DD295839A5 - PROCESS FOR PRODUCING ADDITIONAL OTHER NEW ALKANOPHENONE - Google Patents

Abstract

p-substituted alkanophenones of the general formula 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, n is 1 or 2, R 3 is optionally R4 is optionally esterified or amidated carboxy or 5-tetrazolyl and R5 is hydrogen or lower alkyl, have leukotriene-antagonistic properties and can be used as antiallergic drug 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) {p-substituted alkanophenones; Method; manufacture; antiallergic drugs; Leukotriene antagonistic properties}

Description

Process for the preparation of additional additional new alkanophenones

The invention relates to a process for the preparation of novel substituted alkanophenones of the general formula

OH

IX -alk- (CH = CH) - CH- CH- R ₃

(D,

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 _{3 is} optionally chlorinated Polyfluorniederalkyl, R ₄ optionally esterified or amidated carboxy or 5-tetrazolyl and R _{s is} hydrogen or lower alkyl, and their salts and a process for the preparation of these containing pharmaceutical preparations.

The space representation in formula I above is for the preferred compounds in which the O atom of the hydroxy 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 below the representation plane (or vice versa), which for the depicted formula of the opposite configuration, (RS) - (SR), according to the Kahn-Ingold-Prelog convention at the carbon atom connected to the sulfur atom, (CS-), and the carbon atom bearing the hydroxy group, (C-OH) corresponds. In this case, if η is 2, the enantiomers having an S (CS), R (C-OH) configuration and, if η is 1, the enantiomers with R (CS-), S (C-OH) - Configuration particularly preferred. In the vinylene or buta-1,3-dienyl radical represented by the symbol - (CH =CH) _n , the double bond or the double bond of the butadienylene radical starting from the carbon connected to the radical alk is preferably, but not necessarily, in cis configuration, usually denoted (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 halogen.

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 N, N-di-lower alkylcarbamyl, or preferably N- (benzenesulfonyl) substituted in the phenyl moiety optionally lower alkyl, lower alkoxy and / or halogen ) carbamyl. In the phenyl part, optionally substituted as indicated, substituted N- (benzenesulfonyl) carbamyl is, for example, unsubstituted or, preferably in the ortho position, mono-substituted. If optionally esterified or amidated carboxy substituent, carboxy and esterified carboxy, in particular lower alkoxycarbonyl, are particularly preferred.

For the purposes of the present invention, "lower" radicals and compounds are understood to mean, for example, those which have not more than 7 and, if not stated otherwise, preferably not more than 4 carbon atoms (C atoms).

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 tertiary butyl or pentyl, hexyl or heptyl. Lower alkyl R ₁ , Rs or as a substituent of phenyl or N- (benzenesulfonyl) carbamyl is preferably C ₁ -C ₄ -Alkyl, for example

Methyl, lower alkyl R ₂ preferably C ₂ -C ₅ alkyl, for example propyl.

Mono-, di- or Polyfluorniederalkyl Ri and R ₂ has, for example up to and with 5 fluorine atoms and is for example mono-, di- or TrIfIuOr-C ₁ -C ₇ -BlkYl, especially ω-fluoro- or oü ^ co-trifluoro -CHValkyl, such as trifluoromethyl, 2,2,2-trifluoroethyl or 3,3,3-trifluoropropyl. In particular, fluorinated lower alkyl R ₁ is trifluoromethyl and fluorinated lower alkyl R _{2 is} preferably (,, Cu-trifluoro-C 1 -C 4 -alkyl, eg 3,3,3-trifluoropropyl.

Optionally chlorinated Polyfluoriederalkyl R ₃ has at least 5, for example 5 to and with 9, fluorine atoms or at least 3, for example to and with 7, fluorine atoms and at least 2, for example 2 to 5, chlorine atoms and means, for example, ω, ω, ω, ω -1, ω-1-Ρβηί3ίΙυθΓ-ϋ3-ϋ ₇ -3 ^ γΙ ^ ϊβ2,2,3,3,3-Ρβηί3ίΙυοφΓθργΙ, 3,3,4,4,4-pentafluorobutyl, 4,4,5,5, 5-pentafluoropentyl or 5,5,6,6,6-pentafluorohexyl or cu ^ cu-trifluoro-cu-c-dichloro-Ca-Cs-alkyl, such as "!, I-dichloro-a ^ -trifluoräthyi ^^ Dichloro-S ^^ trifluoropropyl, 3,3-dichloro-4,4,4-trifluorobutyl or 4,4-dichloro-5,5,5-trifluoropentyl.

Lower alkenyl R ₂ is, for example, C 1 -C 12 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 5 -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, furthermore 1,5-pentylene or 1,6-hexylene.

Lower alkoxy is, for example, C ₁ -C ₄ -alkoxy, such as methoxy.

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

Lower alkylamino is, for example, C 1 -C ₄ -alkylamino, such as methyl, ethyl, propyl or isopropylamino.

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

N-mono- or Ν, Ν-di-lower alkylcarbamoyl is, for example, NC ₁ -C ₄ -alkyl or Ν, Ν-di-CHValkylcarbamyl, such as N-methyl, N-ethyl or Ν, Ν-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 carboxy, tetrazolyl or suifamyl groups, can form salts with bases, in particular inorganic bases, preferably physiologically compatible alkali metal salts, especially sodium and potassium salts. Also suitable, however, are ammonium salts with ammonia or physiologically compatible organic amines, such as mono-, di- or tri-lower alkylamines, eg. As 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 pronounced leukotriene antagonism.

For example, in vitro in the concentration range of about 0.001-1.0 μΜοΙ / Ι, they inhibit the smooth muscle contraction induced by leukotriene D ₄ (LTD ₄ ). This so-called LTD ₄ antagonism is experimentally z. In segments taken from the lumbar of a 300-400 g guinea pig and in an organ bath in Tyrode's solution at 38 ° C. and gassed with a mixture of 95% oxygen and 5% carbon dioxide at a load of 1 g are incubated with synthetic leukotriene D ₄ (as potassium salt) contractions and isotonic recorded. The extent of inhibition by the test substance is determined after a preincubation of 2 minutes and evaluated as IC ₆₀ , 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 bronchial in vivo bronchoconstriction test, aerosol administration of a solution containing 0.0001 to 1% by weight of the test substance demonstrated a marked LTD ₄ antagonizing effect.

Surprisingly, many compounds of formula I also exert a pronounced inhibitory effect on other physiologically important enzyme systems. Thus, the inhibition of phospholipase A ₂ from human leukocytes was observed in the tested concentration range of about 0.5-50 μΜοΙ / Ι. Also, the inhibition of phospholipase C from human platelets was observed in the concentration range tested of about 1-100μΜοΙ / Ι.

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 activity, they are anti-inflammatory agents, particularly as external (topical) skin phlogistatics for the treatment of inflammatory dermatoses of any genesis, such as mild skin irritation, contact dermatitis, rashes and burns, as well as mucus main phlogistatics for the treatment of mucositis, e.g. As the eyes, nose, lips, mouth and genital, or anal region suitable. Further, they can be used as a sunscreen.

The invention relates in the first place to compounds of the formula I in which R ^{1 is} lower alkyl or mono-, di- or polyfluoro-lower alkyl, R _{2 is} hydrogen, lower alkyl, lower alkenyl or mono-, di- or polyfluoro-lower alkyl, X is lower alkylene, oxy or thio, Alk lower alkylene, R ₃ Polyfluorniederalkyl having 5 to 9 fluorine atoms or chlorinated Polyfluorniederalkyl having 3 to 7 fluorine atoms and 2 to 5 chlorine atoms, R ₄ carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamyl, N-mono- or Ν, Ν-di-lower alkylcarbamyl or optionally substituted in the phenyl by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl substituted N- (benzenesulfonyl) carbamyl and R _{5 is} hydrogen or lower alkyl, and their salts, especially pharmaceutically acceptable salts.

The invention preferably relates to those compounds wherein the group X is attached para to the Ri-C (= O) group, i. Compounds of the formula

• alk- (CH = CH) -

wherein R ₁ , R ₂ , X, alk, n, R ₃ , R ₄ and R _{5 have} the meanings indicated, and their salts, in particular pharmaceutically acceptable salts.

The invention particularly relates to compounds of the formula I or la, WOHnR _{1 is} Ci-Gt-alkyl, such as methyl, or ω, ω, ω-trifluoro-Cr-Cialkyl, such as trifluoromethyl, R _{2 is} C ₁ -C ₄ - AIkYl, such as propyl, C ₂ -C ₄ alkenyl, such as allyl, co-tu-trifluoro-Ci-Gj-alkyl, such as 3,3,3-trifluoropropyl, or secondarily hydrogen, X is CH ^ alkylene, As is methylene, oxy or thio, alk is straight-chain Qj-Ce-alkylene, such as ethylene, 1,3-propylene or 1,4-ButyIe, represents η is 1 or 2, R ₃ ω, ω, ω, ω-1 , ω-1-pentafluoro-C ₃ -C ₇ -alkyl, such as 2,2,3,3,3-pentafluoropropyl, 3,3,4,4,4-pentafluorobutyl, 4,4,5,5,5- Pentafluoropentyl or 5,5,6,6,6-pentafluorohexyl, or ω, ω, ω-trifluoro-ω-1, ω-dichloro-C ₂ -C 5 -alkyl, such as 1,1-dichloro-2,2,2 trifluoromethyl, 2,2-dichloro-3,3,3-trifluoropropyl, 3,3-dichloro-4,4,4-trifluorobutyl or 4,4-dichloro-5,5,5-trifluoropentyl, R _{4 is} carboxy or N - (Benzo! Sulfonyl) carbamyl, and R _{6 is} hydrogen, wherein, when η is 1, with the sulfurela Preferably, (R) - linked chain C atom has (R) - and the chain-C atom linked to the hydroxy group preferably has (S) -configuration or, if η is 2, preferably the chain C-atom connected to the sulfur atom (S) - and the hydroxy-bearing chain C atom preferably has (R) configuration and the double bond connected to the radical alk is preferably in cis configuration and the optional additional double bond is preferably in trans configuration, preferably those in which R _{1 is} C ₁ -C ₄ -alkyl and R ₂ , X, R ₃ , R ₄ and R _{5 have} the meanings indicated and their salts, in particular pharmaceutically usable salts.

The invention relates, in particular, to compounds of the formula Ia in which R _{1 is} C ₁ -C ₄ -alkyl, such as methyl, R _{2 is} C ₁ -C -alkyl, such as propyl, X is oxyalkoxy, CH 2 -alkylene, such as ethylene, 1, 3-propylene or 1,4-butylene, η is 1 or preferably 2, R _{3 is} üVu, uh), (u-1, uh) -1-pentafluoro-C ₃ -C ₇ -alkyl, such as 2,2 , 3,3,3-pentafluoropropyl, 3,3,4,4,4-pentafluorobutyl or 4,4,5,5,5-pentafluoropentyl, or ω-1, (ui-dichloro-ciVu.o-trifluoro-) CHValkyl, such as ii-dichloro ^^ - trifluoroethyl, 2,2-dichloro-3,3,3-trifluoropropyl, 3,3-dichloro-4,4,4-trifluorobutyl or 4,4-dichloro-5,5,5- trifluoropentyl, R _{4 is} carboxy, and Rs is hydrogen, where, when η is 1, the chain C atom connected to the sulfur atom is preferably (R) - and the chain C atom connected to the hydroxy group is preferably ( S) configuration or, if η is 2, the chain C-atom connected to the sulfur atom preferably (S) - and the chain bearing the hydroxy group chain C-atom vo has preferably (R) configuration and the double bond connected to the radical alk preferably in cis configuration and the optionally present additional double bond is preferably in trans configuration, and their salts, especially pharmaceutically acceptable salts.

The invention relates most especially to compounds of the formula I a, wherein Ri Ci-C ₄ alkyl, such as methyl, R _{2 is} C ₁ -C ₄ -alkyl, such as propyl group, X is oxy, alk is C ₂ - C ₅ -alkylene, such as ethylene, 1,3-propylene or 1,4-butylene, η is 2, R ₃ ω, ω, ω, ω-1, ω-1-pentafluoro-Cs-Cs-alkyl, such as 4,4,5,5,5,5-pentafluoropentyl, or ω-1, Cu-i-dichloro-cu ^ co-trifluoro-Cr-CB-alkyl, such as 4,4-dichloro-5,5,5 trifluoropentyl, R _{4 is} carboxy, and R _{5 is} hydrogen, wherein the chain C atom attached to the sulfur atom is preferably (S) - and the chain C atom carrying the hydroxy group is preferably

(R) configuration and the double bond connected to the radical alk is preferably in cis configuration and the other additional double bond is preferably in 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

S \ X -alk - (CH = CH) - CH- CH- R ₃

wherein R ₁ , R ₂ , X, alk, η and R _{3 have the} above meanings, with a thiol of formula HS. ^ .0. ₄

(ID,

(IH),

wherein R ₄ and R _{5 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 into a salt or a salt obtainable according to the process is converted into the free compound or into another salt. The conversion of epoxides II with thiols III occurs with configuration reversal on the C-atom entering the bond with the thio group and with retention of configuration on the carbon atom carrying the C-atom. In order to arrive at the preferred compounds of opposite configuration at these two carbon atoms, it is therefore preferable to start from the corresponding trans-epoxides II. Starting from R, R epoxides II, compounds I 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 carried out under conditions known per se at temperatures of about -20 ⁰ C to about +50 ⁰ C, preferably at room temperature, ie 18 ° C to 25 ° C, and especially in a basic medium, for example in the presence of an amine, in particular a tertiary aliphatic, araliphatic or saturated heterocyclic amine such as tri-lower alkylamine (e.g., triethylamine, or N-ethyl-N, N-disopropylamine), N, N-di-lower alkyl-N-benzyl-amine (e.g., Ν , Ν-dimethylbenzylamine), Ν, Ν-dialkylaniline (eg Ν, Ν-dimethylaniline) or N-methyl- or N-ethylpiperidine or Ν, Ν'-dimethylpiperazine. Usually, the reaction is carried out in an inert organic solvent such as a lower alkanol, e.g. As methanol or ethanol performed.

In a preferred embodiment starting from components II and III, wherein R ₄ esterified carboxy or tetrazolyl and R _{3 have} the meaning given, hydrolyzed R ₄ (optionally selectively) to carboxy and converts this, if desired, in amidated carboxy.

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

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)

starting from where A and R _{3 have} the meanings given above. This compound is condensed with formylmethyltriphenylphosphorane (or an equivalent reagent) to give the corresponding trans-3-R ₃ -prop-2-enal of the formula

O = CH

is formed. This compound is then epoxidized in a manner known per se, preferably under weakly alkaline conditions (for example 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

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

O Il

X - alk - CH ₂ - P (C ₆ Hg) ₃ Hal

(VII)

wherein R ₁ , R ₂ and alk have the meanings given and Hai is a halogen atom, preferably bromine, and a base, for. As sodium amide, in tetrahydrofuran to the corresponding epoxide II, wherein R _{4 is} esterified carboxy and η is 1, are reacted

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

X - alk - CH ₂ - shark

(VIII)

with triphenyl phosphinine usually prepared. Compounds VIII wherein X is oxy or thio are obtained, for example, by reacting corresponding compounds of the formulas O.

^XH (IX) and

Hai - alk - CH ₂ - shark

condensed together in the usual way.

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

HIGH-

wherein R _{3 has the} above meaning, for example by means of Tertiärbutylhydroperoxid in the presence of Titantertraisopropanolat and a D- or L-tartaric acid, with the use of a D-tartaric acid ester is obtained predominantly 2R, 3R-epoxy-3-R3-propanol XII a or when using an L-tartaric acid ester, predominantly the corresponding 2S, 3S-epoxy-3-R ₃ -propanol XHb

HIGH

HIGH

(XIIa) or

VV ^H

(XIIb)

This is then oxidized, for example, by treatment with oxalyl chloride / dimethyl sulfoxide and then with triethylamine. To the corresponding epoxy aldehyde Vl, which can then be reacted with the corresponding phosphonium salt VIl into the corresponding epoxide II, wherein η is 1.

This gives 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 wherein η is 2, for example, the epoxy alcohol XII a or XII b first by treatment with Ν, Ν'-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of trifluoroacetic acid and pyridine and then with Triphenylphosphoranylidenacetaldehyd first in the corresponding 4R, 5R - or 4S, 5S-4,5-epoxy-5-R ₃ -pent-2-enal of the formulas XIII a and XIII b

OHC-CH = CH. ° .. H OHC-CH = CH S><. .H

^> ^ - ^ C (XIIIa) or "]> ⁵ C ι

W R ₃ H "R ₃

which is then further reacted with the phosphonium halide VII to form the corresponding epoxide II, wherein η is 2.

Preferably, those are obtained in which the double bond linked to the alk radical has cis-stereotaxy and the double bond connected to the oxirane ring has trans-stereotaxy.

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

For example, one may hydrolyze esterified or amidated carboxy groups to free carboxy, preferably under basic conditions, e.g. in the presence of caustic soda, and preferably in a water-miscible organic solvent such as tetrahydrofuran, dioxane or a lower alkanol such as methanol or ethanol. Conversely, carboxy R4 can be esterified in the usual way.

Free or esterified carboxy R ₄ can be further amidated in the usual way, for example by treatment with ammonia or a mono- or di-lower alkylamine. For example, you can Carboxy R ₄ in customary, z. In the presence of a carbodiimide salt, e.g. B. of N-ethyl-NO-dimethylamino-propyO-carbodiimide hydrochloride, and 4-dimethylaminopyridine, with an optionally substituted benzenesulfamide in the corresponding N-Benzolsulfamidoylcarbamylgruppen.

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 be formed from a starting material in the form of a diastereomer by stereoselective reaction conditions or optically active reagents, or racemic mixtures of diastereomers by physical separation methods, optionally under Application of optically active excipients into which individual diastereomers are separated.

However, in stereochemical terms, both the condensation according to the invention of components II and III, as well as the preparation of the starting materials, are carried out primarily by using stereotactically uniform starting materials, the reactions being stereoselective, if possible, e.g. by using stereotactically uniform, optically active reagents and / or excipients, and stereotactically uniform products of reaction mixtures immediately after the reaction is isolated. Thus, e.g. in the preparation of the unsaturated starting materials optionally formed cis and trans isomers immediately separated, including the usual physical separation methods, in particular chromatography, are suitable. In the main reaction is predominantly the stereoisomeric epoxide II with the stereospecific stereotaxy of the double bond (s) in racemic form (as is often formed in the variant of the epoxidation of compound V with hydrogen peroxide) or preferably as an individual diastereomer with the im Ingredient 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 salify salts obtained, for example by acid treatment, into the free acids or free acids obtained by base treatment.

Due to the close relationship between the new compounds in free form and in the form of their salts, the corresponding salts or free compounds should be understood analogously in the preceding and following among the free compounds or their salts.

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 likewise form the subject of the invention.

Preferably, such starting materials are used and the reaction conditions are chosen so as to arrive at the compounds listed above as being particularly preferred.

The present invention also relates to pharmaceutical compositions and pharmaceutical compositions containing one of the compounds of the formula I according to the invention or a pharmaceutically acceptable salt thereof. In particular, the pharmaceutical compositions according to the invention 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 finely sprayed solution, to nipples, 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 skin lotions and cream containing a liquid or semi-solid oil-in-water or water-in-oil emulsions, and ointments (preferably containing a preservative). For the treatment of the eyes are eye drops containing the active compound in aqueous or oily solution, and eye ointments, which are preferably prepared in sterile form. 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 nose drops, which

active compound in aqueous or oily solution, suitable; Also suitable for topical treatment of the oral cavity are lozenges containing the active compound in a mass formed generally of sugar and gum arabic or triaryganth, to which flavors may be added, and lozenges containing the active ingredient in an inert mass, e.g. As gelatin and glycerol or sugar and gum arabic included.

As pharmaceutical compositions for administration in the form of aerosols or sprays are suitable z. As solutions, suspensions or emulsions of the active compound of the formula I according to the invention with a suitable pharmaceutically acceptable solvent, such as 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 volatile, preferably normal atmospheric pressure below the usual room temperature (eg between about -30 ⁰ C 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 storage mixtures for the preparation of the corresponding medicaments in finished form, usually contain the active substance in a concentration of about 0.1 to about 10, in particular from about 0.3 to about 3, 3% by weight. , For the preparation of medicaments in the finished form, such a pharmaceutical composition is filled into suitable containers, such as flasks 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 for mixing. The dosage of the active compound of formula I to be administered and the frequency of administration depend on the respective efficacy or the length of action of each individual of these compounds, on the severity of the disease or symptoms to be treated, and on 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 in a 75kg aspirator (primarily human) will be in the range of about 10 to about 500, preferably between about 25 to about 250mg, which may be conveniently administered as needed can be done several times a 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 antiallergically 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.

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

example 1

oxo-4H-1-benzopyran-2-carbonsäuremethylester

The solution of 1.49 g (eRJSl-iö ^ acetyl-S-hydroxy ^ -propyl-phenoxyl-ej-epoxy-i ^ i ^ -pentafluor-pentadeca-SfEhiOIZ) -diene in 100 ml abs. Methanol is stirred under argon with 3.3 ml of triethylamine and 1.05 g of methyl 7-mecaptochromone-2-carboxylate for 20 hours at room temperature and then evaporated. The residue is dissolved in ethyl acetate and filtered through silica gel. The filtrate is mixed with 25 ml of 1N hydrochloric acid and 4ma! washed with 25 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated. Purification of the residue by chromatography on silica gel with hexane / ethyl acetate (3: 2) as eluant gives the title compound as a pale yellow foam; M.p .: 48-49 ⁰ C; Rf (hexane: ethyl acetate 3: 2): = 0.33; Ia] D ₂₀ (CHCl ₃ , 0.230%) = 67.4 + 4.3 °; UV spectrum (CHCl ₃ ): X max) = 271 (25120), 285 (22080), 324 (14000).

The starting materials are prepared as follows:

a) 5,5,5,4,4-pentafluoro-1-pentene

Method A: In a 11 barrel 3-necked flask equipped with a dry ice condenser and gas inlet tube are introduced at 20 ⁰ C within 20 minutes 39,5g (16OmMoI) of gaseous pentafluoroethyl iodide to a suspension of 20.2 g (18OmMoI) of activated cadmium powder in 100 ml of dry dimethylformamide. After a 5-minute induction period, a strongly exothermic reaction begins. The reaction mixture is stirred for 1 hour at room temperature and then filtered under nitrogen over filter flocks. Thereafter, the light green, cadmium organic solution at 0 ⁰ C with 17.2 g (12OmMoI) copper (l) bromide transmetallated in 100ml of dry hexamethylphosphoric triamide. After 10 minutes of stirring at 0 ⁰ C is added dropwise within 15 minutes 12.1g (10OmMpI) allyl bromide and stirred for 2 hours at 25 ° C. Then the cloudy reaction solution is mixed with 250 ml of cold η-hydrochloric acid. The product is distilled directly from the reaction flask via a Vigreux column. At boiling point 42-44 ° C, the title compound passes as a colorless liquid.

¹ H-NMR spectrum (CDCl ₃ ; 300 MHz): 5.33 + (br.s; 1H); 5,28 (m; 1H), 5,81 (txdxq; J 16,1; 7,0 "1; 1H), 2,89 (txdxq; J 17,2; 7,0; = 0,5; 2H ).

Method B: As described under method A, 39.5 g (16OmMoI) of pentafluoroethyl iodide are introduced under inert conditions for 20 minutes at room temperature into a suspension of 11.8 g (18OmMoI) of activated zinc dust and 160 ml of dimethoxyethane. After approx. 5 minutes, a strongly exothermic reaction sets in, resulting in a yellow-green suspension. The reaction mixture is stirred for 1 hour at 25 ° C and then filtered under inert conditions. The light green filtrate is washed first with 18.6 g (16OmMoI) Ν, Ν, Ν ', Ν'-tetramethylethylenediamine, then at 0 ⁰ C with 17,2g (12OmMoI) copper (l) bromide and then

with 12.1 g (10OmMoI) allyl bromide added. After 5 hours of stirring at 50 ° C, the reaction solution is mixed at room temperature with 250 ml of η-hydrochloric acid and the product is distilled off directly from the reaction vessel. At boiling point 41-45 ⁰ C, the title compound passes as a colorless liquid.

b) 6,6,6,5,5-pentafluoro-hexan-1-al

Under inert conditions, 1.3 g (3.8 mmol) of di-cobalt octacarbonyl are dissolved in 50 ml of absolute benzene in a pressure autoclave. Thereafter, 29,0g (18OmMoI) are 5,5,5,4,4-pentafluoro-1-pentene were added thereto, and pressed at 60 bar according to the saturation carbon monoxide and hydrogen at -50 ⁰ C. The reaction mixture is heated to 100 ° C and held for 5 hours at this temperature and a pressure of 160 bar. It is then cooled and 10 ml (-2OmMoI) of the violet solution fractionally distilled. The boiling point of the destmolabel and air-sensitive aldehyde is 92-93 "C (120 mbar), ¹ H-NMR spectrum (CDCl ₃ ; 300 MHz): 9.77 (s, 1H); 2.61 (t; J 7.0 2H), 2.19 (m, 2H), 1.91 (quint; J 7.0, 2H).

c) 8,8,8,7,7-pentafluoro-2 (E) -octenoic acid ethyl ester

40 ml (6OmMoI) of the benzene 6,6,6,5,5, pentafluorohexane-1-al solution (reaction solution of the preceding stage) are added with 17,4 g (5OmMoI) ethoxycarbonyl-methylene-triphenylphosphorane and refluxed for 14 hours held. The benzene is then distilled off on a rotary evaporator and the residue is separated from the triphenylphosphine oxide by flash chromatography on a silica gel column (eluent petroleum ether). The resulting product is fractionally distilled. . When bp = 103-105 ⁰ C (28 mbar) is trans-ester as a colorless liquid over (The 1st fraction contains small amounts of cis-ester; E / Z ratio before the distillation: 93: 7). 'H-NMR spectrum, Ε-compound (CDCl ₃ ; 60 MHz): 6.70 (dxt; J 15.5; 7; 1H), 5.67 (d; J 15.5; 1H), 4.07 (q; J 7; 2H), 2.2 (m; 2H), 1.8 (m; 4H), 1.24 (t; J 7).

¹ H-NMR spectrum, Z compound (CDCl ₃ ; 60 MHz): 6.73 (dxt; J12; 7; 1H), 5.85 (d; J12; 1H), 4.06 (q; J7; 2H ), 2.6 (m; 2H), 1.9 (m; 4H), 1.12 (t; J 7; 3H).

d) 7,7,8,8,8-pentafluoro-oct-2 (E) -enol

The solution of 40.0 g of 7,7,8,8,8-pentafluoro-oct-2 (E) -carboxylic acid ethyl ester in 300 ml of ether is added dropwise with 380 ml of diisobutylaluminum hydride (1 molar in hexane) and 2 hours at 0-5 ° C stirred. The resulting solution is poured onto a mixture of 480 ml of ice / water and 95 ml of concentrated hydrochloric acid (cooling, exothermic!). It is stirred vigorously until 2 phases have formed. The organic phase washed with 3 times saturated brine, dried over magnesium sulfate and evaporated. The remaining pale yellow oil is distilled on a water jet vacuum. The title compound is obtained from bp = 81-86 ° C (14mmHg); Rf (hexane: ethyl acetate 3: 2) = 0.52; IR spectrum (CH ₂ Cl ₂ ): 3600.2950, 2860, 1450, 1380, ^1, 12, 1130, 1030, 970, 650 cm " ¹ .

e) (2R, 3R) -2,3-epoxy-7,7 _r 8,8,8-pentafluoro-octanol

Under absolutely anhydrous conditions and an argon atmosphere, the solution of 13.3 ml of tetraisopropyl orthotitanate in 100 ml of dichloromethane is cooled to -80 ° C., with 9.1 ml of diethyl D (-) tartaric acid and 14.0 g of 7,7,8,8,8-pentafluoro -oct-2 (E) enol in a little dichloromethane. After 10 minutes of stirring at - 80 ⁰ C 61.7 ml of a 2,7molaren Tertiärbutylhydroperoxidlösung be added in toluene, and the temperature rises to -68 ° C. Now the temperature is allowed to rise to 0 ⁰ C within 2 hours, the resulting yellow solution is poured slowly into a solution of 41.5 g of iron end-sulfate and 16.0 g of L (+) - tartaric acid in 150 ml of water (cooling, exothermic! ) and stirred for 30 minutes at 5-1O ⁰ C.

The aqueous phase is separated and extracted with 4 times for each 100 ml of ether. The combined organic extracts are dried over sodium sulfate and evaporated. The residue is dissolved in 100 ml of ether, cooled to 0-5 ⁰ C, treated with a suspension of 7.0 g of sodium hydroxide in 250 ml of saturated brine and stirred for 1 hour at 0-5 ° C. The aqueous phase is separated and extracted 4 times with 50 ml of ether. The combined ether phases are dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with hexane / ethyl acetate (1: 1) as eluent. The title compound is obtained as a light yellow oil: Ia] D ₂₀ (CHCl _3, 0.49%) = +15.3 ± 2.0 ⁰ C; Rf (hexane: ethyl acetate 1: 1): = 0.36; IR spectrum (CH ₂ Cl ₂ ): 3550, 2900, 1440, 1370, 1120, 130, 1010, 870, 635 cm " ¹ .

f) (4R, 5R) -4,5-epoxy-9,9,10,10,10-pentafluoro-dec-2 (E) -enal

The solution of 11.0 g (2R, 3R) -2,3-epoxy-7,7,8,8,8-pentafluoro-octanol in 200 ml of dimethyl sulfoxide is added under argon with 5.6 ml of pyridine, 2.3 ml of trifluoroacetic acid and 37.0 g of Ν, Ν-dicyclohexylcarbodiimide and stirred for 3 hours at room temperature. After addition of 23.6 g of formylmethyltriphenylphosphorane is stirred for a further 18 hours at room temperature, treated with 500 ml of ethyl acetate and poured after 10 minutes to 1L saturated brine. The resulting suspension is stirred for 15 minutes and filtered through a P4 frit. In the filtrate, the aqueous phase is extracted 3 times with 100 ml of ethyl acetate. The combined organic phases are washed 3 times with saturated brine, dried over sodium sulfate and evaporated. The residue is filtered through silica gel with ether / hexane (4: 1 + 1% triethylamine) as eluent. The filtrate is evaporated and the residue is first filtered through a column filled with 2 kg of silica gel, then chromatographed on a column filled with 500g silica gel with hexane / ethyl acetate (3: 2) as the eluent. The title compound is thus obtained as a yellow oil; Rf (hexane: ethyl acetate 1: 1) = 0.61; Ia] D ₂₀ (0.21% in CDCl ₃ ) = + 19.5 ± 4.8 ° C.

g) (6R, 7S) -15- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -6,7-epoxy-1,1,1,2,2-pentafluoro-pentadeca-8 (E) , 10 (Z) -diene

The suspension of 4.0 g of 5- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -pentyl-triphenylphosphonium bromide in 150 ml of abs. Tetrahydrofuran is added with 1.0 g of (4R, 5R) -4,5-epoxy-9,9,10,10,10-pentafluoro-dec-2 (E) -enal and 0.54 g of sodium amide under argon for 2.5 hours Room temperature stirred. The resulting suspension is poured onto 400 ml of phosphate buffer (pH 7) and extracted 4 times with 25 ml of ether. The combined ether extracts are washed twice with 25 ml of phosphate buffer (pH 7) and once with saturated brine, dried over sodium sulfate and evaporated. The residue is taken up in hexane: ethyl acetate (1: 1 + 1% triethylamine) and prewashed over with a solvent mixture

Silica gel column, filtered. The filtrate is evaporated and the residue purified by chromatography on silica gel with hexane / ethyl acetate (7: 3 + 1% triethylamine). The title compound is thus obtained as a yellow oil; Rf (hexane: ethyl acetate 1: 1) = 0.50; [a] D ₂₀ (CHCl ₃ , 0.20%) = + 15 ± 5 ° C.

Example 2

7 - [(6R, 7S) -15- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-6-hydroxy-pentadeca-8 (E), 10 (Z) -diene-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

1.3 g of the corresponding methyl ester according to Example 1 are dissolved under argon in 40 ml of tetrahydrofuran, mixed with 9.4 ml of 0.2 N sodium hydroxide solution at 0 ⁰ C and stirred for 1 hour at room temperature. Evaporation and purification of the residue on a 240 g Merck Lichroprep® RP-8 column with methanol / water (7: 3) as eluent gives the title compound of the formula

OH

F F

CH

of the mp: 155-158 ° C; Ia] D ₂₀ (0.12%, MeOH) = 44.2 ± 8.3 ° C; UV spectrum (MeOH): Xmax = 221 (ε = 48080), 231 / sh, (ε = 24720), 285 (ε = 22080), 325 / sh; IR spectrum (CH ₂ Cl ₂ ): 3480.2920.1 630, 1450, 1420, 1360, ¹ , 12, 1120, 810 cm ^-1 ; Rf (MeOH / H ₂ O: 3: 1): = 0.20.

Example 3

7 - [(6R, 7S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1 ^, 2-pentafluoro-6-hydroxy-tetradeca-8 (E), 10 (Z) -diene-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The solution of 0.53 g (6R, 7S) -14- (4-acetyl-3-hydroxy-2-propylphenoxy) -6,7-epoxy-1,1,1,2,2-pentafluoro-tetradeca-8 ( E), 10 (Z) -diene in 50 ml abs. Methanol is stirred under argon with 1.3 ml of triethylamine and 0.4 g of methyl 7-Mecaptochromon-2-carboxylate for 20 hours at room temperature and evaporated. The residue is dissolved in ethyl acetate and filtered through silica gel. The filtrate is washed once with 25 ml of 1N hydrochloric acid and 4 times with 25 ml of saturated common salt solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with hexane / ethyl acetate (7: 3) as eluent. The title compound is obtained as a yellow oil; from Rf (hexane: ethyl acetate 3: 2) = 0.25.

The starting material can be prepared as follows:

a) (6R, 7S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -6,7-epoxy-1,1,1 ^, 2-pentafluoro-tetradeca-8 (E), 10 (Z) -diene The suspension of 1.2 g of 4- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -butyl-triphenyl-phosphonium bromide in 50 ml of abs.

Of tetrahydrofuran with stirring at -70 ⁰ C under argon with 0.4 g (4R, 5R) -4,5-epoxy-9,9, i0,10,10-pentafluoro-dec-2- (E) -enal in 10ml Tetrahydrofuran, 0.156 g sodium amide and about 50 mg potassium tertiary butoxide added. Then allowed to warm to room temperature within 2.5 hours. The resulting suspension is poured onto 200 ml of phosphate buffer (pH 7) and extracted with ether. The combined ether phases are washed once with phosphate buffer (pH 7) and twice with saturated brine, dried over sodium sulfate and evaporated. The residue is taken up in hexane / ethyl acetate (3: 2 + 1% triethylamine) and filtered through a silica gel column prewashed with this solvent mixture. The filtrate is evaporated and the residue purified by chromatography on silica gel with hexane / ethyl acetate (7: 3 + 1% triethylamine) as eluent. The title compound is obtained as a pale yellow oil; Rf (hexane / ethyl acetate 3: 2) = 0.50; [Q] D ₂₀ (CHCl ₃ , 0.0955%) = 8.4 ± 10.5 ⁰ C; UV spectrum (CHCl ₃ ): X max = 287 (ε 20920), 330 / sh.

Example 4

4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound of the formula

is prepared analogously to Example 2 from the corresponding methyl ester according to Example 3. Mp 159-160 ⁰ C; [a] D ₂ o (methanol, 0.087%) = + 65.5 ± 11.5 ° C, UV spectrum (methanol): Xmax, (ε), 221 (44480), 231 / sh, 267 (22960) , 285 (20400), 330 / sh; IR spectrum (CH ₂ Cl ₂ ): 3380.2950.1 630.1 500.1420, 1360.1, 270.1, 200, 1120, 810 cm ^-1 .

Example 5

oxo-4H-1-benzopyran-2-carboxylic acid

0.87 g of the corresponding methyl ester according to Example 1 are dissolved under argon in 30 ml of tetrahydrofuran, treated at 0 ⁰ C with 6.3 ml of 0.2 N sodium hydroxide solution and stirred at 0 to 5 ° C for 1 hour. The reaction mixture is freed from tetrahydrofuran on a rotary evaporator and taken up in 20 ml of water and 50 ml of methylene chloride. With 2N hydrochloric acid is acidified to pH 1 and extracted 3 times with 50 ml of methylene chloride. The combined organic phases are dried over sodium sulfate, and evaporated. The evaporation residue is purified over a silica gel column with methylene chloride / methanol (4: 1) to give the title compound as a tough resin.

Example 6

In an analogous manner as described in Examples 1 to 5 can be prepared:

7 - [(6R, 7S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-6-hydroxy-trideca-8 (E), 10 (Z) -dien-7-ylthio] -4-oxo-4H-i-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-5-hydroxy-dodeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(4R, 5S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1 ^^ -pentafluoro-m-hydroxy-trideca-efIII-izidiene-6-yl-thiol ^ -oxo ^ H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(4R, 5S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-4-hydroxy-undeca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-i-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(3R, 4S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-1-dodeca-7 (E), 9 (Z) -dien-4-ylthio] -4-oxo-1H-benzopyrancarboxylic acid, its methyl ester and its sodium salt;

7 [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) 2,2-dichloro-1,1,1-trifluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-OXO-4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 [(3R, 4S) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-deca-5 (E) , 7 (Z) -dien-4-yl-thio] -4-oxo-4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(3R, 4S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-undeca-5 (E ), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(3R, 4S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-trideca-5 (E ), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

7 - [(3R, 4S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-tretradeca-5 (E ), 7 (Z) -dien-4-ylthio] -4-oxo-1H-benzopyrancarboxylic acid, its methyl ester and its sodium salt;

7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-5-hydroxy-tetradeca-7 (E ), 9 (Z) -dien-6-ylthio] -4-oxo-1H-benzopyrancarboxylic acid, its methyl ester and its sodium salt;

7 - [(5R, 6S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-5-hydroxy-trideca-7 (E ), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt, and 7 - [(5R, 6S) -12- (4-acetyl) 3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-5-hydroxy-dodeca- (7E), 9 (Z) -diene-6-ylthio] -4-oxo -4H-1-benzopyran-2-carboxylic acid, its methyl ester and its sodium salt;

Example 7

A propellant-containing, solid aerosol-forming inhalable suspension containing 0.1% by weight of active ingredient, e.g. 7 - [(6R, 7S) -15- (4-acetyl-S-hydroxy ^ -propyl-phenoxy-i ^ .i ^^ - pentafluoro-e-hydroxy-pentadeca-fell ^ OiZl-dien ^ ^ -ylthiol - oxo ^ H -benzopyran-2-carboxylic acid sodium salt can be prepared, for example, as follows:

Composition:% by weight

Active substance, micronized 0.1 sorbitan trioleate 0.5

Propellant A (trichlorotrifluoroethane) 4.4

Propellant B (dichlorofluoromethane and 15.0

1,2-dichlorotetrafluoroethane) 80.0

Preparation: The active ingredient is suspended in the exclusion of moisture with the aid of a conventional homogenizer with the addition of 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 8

A suitable for inhalation, about 2% aqueous solution of an active ingredient in the form of its sodium salt z. From 7 - [(6R, 7S) -15- (4-acetyl-3-hydroxy-2-propylphenoxy) -1,1,1,2,2-pentafluoro-6-hydroxy-pentadeca-8 (e.g. E), 10 (Z) -dien-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt, may be, for. B. be prepared as follows:

Composition:

Active ingredient (K or Na salt) 2000mg

Ethylenediaminetetraacetic acid disodium salt 10 mg

Benzalkonium chloride 10mg

Water, freshly distilled ad 100 ml

Preparation: The active ingredient is dissolved with 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.

Claims (53)

claims: 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 _{3 is} optionally chlorinated Polyfluorniederalkyl means, R _{4 is} optionally esterified or amidated carboxy or 5-tetrazolyl and R _{5 is} hydrogen or lower alkyl, and their salts, characterized in that an epoxide of the formula OX -alk - (CH = CH) - CH- CH- R ₃ wherein Ri, R ₂ , X, alk, η and R _{3 have the} above meanings, with a thiol of the formula (II) wherein R ₄ and R _{5 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 into a salt or a salt obtainable according to the process is converted into the free compound or into another salt. 2. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} lower alkyl or mono-, di- or Polyfluorniederalkyl, R _{2 is} hydrogen, lower alkyl, lower alkenyl or mono-, di- or Polyfluorniederalkyl, X is lower alkylene , Alkoxy or thio, alk is lower alkylene, R _{3 is} polyfluoroloweralkyl having 5 to 9 fluorine atoms or chlorinated polyfluoroloweralkyl having 3 to 7 fluorine atoms and 2 to 5 chloro atoms, R _{4 is} carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamyl, N-mono- or Ν, Ν-di-lower alkylcarbamyl or N- (benzenesulfonyl) carbamyl optionally substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, and R _{5 is} hydrogen or lower alklyl or produces its salts. 3. The method according to claim 1, characterized in that, g), Gu-triflour-C compounds of formula I wherein R _{1 is} C ₁ -C ₄ -alkyl or Cu | -C ₄ alkyl, R ₂ is hydrogen, C ₁ -C ₄ -AlkYl, C ₂ -C ₄ alkenyl or üXü ^ ou-trifluoro-C ^ C ^ alkyl, XC ₁ -C ₃ -AlkYlen. Oxy or thio, alk is straight-chain C ₂ -C ₆ -alkylene, η is 1 or 2, R _{3 is} ω, ω, ω, ω-Ι, ω-1-pentafluoro- C ₃ -C ₇ -alkyl, R _{4 is} carboxy or N- (benzenesulfonyl) carbamyl, and R _{5 is} hydrogen, or their salts are prepared. 4. The method according to any one of claims 1 to 3, characterized in that compounds of formula I, wherein the group X is attached para to the R _r C (= O) group, or their salts. 5. The method according to claim 1, characterized in that compounds of the formula X is -alk- (CH = CH) CH- CH- FU (La), wherein R _{1 is} C ₁ -C ₄ -alkyl, R _{2 is} C ₁ -C ₄ -alkyl, X is oxy, alkC ₂ -C ₆ -alkylene, η is 1 or 2, R _{3 is} ω, ω , ω, ω-1, ω-1-pentafluoro-C ₃ -C ₇ -alkyl, R _{4 is} carboxy, and R _{5 is} hydrogen, or produces their salts. 6. Process according to Claim 5, characterized in that compounds of the formula Ia in which R _{1 is} C ₁ -C ₄ -alkyl, R _{2 is} C-, C ₄ -alkyl, X is oxy, alk C ₂ -C ₅ -alkylene, η is 2, R _{3 is} ω, ω, ω, ω-1, ω-1-pentafluoro-Cs-Cs-alkyl, R _{4 is} carboxy, and R _{5 is} hydrogen, or their Salts produces. Process according to any one of Claims 1 to 6, characterized in that a compound of the formula I or I a or a salt thereof is prepared in which the double bond bonded to the radical alk in (Z) -, i. cis configuration and the optional additional double bond in (E) -, d. H. trans configuration is present. 8. The method according to any one of claims 1 to 7, characterized in that one produces a compound of formula I or I a or a salt thereof, wherein the chain associated with the sulfur atom carbon atom (S) - and the hydroxy group has a supporting chain C atom (R) configuration. 9. The method according to any one of claims 1 to 7, characterized in that 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-6-hydroxy-14- (4-acetyl-3- hydroxy-2-propylphenoxy) -tetradeca-8 (E), 10 (Z) -dien-7-yl-thio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 10. The method according to any one of claims 1 to 7, characterized in that 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-6-hydroxy-14- (4-acetyl-3- hydroxy-2-propylphenoxy) -tetradeca-8 (E), 10 (Z) -dien-7-yl-thio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 11. The method according to any one of claims 1 to 7, characterized in that 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-4-hydroxy-15- (4-acetyl-3- hydroxy-2-propylphenoxy) -pentadeca-8 (E), 10 (Z) -dien-7-yl-thio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 12. The method according to any one of claims 1 to 7, characterized in that 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-4-hydroxy-15- (4-acetyl-3- hydroxy-2-propylphenoxy) -pentadeca-8 (E), 10 (Z) -dien-7-yl-thio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 13. The method according to any one of claims 1 to 7, characterized in that 7 - [(6R, 7S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2 , 2-pentafluoro-6-hydroxy-trideca-8 (E), 10 (Z) -diene-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 14. The method according to any one of claims 1 to 7, characterized in that 7 - [(6R, 7S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2 , 2-pentafluoro-6-hydroxy-trideca-8 (E), 10 (Z) -dien-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 15. The method according to any one of claims 1 to 7, characterized in that man7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1, l, 2, 2-pentafluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 16. The method according to any one of claims 1 to 7, characterized in that man7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2, 2-pentafluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 17. The method according to any one of claims 1 to 7, characterized in that man7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2, 2-pentafluoro-5-hydroxy-dodeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester prepared. 18. The method according to any one of claims 1 to 7, characterized in that man7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2, 2-pentafluoro-5-hydroxy-dodeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 19. The method according to any one of claims 1 to 7, characterized in that man7 - [(4R, 5S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2, 2-pentafluoro-4-hydroxy-trideca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 20. The method according to any one of claims 1 to 7, characterized in that 7 - [(4R, 5S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2 , 2-pentafluoro-4-hydroxy-trideca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 21. The method according to any one of claims 1 to 7, characterized in that 7 - [(4R, 5S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2 , 2-pentafluoro-4-hydroxy-undeca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 22. The method according to any one of claims 1 to 7, characterized in that man7 - [(4R, 5S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2, 2-pentafluoro-4-hydroxy undeca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 23. The method according to any one of claims 1 to 7, characterized in that 7 - [(3R, 4S) -12 (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-3-hydroxy-1-dodeca-7 (E), 9 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 24. The method according to any one of claims 1 to 7, characterized in that man7 - [(3R, 4S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-3-hydroxy-1-dodeca-7 (E), 9 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 25. The method according to any one of claims 1 to 7, characterized in that 7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 26. The method according to any one of claims 1 to 7, characterized in that man7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 27. The method according to any one of claims 1 to 7, characterized in that man7 - [(3R, 4S) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-3-hydroxy-deca-5 (E), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 28. The method according to any one of claims 1 to 7, characterized in that man7 - [(3R, 4S) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-3-hydroxy-deca-5 (E), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 29. The method according to any one of claims 1 to 7, characterized in that man7 - [(3R, 4S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-3-hydroxy-undeca-5 (E), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 30. The method according to any one of claims 1 to 7, characterized in that man7 - [(3R, 4S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-3-hydroxy-undeca-5 (E), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 31. The method according to any one of claims 1 to 7, characterized in that man7 - [(3R, 4S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-3-hydroxy-trideca-5 (E), 7 (Z) -diene-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 32. The method according to any one of claims 1 to 7, characterized in that 7 - [(3R, 4S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-3-hydroxy-trideca-5 (E), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 33. The method according to any one of claims 1 to 7, characterized in that 7 - [(3R, 4S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-3-hydroxy-tetradeca-5 (E), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 34. The method according to any one of claims 1 to 7, characterized in that 7 - [(3R, 4S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-3-hydroxy-tetradeca-5 (E), 7 (Z) -diene ^ -oxo-AH-i-benzopyrancarboxylic acid or a salt thereof. 35. The method according to any one of claims 1 to 7, characterized in that man7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1, 1,1-trifluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 36. Method according to one of claims 1 to 7, characterized in that 7 - [(5R, 6S) -14- ( dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 37. The method according to any one of claims 1 to 7, characterized in that 7 - [(5R, 6S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-5-hydroxy-trideca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 38. The method according to any one of claims 1 to 7, characterized in that 7 - [(5R, 6S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-5-hydroxy-trideca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 39. The method according to any one of claims 1 to 7, characterized in that 7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-5-hydroxy-dodeca-7 (E), 9 (Z) -diene-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester. 40. The method according to any one of claims 1 to 7, characterized in that 7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1 , 1,1-trifluoro-5-hydroxy-dodeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 41. New p-substituted alkanophenones of the general formula ¹ H] X-alk- (CH =CH) -CH-CH-R ₂ HO ^^^ S ^ ^^ ^ O ^ ^ R ₄ (I), R ₂ wherein R 1 is optionally fluorinated lower alkyl, R _{2 is} hydrogen, optionally
X is lower alkylene, oxy, thio or a direct bond, alk is lower alkylene, η is 1 or 2, R _{3 is} optionally chlorinated
Polyfluoriederalkyl means R ₄ optionally esterified or amidated carboxy or
5-tetrazolyl and R _{5 is} hydrogen or lower alkyl, and their salts. 42. Compounds according to claim 1, wherein R _{1 is} lower alkyl or mono-, di- or Polyfluorniederalkyl, R _{2 is} hydrogen, lower alkyl, lower alkenyl or mono-, di- or Polyfluorniederalkyl
X represents lower alkylene, oxy or thio, alk denotes lower alkylene, R ₃
Polyfluoriederalkyl having 5 to 9 fluorine atoms or chlorinated Polyfluorniederalkyl with 3 to 7 fluorine atoms and 2 to 5 chlorine atoms, R ₄ carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamyl, N-mono- or Ν, Ν-Diniederalkylcarbamyl or optionally in the phenyl part
Lower alkyl, lower alkoxy, halogen and / or trifluoromethyl substituted
N- (benzenesulfonyl) carbamyl and R _{5 is} hydrogen or lower alkyl, and their salts. 43. Compounds according to claim 41, where R ₁ R _{1 is} C ₁ -C ₄ -alkyl orGu ₁ -C ₃ -trifluoro-C ₁ -C ₄ -alkyl, R _{2 is} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C -alkenyl or ω, ω , ω-trifluoro-C ₁ -C 4 -alkyl, X represents C ₁ -C ₃ -alkylene, oxy or thio, alk represents straight-chain C ₂ -C ₆ -alkylene, η represents 1 or 2, R ₃
ü ^ co ^ Gu-ou-i-pentafluoro-Cr-Cy-alkyl, R _{4 is} carboxy or N- (benzenesulfonyl) carbamyl
means, and R _{5 is} hydrogen, and their salts. 44. Compounds according to one of claims 1 to 3, wherein the group X in para position to the
RiC (= O) group is bound, and their salts. 45. Compounds according to claim 41, of the formula
O OH X-alk- (CH = CH) CH-CH-R ₃ n I (La). in which R _{1 is} C ₁ -C ₄ -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 _{3 is} ω, ω, ω, ω-1, ω-1 pentafluoro-Cs-Cy-alkyl, R _{4 is} carboxy, and R ₅ Hydrogen is, and their salts.
46. Compounds according to claim 5, of the formula Ia, in which Ri is C ₁ -C ₄ -alkyl, R ₂ is C ₁ -C ₄ -alkyl, X is oxy, alk is C ₂ -C ₅ -alkylene, η is 2 R ₃ ω, ω, ω, ω-1, ω-1-pentafluoro- C ₃ -C ₅ alkyl, R _{4 is} carboxy, and R _{5 is} hydrogen, and their salts. Al. A compound according to any one of claims 1 to 6, wherein the double bond linked to the alk radical is in (Z) -, ie cis-configuration and the optionally present additional double bond in (E) -, ie trans-configuration. 48. A compound according to any one of claims 1 to 7, wherein the chain C atom attached to the sulfur atom has (S) - and the hydroxy group bearing chain C atom (R) configuration. 49. 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-6-hydroxy-14- (4-acetyl-3-hydroxy-2-propylphenoxy) -tetradeca-8 (E), 10 (Z) -diene-7-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester. 50. 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-6-hydroxy-14- (4-acetyl-3-hydroxy-2-propylphenoxy) -tetradeca-8 (E), 10 (Z) -dien-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 51. 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-4-hydroxy-15- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentadeca-SiEhiOfZi-diene ^ - ylthiol- ^ ^ oxo Hi-benzopyran ^ -carboxylate. 52. 7 - [(6R, 7S) -2,2,3,3,3-pentafluoro-4-hydroxy-15- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentadeca-8 (E), 10 (Z) -dien-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof. 53. A compound according to claim 41 selected from 7 - [(6R, 7S) -13- (4-acetyl-3-hydroxy-2-propylphenoxy) -1,1,1 ^^ -pentafluoro-e-hydroxy-trideca-SfEhiOiZi-diene-1-thylthiol oxo ^ ^ Hi-benzopyran carboxylic acid methyl ester; 7 - [(6R, 7S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-6-hydroxy-trideca-8 (E), 10 (Z) -dien-7-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or one of its salts; 7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -diene-6-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; 7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-5-hydroxy-tetradeca-7 (E), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or one of its salts; 7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-5-hydroxy-dodeca-7 (E), 9 (Z) -diene-6-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; 7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propylphenoxy) -1,1,1 ^^ -pentafluoro-6-hydroxy-dodeca-7 (E), 9 ( Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or one of its salts; 7 - [(4R, 5S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-4-hydroxy-trideca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; 7 - [(4R, 5S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-4-hydroxy-trideca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof; 7 - [(4R, 5S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-4-hydroxy-undeca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; 7 - [(4R, 5S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1,1,1,2,2-pentafluoro-4-hydroxy-undeca-6 (E), 8 (Z) -dien-5-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof; 7 - [(3R, 4S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-1-dodeca-7 (e), 9 (Z) -diene-4-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; dodeca ^ iEj ^ ZJ-diene ^ -ylthioM-oxo ^ H-i-benzopyrano-carboxylic acid or one of its salts; y ^ SJ-i-KBR iK ^ acetyl-S-hydroxy ^ -propyl-phenoxyJ ^^ - dichloro-IJJ-tnfluor-B-hydroxytetradeca-TfEJ ^ iZJ-dien-e-oxo-ylthiol- ^ AH-l- benzopyran ^ -carbonsäuremethylesterund tetradeca- ^ IEhSiZj-diene-e-ylthiol ^ -oxo ^ H-i-benzopyran-1-carboxylic acid and its sodium salt. 54. A connection selected from 5 (E), 7 (Z) -diene-4-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; 7 - [(3R, 4S) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -2,2-dichloro-1,1 _/ 1-trifluoro-3-hydroxy-deca-5 (E. ), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or one of its salts; 7 - [(3R, 4S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-undeca-5 (E ), 7 (Z) -diene-4-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; 7 - [(3R, 4S) -11- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2 _/ 2-dichloro-1,1,1-trifluoro-3-hydroxy-undeca-5 (E. ), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or one of its salts; 7 - [(3R, 4S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-trideca-BfEJ ^ iZJ -diene ^ ^ -ylthiol oxo ^ ^ Hi-benzopyran carboxylic acid methyl ester; 7 - [(3R, 4S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxy-trideca-5 (E ), 7 (Z) -dien-4-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or one of its salts; 7 - [(3R, 4S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxytetradeca-BlEjJiZJ-dien ^ - ylthio ^ ^ -oxo Hi-benzopyran ^ -carboxylate; 7 - [(3R, 4S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-3-hydroxytetradeca-BiEJJiZJ-dien ^ - ylthiol ^ -oxo- ^ -Hi-benzopyran ^ -carboxylic acid or one of its salts; 7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-5-hydroxytetradeca tej ^ ^ iZj-dien -e-ylthio ^ ^ -oxo Hi-benzopyran ^ -carboxylate; 7 - [(5R, 6S) -14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-5-hydroxytetradeca ^ ^ iZJ IEL-dien G-ylthiol ^ -oxo ^ hi-benzopyrancarboxylic acid or one of its salts; 7 - [(5R, 6S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-5-hydroxy-trideca-7 (E ), 9 (Z) -diene-6-ylthio] -4-oxo-4H-1-benzopyran-2-carbonsäuremethylester; 7 - [(5R, 6S) -13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1 _/ 1-trifluoro-5-hydroxy-trideca-7 {E ), 9 (Z) -dien-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid or a salt thereof; 7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2,2-dichloro-1,1,1-trifluoro-5-hydroxy-dodeca-7 (E ), 9 (Z) -diene-6-ylthio] -4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester, and 7 - [(5R, 6S) -12- (4-acetyl-3-hydroxy-2-propyl phenoxy) -2,2-dichloro-1,1, l-trifluoro-5-hydroxy-dodeca-7 (e), 9 (Z) -diene-6-ylthio] -4-oxo-4H-1-benzopyran 2-carboxylic acid or one of its salts. 55. A compound according to any one of claims 41 to 54 for use in a method for the therapeutic treatment of the human or animal body. 56. Pharmaceutical preparations, as pharmaceutical active ingredient comprising a compound according to any one of claims 41 to 55.