherein η is 2, is reacted further. In this case, preference is given to obtaining those in which the double bond cis -Sterotaxie connected to the radical alk and the double bond connected to the oxirane ring have trans stereotaxy.

If appropriate, compounds obtainable by the method can be converted into other compounds of the formula I, if desired.

For example, one may hydrolyze esterified or amidated carboxy groups to "-" iem hydroxy, preferably under basic conditions, e.g. in the presence of caustic soda, and preferably in one with water

1 836 ί

• - 15 -

miscible organic solvents such as tetrahydrofuran, dioxane or a lower alkanol, such as methanol or ethanol. Starting from compounds I where Ri _{1 is} esterified carboxy such as lower alkoxycarbonyl and R 3 contains such as substituents, the hydrolysis can be controlled to selectively hydrolyze only R 1, or both R ₁ and the lower alkoxycarbonyl substituent from R 3 to carboxy. Using an equimolar sodium hydroxide solution and choosing mild reaction conditions, 2.B. stirring at room temperature for about 0.5 to 2 hours, practically only alkoxycarbonyl Ri, is hydrolyzed while under drastic conditions, 2.B. at longer reaction times or with heating, both Ri ₄ and the alkoxycarbonyl group in R3 are hydrolyzed to carboxy.

Conversely, one can esterify carboxy Ri, as well as a carboxy substituent of R ₃ in a conventional manner.

Free or esterified carboxy Ri, and such as a substituent of R3 can be further amidated in the usual manner, for example by treatment with ammonia or a mono- or di-lower alkylamine. For example, carboxy Ri, in a conventional manner, e.g. in the presence of a carbodiimide salt, e.g. of N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride, and 4-dimethylaminopyridine, with an optionally substituted benzenesulfonamide to the corresponding N-benzenesulfamidoylcarbamyl groups.

Of course, it is also possible to separate the resulting diastereomer mixtures into the individual components on the basis of different physical properties of the components and / or to separate the enantiomer mixtures obtained into the individual enantiomers by customary racemate resolution methods.

If individual diastereomers are desired, an individual diastereomer of a starting material can advantageously be used at any stage or a diastereomer can preferably be formed from a starting material in the form of a diastereomer by stereoselective reaction conditions or optically active reagents.

QQ ',' Π] -f UQ Cl> ·. ^: ν y ^r - · * \ ' "'

A U O O 3 /

or racemic Diastereomerengeinische by physical separation methods, optionally using optically active auxiliaries are separated into the individual diastereomers.

In stereochemical terms, however, both the inventive condensation of components II and III, as well as the preparation of the starting materials primarily carried out so that each stereotactically uses uniform starting materials, the reactions stereoselectively if possible, for example by using stereotactically uniform, optically active reagents and / or excipients, and stereotactically uniform products isolated from reaction mixtures immediately after the reaction. Thus, for example, in the preparation of the unsaturated starting materials optionally formed ice and trans isomers are separated immediately from one another, for which the customary physical separation methods, in particular chromatography, are suitable. In the. The main reaction is mainly the stereomeric epoxide II with the stereospecific preference in stereospecific of the double bond (s) in Nazemic form (as is often formed in the variant of the epoxidation of compound V with hydrogen peroxide) or preferably as an individual diastereomer with the end I preferred configuration at the (CS -) - C atom of opposite configuration at the oxirane C atom entering the bond with the S atom.

It is likewise possible to convert salts obtained, for example by acid treatment, into salts in the free acids or free acids obtained by base treatment.

As a result of the close relationship between the new compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood by analogy in the preceding and following among the free compounds or their salts.

I ti isiiU. i ϋ ^ ^Ϋ <*> '<»ai *'

2 8 3 * 17

The invention also relates to those embodiments of the process according to which one starts from an intermediate obtainable at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or forms it under the reaction conditions.

The novel starting materials and intermediates occurring in the novel processes and their precursors also form the subject of the invention.

Preferably, such starting materials are used, and the reaction conditions are selected so that one arrives at the compounds listed above as being particularly preferred.

The compounds obtainable by the process are used for the preparation of pharmaceutical compositions and medicaments. In particular, the compounds according to the invention as active ingredient-containing pharmaceutical compositions are those which are suitable for local administration and especially for inhalation administration, e.g. in the form of an aerosol, micropowdered powder or a fine sprayed solution, to mammals, especially humans, and containing the active ingredient alone or together with a pharmaceutically acceptable excipient.

Pharmaceutical preparations for topical and local use are e.g. for the treatment of the skin, lotions and creams containing a liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (preferably containing a preservative). For the treatment of the eyes, eye drops containing the active compound in aqueous or oily solution and ophthalmic ointments, which are preferably prepared in sterile form, are suitable. For the treatment of the nose are aerosols and sprays (similar to those described below for the treatment of the respiratory tract), coarse powders which are administered by rapid inhalation through the nostrils, and especially nasal drops containing the active compound in aqueous or oily solution , suitable; for local treatment of the oral cavity

Ji l'.iui.

ij V »O» JJ

• - 18 - ·

Lollipops containing the active compound in a mass generally formed from sugar and gum arabic or tragacanth to which flavors may be added, and lozenges containing the active ingredient in an inert mass, e.g. from gelatin and glycerine or sugar and gum arabic.

Suitable pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I according to the invention with a suitable pharmaceutically acceptable solvent, in particular ethanol and water, or a mixture of such solvents. They may also contain, as needed, other pharmaceutical excipients, such as nonionic or anionic surfactants, emulsifiers and stabilizers, as well as other active ingredients, and most desirably with a propellant, such as an inert gas under elevated pressure or, in particular, with a highly volatile , preferably under normal atmospheric pressure below the usual room temperature (eg between about -30 and +10 ⁰ C) boiling liquid, such as an at least partially fluorinated polyhalogenated lower alkane, or a mixture of such liquids, is mixed. Such pharmaceutical compositions, which are used predominantly as intermediates or stock mixtures for the preparation of the corresponding medicaments in finished form, usually contain the active ingredient in a concentration of about 0.1 to about 10, in particular from about 0.3 to about 3% by weight. , For the preparation of medicaments in the finished form, such a pharmaceutical composition is filled into suitable containers, such as bottles and pressure bottles, which are provided with a suitable spraying device or valve for such purposes. The valve is preferably constructed as a metering valve which upon actuation releases a predetermined amount of the liquid corresponding to a predetermined dose of the active ingredient. In the preparation of the finished pharmaceutical form can also proceed so that appropriate amounts of the present as a stock solution pharmaceutical composition and the blowing agent are filled separately into the container and come there only to mix. The dosage of the active ingredient of the formula I to be administered and the frequency of administration depend on

oq »ι λ ι * o 3 α -ic; \ r \ ι υ υ. iut ¹ , t. iw * * ~ <- »**« - *

the respective efficacy or length of action of each individual of these compounds, the severity of the disease or symptoms to be treated, and the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the recommended daily dose of a Formula I compound of the invention for a 75 kg aspirator (primarily human) will be in the range of about 10 to about 500, preferably between about 25 to about 250 mg, the administration being appropriate as needed Can be done in several doses per day.

The invention also relates to the use of the active compounds of the formula I according to the invention for alleviating or remedy pathological states and / or symptoms of the body of a mammal, in particular of humans, which are attributable to the action of leukotrienes and occur in particular in asthma. This application or the corresponding healing method is characterized by the treatment of the suffering body or body part with an anti-allergic effective amount of a compound of the formula I alone or in the form of a pharmaceutical, in particular a pharmaceutical composition intended for inhalation. By the term "an anti-allergic effective amount" is meant an amount of the active ingredient sufficient to significantly inhibit the contractions caused by leukotrienes.

embodiments

The following examples further illustrate the present invention without limiting its scope. All temperatures are in degrees Celsius.

3 J .ί j

- 19a -

Example 1; (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-ptienoxy) -octa-5 (E), 5 (Z ) -diene-2-yl-7-thio-4 ~ oxo-4H-1-benzopyran-2-carbonsäuremethylester

The solution of 0.93S (1R, 2E) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (±) "in 25 ml of methanol is stirred under argon with 0.80 g of triethylamine and 0.62 g of methyl 7-mercapto-chromone-2-carboxylate for 20 hours at room temperature and evaporated Filtrate is washed once with 2N hydrochloric acid and 3 times

5 8 3 6

- 20 -

washed with brine, dried over magnesium sulfate and evaporated · Purification of the residue by chromatography on silica gel with hexane / ethyl acetate (1: 1) provides the title compound, mp. 62-63 °; [a] * ° (methanol, 0.135%) = 103 + 7.4 ° UV (methanol): λ (ε) = 216

jj ΙΠ3Χ

(50 ¹ OOO), 235 / sh, 271 (27,940), 285 / sh; 325 (12,900). The starting material is prepared, for example, as follows:

a) (2R, 3R) -2, 3-epoxy-3- (3-trifluorometh-1-vinyl-propanol) Under absolutely anhydrous conditions and argon atmosphere, the solution of 4.62 ml of tetraisopropyl orthotitanate in 100 ml of methylene chloride is cooled to -70 ° with 3 , 2 ml of D (-) tartaric acid diethyl ester and 5.45 g of 3- (3-trifluoromethylphenyl) -prop-2 (E) -enol in a little methylene chloride.After stirring for 10 minutes at -70 °, 21.5 ml of 3-molar Tertiärbutylhydroperoxid Solution in toluene is added, the temperature rising to -60 ° C. The temperature is allowed to rise within 2 hours, the resulting yellow solution is poured slowly into a solution of 14.5 g of ferrous sulfate and 5.8 g L (+) - tartaric acid in 60 ml of water (cooling !, exothermic) and stirred for 30 minutes at 5-10 ° C. The aqueous phase is separated off and extracted with ether, the combined organic extracts are dried over sodium sulphate and evaporated is dissolved in 90 ml of ether, cooled to 0-5 °, with a suspension of 2.32 g of sodium hydroxide in 60 ml brine and stirred for 1 hour at 0-5 °. The aqueous phase is separated and extracted with ether. The combined ether phases are 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 thus obtained as a colorless oil; IR (CH ₂ Cl ₂ ): 3550, 3430, 2950, 2880, 2830, 1310, 1150, 1110, 1050 cm ^-1 , [α] ° (methanol, 0.175%) = 42.3 ± 5.7 °, R = 0.30 ( Hexane / ethyl acetate 3: 2).

b) (4R, 5R) -4,5-Epoxyp-5- (3-trifluoromethylphenyl) pent-2 (E) -enal . The solution of 4.5 g (2R, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanol in 105 ml of dimethyl sulfoxide under argon with 1.7 ml of pyridine, 0.77 ml of trifluoroacetic acid and 12.75 g of Ν, Ν-dicyclohexylcarbodiimide 6 Stirred hours at room temperature. After addition of 8.25 g of formyl

- 21 -

Methylentriphenylphosphoran is stirred for a further 20 hours at room temperature, mixed with 320 ml of ethyl acetate and poured after 10 minutes to 320 ml of brine. The resulting suspension is stirred for 5 minutes and filtered. In the filtrate, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed 3 times with brine, dried over sodium sulfate and evaporated. The residue is filtered through silica gel with ether / hexane = (A: 1). The filtrate is evaporated and the residue is purified by chromatography on silica gel with hexane / ethyl acetate (3: 1). The title compound is thus obtained as a pale yellow OeI; IR (CH ₂ Cl ₂ ): 2780, 2695, 1670, 1620, 1305, 1145, 1105 cm ^-1 , R = 0.31 (hexane / ethyl acetate 3: 1) [ct] ^ ° (chloroform, 0.245%) = 144.5 ± 4.1 °

c). 3- (4-Acetyl-3-hydroxyprop-2-propylphenoxy) propyl-tri-phenvlphos-donium bromide

The solution of 27 g of 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl bromide in 50 ml of toluene is refluxed with 21.85 g of triphenylphosphine for 20 hours. The resulting suspension is cooled to room temperature, treated with 200 ml of ether and stirred for 1 hour. The colorless precipitate is filtered off with suction, washed with ether and dried. The title compound shows a m.p. of 211-212 °.

d) (IR, 2R) -I.2-epoxy-1- (3-trifluoromethvlphenyl) -8- (4-acetyl-3-hydroxyprop-2- propylphenoxy) -octa-3 (E), 5 (Z) - serve .

The suspension of 5.55 g of 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyltriphenylphosphonium bromide in 80 ml of tetrahydrofuran is stirred with 0.78 g of NaNH ₂ and 60 mg of potassium tertiarybutanolate under argon for 1 hour at room temperature, to 0-5 ° cooled, within 5 minutes with 1.7 g of (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) pent-2 (E) -enal in 20 ml of tetrahydrofuran and then stirred for 2 hours at room temperature. The resulting suspension is poured onto phosphate buffer (pH 7) and extracted with ether. The combined ether extracts are washed with phosphate buffer pH 7, dried over sodium sulfate and evaporated. The residue is dissolved in hexane / ethyl acetate / triethylamine (24: 71: 5).

2 83 6

taken and filtered through pre-washed with this solvent mixture silica gel. The filtrate is evaporated to give the title compound as a pale yellow oil; R = 0.75 (hexane / ethyl acetate 3: 2).

Example 2 ; (IR, 2S) -I-Hvdroxv-I- (3-trifluoromethylphenyl) -8- (4-acetyl-3-Hydroxy-2-propylphenoxy) octa-3 (E), 5 (Z) -diene-2- yl-7-thio-A-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt

0.7 g of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - Methyl-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylate are dissolved under argon in 20 ml of tetrahydrofuran, treated with 5.1 ml of 0.2N sodium hydroxide solution and stirred for 1 hour at room temperature. Evaporation and chromatographic purification of the residue on a reversed phase silica gel column (eg Merck Lichroprep® RP-8) with methanol / water (3: 1) gives the title compound, mp 207-209 °, [α] (0.54 %, Methanol) = 96.3 ± 1.9 °

UV (methanol): λ (ε) = 220 (488840), 235 / s, 267 (25940), 285 (22900), max.

Example 3 : (1S, 2R) -l-Hvdroxv-1- (3-trifluoromethylphenvl) -8- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo-4H-l-benzopvran-2-carbonsauremethvlester.

The title compound is prepared analogously to Example 1) from (IS, 2S) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa- 3 (E. ), 5 (Z) -dien; Mp. 68-69 °.

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

a) (2S, 3S) -2,3-Epoxy-3- (3-trifluoromethylphenyD-propanol The title compound is prepared as described in example 1a ) but using L (+) tauric diacetate; colorless oil; IR (CH ₂ Cl ₂ ): 3590, 3480, 2920, 2870, 1330, 1165, 1125, 1070 cm ^-1 ; [α] ™ (methanol, 0.175%) = -41.7 ± 5.7 °; R _f = 0.34 (hexane / Ethyl acetate 1: 1).

iiitiu »-i

2 83 5 1

- 23 -

b) (4S, 5S) -A, 5-epoxy-5- (3-trifluoromethylphenyl) pent-2 (E) -enal .

The title compound is prepared analogously to Example Ib) from the epoxy alcohol geinäss a); pale yellow OeI; IR (CH ₂ Clz): 2780, 2695, 1670, 1620, 1305, 1145, 1110 cm ^-1 ; [αψ (chloroform, 0.15%) - 158.0 ± 6.7 °; R = 0.4 (hexane / ethyl acetate 4: 1 ).

c) (1S, 2S) -l, 2-epoxy-1- (3-trifluorofluorophenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) _T 5 (Z) - serve .

Title compound is analogous to Example Id) from the epoxyaldehyde

produced according to b); light brown OeI; R = 0.61 (hexane / ethyl acetate .5 2). ·

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

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 3; Mp 210-212 °, [o] ^ ° (MeOH,

0.18%) = -86.1 ± 5.6 ° UV (MeOH): λ (ε) = 220 (42820); 235 / sh; 267

Max

(26660); 285 (23760); 320 (15,800).

Example 5 : (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-1-yl ^ - benzopyran-2-carboxylic acid methacrylate.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy / -hex-3 (Z) - bright yellow viscous OeI; [a] ^ ⁰ (MeOH, 0.115%) =

57.4 + 8.7 °; UV (MeOH): λ (ε) = 220 / sh; 271 (5280); 285 / sh; 320 (2800).

Max

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

a) (2S, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyD-propanal The solution of 1.1 g of oxalyl chloride in 15 ml of methylene chloride is cooled to -65-70 ° under argon and 1.5 g in 2 minutes Dimethylsulfoxide in 5 ml of methylene dichloride After stirring for 10 minutes at -65-70 °, 1.7 g of (2R, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) - _r "> panol in 15 ml of methylene chloride are added dropwise After another 30 minutes

2 836 1J

- 24-

Stirring 4 g of triethylamine are added dropwise, the temperature rises to -40 °. The temperature is allowed to rise to 0 ° and the reaction mixture is poured onto phosphate buffer (pH 8). The organic phase is separated and the aqueous phase extracted with methylene chloride. The combined organic extracts are washed twice with brine, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with hexane / ethyl acetate (7: 3) gives the title compound as a colorless oil; IR (methylene chloride): 2820, 1730, 1330, 1165, 1125, 1070 cm ^-1

R _f = 0.36 (hexane / ethyl acetate 3: 2). [o] ^ ⁰ (chloroform, 0.20%) = -17.5 + 5 °

b) (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethyl-phenyl) -6- (4-acetyl-3-hydroxy-2- propylphenoxy) -hex-3 (Z) -ene .

The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to a); pale yellow OeI; R _£ = 0.69 (hexane / Essigester 3: 2).

Example 6 : (IR, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-yl)

hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7-thio-4-oxo-4H-1 -... , - .. j . b.enzopyran-2-carboxylic acid sodium salt ν »<vi _; ; ': I''... _c . . The title compound is prepared analogously to example 2 from the corresponding methyl ester according to example 5; Mp 222-224 °; [a] * ⁰ (MeOH,

0.135%) = 62.2 ± 7.4 °. UV (MeOH): λ (ε) = 267 (22060); 285 (21140);

Max

Example 7 : (IS, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphe -> xy) -hex-3 (Z) -ene -2-yl-7-thio-4-oxo-4H-lbenzopyran-2-carbonsäuremethylester

The title compound is prepared analogously to Example 1 from (IS, 2S) -I, 2-epoxy-l

(3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-

3 (Z) -en produced; colorless powder of the mp. 69-71 °.

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

a) (2R, 3S) -2, 3-epoxy-3- (3-trifluoromethylphenyp-propanal

The title compound is prepared by: (Example 5a) from (2S, 3S) -2,3-epoxy-3- (3-trifluoromethylphenyl) propanol. Pale yellow liquid; IR

20 ι "^."

3 3 4 i "]

- 25 - '(CH ₂ Cl ₂ ): 2820, 1730, 1330, 1165, 1130, 1070 cm ^-1 , [α] ^ ° (chloroform,

0.20%) = 0.0 ± 5; [α] ²⁰ (chloroform, 0.20%) = 475.0 ± 5.0 °;

3 6 5

R = 0.44 (hexane / ethyl acetate 7: 3).

b) (IS, 2S) -I, 2 * -epoxy-1- (3-trifluoromethvlphenyl) -6- (4-acetyl-3-hydroxyprop-2- propylphenoxy) -hex-3 (Z) -ene .

The title compound is prepared analogously to Example ld) from the corresponding epoxyaldehyde according to a). Pale yellow OeI; R = 0.43 (hexane / ethyl acetate 3: 2).

Example 8 : (IS, 2R) -1-Hydroxy-1- (3-trifluorometh-1-phenyl) -6- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -hex-3 (Z) -en-1 - α-thio-A-oxo-AH-I-benzoic-2-carboxylic acid sodium sal2

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 7; Mp 239-241 °; [α] ²⁰ (methanol, 0.15%) = -60.7 ± 6.7 °; UV (methanol): λ. (Ε) = 216

ü ΤΠ3λι

(44080); 268 (22520); 285 (21640) 320 / sh.

Example 9 : (IR, 2S) -l-Hvdroxv-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene -2-vl-7-thio-4-oxo-4H-lbenzopvran-2-carbonsäuremethylester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E) 5 (Z) - diene prepared; light yellow powder of the mp. 71-72 °;

V (MeOH): λ (ε) = 217 (53

Max

(29120); 285 / sh; 325 (13200).

81.7 ± 8.7 ° (MeOH, 0.115%); UV (MeOH): λ (ε) = 217 (53680); 235 / sh;

Max

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

a) (2R.3R) -2,3-Epoxy-3- (3-methylphenyl) -propanol

The title compound is prepared analogously to Example 1a) from 3- (3-methylphenyl) prop-2 (E) -enol; colorless, tough oil; IR (CH ₂ Cl ₂ ) 3560, 3410, 2880, 2830, 1590, 1050 cm ^-1 , R _f = 0.39 (hexane / ethyl acetate 1: 1), [o] _D ²⁰ = 38.9 ± 5.3 ° (chloroform, 0.19% )

- 26 -

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

The title compound is prepared analogously to Example Ib) from the epoxy alcohol according to a); pale yellow powder, mp 60-61 °; IR (CH 2 Cl 2):

2920, 2820, 27AO, 1690 _:

(Hexane / ethyl acetate 4: 1)

2920, 2820, 27AO, 1690, 16A0, 1610, 1155, 1130-cm ¹ JR _f = 0.3A

c) (1R, 2R) -l, 2-epoxy-1- (3-methylphenyl) -8- (A-acetyl-3-hydroxyprop-2- propylphenoxv) -octa-3 (E), 5 (Z) -thien .

The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to a); pale yellow OeI; R = 0.63 (hexane / ethyl acetate 3: 2).

Example 10 : (1R, 2S) -1-Hydroxy-1- (3-methvlphenyl) -8- (A-acetyl-3-hydroxyprop-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene -2-vl-7-thio-4-oxo-4H-l-benzopvran-2-carboxylic acid sodium salt

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 9; beige powder of mp. 217 (decomp.); [a] ™ (methanol, 0.15%) = 71.3 + 6.7 °; UV (methanol):

λ (ε) = 219 (51520); 234 / sh; 267 (26A6O); 28A (23280); 322 / sh.

Max ·

Example 11 : (IS.2R) -l-Hvdroxv-1- (3-methvlphenyl) -8- (A-acetyl-3-hydroxyprop-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene -2-vl-7-thio-4-oxo-4H-l-benzopvran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (IS, 2S) -I, 2-epoxy-1- (m-tolyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) , 5 (Z) -dien produced; [a] ™ (MeOH, 0.148%) = -75.7 ± 6.8 °; UV (MeOH):

λ (ε) = 217 (51760); 240 / sh; 271 (27860); 290 / sh; 328 (12600). Max

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

a) (2S, 3S) -2,3-Epoxyc-3- (3-methylphenyl) -propanol

The title compound is prepared analogously to Example la) from 3- (3-methylphenyl) prop-2 (E) -enol, but using L (+) Weinsaurediäthylester; colorless oil; IR (CH ₂ Cl ₂ ): 3550, 3470, 2940, 2880, 2830, 1590, 1050 cm ^-1 , R = 0.31 (hexane / ethyl acetate 3: 2)

§ ρ 1 .ί Ι

-6 sj> jm

- 27 -

b) (AS, 5S) -A, 5-epoxy-5- (3-niethylphenyl) pent-2 (E) -enal .

The title compound is prepared analogously to Example Ib) from the epoxy alcohol according to a); pale yellow OeI; IR (CH ₂ Cl ₂ ): 2920, 2820, 2740, 1690, 1640,

ester 4: 1).

1690, 1640, 1610, 1155, 1130, 1085 cm ^l. R = 0.29 (hexane / acetic acid)

c) (IS, 2S) -I, 2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxyprop-2- propylphenoxy) -octa-3 (E), 5 (Z) -dia .

The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to b); pale yellow OeI; R = 0.51 (hexane / ethyl acetate 7: 3).

Example 12 : (IS, 2R) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxv-2-propylphenoxy) -octa-3 (E), .5 (Z) - dien-2-vl-7-thio-4-oxo-4H-l-benzopvran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 1 from the corresponding methyl ester according to Example 11; Mp 197-198 °; [A] ^ °

(0.14% methanol) = -72.1 ± 7.1 °, UV (MeOH): λ. (Ε) = 218 (50,700);

in 3 χ

235 / sh; 267 (25780); 285 (22,600); 321 (15000).

Example 13 : (IR, 2S) -1-hydroxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -hex-3 (Z) -en-2 yl-7-thio-4-oxo-4H-l-benzopvran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxyl- (3-tolyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en manufactured; colorless powder, mp. 136-138 ° [a] ^ ° = 28.1 ± 7.4 °

(Methanol, 0.135%) UV (methanol): λ (ε) = 271 (26020; 282 / sh;

Max

323 (13700).

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

a) (2S, 3R) -2,3-epoxy-3- (3-methylphenyl) -propanal.

The title compound is prepared analogously to Example 5a) from (2R, 3R) -2,3-epoxy-3- (3-methylphenyl) propanol; pale yellow OeI. IR (methylene chloride): 2920, 2820, 1730, 1610, 1140, 1070 cm ^-1 , R _f = 0.49 '(hexane / ethyl acetate 3: 2).

2A! "Tf. 1 * 3 *

2 53 6!

- 28 - ·

b) (IR, 2R) -I, 2-epoxy-1- (3-methyl-dithecl) -6- (4-acetyl-3-hydroxy-2- propylphenoxy) -hex-3 (Z) -ene .

The title compound is prepared analogously to Example ld) from the corresponding epoxyaldehyde according to a); pale yellow OeI; R_ = 0.73 (hexane / ethyl acetate 3: 2).

Example 14 : (IR, 2S) -I-hydroxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl 7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 13; beige powder of mp. 238-240 °; [a] ™ (methanol 0.135%) = 31.1 ± 7.4 °; UV (methanol):

λ (e) = 268 (21,800); 285 (20860); 322 / sh

 Max

Example 15 : (IR, 2S) -l-Hvd-roxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-ben2opvran-2-carbonsä * uremethvlester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxyl- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E), 5 (Z) dien produced; [a] ^ ° (methanol, 0.14%) = 27.9 ± 7.1 °; UV

(Methanol): λ (ε) = 221 (53560); 234 / sh; 270 (28980); 285 / sh; Max

326 (13860).

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

a) (2R, 3R) -2,3rEpoxv-3- (3-methoxycarbonylphenol) -propanol

The title compound is prepared analogously to Example la) from (E) -3-Methoxcarbonylzimtalkohol; pale yellowish oil; R _£ = 0.3 (hexane / Essigester 1: 1).

b) (AR, 5R) -4,5-Epoxyp-5- (3-methoxycarbonylphenyl) -pent-2 (E) -enal .

The title compound is prepared analogously to Example Ib) from the corresponding epoxyalkohl; pale yellow OeI; R _f = 0.35 (hexane / ethyl acetate 3: 2).

^: - 2: J3 6

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

The title compound is prepared analogously to Example ld) from the corresponding epoxyaldehyde according to b); tough yellow oil; R. = 0.50 (hexane / ethyl acetate 3: 2).

Example 16 : (1R, 2S) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene -2-vl-7-thio-oxo-A-AH-l-benzopvran-2-carboxylic acid sodium salt. The title compound is prepared analogously to Example 2 from (1R, 2S) -1-hydroxyl- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E), 5 (Z ) -dien-2-yl-7-thio-4-oxo-AH-1-benzopyran-2-carboxylic acid methyl ester prepared according to Example 15; light brown powder of mp. 181 (Zers.); [a] ^ ° (Nethanoi, 0.15%) = 32.0 ± 6.7 °; UV (methanol):

λ (ε) = 222 (51600); 232 / sh; 26-7 (24160); 284 (22940); 320 / sh .; 400 / sh. Max

Example 17 : (1S, 2R) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E) -5 (Z) -diene -2-vl-7-thio-4-oxo-4H-l-berizopyran-2-carbonsäuremethylester.

The title compound is prepared analogously to Example 1 from (IS, 2S) -I, 2-epoxyl- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien prepared; Mp 77-78 ° (colorless powder)

[α] ²⁰ (methanol, 0.15%) = -52.7 + 6.7 °; UV (methanol): λ (ε) = D max

(57420); 235 / sh; 271 (29980); 288 / sh; 326 (14320). The starting material is e.g. made as follows:

a) (2S, 3S) -2,3-Epoxyc-3- (3-methoxycarbonylphenyl) -propanol

The title compound is prepared analogously to Example la) from (E) -3-Methoxcarbonylzimtalkohol, but using L (+) Diethyl tartrate; colorless oil; R _£ = 12:48 (hexane / Essigester 1: 1).

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

The title compound is analogous to Example Ib) from the corresponding

f.

2 8 3 -5 i.

Epoxyalkaline produced; colorless oil; IR (methylene chloride): 3050, 2990 ,. 2945, 2820, 2730, 1725, (hexane / ethyl acetate 3: 2).

2945, 2820, 2730, 1725, 1695, 1640, 1290, 1255 cm ¹ JR _f = 0.34

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

The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to b); pale yellow OeI; R = 0.54 (hexane / ethyl acetate 3: 2).

Example 18 : (IS, 2R) -l-Hvdroxv-1- (3-methoxycarbonylphenyl) -8- (A-acetyl-3-hydroxyprop-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene -2-vl-7-thio-4-oxo-4H-l-benzopvran-2-carboxylic acid Natriumsal2. The title compound is prepared analogously to example 2 from the corresponding methyl ester according to example 17; beige powder of mp. 174-176 °; [a] ²⁰ (methanol, 0.155%) = -80.6 ± 6.5 °; UV (methanol):

λ (ε) = 223 (59,300); 235 sh .; 267 (27300); 284 (24,800); 321 (16200). Max

Example 19 : (IR.2S) -l-hydroxy-1- (3-methoxycarbonylohenyl) -6- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -hex-3 (Z) -en-2-vinyl-1-one 7-thio-4-oxo-4H-1-benzopvran-2-carbonsauremethvlester

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2REpoxyl- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en; colorless oil; [et] * ⁰ = (methanol, 0.11%) = 24.5 ± 9.1 °; UV (methanol): λ (ε) = 270 (22400); 322 (12000).

Max

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

a) (2S, 3R) -2,3-Epoxyc-3- (3-methoxycarbonylphenyl) -propanal The title compound is prepared analogously to Example 5a) from (2R, 3R) -2,3-epoxy-3- (3-methoxycarbonylphenyl ) -propanol; pale yellow OeI; IR (methylene chloride): 2950, 2820, 1725, 1610, 1590, 1430, 1290, 1255 cm ^-1 , \ _f = 0.33 (hexane / ethyl acetate 3: 2)

i tt -1 VWJ ' iJ ' if 1 · tj i. ^

2 83 6 ί

- 31 - ·

b) (IR, 2R) -I, 2-epoxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy- 2-propylphenoxv) -hex-3 (Z) -ene .

The title compound is prepared analogously to Example ld) from the epoxyaldehyde according to a); pale yellow OeI; R = 0.39 (hexane / ethyl acetate 3: 2).

Example 20 : (IR, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (A-acetyl-3-hydroxyprop-2-propylphenoxy) -hex-3 (Z) -en-2 vl-7-thio-A-oxo-4H-1-benz-2-pyran-2-carboxylic acid sodium salt (A), and (1R, 2S) -l-hydroxypropyl-1 - (- 3-carboxy-phenyl) -6- (4- acetyl-3-hydroxyprop-2-propylphenoxv) -hex-3 (Z) -en-2-vl-7-thio-A-oxo-4H-1-ben2opyran-2-carboxylic acid dinatrium salt (B).

The solution of 0.5 g of (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (A-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en- 2-yl-7-thio-A-oxo-AH-1-benzopyran-2-carboxylic acid methyl ester according to Example 19 in 20 ml tetrahydrofuran is stirred under argon AO hours with 7.5 ml of 0.2N sodium hydroxide solution at room temperature and then evaporated Residue is purified by chromatography on Lichroprep® RP-8, Merck with methanol / water (3: 1) and yields in Fractions 2-5 the title compound B, mp 262-26A ⁰ ; [α] * ^α (methanol, 0.105 %) = 17.1 ± 9.5 °, UV (methanol):

λ (ε) = 268 (19680); 28A (19060); 325 / sh; and in fractions 8-12 the max

Title compound A; Issue 155 (Zers.); [a] ^ ° (methanol, 0.12%)

22.5 ± 8.3 °; UV (methanol): λ (ε) = 268 (26200); 286 (29220); 325 / sh.

Max

Example 21 : (IS, 2R) -l-Hvdroxv-1- (3-methoxycarbonylphenvl) -6- (A-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-vinyl-1-one 7-thio-oxo-A-AH-l-benzopvran-2-carbonsäuremethvlester

The title compound is prepared analogously to Example 1 from the (IS, 2S) -I, 2-epoxyl- (3-carboxymethylphenyl) -6- (A-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) - made; colorless oil, which solidifies in the refrigerator, mp 90-91 °; [o]. ^ ° = -41.517.7 ° (0.13% methanol); UV (methanol):

λ (ε) = 271 (25120); 322 (13280).

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

L Gi, ii ·. '. L ι i U «"t> L ti t \ >> -.

• Λ

IBS 6 ί

- 32 - ·

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

The title compound is prepared analogously to Example 5 from (2S, 3S) -2,3-epoxy-3- (3-methoxycarbonylphenyi) propanol; colorless oil; IR (methylene chloride): 2910, 2780, 1705, 1590, 1570, 1415, 1270, 1235 cm ^-1 , R _f = 0.36 (hexane / ethyl acetate 3: 2).

b) (IS, 2S) -I, 2-Epoxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -hex-3 (Z) -ene .

The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to a); colorless OeI, not further characterized.

Example 22 : (IS, 2R) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2 vl-7-thio-4-oxo-4H-l-benzopvran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 21; beige powder of the mp 208-210 °; [a] jL ° (methanol, 0.12%) = -41.7 + 8.3 °, UV (methanol):

λ (ε) = 268 (21060); 285 (21540); 325 / sh

 Max

Example 23 : (AR, 5S) -1,1,1-trifluoro-4-hydroxypropyl-1- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) - dien-5-vl-7-thio-4-oxo-4H-l-benzopvran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-II- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E. ), 8 (Z) -dien; beige powder of mp. 64-66 °, [u] l ° (methanol 0.15%) = 147.3 + 6.7 °. UV (methanol): λ (ε) = 220 (48960);

Max

270 (28500); 283 / sh; 325 (13400).

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

a) (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanol.

The title compound is prepared analogously to Example la) from the 6,6,6-trifluorohex-2 (E) -enoi; colorless oil; [a] 2 ° (chloroform, 0.17%) = 35.9 ± 5.9 °; IR (methylene chloride): 3550, 3420, 2950, 2890, 2830,

1125 cm " ¹ .

& U ill.i -'.- ·

Λ -> -Λ /

I υ, 5 ο

- 33 -

b) (4R, 5R) -4,5-epoxy-8,8,8-trifluoro-oct-2 (E) -enal.

The title compound is prepared analogously to Example Ib) from the corresponding epoxy alcohol according to a); pale yellow OeI; IR (CH 2 Cl 2): 3050, 2980, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm ^-1 , R = 0.41 (hexane / ethyl acetate = 3: 2).

c) (4R, 5R) -4,5-epoxy-1, 1, 1-trifluoro-II- (4-acetyl-3-hydroxypropyl-2- propylphenoxy) -undeca-6 (E), 8 (Z) -thien .

The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to b); pale yellow OeI; R _£ = 12:48 (hexane / Essigester 3: 2).

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

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 23; beige powder, mp 198-200 °, [a] ^ ° (methanol, 0.15 X) = 127.3 ± 6.7 °; UV (methanol):

λ (ε) = 221 (48,820); 230 / sh .; 267 (25440); 285 (23080); 322 / sh. Max

Example 25 : (4S, 5R) -I, 1,1-Trifluoro-4-hydroxy-II- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -undeca-6 (E), 8 (Z) -diene-5-v1-7-thio-4-οχο-4H-l-benzopyran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (4S, 5S) -4,5-epoxy-1,1,1-trifluoro-II- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E) , 8 (Z) -dien prepared; colorless powder of mp. 69-71 °; [«] I ° = -153.3 ± 6.7 ° (methanol, 0.15 X). UV (methanol): λ (ε) = 220 (49560);

Max

235 / sh; 270 (29220); 285 / sh; 325 (12990).

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

a) (2S, 3S) -2,3-epoxy-6,6,6-trifluoro-hexanol The title compound is prepared analogously to Example 1a) from 6,6,6-trifluorohex-2 (E) -enol, but using of L (+) tartaric acid diethyl ester; colorless oil; [a] ^ ° (chloroform 0.17 X) = -25.9 ± 5.9 °; IR (methylene chloride): 3550, 3430, 2940, 2880, 2830, 1125 cm ^-1 .

- 34 -

"b) (4S, 5S) -4,5-Epoxy-S, 8,8-trifluoro-oct-2 (E) -enal.

The title compound is prepared analogously to Example Ib) from the corresponding epoxy alcohol according to a), pale yellow OeI; IR (methylene chloride) 5050, 2990, 2930, 2820, 2730, 16! R _f = 0.36 (hexane / ethyl acetate 3: 2)

3050, 2990, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm Λ

c) (4S, 5S) -4,5-epoxy-1,1,1-trifluoro-1-1- (4-acetyl-3-hydroxyprop-2- propylphenoxy) -undeca-6 (E), 8 ( Z) -dies .

The title compound is prepared analogously to Example Id) from the corresponding epoxyaldehyde according to b); pale yellow OeI.

Example 26 : (4S, 5R) -1,1,1-Trifluoro-4-h, vydroxy-ll- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) -diene-5-yl-7-thio-4-oxo-4H-l-benzopvran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 25; beige "powder of mp 201-203 °; [α] ™ (methanol, 0.15%) = -117.3 ± 6.7 °; UV (methanol):

λ (e) = 222 (48320); 233 / sh .; 267 (26440); 285 (24440); 330 / sh. Max

Example 27 : (AR, 5S) -I.1,1-Trifluoro-4-hydroxy-9- (4-acetyl-3-hydroxyprop- 2-propylphenoxy) -non-6 (2) -ene-5-vinyl- 7-thio-4-oxo-4H-l-benzopvran-2-carbonsa'uremethvlester.

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

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

a) (2S, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanal The title compound is prepared analogously to Example 5a) from the (2R, 3R) -2,3-epoxy-6,6,6 trifluoro-hexanol prepared, colorless liquid of boiling point 8O-81 ° / 26 mbar .; [α] ™ (chloroform, 0.15%) = -10.7 ± 6.7 °.

- 35 -

b) (4R, 5R) -4,5-epoxy-1, 1,1-trifluoro-9- (A-

phenoxy) -non-6 (Z) -en .

The title compound is prepared analogously to Example ld) from the epoxyaldehyde according to a); pale yellow OeI.

Example 28 : (4R, 5S) -I, 1,1-trifluoro-A-hydroxy-g-CA-acetyl-S-hydroxy- 2-propylphenoxy) -non-6 (Z) -en-5-yl-7 -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 27; light yellow powder, mp 20A-206 ⁰ ; [a] ™ (methanol, 0.15%) = 42.7 ± 6.7 °, UV (methanol):

λ (ε) = 218 (36,920); 268 (20280); 285 (20180); 325 / sh.

Example 29 : (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyldhenoxv) - __. dodec-7 (Z) -en-6-yl-7-thio-4-oxo-4H-1-benzopvran-2- carboxylic acid methacrylate.

The title compound is prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7- (Z) -en; pale yellow OeI; R = 0.37 (hexane / ethyl acetate 1: 1).

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

a) 5- (4-Acetyl-3-hydroxy-2-propylphenoxy) pentyl-triphenylphosphonium bromide

The title compound is prepared as in Example Ic) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentylbromide; colorless crystals of mp. 82-85 °.

b) (2S, 3R) -2,3-epoxy-heptanal .

The title compound is prepared analogously to Example 5a) from (2R, 3R) -2,3-epoxyheptanol; [a] ™ = -99.4 + 0.1 °.

c) (5R ₁ 6R) -5,6-Epoxyd-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7- (Z) -ene .

The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to a), pale yellow oil.

2 a 3 6 Ί

- 36 -

Example 30 : (5R, 6S) -5-Hydroxy-12- (4-acetyl-3-hydroxv-2-propylphenoxv) -dodec-7 (Z) -en-6-yl-7-thio-1-oxo -AH-l-ben2opyran-2-carboxylic acid sodium salt. ' ,

The title compound is prepared analogously to example 2 from the corresponding methyl ester according to example 29; Mp 192-194 °; [&] 1 ° (methanol, 0.125%) = +5.6 + 8.0 °; UV (methanol): λ (ε) = 218 (38,000);

Max

(22040); 285 (21120); 325 sh.

Example 31 : (5S, 6R) -5H-Hydroxy-12- (4-acetyl-3-hydroxyprop-2-propylphenoxv) -dodec-7 (Z) -en-6-yl-7-thio-4-oxo 4H-l-ben2opvran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) dodec-7- (Z) -en; pale yellow OeI; R _f = 0.41 (hexane / ethyl acetate 1: 1).

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

a) (2R, 3S) -2,3-epoxy-heptanal . '.

The title compound is prepared analogously to Example 5a) from (2S, 3S) -2,3-epoxyheptanol; [ci] ² ° = +104.3 + 0.4 °.

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

The title compound is prepared analogously to Example Id) from the epoxyaldehyde according to a); light yellow oil, R = 0.42 (hexane / ethyl acetate 3: 2).

Example 32 : (5S, 6R) -5-Hydroxy-12- (4-acetyl-3-hydroxv-2-propylphenoxv) -dodec-7 (Z) -en-6-vl-7-thio-4-oxo 4H-l-benzopyran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 31; Mp 192-194 °; [α] ²⁰ (methanol, 0.145%) = 0 + 6.9 °; UV (methanol): λ (ε) = 218 (37060); 268

ΓΠ3Χ

(21760); 286 (20520); 325 sh.

no i? rw L Cs. .! Ί -., Ί.

2 83 ^ 17

- 37 -

Example 33 : (AR, 5S) -1,1,1-Trifluoro-A-hydroxy-1-1- (A-acetyl-3-hydroxy- 2-propylphenoxy) -undec-6 (Z) -en-5 y1-7-thio-oxo-A-AH-I-benzopyran-2-carbonsäuremethvlestpr

The title compound is prepared analogously to Example 1 from (AR, 5R) -A, 5-epoxy-1, Γ, 1-trifluoro-II- (A-acetyl-3-hydroxy-2-propylphenoxy) -undec-6 (Z) -en prepared, light yellow OeI; R _f = 0.A7 (hexane / ethyl acetate 1: 1).

The starting material is e.g. analogous to Example Id) prepared from (2S, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanal; pale yellow OeI.

Example 3A : (AR, 5S) -I, 1,1-trifluoro-A-hydroxv-1l- (A-acetyl-3-hydroxy- 2-propylphenoxy) -undec-6 (Z) -en-5 vl-7-thio-oxo-A-AH-l-benzopvran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 33; Mp 193-195 °; M * ⁰ (methanol, 0.135%) = + 16.3 ± 7.A °; UV (MeOH): λ (ε) = 218 (37380),

Max

(21380), 286 (21020), 325 / sh.

Example 35 : (5R.6S) -5-Hydroxy-10- (A-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (2) -en-6-yl-7-thio-A- oxo-AH-I-benζopvran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-10- (A-acetyl-3-hydroxy-2-propylphenoxy) dec-7 (Z) -enes, pale yellow OeI; [a] * ° (methanol, 0.135%) = + A8.9 ± 7.A °, UV (methanol):

λ (ε) = 216 (381A0); 271 (2A0A0); 285 sh, 322 (12700). Max

The starting material is prepared, for example, analogously to Example Id) from (2S, 3R) -2,3-epoxy-heptanal; pale yellow OeI. R _f = 0.A5 (hexane / ethyl acetate 7: 3).

Example 36 : (5R, 6S) -5-hydroxy-10- (A-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7-thio-A-oxo AH-l-benzopyran-2-carboxylic acid.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 35 and with hydrochloric acid

0 0 '? w 7 -Ui QQ

L Ca in ";!. Iv / Qj

, 2 8 3 6 y

- 38 - ·

converted to the free acid; Snip. 58-60 °; [aU ⁰ (methanol, 0.130%) = + 36.2 ± 7.7 °; UV (methanol): λ (ε) = 218 (35240); 269 (20760); 283

Max

(19800); 330 sh. ,

Example 37 : (5S, 6R) -5-Hvdroxv-10- (4-acetyl-3-hydroxy-2-propylphenoxv) -dec-7 (Z) -en-6-vl-7-thio-4-oxo 4H-r-benzopvran-2-carbonsäuremethylester

The title compound is prepared analogously to Example 1 from (5S, 6S) -5,6-epoxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) dec-7 (Z) -enes, pale yellow oil; [et] ^ ⁰ (methanol, 0.115%) = -50.4 ± 8.7 °; UV (MeOH):

λ (ε) = 217 (38,000); 271 (24100); 285 sh, 321 (12800).

The starting material is e.g. analogous to Example Id) prepared from (2R, 3S) -2,3-epoxy-heptanal; light brown OeI; R = 0.52 (hexane / ethyl acetate 7: 3).

Example 38 : (5S, 6R) -5-Hvdroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxv) -dec-7 (Z) -en-6-yl-7-thio-4-oxo 4H-l-benzopvran-2-carboxylic acid Katriumsalz. , ^.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester according to Example 37; Mp 224-226 °, [cc] * ⁰ (methanol, 0.145%) = -29.0 + 6.9 °; UV (methanol): λ (ε) = 219 (38760);

Max

(21880); 285 (21260); 325 sh.

Example 39 : (5S.6R) -5-Hvdroxy-10- (4-acetyl-3-hydroxy-2-propyl-d-methoxy) -dec-7 (Z) -en-6-yl-7-thio-4-oxo 4H-1-benzopvran-2- (N -benzenesulfonamidecarboxamide.

The solution of 0.20 g of (5S, 6R) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) dec-7 (Z) -en-6-yl-7-thio-4- oxo-4H-1-benzopyran-2-carboxylic acid in 10 ml of methylene chloride is stirred under argon with 60 mg of benzenesulfonamide, 44 mg of 4-dimethylaminopyridine and 70 mg of N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride for 24 hours Room temperature stirred. The resulting solution is diluted with 30 ml of methylene chloride, washed twice with 1N-hydrochloric acid and 2 times with brine, over magnesium sulfate

2 B3 6 1

• - 39 -

dried and evaporated. Chormatography of the residue on silica gel with methylene chloride / methanol (9: 1) yields the title compound of mp 140-142 °. ,

Example 40 : (4RS, 5SR) -1-Methoxycarbonyl-4-hydroxv-9- (4-acetyl-3- hydroxv-2-propylphenoxy) -non-6 (Z) -en-5-vl-7-thio 4-oxo-4H-l-benzopvran-2-carbonsäureniethvlester.

The title compound is prepared analogously to Example 1 from (4RS, 5RS) -4,5-epoxy-methoxycarbonyl-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z) -en; colorless oil; [a] ^ ° (methanol, 0.125%) = 0.0 + 8.0 °, UV

(Methanol): λ (ε) = 270 (24,000); 340 (13200). Max

The starting material is e.g. prepared analogously to Example 1 d) from 5,6-epoxy-6-formylhexansäuremethylester; pale yellow OeI; R ^ = 0.35 (hexane / ethyl acetate 3: 2).

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

0.24 g of the methyl ester according to Example 40 are dissolved under argon in 15 ml of tetrahydrofuran, mixed with 3.8 ml of 0.2N sodium hydroxide solution and stirred for 20 hours at room temperature. Evaporation and chromatographic purification of the residue on a reversed phase silica gel column (e.g., Merck Lichroprep® RP-8) with methanol / water (7: 3) gives the title compound of mp 248-250 ° (dec.); UV (methanol):

λ (e) = 218 (33,900); 268 (18580); 284 (18240); 330 sh. Max

Example 42 : (IR, 2S) -l-hydroxy-1- (3-trifluoromethyl-phenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo-4H-l-benzopvran-2-carbonsäuremethylester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxyl- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E), 5 (Z) -dien produced; pale yellow OeI. [Cl ^ O 0.363%) = 46.6 ± 2.8 ° UV (CHCl ₃ ): λ (ε) = 270 (265

Max

322 (15200).

• .2835.1

  - 40 - · ·

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

a) (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - serving. The title compound is prepared analogously to Example Id from 5- (A-acetyl-3-hydroxy-2-propylphenoxy) pentyltriphenylphosphonium bromide (Example 29a) and (AR, 5R) -A, 5-epoxy-5- (3-trifluoromethylphenyl) - pent-2 (E) -enal (Example Ib) prepared; light brown OeI;

0.224%) = 70.8 + 1.0 ° R _f = 0.50 (hexane / ethyl acetate = 1: 1) IR (CH ₂ Cl ₂ ): 2960, 2930, 2865, 1735, 1625, 1330, 1125.Cm " ¹ .

Example A3 : (IR, 2S) -I-hydroxy-1- (3-trifluoromethylphenol) -10- (A-acetyl-3-hydroxyprop-2-propylphenoxy) -deca-3- (E), 5 (Z) - dien-2-yl-7-thio-4-BXO-4H-l-benzopyran-2-carboxylic acid sodium salt. The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 42); Mp 217-219 °; [a] ^ ° (MeOH;

0.160%) = 145.6 ± 6.3 ° UV (MeOH): λ (ε) = 220 (50480), 230 (sh),

Max

267 (26240), 284 (23000), 320 (sh).

Example A4 : (IR.2S) -l-hydroxy-1- (3-methvl-phenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo-4H-1-benzopvran-2-carbonsauremethvlester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E) , 5 (Z) -dien produced; Mp 59-60 °; [ex] ² ^ (CHCl ₃ , 0.163%)

31.9 + 6.1 °; UV (CHCl _3): λ (ε) = 241 (31A20); 286 (23060).

Max .

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

a) (IR, 2R) -I, 2-epoxy-1- (3-methylphenyl) -10- (A-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - serving.

The title compound is prepared analogously to Example Id from 5- (A-acetyl-3-hydroxy-2-propylphenoxy) pentyltriphenylphosphonium bromide (Example 29a) and (AR, 5R) -A, 5-epoxy-5- (3-methylphenyl) - pent-2 (E) -enal (Example 9b) prepared; pale yellow OeI; [a] ^ ° (CHCl ₃ , 0.273%) = 118.7 ° ± 3.7.

R _f = 0.62 (hexane / ethyl acetate = 3: 2).

2 a IuU 12 3

2-334 ί

• - 41 - ·

Example 45 : (IR, 2S) -l-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-benzopvran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 44); Mp 208-210 °; ["Ii ⁰ (MeOH, 0.30%) = 50.7 ± 3.3 ° UV (MeOH): λ (ε) = 219 (52420), 230 (sh), 267

wax

(26620), 285 (23520), 325 (sh).

Example 46 : (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene -2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (IS, 2S) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca (3E), 5 (Z) -dien prepared; tough mass;

R = 0.48 (hexane / ethyl acetate = 1: 1).

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

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

The title compound is prepared analogously to Example Id from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyltriphenylphosphonium bromide (Example 29a) and (4S, 5S) -4,5-epoxy-5- (3-trifluoromethylphenyl) - prepared pent-2 (E) -enal (Example 3b); pale yellow OeI; [α] * ⁰ (chloroform, 0.454% = -86.8 + 2.2 °, R = 0.46 (hexane / ethyl acetate = 1: 1) IR (methylene chloride): 2960, 2930, 1730, 1625, 1330, 1130 cm ^-1 .

Example 47 : (IS, 2R) -l-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo-AH-1-ben2opyran-2-carboxylic acid sodium salt The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 46); Mp 168-170 °; [A] ^ ° (methanol,

0.150%) = -66.7 ± 6.7 °; UV (MeOH): λ (ε) = 220 (49640), 230 (sh),

Max

(25640), 285 (22140), 320 (sh).

i83 6 ί

• - 42 -

Example 48 : (IR, 2S) -I-Hvdroxy-1-C3-trifluoromethylphenyl) -8- [4-acetyl-3- hydroxv-2- (3,3,3-trifluoropropyl) -phenoxy] -octa-3 ( e), 5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benζopyran-2-carbonsaureinethvlester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -octa-3 (E), 5 (Z) -dien; pale yellow OeI; R _f = 0.34 (hexane / ethyl acetate = 1: 1).

The starting material is E.B. made as follows:

a) (IR, 2R) -I, 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 is prepared analogously to Example Id from 3- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] propyltriphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal (Example Ib); pale yellow OeI; [all ⁰ (chloroform, 0.406%) = -58.6 + 2.5 °; R _f = 0.45 (hexane / ethyl acetate = 7: 3). IR (methylene chloride: 2945, 1670, 1610, 1310, 1055 cm ^-1) .

b) 3- [4-Acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] propyl-triphenylphosphonium bromide.

The title compound is prepared analogously to Example Ic from 3- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] propyl bromide. Mp. 184-185 °.

Example 49 : (IR, 2S) -I-Hvdroxv-1- (3-trifluoromethylphenyl) -8-f4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -octa-3 ( e), 5 (Z) -diene ^ -yl ^ -oxo ^ Hl ^ -thio-benzopyran ^ -carboxylic acid, sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 48); Mp 238-240 °; [α] ^ ° (methanol, 0.150%) = 208 ± 6.6 °; UV (MeOH): λ (ε) = 216 (50040), 230 (sh), 267

ΓΠ3Χ

(28960), 280 (sh), 320 (16020).

ili ι ί 4. SvJW -ii ^ i ^ t iS '

2-6 3.6) 7

- A3 - ·

Example 50 : (IR, 2S) -1-Hydroxy-1- (3-methylphenyl) -8- [A-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxv] -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-A-oxo-AH-1-benzopvran-2-carboxylic acid ^ ester! The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-methylphenyl) -8- [A-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -octa-3 (E), 5 (Z) -dien; pale yellow tough oil; R _£ = O.Al (hexane / ethyl acetate = 1: 1). [α] * ° (chloroform, 0.155%) = 32.3 ± 6.5 °. UV (chloroform): λ (ε) = 271 (32320), 318 (16100).

Max . ... ·.

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

a) (IR, 2R) -I, 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 is prepared analogously to Example Id from 3- [A-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] propyltriphenylphosphonium bromide (Example A3b) and (AR, 5R) -A, 5- Epoxy-5- (3-methylphenyl) pent-2 (E) -enal (Example 9b), light yellow OeI; R = 0.38 (hexane / ethyl acetate = 3: 2).

Example 51 : (IR, 2S) -l-Hvdroxv-1- (3-methvlphenyl) -8- [A-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] octa-3 (e), 5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt. The title compound is prepared analogously to Example 2 from the corresponding Mechylester (Example 50); Mp 233-235 °; [ot] * ° (methanol, 0.195%) = 69.7 ± 5.1 °; UV (MeOH): λ (ε) = 218 (52320), 230 (sh),

Max

(290A0), 280 (sh), 320 (16000).

Example 52 : (IR, 2S) -l-hydroxy-1- (2-trifluoromethylphenyl) -8- (A-acetyl-3-hydroxyprop-2-propyl-phenoxy) -octa-3 (E), 5 ( Z) ^ dien-2-yl-7-thio-A-QXO-AH-I -ben ζ-opyran-2-carbon acid pure thy le st er.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (2-trifluoromethylphenyl) -8- (A-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E) , 5 (Z) -dien produced; Mp 66-68 ° R = 0.23 (hexane / ethyl acetate = 3: 2). [a] ^ ⁰ (methanol, 0.150%) = 22.0 ± 6.7 °; UV (MeOH): λ (ε) = 216 (50,000), 238 (sh), 271 (27860), 285 (sh), 32A (13900).

1 33ΰ!

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

a) (IR, 2R) -1,2-E-poxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-p-rhenoxy) -octa-3 (E), 5 (Z ) -diene.

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propyltriphenylphosphoniumbromid (Example Ic) and (4R, 5R) -4,5-epoxy-5- (2-trifluoromethylphenyl ) -pent-2 (E) -enal; light brown OeI; [a] ™ (chloroform, 0.207%) = -5.8 + 4.8 ° R _f = 0.25 (hexane / ethyl acetate = 4: 1).

b) (4R, 5R) -4.5-epoxy-5- (2-trifluoromethyl-phenyl) -pent-2 (E) -enal.

The title compound is prepared analogously to Example Ib from (2R, 3R) -2,3-epoxy-3- (2-trifluoromethylphenyl) propanol; yellow crystals; R = 0.36 (hexane / ethyl acetate = 4: 1). [et] ™ (methanol, 0.165%) = 23.0 ± 6.1; UV (MeOH): λ (ε) = 216 (14400), 235 (17240).

ΙΏ3Χ

c) (2R, 3R) -2,3-epoxy-3- (2-trifluoromethylphenyl) -propanol. The title compound is prepared analogously to Example 1a from 3- (2-trifluoromethylphenyl) prop-2 (E) -enol; colorless crystals; R = 0.38 (hexane / ethyl acetate = 3: 2); IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm ^-1 .

Example 53 : (IR.2S) -l-Hvdroxv-1- (2-trifluoromethvlphenyl) -8- (4-acetyl-3-hydroxv-2-propyl-phenoxy) -octa-3 (E) .5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benzopvran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 52); Mp 155-157 °; [et] * ⁰ (methanol, 0.180%) = 12.8 ± 5.6 °; UV (MeOH): λ (ε) = 219 (48400), 230 (sh), 266

Max

(25480), 284 (22540), 325 (sh).

Example 54 : (1S-2R) -1-hydroxy-1- (2-trifluoromethvlphenyl) -8- (4-acetyl-3-hydroxyprop-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (IS, 2S) -1,2-epoxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa

Λ - j n / Jf

- 45 -

3 (E), 5 (Z) -dien prepared; Mp 71-73 °; R _£ = 12:25 (hexane / Essigester = 3: 2). [a] ™ (methanol, 0.170%. = -27.1 + 5.9 °; UV (MeOH):

X (ε) = 216 (51040), 235 (sh), 271 (28140), 285 (sh), 324 (13500).

Max . ,

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

a) (IS, 2S) -I, 2-epoxy-1- (2-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -diene.

The title compound is prepared analogously to Example Id from 3 - (. 4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example Ic) and (4S, 5S) -4,5-epoxy-5- (2 -trifluoromethylphenyl) -pent-2 (E) -enal; reddish oil; [a] J ° (chloroform, 0.207%) = 5.4 ± 4.8 °; R _f = 0.29 (hexane / ethyl acetate = 4: 1).

b) (4S, 5S) -4,5-epoxy-5- (2-trifluoromethylphenyl) pent-2 (E) -enal. The title compound is prepared analogously to Example Ib from (2S, 3S) -2,3-epoxy-3- (2-trifluoromethylphenyD-propanol; yellow crystals; R = 0.38 (hexane / ethyl acetate = 4: 1); [a] £ ° (methanol, 0.180%) = -25.0 ± 5.6 °; UV (MeOH): λ (c) = 215 (13960), 236 (17060).

Max

c) (2S, 3S) -2,3-epoxy-3- (2-trifluoromethylphenyl) -propanol. The title compound is prepared analogously to Example 1a from 3- (2-trifluoromethylphenyl) prop-2 (E) -enol; colorless crystals; R _f = 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-trifluoromethvlphenylene) -8- (A-acetyl-3-hydroxyprop-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene-2-yl-7-thio-4-oxo-4H-l-benzopvran-2-carboxylic acid sodium salt

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 54); Mp 182-184 °; [a] i ° (methanol, 0.205%) = -16.6 + 4.9 °; UV (MeOH): λ (ε) = 219 (47680), 235 (sh),

Max

(24960), 284 (22100), 330 (sh).

Example 56 : (1R, 2S) -l-hydroxy-1- (^ -trifluoromethylphenyl) -8- (A-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-A-oxo-AH-1-bGnzopyran-2-carboxylic acid diethyl styrene.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (A-trifluoromethylphenyl) -8- (A-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 ( E), 5 (Z) -dien prepared; Mp 68-70 ° R _f = 0.16 (hexane / ethyl acetate = 3: 2). [ct] ^ ° (methanol, 0.155%) = 110.3 + 6.5 °; UV (MeOH): λ (ε) = 217 (52880), 236 (sh), 270 (28880), 285 (sh), 326 (13700).

ITl 3X

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

a) (IR, 2R) -I, 2-epoxy-1- (A-trifluoromethyl-phenyl) -8- (A-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -diene.

The title compound is prepared analogously to Example Id from 3- (A-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example Ic) and (AR, 5R) -A, 5-epoxy-5- (A-) trifluoromethylphenyl) pent-2 (E) -enal; yellow OeI; [a] V> (chloroform, 0.220%) = 6.5 ± 4.5 °; R = 0.35 (hexane / ethyl acetate = A: l).

b) (AR, 5R) -A, 5-epoxy-5- (A-trifluoromethylphenyl) -pent-2 (E) -enal.

The title compound is prepared analogously to Example Ib from (2R, 3R) -2,3-epoxy-3- (A-trifluoromethylphenyD-propanol; yellow crystals, mp 67-70 °, R = 0.2A (hexane / ethyl acetate = 4 : 1). [ A] ² J (methanol,

0.150%) = 171.3 ± 6.7 °; UV (MeOH): λ (ε) = 237 (19660).

Max

c) (2R, 3R) -2,3-epoxy-3- (A-trifluoromethyl-phenyl) -propanol.

The title compound is prepared analogously to Example 1a from 3- (A-trifluoromethylphenyl) prop-2 (E) -enol; colorless crystals; R ,. = 0.25 (hexane / ethyl acetate = 3: 2). IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm ^-1 .

Example 57 : (IR, 2S) -I-H-hydroxy-1- (A-trifluoromethyl-phenyl) -8- (A-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene-2-yl-7-thio-A-oxo-AH-l-benzopvran-2-carboxylic acid sodium salt. _:

The title compound is analogous to Example 2. the corresponding methyl ester (Example 56); Mp 229-231 °; [a] ^ ° (methanol,.

2A:;, R. M. ^ 39 * ä & s3-i2

2 836 i'-γ

- 47 -

0.160%) = 118.8 ± 6.3 °; UV (MeOH): λ (ε) = 220 (53060), 235 (sh),

Max

267 (27280), 284 (23880), 320 (16300).

Example 58 : (1S.2R) -l-Hvdroxv-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxypropyl-3-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (IS, 2S) -1,2-epoxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 ( E), 5 (Z) -dien prepared; M.p. 67-69 °; R _f = 0.13 (hexane / ethyl acetate = 3: 2). [a]? ° (methanol, 0.155%) = -109.7 ± 6.5 °; UV (MeOH):

λ (ε) = 217 (52640), 235 (sh), 270 (28660), 285 (sh), 326 (13680).

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

a) (IS, 2S) -I, 2-epoxy-1- (4-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -diene.

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example Ic) and (4S, 5S) -4,5-epoxy-5- (4- trifluoromethylphenyl) pent-2 (E) -enal; reddish oil; [ct] ^ ° (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 is prepared analogously to Example Ib from (2S, 3S) -2,3-epoxy-3- (4-trifluoromethylphenyD-propanol; yellow crystals, mp 67-69 °, R _f = 0.18 (hexane / ethyl acetate = 4 : 1). [Ct] ^ ° (methanol,

0.150%) = -180.0 ± 6.7 °; UV (MeOH): λ (ε) = 236 (19740).

Max

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

2 3 3 6 ί

· 48 ·

Example 59 : (IS, 2R) -l-Hvdroxv-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3- hydroxy-2-propyl-phenoxv) -octa-3 (E), 5 (Z ) -diene-2-yl-7-thio-4-oxo-4H-1-benζopyran-2-carboxylic acid NatriumsaIz.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 58); Mp 228-230 °; [et] * ⁰ (methanol, 0.175%) = -99.4 ± 5.7 °; UV (MeOH): λ (ε) = 220 (49800), 235 (sh), 267

Max

(25320), 284 (22200), 320 (15600).

Example 60 : (IR, 2S) -11-Hydroxv-1- (3-trifluoromethvlphenyl) -8- (4-acetyl-3-hydroxv-2-propyl-phenoxy) -octa-3 (Z) -en-2 vl-7-thio-4-oxo-4H-l-benzopvran-2-carbonsäureniethvlester. -

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-Zpoxyl- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (Z) -en produced; colorless oil; R _f = 0.41 (hexane / ethyl acetate = 1: 1). [a] ^ ° (chloroform, 0.150%) = 46.7 + 6.7 °; UV (MeOH):

λ (ε) = 271 (22760), 288 (20060), 270 (28880), 324 (14460). Max

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

a) (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (Z) -ene. ,

The title compound is prepared analogously to Example Id from 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); pale yellow OeI; [α] * ⁰ (chloroform, 0.221%) = 25.3 ± 4.5 °; R _f = 0.56 (hexane / ethyl acetate = 3: 2).

Example 61 : (IR, 2S) -l-hydroxy-1- (3-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxv) -octa-3 (Z) -ene-2 yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 60); Mp 231-233 °; [a] ^ ° (methanol, 0.190%) = 51.1 ± 5.3 °; UV (MeOH): λ (ε) = 215 (42320), 267 (22220),

ITl 3X

286 (20800), 320 (sh). -

2 3. LViU. Ii) 3 3 * ü &s; s -i, J

2 B36

- 49 - '

Example 62 : (IR, 2S) -I-Hydroxyl- (3-trifluoromethylphenyl) -9- (A-acetyl-3- hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene-2 yl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsHuremethy! ester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E) , 5 (Z) -dien produced; pale yellow tough oil; [αΡ ° (chloroform, 0.155%) = 44.5 + 6.5 °; R _f = 0.50 (hexane / ethyl acetate = 1: 1); UV (CHCl _3): (ε) = 270 (26800), 284 (23100), 323 (14480)

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

a) 3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -butyl-triphenylphosphonium bromide.

The title compound is prepared analogously to Example Ic from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) butyl bromide. Mp. 167-169 °.

b) (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) - serving.

The title compound is prepared analogously to Example Id from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) butyl-triphenylphosphonium bromide and (4R.5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) pent-2 (E) -enal (Example Ib) prepared; pale yellow OeI; [ct] ^ ° (chloroform, 0.308%)

40.7 ± 3.2 °; R = 0.70 (hexane / ethyl acetate = 3: 2); IR (methylene chloride):

2950, 2860, 1625, 1325, 1120 cm " ¹ .

Example 63 : (IR.2S) -I-hydroxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxyprop-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene -2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid Natriumsalζ.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 62); Mp 204-206 °; [α] * ° (chloroform, 0.289%) = 8.0 ± 3.5 °; [a] ^ ° = 55.5 ± 6.5 ° (methanol, 0.155%);

UV (methanol): λ

ma

(22060), 330 (sh).

UV (methanol): λ (ε) = 219 (49320), 232 (sh), 266 (25800), 285

Max

236 ί

- 50 - ·

Example 64 : (IR, 2S) -1-Hydroxy-1- (3-trifluorothiomethylphenyl) -II- (4-acetyl- 3-hydroxyprop-2-propylphenoxy) -undeca-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo-AH-l-ben2opvran-2-carbonsäurcmethvlester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethyl-phenyl) -II- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E) , 5 (Z) -dien produced, light yellow viscous oil; [α] ^ ° (chloroform, 0.160%) = 48.1 ± 6.3 °; R _f = 0.50 (hexane / ethyl acetate = 1: 1). UV (CHCl _3): λ (ε) = 270 (27120), 286 (23300), 323 (14740).

ITl 3X

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

a) 3- (4-Acetyl-3-hydroxy-2-propylphenoxy) hexyl-triphenylphosphonium bromide.

The title compound is prepared analogously to Example Ic from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) hexyl bromide; Compound crystallizes very slowly.

b) (IR, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -II- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) - serving.

The title compound is prepared analogously to Example Id from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) hexyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) pent-2 (E) -enal (Example Ib) prepared; pale yellow OeI; [erF ⁰ (chloroform, 0.450%) = 41.1 ± 2.2 °; R = 0.66 (hexane / ethyl acetate = 3: 2); IR (methylene chloride): 2960, 2860, 1625, 1325, 1120 cm ^-1 .

Example 65 : (IR, 2S) -I-Hydroxy-1- (3-trifluoromethylphenyl) -II- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), -5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt. The title compound is prepared analogously to Example 2 from the entsprehcenden methyl ester (Example 64); Mp 216-218 °; [a] ^ ° (chloroform, 0.258%) = 34.9 ± 3.9 °; [α] = = 73.8 ± 6.3 ° (methanol, 0.160%); UV (methanol): λ (ε) = 219 (50140), 232 (sh), 266 (26120), 286 (22460), 320 (15600).

836

- 51 -

Example 66 ; (lR, 2S) -l-Hvdroxv-l-phenvl-8- (4-acetvl-3-hydroxy-2-propylphenoxy) octa-3 (E),

pyran ^ -carboxylate.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1-phenylene. ^ - 8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien prepared ^ pale yellow foam; | U_: i__0.41 (hexane / ethyl acetate = 1: 1); _ [a] y> = 47.3 ± 2.6 ° (chloroform, 0.385%).

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

a) (IR, 2R) -I, 2-epoxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene.

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-t-riphenylphosphoniumbromid (Example Ic) and (4R, 5R) -4,5-epoxy-5-phenyl pent-2 (E) -enal produced; pale yellow OeI; R = 0.60 (hexane / ethyl acetate = 3: 2).

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

The compound is prepared analogously to Example Ib from (2R "3R) -2, i-epoxy-S-phenyl-propanol; yellow OeI which crystallizes on standing; R _f = 0.38 (hexane / ethyl acetate = 3: 2); [a] ^ ° = 185 + 5.0 ° (chloroform, 0.200 %)

c) (2R, 3R) -2, S-epoxy-S-phenyl-propanol.

The title compound is prepared analogously to Example Ia from 3-phenyl-prop-2 (E) -enol; colorless oil, which crystallizes in the cold.

R _f = 0.49 (hexane / ethyl acetate = 1: 1); IR (methylene chloride): 3590, 3040,

2980, 2920, 2870, 1605, 1080, 1070 cm ^-1 , [α] ⁰ (chloroform, 0.279%) = 47.7 + 3.6 °;

Example 67 : (1R, 2S) -1-hydroxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propylphenoxy) -or ': a-3 (E), 5 (Z) -diene 2-yl-7-thio-4-oxo-4H-l-ben2opyran-2-carbonsä'ure sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 66); Mp 219-221 °; [A] ^ ° (chloroform

2 8 3 ^ S

- 52 -

form, 0.160%) = 103.1 ± 6.3 °; UV (methanol): λ (ε) = 221 (51180), 232

Max

(sh), 267 (27040), 284 (23840), 321 (16200); UV (chloroform):

λ (ε) = 274 (26080), 286 (sh), 330 (sh).

Example 68 : (IR, 2S) -I-hydroxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propyl-phenoxy) -octa-3 (E) .5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethviester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propyl-phenoxy) -octa-3 ( Z), 5 (Z) -dien prepared; R _f = 0.21 (hexane / ethyl acetate, 3: 2).

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

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 methyl ethyl ketone 6.2 g of potassium carbonate and 0.5 g of potassium iodide are added. The reaction mixture is heated to reflux for 24 hours. It is then poured onto 300 ml of ice-water, acidified with hydrochloric acid and extracted with dichloromethane (3 × 150 ml). The combined extracts are washed with 50 ml of water and dried over sodium sulfate. After filtration and evaporation in vacuo, the residue is chromatographed on 400 g of silica gel with dichloromethane. In the first traction, elute the title compound, which is obtained after evaporation in the form of light yellow crystals of mp 69-70 °.

b) 3- (3-acetyl-4-hydroxy-5-propylphenoxy) propyltriphenylphosphonium bromide

The title compound is prepared analogously to Example Ic) from 3- (3-acetyl-4-hydroxy-5-propyl-phenoxy) propyl bromide and triphenylphosphine; Mp. 103-105 °.

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

The title compound is prepared analogously to Example Id) from 3- (3-acetyl-4-

2 8 3 *

- 53 -

hydroxy-5-propylphenoxy) propyltriphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) pent-2 (E) -enal; R _f = 0.5A (hexane / ethyl acetate, 2: 1).

Example 69 : (IR ₁ 2S) -1-hydroxy-1- (3-trifluoromethylphenol) -8- (3-acetyl-4-hydroxy-5-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt.

The title compound is prepared analogously to Example 2 from (IR, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-A-hydroxy-5-propyl-phenoxy) -octa-3 (E) , 5 (Z) -dien-2-yl-7-thio-4-oxo-AH-1-benzopyran-2-carboxylic acid methyl ester; yellow foam; 1 H NMR (CD ₃ OD): 6 = 7.91, 7.76-7.56, 7.50, 7.36, 7.05, 6.82, 6.41, 6.00, 5.75, 5.47, 5.12, 4.45, 3.78, 2.65-2.35, 1.88, 1.58, 0.94 ppm.

Example 70 : (IR.2S) -I-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 methyl ester .

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-chlorophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 ( E), 5 (Z) -dien prepared; Mp. 76-77 °; [a] ^ ° (chloroform, 0.215%)

51.2 + 4.7 °; UV (chloroform): λ (ε) = 271 (28160), 285 (sh),

Max

321 (15380).

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

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

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example Ic) and (4R, 5R) -4,5-epoxy-5- (3 chlorophenyl) -pent-2 (E) -enal prepared; pale yellow OeI; [a] ^ ° (chloroform, 0.541%) = 63.9 ± 1.8

0 0 * Γν £ ΐ- X Ud * tV C -LJ I)

    , 2 03 ο 1

- 54 - ·

b) (4R, 5R) -4,5-epoxy-5- -pent (3-chlorophenyl) - 2 (E) -enal, -, '. The title compound is prepared analogously to Example Ib from (2R, 3R) -2,3-epoxy-3- (3-chlorophenyl) propanol; dark yellow OeI; R _f = 0.23 (hexane / ethyl acetate = 4: 1). [α] 2 ° (chloroform, V '"0.30%) = 184.7 +3.3.

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

The title compound is prepared analogously to Example 1a from 3- (3-chlorophenyl) prop-2 (E) -enol; pale yellow OeI; R _f = 0.22 (hexane / ethyl acetate = 7: 3). IR (methylene chloride): 3580, 3040, 2980, 2910, 2860, 1600, 1570, 1070 cm ^-1 , [α] ²⁰ (chloroform, 0.334%) = 47.3 ± 3.0 °.

Example 71 : (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -8- (4-acetyl-3-hydroxyprop-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene-2-vl-7-thio-4-oxo-4H-1-benzopvran-2-carboxylic acid sodium salt .

The title compound is prepared analogously to Example 2 from the corresponding Methylcster (Example 70); Mp 217-9 °; [a] ^ ° = (methanol, 0.160%) = 107.5 ± 6.3 °; UV (methanol): λ. (Ε) = 219 (55060), 235 (sh),

ΙΏ3Χ

267 (27340), 284 (23920), 320 (16500).

Example 72 : (IR.2S) -1-Hydroxv-1- (3-chlorophenol) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxv) -deca-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-ben2opvran-2-carboxylic acid methacrylate .

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 ( E), 5 (Z) -dien prepared; Mp. 61-62 °.

[a] ² ° (chloroform, 0.170%) = 52.9 ± 5.9 °; UV (chloroform): λ (ε) = D max

271 (27120), 286 (24800), 322 (15400).

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

a) (IR, 2R) -I, 2-epoxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - serving.

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy

Q j UQ

λ α ο ο ι

- 55 -

2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- (3-chlorophenyl) -pent-2 (E) -enal (Example 7Ob); pale yellow OeI; [ce] ^ ° (chloroform, 0.391%) = 61.4 + 2.5

Example 73 : (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxyprop-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsa'ure sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 72); Mp 204-206 °; [cr] ^ ° (methanol, 0.205%) = 58.5 + 4.9 °; UV (MeOH): λ (ε) = 218 (27940), 267 (13140),

ITl 3. j \

(11600), 320 (sh).

Example 74 : (IR, 2S) -l-hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3- hydroxv-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-vl-7-thio-4-Qo-4H-1-benzo-pyran-2-carboxylic acid ester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 ( E), 5 (Z) -dien prepared; Mp 65-67 °, UV (chloroform: λ (e) =

ΙΠαΧ

271 (30360), 285 (sh), 323 (16600).

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

a) (IR, 2R) -I, 2-epoxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - serving.

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example Ic) and (4R, 5R) -4,5-epoxy-5- (3 methoxyphenyl) -pent-2 (E) -enal; pale yellow OeI; [a] jL ⁰ (chloroform, 0.315%) = 78.4 ± 3.2.

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

The title compound is prepared analogously to Example Ib from (2R, 3R) -2,3-epoxy-3- (3-methoxyphenyl) propanol; yellow OeI; R = 0.41 (hexane / ethyl acetate = 3: 2); [aP ° (chloroform, 0.567%) = 168.9 ± 1.8 °.

2 a;:?. L 13 8 9 * r · fs * ^: *

2- ä °, A 1

\ * · -Q \ l Q ι j

- 56 - '

c) (2R, 3R) -2,3-epoxy-3- (3-methoxyphenyl) -propanol. '

The title compound is prepared analogously to Example 1a from 3- (3-methoxyphenyl) prop-2 (E) -enol; pale yellow OeI; R, - =. 0.31 (hexane / ethyl acetate = 3: 2). IR (methylene chloride): 3550, 2890, 1580, 1565, 1465, 1445, 1130 cm ^-1 .

Example 75 : (1R, 2S) -l-hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3- hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsä'ure sodium salt.

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 74); Mp 206-208 °; [a] ^ ° (methanol, 0.293%) = 99.7 ± 3.4 °; UV (methanol): λ (ε) = 221 (57840), 235 (sh),

ΓΠ3Χ

268 (29360), 282 (26400), 320 (16,800). ,

Example 76 : (IR, 2S) -1-hydroxy-1- (3-methoxyphenvl) -10- (4-acetyl-3- hydroxyprop-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -dien-2-vl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethvlester.

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -dien prepared; Mp 53 ° (sublimated in part); UV (chloroform):

λ (ε) = 272 (29920), 285 (sh), 323 (15540); [α] * ⁰ (chloroform, max ΰ

0.180%) = 44.4 + 5.6 °.

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

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

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- (3 methoxyphenyl) pent-2 (E) -enal (Example 74b); pale yellow OeI; [aU ⁰ (chloroform, 0.375%) = 72.5 ± 2.7.

Example 77 : (1R, 2S) -1-Hydroxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxyprop-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -diene-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt.

The title compound is analogous to Example 2 from the corresponding

2 α 3 6!

- 57 - ·

Methyl ester (Example 76) prepared; Mp 187-8 °; [α] * ⁰ (methanol, 0.150%) = 72.0 ± 6.7 °; UV (methanol): λ (ε) = 222 (55780),

Max

268 (27820), 282 (25200), 321 (16200).

Example 78 : (IR, 2S) -I-hydroxy-1- (3-trifluoromethyl-phenyl) -8- (A-trifluoroacetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) -diene-2 yl-7-thio-4-qxq-4H-l-benzopyran-2-carbonsäureinethvlester

The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl) -3-hydroxy-phenoxy) -oeta-3 (Z), 5 (Z) -dien produced; R _f = 0.23 (hexane / ethyl acetate 3: 2).

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

a) 3- (A-trifluoroacetyl-3-hydroxy-phenoxy) propyl bromide. The TJUtelverbindung is prepared analogously to Example 68a from 2,4-dihydroxytrifluoroacetophenone and is 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) propyltriphenylphosphonium bromide.

The title compound is prepared analogously to Example Ic from 3- (4-trifluoroacetyl-3-hydroxy-phenoxy) propyl bromide and triphenylphosphine; Mp 125-130 ° C.

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

The title compound is prepared analogously to Example Id from 3- (4-trifluoroacetyl-3-hydroxy-phenoxy) propyltriphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) pent-2 (E. ) -already produced; R ,. = 0.56 (hexane / ethyl acetate 2: 1).

Example 79 : (IR, 2S) -1-hydroxy-1- (3-trifluoromethylphenol) -8- (4-trifluoroacetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) -diene-2 -vl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt

To a cooled to 10 ⁰ C solution of 708 mg of the methyl ester of

9 Ρ ^! * V- 1! UP '-Ί; £ -; k ^; : ΐ S, '' · - '-''"' ι ij UWW Vj ϊ_; ti- Λ γ ·.

a:;

  , 2 3361

"- 58 -

Title compound (see Example 78) in 25 ml of tetrahydrofuran is added "10 ml of 0.1 N aqueous sodium hydroxide solution." The reaction mixture is stirred for 24 h at room temperature, freed from the solvent under reduced pressure and the residue is taken up in water The title compound is obtained as an olive-green, amorphous powder;

¹ H-NMR (CD ₃ OD): 6 = 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 ; (lR, 2S) -l-hydroxy-l- (3-trifluormethylphenvl) -8- (4-Hydroxy-3-trifluoracetvl-2-propyl-phenoxy) octa-3 (E), 5 (Z) -diene 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methacrylate The title compound is prepared analogously to Example 1 from (IR, 2R) -I, 2-epoxy-1- (3-trifluoromethylphenyl) - 8- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene; R _f = 0.18 (toluene / ethyl acetate 5: 1).

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

a) 3- (4-trifluoroacetyl-3-hydroxy-2-propylphenoxy) propyl bromide.

The title compound is prepared analogously to Example 68a from 2,4-dihydroxy-3-propyl trifluoroacetophenone and is obtained as yellow OeI; IR (dichloromethane): 3150, 2950, 2860, 1640, 1620, 1500, 1295, 1210, 1150, 1120, 1070 cm ^-1 .

b) 3- (4-trifluoroacetyl-3-hydroxy-2-propylphenoxy) propyltriphenylphosphonium bromide

The title compound is prepared analogously to Example Ic from 3- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) propyl bromide and triphenylphosphine; Mp. 17O-19O ° C.

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

The title compound is prepared analogously to Example Id from 3- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent -2 (E) -enal produced; R _f = 0.55 (hexane / ethyl acetate 2: 1).

2 8 3 6 ί "

- 59 -

Example 81 : (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) -osta-3 (E), 5 (Z) -diene-2-yl-T-thio-a-oxo-AH-l-benzopyran-Z-carboxylic acid Natriuinsalz to a cooled to 10 ⁰ C solution of 500 mg of Methylesters the "^ telverbindung (see. example 80) in 20 ml of tetrahydrofuran are added 6.6 ml of 0, T ~ N ~ aqueous sodium hydroxide solution. The reaction mixture is stirred for 1 h at 10 ⁰ C, freed from tetrahydrofuran in vacuo and the remaining solution is lyophilized. The title compound is obtained as a yellow-green, amorphous powder; ¹ H-NMR (CT) ₃ OD) 'δ = 7.93, 7.77-7.60, 7.50, 7.36, 6.92, 6.43, 6.04, 5.73, 5.47, 5.12 ", 4.47, 4.00, 2.50, 2.38, 0.72 ppm.

Example 82 : (IR, 2S) -l-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester . The title compound is prepared analogously to Example 1 from (IR, 2S) -I, 2-epoxy-1- (3-trifluoromethylphenyl ) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E), 5 (Z) -diene; R _f »0.19 (hexane / ethyl acetate 3: 2).

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

a) 3- (4-Acetyl-3-hydroxy-2-propyl-phenylthio) propyl bromide

The title compound is prepared analogously to Example 68a from 2-hydroxy-4-mercaptoacetophenone: pale yellow oil,

b) 3- (4-acetyl-3-hyil _i .oxy-2-propyl-phenylthio) propyl-triphenylphosphonium bromide

The title compound is prepared analogously to Example 1 from 3- (4-acetyl-3-hydroxy-2-propyl-phenylthio) propyl bromide and Tripheny! Phosphine.

c) (IR, 2S) -I, 2-epoxy-1- (3-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E), 5 (Z ) -diene

l / j. Title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenylthio) propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethyxphenyl) -pent-2 (E) -enal produced.

283έ 1

- 60 -

Example 83 ; (IR, 2S) -l-hydroxy-l- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) octa-3 (E), 5 (Z) -diene 2-yl-7-thio-4-oxo-4H-benzopyran-2-carboxylic acid Natriuinsalz

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

Example 84; "(IR, 2S) -l-Hydroxy-i" - ("3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-p'-propyl-phenylthio) -deca-3 ( e), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-benzopyran-2-carbonsäureinethylester

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

The starting material may e.g. be prepared as follows:

a) 5- (4-acetyl-3-hydroxy-2-propyl-phenylthio) pentylbromide

The title compound is prepared analogously to Example 68a from 2-hydroxy-4-mercaptoacetophenone; pale yellow OeI.

- -Ki: · ^; »" Ni ¹ " ¹ " - f ··· [

b) 5- (4-Acetyl-3-hydroxy-2-propyl-phenylthio) -pentyl-triphenylphosphonium bromide

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

c) (1R, 2S) -l, 2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -deca-3 (E), 5 (Z ) -diene

The title compound is prepared from 5- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -pentyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent analogously to Example -2- (E) -enol produced.

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

The liSelverbindung is prepared analogously to Example 2 from the corresponding methyl ester (Example 84).

^vw ^ '0 eJ iJ \ L c * j

- 61 -

Example 86: (5R, 6S) -I, 1,1-trifluoro-S-

propvl-phenoxy) dodeca-7 (E), 9 (Z) -diene-6-yl-7-thio-4-oxo- 4H-l-benzopyran-2-carbonsäuremethylester

The title compound is prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 ( E), 9 (Z) -dien prepared; pale yellow foam; R ,. = 0.24 (hexane / ethyl acetate = 3: 2)

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

a) (2R, 3R) -2,3-epoxy-7,7,7-trifluoro-heptanol The title compound is prepared analogously to Example 1a from 7,7,7-trifluoro-hept-2 (E) -enol; pale yellow OeI; R = 0.38 (hexane / ethyl acetate = 3: 2). [α] ™ (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 is prepared analogously to Example Ib from (2R, 3R) -2,3-epoxy 7, 7,7-trifluoro-heptanol prepared; OeI, which crystallizes in the refrigerator. R = 0.63 (hexane / ethyl acetate = 1: 1). [a] ™ (chloroform, 0.210%) = 19.5 + 4.8 °.

c) (5R, 6R) -5,6-epoxy-1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodeca-7 (E), 9 (Z) - serving

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyltriphenyl-phosphonium bromide (Example Ic) and (4R, 5R) -4,5-epoxy-9,9,9- trifluoron-2 (E) -enal; yellow OeI; R = 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) -diene-6-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 86); Mp 190-191 °; [a] * ° (methanol, 0.268% = 105.2 ± 3.7 °, UV (methanol): λ '(ε) = 222 (48800), 235 (sh),

Max

267 (25920), 285 (22920), 320 (16000).

ί. U In Hi! '.J W

! 'JJ W ^ C .; I ^ j .; , j V

σ 3 ο 1

- 62 -

Example 88; (4R, 5S) -1,1,1-trifluoro-hydroxy-1S-4-acetyl-3-hydroxy-2-propyl-phenoxy) -trideca-6 (E), 8 (Z) -diene 5-yl-7-thio-4-oxo-4H-1-benzopvran-2-carboxylic acid chyle's ter

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

The starting material, e.g. made as follows:

a) (4R, 5R) -4,5-epoxy-8,8. ~ trifluoro-oct-2 (E) -enal

The title compound is prepared analogously to Example Ib from (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanyl; pale yellow oil which crystallizes in the refrigerator; R _f = 0.53 (hexane / ethyl acetate = 3: 2). [et] "(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-1,11,1-trifluoro-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E), 8 (Z) - serving.

The reaction is analogously to Example Id from 3 - (^ 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 prepared; yellow OeI; R _f = 0.69 (hexane / ethyl acetate = 3: 2).

Example 89: (4R, 5R) -I, 1,1-trifluoro-4-hydroxy-l3- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E), 8 (Z) -diene -5-yl-7-thio-4-OXO-4H "l-benzopyran-2-carboxylic acid sodium salt ·

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 88); Mp 150-152 °; [a] ^ ⁰ (methanol, 0.265%) = 72.5 ± 3.8 °; UV (methanol): λ (e) = 221 (44680), 231 (sh),

ΪΏ3Χ

266 (22560), 285 (20560), 330 (sh).

Example 90: (4R, 5S) -I, 1,1-trifluoro-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E), 8 (Z) -diene-5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethylester

The title curve is determined analogously to Example 1 from (4R, 5R) -4,5-epoxy

2 ig 3 Ο J /

- 63 -

1, 1, 1-trifluoro-12- (A-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E), 8 (Z) -diene; yellow at; R ,. = 0.31 (hexane / ethyl acetate = 3: 2).

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

a) (4R, 5R) -4,5-epoxy-1,1,1-trifluoro - ^ - ^ - acetyl-S-hydroxy-1-propylphenoxy-1-dodeca-ethyl), 8 (Z) -diene

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3- Uj 'roxy-2-propyl-phenoxy) butyl-triphenylphosphoniumbromid (Example 62b) and (' + R, 5R) -4,5-epoxy-8 , 8,8-trifluoro-oct-2 (E) -enal (Example 88a); yellow OeI; R = 0.64 (hexane / ethyl acetate = 3: 2).

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

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 90); Mp 180-182 °; [a] ^ ° (methanol), 0.292 %) = 77.1 ± 3.4 °; UV (methanol): λ (ε) -

ΙΠ3Χ

222 (47480), 231 (sh), 267 (24840), 285 (22120), 321 (15800).

Example 92: (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-5-yl-7 thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethylester

The title compound is prepared analogously to Example 1 from (5R, 6R) -5, f-epoxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) - produced; pale yellow foam; R _f = 0.43 (hexane / ethyl acetate = 1: 1); [o] ^ ° (methanol), 0.150%) = 22.0 + 6.7 °; IR (methylene chloride): 3580, 2950, 1745, 1655, 1625, 1600 cm ^-1 .

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

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

The title compound is prepared analogously to Example Ib from (2R, 3R) -2,3-epoxyheptanol; yellow OeI; R _£ = 12:29 (hexane / Essigester = 4: 1); [B] Jj ⁰ (chloroform, 0.390%) = 21.3 ± 2.6 °; IR (methylene chloride): 2950, 2920, 2860, 1690, 1640, 1100, 970 cm ^-1 .

JO. »> \ U .. Vid'j '* -JC- ti 45 -i! J

2 3.36 1

- 64 -

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

The title compound is prepared analogously to Example ld from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propyltriphenylphosphonium bromide (Example Ic) and (4R, 5R) -4,5-epoxy-non-2 (E) - produced enal; pale yellow OeI; [a] l ° (chloroform, 0.650%) = 23.7 + 1.5 °.

Example 93; (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-6-yl-7-thio -4-oxo-4H-l-benzopyran-2-carborisäure sodium salt

The title compound is prepared analogously to Example 2 from the corresponding Meyl ester (Example 92) ; Mp 205-207 °; [cf] ^ ° (methanol, 0.275%) = 115.1 ± 3.6 °; UV (methanol): λ (ε) = 222 (50960), 232 (sh),

ΤΠ3Χ

267 (27400), 285 (24000), 321 (16400).

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

The title compound is prepared analogously to Example 1 from (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) - produced; colorless foam; [a] * ° (methanol, 0.260%) = 136.2 + 3.8 °;

UV (methanol): λ (ε) = 221 (48040), 271 (28320), 327 (13200). Max

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

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

The title compound is prepared analogously to Example Ib from (2S, 3S) - ^,? - Epoxyheptanol; yellow OeI: R. = 0.27 (hexane / ethyl acetate = 5: 1; [cx] ^ ⁰ (chloroform, 0.325%) = 23.1 + 3.0 °.

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

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyltriphenylphosphonium bromide (Example Ic) and

i ·

- (- IJ -J <

- 65 -

(4S, 5S) -4,5-epoxy-non-2 (E) -enal prepared; pale yellow OeI; [α] ^ ° (chloroform, 0.600%) = 24.8 + 1.6 °.

Example 95: (5S, 6R) -5-Hvdroxv-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-6-yl-7 -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 94); Mp 204-206 °; [et] * ⁰ (methanol, 0.570 %) = 121.1 ± 1.8 °; UV (methanol) ίλ ^ ίε) = 222 (.51240), 235 (sh), 267 (27360), 284 (21400), 320 (16400).

Max

Example 96: (5R, 6S) -5-hydroxy-14- (4-acetyl-3-hydroxyprop-2-propyl-phenoxv) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7 thio-4-ox _o-AH l-benzopvran-2-carbonsäuremethvlester

The title compound is prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) - produced; pale yellow tough oil; [a] ^ ° (chloroform, 0.424%) = 66.5 + 2.4 °; UV (chloroform): λ (ε) = 270 (28560), 288 (sh), 325 (15240). '

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

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

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-non-2 (E. ) -enal (Example 92a); pale yellow OeI; [ct] ^ ° (chloroform, 0.441%) = 20.6 ± 2.3 °.

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

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 96); Mp 193-195 °; [a] * ° (methanol, 0.284%) = 71.1 + 3.5 °. UV (methanol): λ (ε) = 222 (49320), 232 (sh),

ΓΠ3λ

267 (25520), 286 (22680), 321 (16000).

2 3 3 d V7

- 66 -

Example 98: (5S, 6R) -5-Hvdroxv-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7 thio-4-oxo-4H-l-benzopvran-2-carbonsäuremethylester

The title compound is prepared analogously to Example 1 from (5S, 6S) -5,6-epoxy-14- (4-aceCyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) - produced; pale yellow viscous mass; [a] * ° (chloroform, 0.463%) = 79.0 + 2.2 °. UV (chloroform): λ (ε) = 270 (27120), 288 (sh),

ΓΠ3λ

326 (14960).

The starting material is prepared, for example: as follows:

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

The title compound is prepared analogously to Example Id from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4S, 5S) -4,5-epoxy-non-2 (E. ) -enal (Example 94a); pale yellow OeI; [ce] ^ ° (chloroform, 0.472%) = 18.8 ± 2.1 °.

Example 99: (5S.6R) -5-Hvdroxv-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene-6-vl-7 -thio-4-oxo-4H-1-benzopvrane- 2-carboxylic acid sodium salt

The title compound is prepared analogously to Example 2 from the corresponding methyl ester (Example 98); Mp 193-195 °; [all ⁰ (methanol, 0.296%) = 65.9 + 3.4 °. UV (methanol): λ (ε) = 222 (49760), 232 (sh),

Max

267 (25800), 285 (22520), 320 (16000).

Example 100: (5R.6S) -1,1,1-trifluoro-5-hydroxv-14- (4-acetyl-3-hydroxyprop-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene-6-yl-7-thio-4-oxo-4H-l-benzopyran-2-carbonsäuremethylester

The title compound is prepared analogously to Example 1 from (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-14- (4-acetyl-3-hydroxy-2-propylphenoxy) -tetradeca-7 (E. ), 9 (Z) -dien; pale yellow OeI; R _f = 0.32 (hexane / ethyl acetate 3: 2).

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

i. Oil: IUI. i -JUJO La * .i *>"i -W

O u "% 4 j ™? - 67 -

a) (5R, 6R) -5,6-epoxy-1,1-trifluoro-14- (4-acetyl-3-hydroxy-2-propylphenoxy) -tetradeca-7 (E) 9 (Z) -diene

The title compound is prepared analogously to Example 1 from 3- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyltriphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-9,9, 9-trifluoro-non-2 (E) -enal (Example 86b); yellow OeI; R _£ = 0.72 (hexane / Essigester = 3: 2).

Example 101: (5R, 6S) -I, 1,1-trifluoro-5-hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene-6-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid Natriunisalz

The 'i.j.isjverbindung is prepared analogously to Example 2 from the corresponding methyl ester (Example 100); UV (methanol): λ (e) =

into the x

222 (48800), 235 (sh), 267 (25920), 285 (22920), 320 (16000).

Example 102 : Aneloger is described in Examples 1-77, it is also possible to produce

(lR, 2S) -l-hydroxy-l-phenyl-ll- (4-acetyl-3-hydroxy ^{i-2-propyl-phenoxy)} -undeca-3 (E), 5 (Z) -dien-2-yl -7-thio-4-oxo-4H-l-benzoypran-2-carboxylic

Sodium ^{salt'5 !! ;} - '>^;;; ~ ' -' · ''. ' ^: -, -. . ^*;

(IR, 2S) -l-hydroxy-l-phenyl-10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) deca-3 (E), 5 (Z) -dien-2-yl 7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt; ·

(1R, 2S) -l-hydroxy-1-phenyl-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -dien-2-yl . "nsalz 7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid Natriu;

(1R, 2S) -1-hydroxy-1 · (3-chlorophenyl) -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 sodium salt;

(LR, 2S) -l-hydroxy-l- (3-chlorophenyl) -LL (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyian-2-carboxylic acid sodium salt;

π -ι -T'i-, i , ι α Q q -t r. c ~ ";:". '

2 3 3 6 1

• - 68 - ·

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

(LR, 2S) -l-hydroxy-l- (3-fluorophenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-ben2opyran-2-carbonsHure-Natriurnsalz;

(LR, 2S) -l-hydroxy-l- (3-fluoro-phenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (3-fluorophenyl) -LL (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt; ,

(LR, 2S) -l-hydroxy-l- (3-methoxyphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (3-methoxyphenyl) -LL (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (3-carboxyphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid di-sodium salt;

(IR, 2S) -l-hydroxy-l- (3-carboxyphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid di-sodium salt;

(LR, 2S) -l-hydroxy-l- (3-carboxyphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid di-sodium salt;

.2 8 3 6 A

• - 69 -

(lR, 2S) -l-hydroxy-l- (3-carboxyphenyl) -LL (4-acetyl-3-hydroxy-2-propyl ^- phenoxy) -undeca-3 (E), 5 (Z) - dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-e.arbonsäure-di-sodium salt;

C, lR, 2S) -l-hydroxy-l- (3-methoxycarbonylphenyl) -9- (A-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo ^ 4H-l-benzopyran-2-c.arbonsäure sodium salt;

ClR, 2S) -l-hydroxy-l- (3-methoxycarbonylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy ^v) deca-3 (E), 5 (Z) -diene 2-yl-7-thio-A-oxo-4H-l-benzopyran-Z-carboxylic acid sodium salt;

ClR, 2S) -l-hydroxy-l- (3-methoxycarbonylphenyl) -LL ((4-acetyl-3-hydroxy-2-p.ropyl-phenoxy) -undeca-3 E), 5 (Z) -diene -2-yl-7-thio-A-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (3,4-dichlorophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E), 5 (Z) -diene 2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(IR, 2S) -I-hydroxy (2,4-dichlorophenyl) -l0- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid Natriurasalz;

(LR, 2S) -l-hydroxy-l- (3,4-dimethoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) deca-3 (E), 5 (Z) - dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (2,4-dimethoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) deca-3 (E)., 5 (Z) -diene-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (2,4-dimethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E), 5 (Z) -diene 2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

2 8 3 6

• - 70 - ·

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

Example 103: In a manner analogous to that described in Examples 1-101, it is also possible to prepare the following compounds: (1R, 2S) -1-hydroxy-1- (3-bromophenyl) -8- (A-acetyl-3-hydroxy -2-propylphenoxy) octa-3 (e), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (3-bromophenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -diene-2- yl-7-thio-A-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(LR, 2S) -l-hydroxy-l- (3-bromophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt; ,

(LR, 2S) -l-hydroxy-l- (3-broinphenyl) -LL (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) -diene-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(5R, 6S) -1,1, l-trifluoro-5-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-7 (E), 9 (Z) -diene-6- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(5R, 6S) -1,1, l-trifluoro-5-hydroxy-15- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentadeca-7 (E), 9 (Z) -diene-6- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

(5R, 6S) -5-hydroxy-l3- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-7 (E), 9 (Z) -diene-6-y1-7-thio-4- oxo-4H-l-benzopyran-2-carboxylic acid sodium salt;

• - 71 - ·

(5R, 6S) -5-hydroxy-15- (A-acetyl-3-hydroxy-2-propylphenoxy) -pentadeca-7 (E), 9 (Z) -dien-6-yl-7-thio-4 -oxo-AH-l-benzopyran-2-carboxylic acid Natriuinsalz;

(4R, 5S) -l-carboxy-4-hydroxy-ll- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), SiZ

(4R, 5S) -l-carboxy-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodeca-6 (E), 8 (Z) -dien-5-yl-7 thio-4-PXO-4H-l-benzopyran-2-carbons'aure disodium salt;

(4R, 5S) -l-carboxy-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E), 8 (Z) -dien-5-yl-7- thio-4-oxo-4H-l-benzopyran-2-carboxylic acid disodium salt;

C'4R, 5S) -l-carboxy-4-hydroxy-14- (4-acetyl-3-hydroxy-2-propylphenoxy) -tetradeca-6 (E), 8 (Z) -dien-5-yl-7 -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt.

Examples of pharmaceutical compositions and corresponding finished drug forms

The term "active ingredient" is to be understood as meaning a compound of the formula I according to the invention, in particular one which is described as a product in Examples 1-9, such as, for example, (IR, 2S) -1-Hydroxyl- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-yl 7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt.

Example A : A propellant-containing, solid-aerosol-forming inhalable suspension containing 0.1% by weight of active ingredient

Composition ; Wt .-%

Active ingredient, micronized 0.1

Sorbitan trioleate 0.5

L 0., u.'vL i ii 0 i i. ' O (,! ' "Ϊ ''.Lal

  2 3 3 £

  · - 72 ·

Propellant A. '

(Trichlorotrifluoroethane) 4.4

Propellant B

(Dichlorodifluoromethane and 15.0

1 ^ -dichlorotetrafluoroethane) 80.0

Preparation : The active ingredient is suspended under exclusion of moisture with the aid of a conventional homogenizer with addition of the sorbitan trioleate in trichlorotrifluoroethane, the suspension is filled into a metered-dose aerosol container; this is closed and filled with the blowing agent B under pressure.

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

composition

Active substance (K or Na salt) 2000 mg

ethylenediaminetetraacetic

Disodium salt 10 mg

Benzalkonium chloride 10 mg

Water, freshly distilled ad 100 ml

Preparation : The active ingredient is dissolved in about 60 ml of freshly distilled water and the stabilizer (ethylenediaminetetraacetic acid disodium salt) and the preservative (benzalkonium chloride) are added. After complete dissolution of all components, the resulting solution is made up to 100 ml, filled into pressure vials and sealed gas-tight. The propellant is added in gaseous form as needed under pressure or in liquid form.

*. Q. itn '. i .. i V <V V i> Vi «J t J" Ji rsj

2 83417

• - 73 - '

ANNEX - PHARMACOLOGICAL TEST METHODS Inbred pig bronchoconstriction test (in vivo, aerosol) ; ,

Male guinea pigs, 400-700 g, are anesthetized intraperitoneally with 1.4 g / kg urethane and injected with a polyethylene cannule into the jugular vein. A second polyethylene channel is introduced into the trachea. By means of a cannula inserted in the esophagus, which is connected to a Statham pressure transducer, the pressure in the esophagus is recorded. The animal is placed in an airtight sealable plexiglass chamber connected to a meat # ¹ tube and a Validyne MP 45-1 transducer. With this arrangement, the flow is measured.

After the surgical preparation of the test animals one waits for a certain time for the pulmonary functions to stabilize. The compound to be tested is then administered according to the following protocol. The test animals are exposed for 1 minute to a 1% aerosol solution of the compound to be tested (w / v) or distilled water (for control purposes). All test compounds administered by inhalation use a Monaghan Model 670 Ultrasonic Sprayer whose particle size ranges from 1 to 8 microns, with a major portion of 3 microns.

Aqueous solutions are freshly prepared and introduced with a 0n-stream drug vial into the chamber of the sprayer. The produced spray is administered to the experimental animals via a 65 ml glass chamber connected to the trachea with a cannula. At the end of the treatment period, LTDi ₄ (0.3 pg / ml) is administered for 2 minutes with a second Monaghan ultrasound sprayer (model 670) and through a similar glass chamber.

2 Β 3 6 ι J

- 74 -

The decrease in compliance in the third minute after LTDi application is read, namely the mean of three animals is compared with the mean of three control animals and the percentage inhibition of the compliance is calculated according to the following formula:

(100 - compliance preparation) · 100% inhibition = 100 - -

(100 - compliance control)

When different drug concentrations are assayed, the percent inhibition is plotted for each concentration, and the log concentration on the abscissa is plotted against the percent inhibition on the ordinate. The IC50 is then determined by linear regression analysis.

In vitro test to determine the inhibition of phospholipase A? from human leukocytes

Keutrophile polymorphonuclear human leukocytes are isolated from "buffy coats" by multi-stage fractionated sedimentation and deep-frozen. The phospholipase A2 is extracted from the cell suspension by homogenization with the addition of ice cold 0.36 N H2SO1, in 2N NaCl and the supernatant obtained after centrifugation at 10Ό00 χ g dialyzed against sodium acetate buffer pH 4.5

For the determination of the enzyme activity enzyme (10-30 pg protein) in 0.1 M Tris / HCl buffer pH 7 with the addition of 1 inM CaCl 2 and substrate consisting of biosynthetically with ^II4 C-oleic acid radiolabelled phospholipids (2 μΜ) of Escherichia coli at 37 ° for 1 hour. The reaction is stopped by addition of Dole's reagent (isopropanol / heptane / lN H2S0i, 40: 10: 1, v / v) and the ¹¹¹ C-OeISaUTe selectively liberated by phospholipase A2 is extracted. Also co-extracted substrate is completely removed by filtration of the extract through a column of silica gel. The determination of the ¹¹¹ C-OeISaUTe in the eluate is carried out by radiometry.

- c "'"' ^lf

; 2 8 3 6 ί

• - 75 -

To determine an inhibitory effect of test substances on the phospholipase A2 these are added as solutions in water, dimethyl sulfoxide (final concentration in the batch to 5%, v / v) or ethanol (final concentration in the batch to 2.5% v / v) the Incubationsumsatz. The potency of the test substances is expressed by the IC50, i. the concentration which causes an inhibition of 50% of the control activity. The IC50 is plotted by plotting the percent inhibition on the ordinate against the log of the concentration (μΜ) on the abscissa.

Under the experimental conditions described, mepacrine inhibits the phospholipase Az with an IC ₅₀ of 1600 μΜ.

In vitro test for the determination of inhibition of phospholioase C from human thrombocytes

Human platelets are obtained from "Buffy coats" by fractional centrifugation and then deep-frozen. The phospholipase C is released by sonication of the cell suspension and is found after supercentrifugation (150Ό00 g for 1 hour) in a soluble form in the supernatant.

For the determination of enzyme activity, enzyme (20-100 μg protein) in 0.025 M Tris / maleate buffer pH 6 with the addition of 0.2 mM CaCl ₂ and 0.02 mM radioactively labeled substrate, phosphatidyl - [* "* C] -inositol, at The reaction is stopped by shaking with CHCl 3 / CH 3 OH 2: 1 (v / v), whereby unconsumed substrate is extracted into the organic phase while the reaction product ^Ik C-inositophosphate remains in the aqueous phase and passes through Radiometry of an aliquot can be measured.

To determine an inhibitory effect of test substances on the phospholipase C these are added as solutions in water, dimethyl sulfoxide (final concentration in the batch to 5%, v / v) or ethanol (final concentration in the batch to 2.5%, v / v) the incubation mixture. The potency of the test substances is expressed by the IC50, i. the concentration, which is an inhibition of 50% of the control activity

d. u \ n \\ L i ^ 3 «i ^^ υ υ · · ' ^ι -ΐ ·«>

    , "2Q3-S-I7

• - 76 - ·

causes. The IC ₅₀ is plotted by plotting the percent inhibition on the ordinate against the log of the concentration (μΜ) on the abscissa. ·.

Under the experimental conditions described mepacrine inhibits the. Phospholipase C with an IC50 of 20 μΜ.

O. mil / .. I j α 1ί * D α J ii = 1 _N

Claims (88)

-77- claims 1. A process for the preparation of new substituted alkanophenones of the general formula 0
¹ j -jr-X-alk-CCH-CH) -CH-CH-R ₅ (I), R ₅ -U Il II It wherein R 1 is optionally fluorinated lower alkyl, R _{2 is} hydrogen, optionally fluorinated lower alkyl or lower alkenyl, X is lower alkylene, oxy, thio or a direct bond, alk is lower alkylene, η is 1 or 2, R ^ is unsubstituted or optionally fluorinated lower alkyl , etherified or esterified hydroxy, optionally lower alkylated amino and / or optionally substituted or amidated carboxy-substituted phenyl or optionally fluorinated or optionally esterified or amidated carboxy-substituted lower alkyl, R ^, optionally esterified or amidated carboxy or f-tetrazolyl and Rr is hydrogen or lower alkyl, and their salts, characterized in that an epoxide of the formula 11 110 ' " I -HX-alk- (CH =CH) -CH CH-R _x (II), "V
R ₂ t 83 51 7 wherein E _x , E ₂ , X, alk, η land E, have the above meanings, with a thiol of the formula HS. 0 E,
N S \ / \ / ^ E.-i (in), Il wherein E ^ and He have the above meanings, or a salt thereof and, if desired, converts a compound obtainable by the process into another compound of formula I, separates a stereoisomer mixture obtainable according to the process into the components and / or a free compound obtainable in accordance with the process in a salt or a salt obtainable according to the procedure is converted into the free compound or into another salt. 2. The method according to claim i, characterized in that compounds of the formula I, wherein E _x . Lower alkyl and E _{2 is} optionally fluorinated lower alkyl or lower alkenyl, and their salts are prepared. 3. The method according to claim 1, characterized in that compounds of the formula I, wherein E _x , lower alkyl or mono-, di- or Polyfluorniederalkyl means E _{2 is} hydrogen, lower alkyl, lower alkenyl or mono-, di- or Polyfluorniederalkyl, X is lower alkylene, oxy or thio, alk is lower alkylene, E is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, carboxy, lower alkoxy , carbonyl, amino, N-mono- or N, N-di-lower alkylamino, carbamyl, N-mono- or Ν, Ν-di-lower alkylcarbamyl and / or trifluoromethyl-substituted phenyl, lower alkyl, mono-, di- or trifluoroloweralkyl ^ carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamyl-lower alkyl or N-mono- or Ν, Ν-di-lower alkylcarbamyl-lower-alkyl, E ^ carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamyl, I 3 3 6 1 7 - 73- N-mono- or Ν, Ν-di-lower alkylcarbamyl or N- (benzenesulphonyl) -carbamoyl optionally substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl; and R ₁ - represents hydrogen or lower alkyl and their salts are prepared. 4. The method according to claim 3, characterized in that compounds of the formula I, wherein R ,. Lower alkyl means, and their salts are prepared. 5. The method according to claim Ί, characterized in that compounds of the formula I, wherein R ^ C ^ -C ^ alkyl or _ω , ω, d trifluoro-C ^ -C ^ alkyl, R _{2 is} hydrogen, .C ^ -C ^ alkenyl or w, ω, ü represents trifluoroC ^ -C ^ alkyl, XG ^ -C, alkylene, oxy or thio, alk represents straight-chain Cg-Cg alkylene, η is 1 or 2 R 1 is phenyl which is unsubstituted or substituted by C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen of the atomic number up to and including trifluoromethyl, carboxy and / or C 1 -C 4 -alkoxycarbonyl, Cg-alkyl, ο, ω, co - - trifluoro-C ₂ -C, -alkyl, carboxy-C ^ C ^ -alkyl or C ^ -C ^ - alkoxycarbonyl-Co-Gc-alkyl, R ^ is carboxy or N- (benzenesulphonyl) carbamyl, and Rc - is hydrogen, and their salts are produced. 6. The method according to claim 5, characterized in that compounds of the formula I, wherein R _x , C ^ -C ^ alkyl, and their salts are prepared. 7. The method according to any one of claims 1, 3 and 5 »characterized in that compounds of formula I, wherein the group X is attached in the p_ara position to the R ^ .- C (= 0) group, and their salts are prepared , 8. The method according to any one of claims 2, 4 and 6, characterized in that compounds of. Formula I wherein the group X is in the para position; to the R ^ -CC = O) group, and their salts are prepared. V » '<A \ 9. The method according to claim 1, characterized in that compounds of the formula Il i oh • · I HO ^/ \ / ^N X-alk (CH = GH ^ -CH-CH-E ₅ (Ia), R.-4 Il Il ^ where R _x . C _{x represents} JC ^ alkyl, R _{2 represents} 0, - C ^ alkyl, C ₂ -C ^ -J or, ", ω, cj -Trif IuOr-C _x . -C ^ alkyl, XC ^ -C Alkylene is alkoxy, oxy or thio, alk is straight-chain C 1 -C 4 -alkylene, in which -A- C 1 -C 4 -alkylene, phenylene or a direct bond and R 1 is C _x . -C, - Alkyl, trifluoromethyl, carboxy or C _x ^ -C ^, - alkoxycarbonyl, R ^. Carboxy or N- (benzenesulphonyl) carbamyl, and Rj- is hydrogen, and their salts are prepared. 10. The method according to claim 1, characterized in that compounds of the formula Il ^{Ei /} Y ^X | j? ^H / ^ X-SIk- (CH = CH) _n -CH-CH-R, (Ia), ₅ ^ Il I 2 33 Si j wherein EC-G ^ alkyl, R _{2 is} C 1 -C 4 alkyl, X is oxy, alk is C ₂ -C ₆ alkylene, η is 1 or 2, R, by C.-C C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen of stomnone bis and phenyl which is substituted by trifluoromethyl or C 1 -C 4 -alkoxycarbonyl, C 1 -C 6 -alkyl, ω, ω, to trifluoroC 1 -C 3 -cycloalkyl alkyl or C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, R 1 is carboxy, and R _{n is} hydrogen, and their salts are prepared. 11. The method according to claim 9j characterized in that compounds of the formula Ia, wherein R ^ is C ^ -C ^ alkyl, R _{2 is} Cj-C ^ alkyl, X is oxy, alk represents Cg-Cg-alkylene , η is 1 or 2, R, is a group of formula -AR ₅ I represents, is on the -A- is C ^ -C ^ alkylene or phenylene, and R, _t C ^ C ^ alkyl, trifluoromethyl or C 1 -C 4 alkoxycarbonyl, R 1 is carboxy or N- (benzenesulphonyl) carbamyl, and E _{1 is} hydrogen, and their salts are prepared. 12. The method according to claim 10, characterized in that compounds of the formula Ia, wherein R _x . 0, - C ^ alkyl, means Ep • C 1 -C 4 -Alkyl, X is oxy, alk is C ₂ -C 6 -alkylene, η is 2, R 1 is C 1 -C 4 -alkyl, such as methyl, trifluoromethyl or C 1 -C 4 -alkyl Alkoxycarbonyl substituted phenyl, C, -C, alkyl, co, ω, ω-trifluoro-C ^ -C ^ alkyl or C ^ -C ^ alkoxycarbonyl cyj-C ^ alkyl, R ^ represents carboxy , and He is hydrogen, and their salts are made. 13. A process as claimed in any one of claims 1, 3, 5 and 7, characterized in that compounds of the formula I in which X is oxy and their salts are prepared. if 'J' J. ' / 14. The method according to any one of claims 2, 4, 6, 8 and 10, characterized in that compounds of formula I or Ia, wherein X is oxy, and their salts are prepared. Process according to either of Claims 9 and 11, characterized in that compounds of the formula I or Ia in which X 'is oxy and their salts are prepared. 16. The method according to any one of claims 1, 3, 5, 7 and 13, characterized in that compounds of formula I, wherein η is 2, and their salts are prepared. Process according to one of Claims 2, 4, 6, 8, 10 and 14, characterized in that compounds of the formula I or Ia in which η is 2 and their salts are prepared. 18. The method according to any one of claims 1, 9 and 15, characterized in that compounds of formula I or Ia, wherein η is 2, and their salts are prepared. 19 «Process according to one of claims 1, 3, 5, 7, 13 and 16, characterized in that compounds of the formula I, wherein R, mC ^ -C ^ alkylphenyl or m-trifluoromethylphenyl, R ^ carboxy and R, - Hydrogen means, and their salts are produced. , 20. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14 and 1.7, characterized in that compounds of the formula I or Ia, wherein R, mC ^ -C ^ alkylphenyl or m-trifluoromethylphenyl, R ^ carboxy and Rr is hydrogen, and their salts are prepared. 21. The method according to any one of claims 1, 9, 15 and 18, characterized in that compounds of the formula I or Ia, wherein R, m-CpC ^ -Alky! Phenyl or m-trifluoromethylphenyl, R ^ U νΐ O ι J Carboxy and R _n - hydrogen ", and their salts are prepared. 22. The method according to any one of claims i, 3 »5> 7» 13 »16 and 19, characterized in that compounds of the formula I, wherein the radical alk adjacent to the double bond of the radical - (CH = CH) - in (Z) -, d. H. cis configuration and the optional additional double bond of the radical - (CH = CH) in (E) -, d. H. trans configuration, and their salts are prepared. 23. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, and 20, characterized in that compounds of formula I or Ia, wherein the radical alk adjacent to the double bond of the radical - (CH = CH ) - in (Z) -, ie cis configuration and the optional additional double bond of the radical - (CH = CH) _n - in (E) -, ie trani
their salts are produced. - (CH = CH) _n - in (E) -, ie trans configuration is present, and 24. The method according to any one of claims 1, 9 »15 * 18 and 21, characterized in that compounds of the formula I or Ia, wherein the radical alk adjacent to the double bond of the radical - (CH = CH) - - in (Z) -, ie cis configuration and the optional additional double bond of the radical - (CH = CH) _n - in (E) -, ie trans configuration is present, and their salts are prepared. 25- Process according to one of claims 1, 3, 5, 7, 13 »16, 19 22, characterized in that compounds of the formula I, wherein the chain atom connected to the sulfur atom (S) - and the hydroxy group has bearing chain C atom (R) configuration, and its salts are prepared 26. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 17 »20 and 23, characterized in that compounds of the formula I" or Ia, wherein the linked to the sulfur atom chain C- Atom (S) - and has the hydroxy group-bearing chain C atom (R) configuration, and their salts are prepared. Process according to one of Claims 1, 9, 15, 18, 21 and 24, characterized in that compounds of the formula I or Ia in which the chain C atom (S) linked to the sulfur atom and the hydroxyl group has bearing chain C atom (R) configuration, and its salts are prepared. 28. The method according to claim 1, characterized in that (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 methyl ester is produced. Process according to Claim 1, characterized in that (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 method according to claim 1, characterized in that (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene-2 -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 31. The method according to claim 1, characterized in that (1S, 2R) -I-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. i ° S, - "" / Λ 32. The method according to claim 1, characterized in that (1E, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z ) -en-2-yl-7-thio-4-oxo-4H-1-TDenzopyrancarbonsäuremethylester is prepared. 33. The method according to claim 1, characterized in that (1R, 2S) -1-hydroxy ~ 1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z ) -en-2yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 34. The method according to claim i, characterized in that (iS, 2E) -1-hydroxy-1- (3-trifluoromethylphenyl) -6 - (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 ( Z) -en-2-yl-7-thio-4-oxo-4H-1-benzopyrancarboxylic acid methyl ester is prepared. .35 · The method of claim 1, characterized in that cis, 2R) -1-hydroxy-r ^y 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. 36. The method according to claim '!, characterized in that (1E, 2S) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-i-benzopyran-2-carboxylic acid methyl ester is prepared. Process according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -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. 38. The method according to claim Ί, characterized in that (1S, 2R) -1-hydroxy-1- (3-methylphenyl) -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 methyl ester. <5 (s> ~ Process according to Claim 1, characterized in that (1S, 2R) -I-hydroxy-1- (3-methylphenyl) -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 method according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -6- (4-acety1-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7-thio 4-oxo-4H-1-be'nzopyran-2-carboxylic acid methyl ester is produced. 41. The method of claim 1, characterized in that C ^/ lE, 2S) ^-1-hydroxy-y l- (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 method according to claim 1, characterized in that (1R, 2S) -I-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E ), 5 (Z) -dien-2-yl -? - thio-4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (e), 5 (Z) -dien-2-yl-7- Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester is produced. Process according to Claim 1, characterized in that (1R, 2S) -I-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa-3 (E ), 5 (Z) -dien-2-yl-7-thio-4-Oxy-4H-1-benzopyran-2-carboxylic acid. 44. The method according to claim 1, characterized in that (1S, 2R) -I-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-benzopyrazL-2-carboxylic acid methyl ester. 45. The method according to claim 1, characterized in that (1S, 2E) -I-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. 46. The method according to claim 1, characterized in that (1R, 2S) -I-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z ) -en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 47. The method according to claim 1, characterized in that (1R, 2S) -I-Hydroxy-1- (3-methoxycarbonyl-phenyl) -6- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -hex-3 (Z) -ene-2H-1-7- ^ 10-4-0X0-4H-1-benzopyran-2-carboxylic acid is produced. 48. The method according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-carboxyphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex- 3 (Z ) -en-2 ^ 1-7- ^ 10-4-0X0-4H-1-benzopyran-2-carboxylic acid or its disodium salt. 49. The method according to claim 1, characterized in that (1S, 2E) -I-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 50. The method according to claim 1, characterized in that (1S, 2E) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7-thio 4-oxo-4H-1-benzopyran-2-carboxylic acid is produced. 51. The method according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E ), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 2 -8 3 6 ί -Mr: .. -: 52. The method according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E ), 8 (Z) -dien-5-yl-7-thio-4-oxo-4Ξ-1-benzopyran-2-carboxylic acid. 53. Method according to claim 1, characterized in that (4S, 5R) -1,1,1-trifluoro - ^ - hydroxy-ii-C 1-6 acetyl-J-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) -diene-5 ethyl 7-thio-bhio-4-oxo-4H-i-benzopyrano-2-carboxylate]. 54. The method according to claim 1, characterized in that (4S, 5R) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E ), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. Process according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z ) -5-yl-7-thio-4-oxo-4H-1- "benzopyran-2-carboxylic acid methyl ester. 56. The method according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z ) -5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. Process according to claim 1, characterized in that (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 methyl ester is produced. 58. The method according to claim 1, characterized in that (5R, 6S) -5-hydroxy-12- (4-ac ety1-3-hydroxy-2-propylphenoxy) dodec-7 (Z) -en-6-yl- 7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid is produced. 2 83 6 Process according to claim 1, characterized in that (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 methyl ester is prepared. 60. The method according to claim 1, characterized in that (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 is produced. 61. The method according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undec-6 (Z ) -5-yl-7-thio-4-oxo, - '4H-1-benzopyran-2-carboxylic acid methyl ester. 62. The method according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undec-6 (Z ) -5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. Process according to claim 1, characterized in that (5R, 6S) -5-hydroxy-i0- (4-acyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl -7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester is prepared. 64. The method according to claim 1, characterized in that (5R, 6S) -5-hydroxy-IO- (4-ac etyl-3-hydroxy-2-propylphenoxy) dec-7 (Z) -en-6-yl 7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. Process according to Claim 1, characterized in that (5S, 6R) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deo-7 (Z) -en-6-yl 7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester is produced. it C J t * -30- 66. The method according to claim 1, characterized in that (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 is produced. 67 "" Process according to Claim 1, characterized in that (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-benzenesulfonamido) carboxamide. 68. The method according to claim 1, characterized in that (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-4-H-1-benzopyran-2-carboxylic acid methyl ester. 69 "" Process according to Claim 1, characterized in that (iR, 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. 70. The method according to claim 1, characterized in that (4RS, 5SR) -1-methoxycarbonyl-4-hydroxy-9- (4-acety-3-hydroxy-2-propylphenoxy) -non-6 (Z) - en-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester is prepared. 71. The method according to claim 1, characterized in that (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 method according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca-3 (E. ) "5 (Z) -dien-2-yl-7- ^ LiIo- 2 d 3 6 4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester is produced. 73. The method according to claim 1, characterized in that (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 method according to claim i, characterized in that (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 methyl ester. Process according to claim 1, characterized in that (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-carboic acid. 76. The method according to claim 1, characterized in that (1S, 2E) -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 methyl ester. Process according to claim 1, characterized in that (1S, 2R) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E. ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 78. The method according to claim 1, characterized in that (1R, 2S) -I-Hy droxy-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 methyl ester. Process according to claim 1, characterized in that (1E, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3i3> 3-trifluoropropyl) - phenoxy] octa-3 (e), 5 (Z) ^{-dien-2-yl-7-thio-i} i-oxo-4H-1-'benzopyran-2-carboxylic acid is prepared. 80. The method according to claim 1, characterized in that (1E, 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 methyl ester. 81. The method of claim. 1, characterized in that (1E, 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 method according to claim 1, characterized in that (1E, 2S) -I-hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-tertio-4-oxo-4-H-1-benzopyran-2-carboxylic acid methyl ester is produced. 83. The method according to claim 1, characterized in that (1E, 2S) -1-hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 84. The method according to claim 1, characterized in that (1S, 2E) -1-hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 2 3361? Process according to claim 1, characterized in that (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 method according to claim 1, characterized in that (1R, 2S) -I-hydroxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 87. The method according to claim 1, characterized in that (1R, 2S) -I-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 method according to claim 1, characterized in that (1S, 2R) -1-hydroxy-1- (4-trifluoromethylphenyl) -S- (4-acetyl-3-hydroxy-3-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 89- The method of claim 1, characterized in that (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 method according to claim 1, characterized in that (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-acarboxylic acid methylene is prepared. 91. The method according to claim 1, characterized in that (iE _> 2S) -1-hydroxy-1- (5-trifluoromethylphenyl) ~ 8- (4-acetyl-3-hydroxy-2 ^ propyl-phenoxy) -octa-3CZ ) -en-2-yl-7-thio-4-oxo-4-H-1-benzopyran-2-cart) onsäure acid is produced. 92. The method according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (S. ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. Process according to Claim 1, characterized in that (1E, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E ), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 94-. Process according to Claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) -dien ^ -yl-V-thio - ^ - oxo ^ Hi-benzopyran ^ -carboxylic acid methyl ester is prepared. Process according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E. ), 5 (Z) -diene ^ ^ yl thio - ^ - oxo - ^ - ^ hi-benzopyran carboxylic acid
will be produced. 96. The method according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1-phenyl-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 methyl ester is prepared. Process according to Claim 1, characterized in that (1R, 2S) -1-hydroxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E) _t 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-i-benzopyran-2-carboxylic acid. 98. The method according to claim 1, characterized in that (1E, 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 methyl ester. Process according to claim 1, characterized in that (iE, 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. 100. The method according to claim 1, characterized in that (1E, 2S) -1-hydroxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -dien-2-yl-7-thio-Ψ-οχο-4H-1-benzopyran-2-carboxylic acid methyl ester is prepared. 101. The method according to claim 1, characterized in that (1S, 2S) -. 1-Hydroxy-1- (3-chlorophenyl) -10-C4-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.A method according to claim 1, characterized in that (1R, 2S) -I-hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 103. The method according to claim 1, characterized in that (iR, 2S) -1-hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 104. Process according to. Claim 1, characterized in that (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-carotonic acid methyl ester is prepared. 105. The method of claim 1, characterized in that (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-cartoic acid. 106. The method according to claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy.) «& Cta -3 (e) methyl ester is produced. 107. The method according to claim 1, characterized in that (1R, 2S) -I-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-phenoxy) -octa-3 (E) » 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 108. The method according to claim 1, characterized in that (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-benzopyran-2-carboxylic acid. Process according to claim 1, characterized in that C1R, 2S) -I-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. 2 Ö 3 δ 110. The method according to claim 1, characterized in that (5R, 6S) -1,1,1-trifluoro-5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carot-acid methyl ester. Ί11. Process according to Claim 1, characterized in that (5R, 6S) -1,1,1-trifluoro-5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E ), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 112. The method according to claim 1, characterized in that (4E, 5S) -1,1,1-trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) trideca-6 (E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-benzopyran-2-carboxylic acid methyl ester is prepared. Process according to Claim 1, characterized in that (4R, 5 * 0-1,1,1-trifluoro-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. 114. The method according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E), 8 (Z) -dien-5-yl-7- "-fichio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. Process according to claim 1, characterized in that (4R, 5S) -1,1,1-trifluoro-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 116. The method according to claim 1, characterized in that (5R, 6S) -5-hydroxy-12- (4-acetyl) 3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 117- procedure after. Claim 1, characterized in that C5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) dodeca-7 (E), 9 (Z) -dien-6-yl 7-tliio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 118. The method according to claim 1, characterized in that (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) 2-carboxylic acid methyl ester is produced. Process according to claim 1, characterized in that (5S, 6R) -5-hydroxy-12 ~ (A ~ acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) ~ dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 120. The method according to claim 1, characterized in that (5R, 6S) -5-hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 121. The method according to claim 1, characterized in that (5R, 6S) -5-hydroxy-14- (4-acyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7-thio 4-oxo-4H-1-benzopyran-2-carboxylic acid is produced. 122. The method according to claim 1, characterized in that (5S, 6R) -5-hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. Process according to claim 1, characterized in that (5S, 6R) -5-hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 124-, Process according to Claim 1, characterized in that (5R, 6S) -1,1,1-trifluoro-5-hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradecane 7 (E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 125 "" Process according to Claim 1, characterized in that (5R, 6S) -1,1,1-trifluoro-5-hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradecane 7 (E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid. 126. Method according to 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 , and 125, characterized in that one prepares the sodium salt of the compound obtainable by the method of the formula I or Ia.