IE903376A1

IE903376A1 - Additional further novel alkanophenones

Info

Publication number: IE903376A1
Application number: IE337690A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1989-09-19
Filing date: 1990-09-18
Publication date: 1991-04-10
Also published as: AU634286B2; FI904571A0; PT95337A; CA2025471A1; EP0419411A3; JPH03112979A; HUT54672A; EP0419411A2; NZ235336A; KR910006268A; IL95679A0; HU207060B; MX22431A; NO904070D0; ZA907423B; NO174927B; DD295839A5; AU6260590A; NO904070L; NO174927C

Abstract

p-Substituted alkanophenones of the general formula in which R1 is optionally fluorinated lower alkyl, R2 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, R3 is optionally chlorinated polyfluoro-lower alkyl, R4 is optionally esterified or amidated carboxyl or 5-tetrazolyl, and R5 is hydrogen or lower alkyl, act as leukotriene antagonists and can be used as antiallergic active ingredients in pharmaceuticals. The process for their preparation is characterised in that an epoxide of the formula in which R1, R2, X, alk, n and R3 have the above meanings, is reacted with a thiol of the formula in which R4 and R5 have the above meanings, or with a salt thereof, and, if desired, a compound which can be obtained by the process is converted into another compound of the formula I, a stereoisomer mixture which can be obtained by the process is separated into the components, and/or a free compound which can be obtained by the process is converted into a salt, or a salt which can be obtained by the process is converted into the free compound or into a different salt.

Description

The invention relates to novel substituted alkanophenones of the general formula (I), wherein Rj is unsubstituted or fluorinated lower alkyl, R2 is hydrogen, unsubstituted or 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, R3 is unsubstituted or chlorinated polyfluoro-lower alkyl, R4 is free, esterified or amidated carboxy or 5-tetrazolyl, and R5 is hydrogen or lower alkyl, and their salts, to processes for their preparation, to pharmaceutical preparations containing them as active ingredient, and to their use as active ingredients in medicaments.

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

Unsubstituted or fluorinated lower alkyl is lower alkyl or mono-, di- or poly-fluoro-lower alkyl.

Etherified or esterified hydroxy is, for example, lower alkoxy or halogen, respectively.

Unsubstituted or lower alkylated amino is, for example, amino, lower alkylamino or especially di-lower alkylamino.

Free, esterified or amidated carboxy is carboxy, esterified carboxy, such as lower alkoxycarbonyl, or amidated carboxy, such as carbamoyl or N-mono- or N,N-di-lower alkylcarbamoyl, or N-(benzenesulfonyl)-carbamoyl that is unsubstituted or substituted, preferably in the phenyl moiety, by lower alkyl, lower alkoxy and/or by halogen. N-(benzenesulfonyl)-carbamoyl that is unsubstituted or substituted in the phenyl moiety as indicated is, for example, unsubstituted or monosubstituted, preferably in the ortho-position. As a free, esterified or amidated carboxy substituent carboxy and esterified carboxy, especially lower alkoxycarbonyl, are especially preferred.

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

Lower alkyl is, for example, C1-C7alkyl, especially straight-chain C1-C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or secondary butyl, but may also be a branched CpC^alkyl, such as isobutyl or tertiary butyl or a pentyl, hexyl or heptyl radical. Lower alkyl Rb R5 and as a substituent of phenyl or N-(benzenesulfonyl)-carbamoyl is preferably CpQalkyl, for example methyl; lower alkyl R2 is preferably C2-C5alkyl, for example propyl.

Mono-, di- or poly-fluoro-lower alkyl Rj and R2 has, for example, up to and including 5 fluorine atoms and is, for example, mono-, di- or tri-fluoro-Q-Cjalkyl, especially -3,ββΜ’16 ω-fluoro- or (D.G^co-trifluoro-Cj-C^alkyl, such as trifiuoromethyl, 2,2,2-trifluoroethyl or 3,3,3-trifluoropropyl. Fluorinated lower alkyl R3 is especially trifiuoromethyl and fluorinated lower alkyl R2 is preferably Q,ro,ro-trifluoro-C2-C4alkyl, for example 3,3,3-trifluoropropyl.

Unsubstituted or chlorinated polyfluoro-lower alkyl R3 has at least 5, for example from 5 up to and including 9, fluorine atoms, or at least 3, for example up to and including 7, fluorine atoms and at least 2, for example from 2 to 5, chlorine atoms, and is, for example, a>,3-C7alkyl, 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-pentafluorohexyI, or -trifluoro-co-l,a)-dichloro-C2-C5alkyl, such as l,l-dichloro-2,2,2-trifluoroethyl, 2,2-dichloro-3,3,3-trifluoropropyl, 3,3-dichloro-4,4,4-trifluorobutyl or 4,4-dichloro-5,5,5trifluoropentyl.

Lower alkenyl R2 is, for example, C2-C4alkenyl, such as vinyl, prop-l-enyl or especially prop-2-enyl (allyl).

Loweralkylene is, for example, straight-chain Cj-Cyalkylene, in the case of X especially Ci-C3alkylene, such as methylene or ethylene, and in the case of alk especially C2-C6alkylene, such as ethylene, 1,3-propylene, 1,4-butylene, and also 1,5-pentylene or 1,6-hexylene.

Lower alkoxy is, for example, Ci-C4alkoxy, such as methoxy.

Lower alkoxycarbonyl is, for example, CpQalkoxycarbonyl, such as methoxy-, ethoxy-, propoxy- or butoxy-carbonyl.

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

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

N-Mono- or N,N-di-lower alkylcarbamoyl is, for example, N-C1-C4alkyl- or N,N-di-Cj-C4alkyl-carbamoyl, such as Ν-methyl-, N-ethyl- or N,N-dimethyl-carbamoyl. -4Halogen is, for example, halogen having an atomic number of up to and including 35, such as fluorine, chlorine or bromine.

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

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

For example, in vitro in a concentration range of approximately from 0.001 to 1.0 pmol/l, they inhibit the contraction of a smooth muscle induced by leucotriene-D4 (LTD4). This so-called LTD4-antagonism is detected experimentally, for example, as follows: in segments which have been removed from the ileum of a guinea pig weighing 300-400 g and which have been incubated in an organ bath in Tyrode’s solution at 38°C and while being gassed with a mixture of 95 % oxygen and 5 % carbon dioxide at a load of 1 g, contractions are induced with synthetic leucotriene-D4 (in potassium salt form) and are registered isotonically. The extent of the inhibition by the test compound is detected after a preliminary incubation of 2 minutes and is evaluated as IC50, that is to say the concentration which reduces the test contraction by 50 %. The compounds of formula I also have excellent activity in vivo. In addition, they have a relatively long duration of action which is a very significant advantage both specifically and therapeutically. For example, in an in vivo bronchoconstriction standard test on guinea pigs, with aerosol administration of a solution containing from 0.0001 to 1 % by weight of the test compound, a marked LTD4-antagonistic effect was demonstrated.

Surprisingly, many compounds of formula I also exert a pronounced inhibitory action on other physiologically important enzyme systems. For example, the inhibition of phospholipase A2 obtained from human leucocytes was observed in the tested concentration range of approximately from 0.5 to 50 pmol/l. Likewise, the inhibition of phospholipase C obtained from human thrombocytes was observed in the tested concenIE 903376 -5tration range of approximately from 1 to 100 pmol/l.

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

The invention relates especially to compounds of formula I wherein is lower alkyl or mono-, di- or poly-fluoro-lower alkyl, R2 is hydrogen, lower alkyl, lower alkenyl or mono-, di- or poly-fluoro-lower alkyl, X is lower alkylene, oxy or thio, alk is lower alkylene, R3 is polyfluoro-lower alkyl having from 5 to 9 fluorine atoms or chlorinated polyfluoro-lower alkyl having from 3 to 7 fluorine atoms and from 2 to 5 chlorine atoms, R4 is carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, or N-(benzenesulfonyl)-carbamoyl that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl, and R5 is hydrogen or lower alkyl, and their salts, especially pharmaceutically acceptable salts.

The invention relates preferably to those compounds wherein the group X is bonded in the para-position to the RrC(=O) group, that is to say compounds of the formula -6IE 903376 O II C R HO OH X — alk—(CH= CH)-CH- CH— R3 η I O (Ia), wherein Rb R2, X, alk, n, R3, R4 and R5 are as defined above, and their salts, especially pharmaceutically acceptable salts.

The invention relates especially to compounds of formula I and Ia wherein Ri is CrC4alkyl, such as methyl, or ω,ω,ω-trifluoro-Cj-^alkyl, such as trifluoromethyl, R2 is CrC4alkyl, such as propyl, C2-C4alkenyl, such as allyl, G^oxto-trifluoro-Cj-C^alkyl, such as 3,3,3-trifluoropropyl, or secondly hydrogen, X is C7-C3 alkylene, such as methylene, oxy or thio, alk is straight-chain C2-C6alkylene, such as ethylene, 1,3-propylene or 1.4- butylene, n is 1 or 2, R3 is co,G),G),co-l,o)-l-pentafluoro-C3-C7alkyl, such as 2,2,3,3,3pentafluoropropyl, 3,3,4,4,4-pentafluorobutyl, 4,4,5,5,5-pentafluoropentyl or 5,5,6,6,6pentafluorohexyl, or o^,2-C5alkyl, such as 1,1-dichloro2,2,2-trifluoroethyl, 2,2-dichloro-3,3,3-trifluoropropyl, 3,3-dichloro-4,4,4-trifluorobutyl or 4.4- dichloro-5,5,5-trifluoropentyl, R4 is carboxy or N-(benzenesulfonyl)carbamoyl, and R5 is hydrogen, and when n is 1, the chain carbon atom bonded to the sulfur atom preferably has the (R)-configuration and the chain carbon atom bonded to the hydroxy group preferably has the (S)-configuration, or, when n is 2, the chain carbon atom bonded to the sulfur atom preferably has the (S)-configuration and the chain carbon atom carrying the hydroxy group preferably has the (R)-configuration and the double bond joined to the radical alk is preferably in the cis-configuration and the additional double bond which may be present is preferably in the trans-configuration, preferably those compounds wherein Rj is Cj-C4alkyl and R2, X, R3, R4 and R5 are as defined above, and to their salts, especially pharmaceutically acceptable salts.

The invention relates especially to compounds of formula Ia wherein R1 is Cj-C4alkyl, such as methyl, R2 is Ci-C4alkyl, such as propyl, X is oxy, alk is C^-C^alkylene, such as -7ethylene, 1,3-propylene or 1,4-butylene, n is 1 or preferably 2, R3 is C3-C5alkyl, such as ci},ro,(D,G)-l,tt>-l-pentafluoro-C3-C7alkyl, such as 2,2,3,3,3-pentafluoropropyl, 3,3,4,4,4pentafluorobutyl or 4,4,5,5,5-pentafluoropentyl, or co-l,(t)-l-dichloro-co,o),2-C5alkyl, such as 1,l-dichloro-2,2,2-trifluoroethyl, 2,2-dichloro-3,3,3-trifluoropropyl, 3,3-dichloro-4,4,4-trifluorobutyl or 4,4-dichloro-5,5,5-trifluoropentyl, R4 is carboxy, and R5 is hydrogen, and when n is 1, the chain carbon atom bonded to the sulfur atom preferably has the (Reconfiguration and the chain carbon atom bonded to the hydroxy group preferably has the (S)-configuration, or, when n is 2, the chain carbon atom bonded to the sulfur atom preferably has the (S)-configuration and the chain carbon atom carrying the hydroxy group preferably has the (R)-configuration and the double bond joined to the radical alk is preferably in the cis-configuration and the additional double bond which may be present is preferably in the trans-configuration, and to their salts, especially pharmaceutically acceptable salts.

The invention relates most especially to compounds of formula Ia wherein Rj is CrC4alkyl, such as methyl, R2 is CrC4alkyl, such as propyl, X is oxy, alk is C2-C5alkylene, such as ethylene, 1,3-propylene or 1,4-butylene, n is 2, R3 is ω,ω,ω,ω-1,ω-1pentafluoro-C3-C5alkyl, such as 4,4,5,5,5-pentafluoropentyl, or ω-Ι,ω-1-dichloroa),0),co-trifluoro-C3-C5alkyl, such as 4,4-dichloro-5,5,5-trifluoropentyl, R4 is carboxy, and R5 is hydrogen, and the chain carbon atom bonded to the sulfur atom preferably has the (S)-configuration and the chain carbon atom carrying the hydroxy group preferably has the (R)-configuration and the double bond joined to the radical alk is preferably in the cisconfiguration and the other, additional double bond is preferably in the transconfiguration, and to their salts, especially pharmaceutically acceptable salts.

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

The process according to the invention for the preparation of compounds of formula I and their salts is based on methods known per se and is carried out as follows: an epoxide of formula -8IE 903376 (Π), wherein Rb R2, X, alk, n and R3 are as defined above, is reacted with a thiol of formula (HI), wherein R4 and R5 are as defined above, or with a salt thereof, and, if desired, a compound obtainable in accordance with the process is converted into a different compound of formula I, a stereoisomeric mixture obtainable in accordance with the process is separated into the components and/or a free compound obtainable in accordance with the process is converted into a salt, or a salt obtainable in accordance with the process is converted into the free compound or into a different salt.

In the reaction of epoxides II with thiols ΠΙ, the configuration at the carbon atom bonding with the thio group is reversed and the configuration at the carbon atom carrying the hydroxy group is retained. In order to obtain the preferred compounds having the opposite configuration at those two carbon atoms, it is therefore preferable to use the corresponding trans-epoxides II as starting materials. Starting from R,R-epoxides II there are obtained compounds I having the S(C-S-),R(C-OH)-configuration, and starting from S,S-epoxides II there are obtained compounds I having the R(C-S-),S(C-OH)-configuration. The reaction is effected under conditions known per se at temperatures of from approximately -20°C to approximately +50°C, preferably at room temperature, that is to say from 18°C to 25°C, and especially in a basic medium, for example in the presence of an amine, especially a tertiary aliphatic, araliphatic or saturated heterocyclic amine, such as a tri-lower alkylamine (for example triethylamine, or N-ethyl-N,N-diisopropylamine), N,N-di-lower alkyl-N-benzylamine (for example N,N-dimethylbenzylamine), Ν,Ν-dialkylaniline (for example Ν,Ν-dimethylaniline) or N-methyl- or N-ethyl-piperidine -9or Ν,Ν’-dimethylpiperazine. The reaction is usually carried out in an inert organic solvent, such as a lower alkanol, for example methanol or ethanol.

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

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

The epoxide of the above-defined formula II used as starting material can be prepared especially by means of the same processes as those used in the synthesis of leucotrienes.

In a typical general method of synthesis for compounds Π in which n is 1, for example, an aldehyde of formula O = CH- R3 (IV) in which A and R3 are as defined above, is used as starting material. That compound is condensed with formylmethylenetriphenylphosphorane (or an equivalent reagent), the corresponding trans-3-R3-prop-2-enal of formula O = CH (V), being formed. That compound is then epoxidised in a manner known per se, preferably under weakly alkaline conditions (for example in the presence of alkali metal carbonates), with aqueous hydrogen peroxide, to produce a trans-, that is to say 2(RS),3(RS)-epoxy-3-R3-propanal of formula IE**316 - 10O = CH Ο H · The epoxyaldehyde VI can then be reacted to form the corresponding epoxide II in which R4 is esterified carboxy and n is 1 by condensation with a phosphonium halide Hal (VII), wherein Rj, R2 and alk are as defined above and Hal is a halogen atom, preferably bromine, and with a base, for example sodium amide, in tetrahydrofuran.

Compounds VII are prepared especially by reaction of a corresponding compound of formula (VIII) with triphenylphosphine in customary manner. Compounds VIII in which X is oxy or thio are obtained, for example, by condensing with one another corresponding compounds of formulae in customary manner. - 11 In another method of preparing compounds Π, trans-3-R3-prop-2-enol of formula HOCH (XI), wherein R3 is as defined above, is epoxidised, for example by means of tert.-butyl hydroperoxide in the presence of titanium tetraisopropanolate and a D- or L-tartaric acid di-lower alkyl ester, and when a D-tartaric acid ester is used there is obtained predominantly 2R,3R-epoxy-3-R3-propanol Xlla, and when an L-tartaric acid ester is used there is obtained predominantly the corresponding 2S,3S-epoxy-3-R3-propanol Xllb HOCH2 O HOCH, H' R, (Xlla) and (Xllb).

That compound is then oxidised, for example by treatment with oxalyl chloride/dimethyl sulfoxide and then with triethylamine, to the corresponding epoxyaldehyde VI which can then be reacted with the corresponding phosphonium salt VII to form the corresponding epoxide II.

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

For the preparation of epoxides II in which n is 2, for example the epoxy alcohol Xlla or Xllb is first converted by treatment with Ν,Ν’-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of trifluoroacetic acid and pyridine and then with triphenylphosphoranylideneacetaldehyde into the corresponding 4R,5R- or 4S,5S-4,5-epoxy-5-R3pent-2-enal of formula Xllla or XHIb OHC —CH=CH which is then reacted further with the phosphonium halide VII to form the corresponding epoxide II in which n is 2. It is preferable to obtain those epoxides in which the double bond joined to the radical alk has cis-stereoconfiguration and the double bond joined to the oxirane ring has trans-stereoconfiguration.

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

For example, esterified or amidated carboxy groups can be hydrolysed to free carboxy, preferably under basic conditions, for example in the presence of sodium hydroxide solution, and preferably in a water-miscible organic solvent, such as tetrahydrofuran, dioxane or a lower alkanol, such as methanol or ethanol. Conversely, carboxy R4 can be esterified in customary manner.

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

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

If individual diastereoisomers are desired, then advantageously an individual diastereoisomer of a starting material can be used at any stage or one diastereoisomer can be formed preferentially from a starting material in diastereoisomer form by means of - 13 stereoselective reaction conditions or optically active reagents, or racemic diastereoisomeric mixtures can be separated into the individual diastereoisomers by physical separation methods, optionally using optically active auxiliaries.

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

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

In view of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood, where appropriate, as including also the corresponding salts or free compounds, respectively.

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

The invention relates also to the novel starting materials and intermediates occurring in the processes according to the invention and their preliminary stages. - 14IE 903376 Preferably, the starting materials used and the reaction conditions chosen are such that the compounds listed above as being especially preferred are obtained.

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

Pharmaceutical preparations for topical and local use are, for example, for the treatment of the skin, lotions and creams which contain a liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (which preferably contain a preservative). Suitable for the treatment of the eyes are eye drops which contain the active ingredient in aqueous or oily solution, and eye ointments which are preferably manufactured in sterile form. Suitable for the treatment of the nose are aerosols 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 contain the active ingredient in aqueous or oily solution; suitable for local treatment of the buccal cavity are lozenges which contain the active ingredient in a mass generally formed of sugar and gum arabic or tragacanth, to which flavourings may be added, and pastilles which contain the active ingredient in an inert mass, for example of gelatine and glycerine or sugar and gum arabic.

Pharmaceutical preparations suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compound of formula I according to the invention with a suitable pharmaceutically acceptable solvent, such as, especially, ethanol and water, or a mixture of such solvents. They may, as necessary, also contain other pharmaceutical adjuncts, such as non-ionic or anionic surface-active agents, emulsifers and stabilisers, and also active ingredients of other kinds, and especially advantageously they can be mixed with a propellant gas, such as an inert gas under elevated pressure or especially with a readily volatile liquid, preferably a liquid that boils under normal atmospheric pressure below customary room temperature (for example from IE 903376 - 15approximately -30 to +10°C), such as an at least partially fluorinated polyhalogenated lower alkane, or a mixture of such liquids. Such pharmaceutical preparations, which are used predominantly as intermediates or stock mixtures for the preparation of the corresponding medicaments in finished form, contain the active ingredient customarily in a concentration of from approximately 0.1 to approximately 10 % by weight, especially from approximately 0.3 to approximately 3 % by weight. For the preparation of medicaments in finished form, such a pharmaceutical preparation is introduced into suitable containers, such as flacons and pressurised bottles, which are provided with a spray device or valve suitable for such purposes. The valve is preferably constructed in the form of a metering valve which on operation releases a predetermined amount of liquid, corresponding to a predetermined dose of the active ingredient. In the preparation of the finished medicament form, it is also possible for corresponding amounts of the pharmaceutical preparation in stock solution form and of the propellant to be introduced separately into the containers and to be mixed with one another only at that stage. The dosage of the compound of formula I to be administered and the frequency of administration depend upon the effectiveness and the duration of action of each individual compound, upon the severity of the disease to be treated and its symptoms, and upon the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the recommended daily dose of a compound of formula I according to the invention for a mammal (especially a human) weighing 75 kg might be in the region of from approximately 10 to approximately 500 mg, preferably from approximately 25 to approximately 250 mg, which can advantageously be administered in several doses per day, as necessary.

The invention relates also to the use of the compounds of formula I according to the invention for alleviating or eliminating pathological conditions and/or symptoms of the body of a mammal, especially of a human, which can be attributed to the action of leucotrienes and occur especially in asthma. This use or the corresponding curative method comprises the treatment of the affected body or part of the body with an anti-allergically effective amount of a compound of formula I on its own or in the form of a medicament, especially a pharmaceutical preparation intended for inhalation. The expression an anti-allergically effective amount is to be understood as being that amount of the active ingredient which is sufficient to produce a significant inhibition of the contractions caused by leucotrienes.

The following Examples illustrate the present invention in more detail but do not limit the -16scope thereof. All temperatures are given in degrees Celsius.

Example 1: 7-f(6R,7S)-15-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro6-hydroxy-pentadeca-8(E),10(Z)-dien-7-ylthiol-4-oxo-4H-l-benzopyrane-2-carboxyIic acid methyl ester A solution of 1.49 g of (6R,7S)-15-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-6,7-epoxyl,l,l,2,2-pentafluoro-pentadeca-8(E),10(Z)-diene in 100 ml of absolute methanol is stirred under argon with 3.3 ml of triethylamine and 1.05 g of 7-mercaptochromone-2-carboxylic acid methyl ester for 20 hours at room temperature and then concentrated by evaporation. The residue is dissolved in ethyl acetate and filtered over silica gel. The filtrate is washed with 25 ml of IN hydrochloric acid and then four times using 25 ml of saturated sodium chloride solution each time, dried over sodium sulfate and concentrated by evaporation. Purification of the residue by chromatography on silica gel with hexane/ethyl acetate (3:2) as eluant yields the title compound in the form of a light-yellow foam; m.p.: 48-49°C; Rf (hexane:ethyl acetate 3:2): = 0.33; [a]D20 (CHC13, 0.230 %) = 67.4 ± 4.3°; UV spectrum (CHCI3): λ max (e) = 271 (25120), 285 (22080), 324 (14000).

The starting materials are prepared as follows: a) 5,5,5,4,4-Pentafluoro-l-pentene Method A: In a 1 litre capacity three-necked flask having a dry ice cooler and a gas introduction tube, 39.5 g (160 mmol) of gaseous pentafluoroethyl iodide are introduced at 20° within a period of 20 minutes into a suspension of 20.2 g (180 mmol) of activated cadmium powder in 100 ml of dry dimethylformamide. After an induction period of 5 minutes a strongly exothermic reaction begins. The reaction mixture is stirred at room temperature for 1 hour and then filtered over filter flocks under nitrogen. The light-green organocadmium solution is then transmetallated at 0° with 17.2 g (120 mmol) of copper(I) bromide in 100 ml of dry hexamethylphosphoric acid triamide. After stirring for 10 minutes at 0°, 12.1 g (100 mmol) of allyl bromide are added dropwise within a period of 15 minutes and the mixture is stirred for 2 hours at 25°. 250 ml of cold IN hydrochloric acid are then added to the cloudy reaction solution. The product is distilled directly from the reaction flask via a Vigreux column. The title compound distils over in the form of a colourless liquid at b.p. 42-44°C. - 17 ^-NMR spectrum (CDC13; 300 MHz): 5.33 (br.s; 1H); 5.28 (m; 1H), 5.81 (t x d x q; J 16.1; 7.0; -1; 1H), 2.89 (t x d x q; J 17.2; 7.0; =0.5; 2H).

Method B: As described under method A, 39.5 g (160 mmol) of pentafluoroethyl iodide are introduced under inert conditions over a period of 20 minutes at room temperature into a suspension of 11.8 g (180 mmol) of activated zinc dust and 160 ml of dimethoxyethane. After approximately 5 minutes, a strongly exothermic reaction begins and a yellowish green suspension is formed. The reaction mixture is stirred for 1 hour at 25° and then filtered under inert conditions. There are then added to the light-green filtrate first 18.6 g (160 mmol) of Ν,Ν,Ν’,Ν’-tetramethylethylenediamine, then, at 0°, 17.2 g (120 mmol) of copper(I) bromide followed by 12.1 g (100 mmol) of allyl bromide. After stirring for 5 hours at 50°, the reaction solution is mixed at room temperature with 250 ml of IN hydrochloric acid and the product is distilled off directly from the reaction vessel. The title compound distils over in the form of a colourless liquid at b.p. 41-45°C. b) 6,6,6,5,5-Pentafluoro-hexan-l-al In a pressurised autoclave, 1.3 g (3.8 mmol) of dicobalt octacarbonyl are dissolved under inert conditions in 50 ml of absolute benzene. Then, at -50°, 29.0 g (180 mmol) of 5,5,5,4,4-pentafluoro-l-pentene are added and, in each case at 60 bar, carbon monoxide and hydrogen are introduced under pressure until saturation point is reached. The reaction mixture is heated to 100° and maintained at that temperature and at a pressure of 160 bar for 5 hours. The reaction mixture is then cooled and 10 ml (~ 20 mmol) of the violet solution are subjected to fractional distillation. The boiling point of the thermolabile and air-sensitive aldehyde is 92-93° (120 mbar), JH-NMR spectrum (CDC13; 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 17.4 g (50 mmol) of ethoxycarbonylmethylene-triphenylphosphorane are added to 40 ml (60 mmol) of the benzenic 6,6,6,5,5-pentafluorohexan-l-al solution (reaction solution from the preceding step) and maintained at reflux for 14 hours. The benzene is then distilled off in a rotary evaporator and the residue is separated from the triphenylphosphine oxide by flash chromatography over a column of silica gel (eluant; petroleum ether). The precipitated product is subjected to fractional distillation. The trans-ester distils over at b.p. = 103-105° (28 mbar) in the form of a colourless liquid. (The first IE 90337® - 18fraction contains small amounts of cis-ester; E/Z ratio before the distillation: 93:7). ^-NMR spectrum, E-compound (CDC13; 60 MHz): 6.70 (d x t; J 15.5; 7; IH), 5.67 (d; J 15.5; IH), 4.07 (q; J 7; 2H), 2.2 (m; 2H), 1.8 (m; 4H), 1.24 (t; J 7).

'H-NMR spectrum, Z-compound (CDC13; 60 MHz): 6.73 (d x t; J 12; 7; IH), 5.85 (d; J 12; IH), 4.06 (q; J 7; 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 380 ml of diisobutylaluminium hydride (1-molar in hexane) are added dropwise to a solution of 40.0 g of 7,7,8,8,8-pentafluoro-oct-2(E)ene-carboxylic acid ethyl ester in 300 ml of ether and the mixture is stirred for 2 hours at 0-5°. The resulting solution is poured onto a mixture of 480 ml of ice/water and 95 ml of concentrated hydrochloric acid (cooling, exothermic!). The mixture is stirred vigorously until two phases have formed. The organic phase is washed three times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The light-yellow oil that remains is distilled under a water-jet vacuum, yielding the title compound of b.p. = 81-86°C (at 14 mm Hg); Rf (hexane.-ethyl acetate 3:2) = 0.52; IR spectrum (CH2C12): 3600, 2950, 2860, 1450, 1380, 1200, 1130, 1030, 970, 650 cm-1. e) (2R,3R)-2,3-Epoxy-7,7,8,8,8-pentafluoro-octanol Under totally anhydrous conditions and an argon atmosphere, a solution of 13.3 ml of tetraisopropyl orthotitanate in 100 ml of dichloromethane is cooled to -80°, and 9.1 ml of D(-)-tartaric acid diethyl ester and 14.0 g of 7,7,8,8,8-pentafluoro-oct-2(E)enol in a small amount of dichloromethane are added. After stirring for 10 minutes at -80°, 61.7 ml of a 2.7-molar tert.-butyl hydroperoxide solution in toluene are added, the temperature rising to -68°. The temperature is then allowed to rise to 0° within a period of 2 hours, and the resulting yellow solution is poured slowly into a solution of 41.5 g of iron(II) sulfate and 16.0 g of L(+)-tartaric acid in 150 ml of water (cooling, exothermic!) and stirred for 30 minutes at 5-10°.

The aqueous phase is separated off and extracted four times using 100 ml of ether each time. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in 100 ml of ether and cooled to 0-5°, and a suspension of 7.0 g of sodium hydroxide in 250 ml of saturated sodium chloride solution is added and the mixture is stirred for 1 hour at 0-5°. The - 19aqueous phase is separated off and extracted four times using 50 ml of ether each time.

The combined ether phases are dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel using hexane/ethyl acetate (1:1) as eluant. The title compound is obtained in the form of a light-yellow oil: [a]D20 (CHC13, 0.49 %) = + 15.3 ± 2.0°; Rf (hexane:ethyl acetate 1:1): = 0.36; IR spectrum (CH2C12): 3550, 2900, 1440,1370,1180, 1130,1010, 870, 635 cm-1. f) (4R,5R)-4,5-Epoxy-9,9,10,10,10-pentafluoro-dec-2(E)-enal .6 ml of pyridine, 2.3 ml of trifluoroacetic acid and 37.0 g of N,N-dicyclohexyl carbodiimide are added under argon to a solution of 11.0 g of (2R,3R)-2,3epoxy-7,7,8,8,8-pentafluoro-octanol in 200 ml of dimethyl sulfoxide and the mixture is stirred at room temperature for 3 hours. After the addition of 23.6 g of formylmethylenetriphenylphosphorane, stirring is continued for a further 18 hours at room temperature; 500 ml of ethyl acetate are added and after 10 minutes the mixture is poured onto 1 litre of saturated sodium chloride solution. The resulting suspension is stirred for 15 minutes and filtered through a P4-frit. In the filtrate the aqueous phase is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed three times with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is filtered over silica gel using ether/hexane (4:1 + 1 % triethylamine) as eluant. The filtrate is concentrated by evaporation and the residue is filtered first over a column filled with 2 kg of silica gel and then chromatographed over a column filled with 500 g of silica gel using hexane/ethyl acetate (3:2) as eluant. The title compound is thus obtained in the form of a yellow oil; Rf (hexane:ethyl acetate 1:1) = 0.61; [a]D20 (0.21 % in CDC13) = +19.5 ± 4.8°. g) (6R,7S)~ 15-(4-Acetyl-3-hydroxy-2-propyI-phenoxy)-6,7-epoxy-1,1,1,2,2-pentafluoropentadeca-8(E),10(Z)-diene A suspension of 4.0 g of 5-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-pentyl-triphenylphosphonium bromide in 150 ml of absolute tetrahydrofuran is stirred at room temperature under argon for 2.5 hours with 1.0 g of (4R,5R)-4,5-epoxy-9,9,10,10,10pentafluoro-dec-2(E)-enal and 0.54 g of sodium amide. The resulting suspension is poured onto 400 ml of phosphate buffer (pH 7) and extracted four times using 25 ml of ether each time. The combined ether extracts are washed twice with 25 ml of phosphate buffer (pH 7) and once with saturated sodium chloride solution, dried over sodium sulfate -20and concentrated by evaporation. The residue is taken up in hexane:ethyl acetate (1:1 + 1 % triethylamine) and filtered over a column of silica gel that has been prewashed with that solvent mixture. The filtrate is concentrated by evaporation and the residue is purified by chromatography on silica gel using hexane/ethyl acetate (7:3 + 1 % triethylamine). The title compound is thus obtained in the form of a yellow oil; Rf (hexane:ethyl acetate 1:1) = 0.50; [a]D20 (CHC13, 0.20 %) = + 15 ± 5°.

Example 2: Sodium salt of 7-[(6R,7S)-15-(4-acetyl-3-hydroxy-2-propyl-phenoxy)1,1,1,2,2-pentafluoro-6-hydroxy-pentadeca-8(E), 10(Z)-dien-7-ylthiol-4-oxo-4H-1 -benzopyrane-2-carboxylic acid 1.3 g of the corresponding methyl ester according to Example 1 are dissolved under argon in 40 ml of tetrahydrofuran; 9.4 ml of 0.2N sodium hydroxide solution are added at 0°C and the mixture is stirred for 1 hour at room temperature. Concentration by evaporation and purification of the residue over a 240 g Merck Lichroprep® RP-8 column with methanol/water (7:3) as eluant yield the title compound of formula of m.p.: 155-158°; [a]D20 (0.12 %, MeOH) = 44.2 ± 8.3°; UV spectrum (MeOH): Xmax = 221 (€ = 48080), 231/sh, 267 (e = 24720), 285 (t = 22080), 325/sh; IR spectrum (CT^CIJ: 3480, 2920, 1630, 1450, 1420, 1360, 1200,1120, 810 cm-1; Rf (MeOH/H2O: 3:1): = 0.20.

Example 3: 7-F(6R,7S)-14-(4-Acetvl-3-hydroxv-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro6-hydroxv-tetradeca-8(E),10(Z)-dien-7-ylthio1-4-oxo-4H-1 -benzopyrane-2-carboxylic acid methyl ester A solution of 0.53 g of (6R,7S)-14-(4-acetyl-3-hydroxy-2-propylphenoxy)-6,7-epoxyIE 903376 - 21 1.1.1.2.2- pentafluoro-tetradeca-8(E),10(Z)-diene in 50 ml of absolute methanol is stirred under argon with 1.3 ml of triethylamine and 0.4 g of 7-mercaptochromone-2-carboxylic acid methyl ester for 20 hours at room temperature and then concentrated by evaporation. The residue is dissolved in ethyl acetate and filtered over silica gel. The filtrate is washed once with 25 ml of IN hydrochloric acid and four times using 25 ml of saturated sodium chloride solution each time, dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel using hexane/ethyl acetate (7:3) as eluant. The title compound is obtained in the form of a yellow oil of 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-1,1,1,2,2-pentafluorotetradeca-8(E),10(Z)-diene 0.4 g of (4R,5R)-4,5-epoxy-9,9,10,10,10-pentafluoro-dec-2(E)-enal in 10 ml of tetrahydrofuran, 0.156 g of sodium amide and about 50 mg of potassium tert.-butanolate are added, with stirring, at -70° under argon to a suspension of 1.2 g of 4-(4-acetyl-3-hydroxy-2-propyl-phenoxy)butyl-triphenylphosphonium bromide in 50 ml of absolute tetrahydrofuran. The temperature is then allowed to rise to room temperature within a period of 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 sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is taken up in hexane/ethyl acetate (3:2 + 1 % triethylamine) and filtered over a column of silica gel that has been prewashed with that solvent mixture. The filtrate is concentrated by evaporation and the residue is purified by chromatography on silica gel using hexane/ethyl acetate (7:3 + 1 % triethylamine) as eluant. The title compound is obtained in the form of a light-yellow oil; Rf (hexane/ethyl acetate 3:2) = 0.50; [a]D20 (CHC13,0.0955 %) = 8.4 ± 10.5°; UV spectrum (CHC13): Xmax = 287 (e 20920), 330/sh.

Example 4: Sodium salt of 7-i(6R,7S)-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)1.1.1.2.2- pentafluoro-6-hydroxy-tetradeca-8(E), 10(Z)-dien-7-ylthio1-4-oxo-4H-1 benzopyrane-2-carboxylic acid The title compound of formula -22IE 903376 is prepared analogously to Example 2 from the corresponding methyl ester according to Example 3. M.p. 159-160°; [a]D20 (methanol, 0.087 %) - + 65.5 ± 11.5°, UV spectrum (methanol): Zmax, (e), 221 (44480), 231/sh, 267 (22960), 285 (20400), 330/sh; IR spectrum (CH2C12): 3380, 2950, 1630, 1500, 1420,1360, 1270, 1200, 1120, 810cm-l.

Example 5: 7-[(6R,7S)-15-(4-Acetyl-3-hvdroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro6-hydroxy-pentadeca-8(E),10(Z)-dien-7-ylthiol-4-oxo-4H-l-benzopyrane-2-carboxylic acid 0.87 g of the corresponding methyl ester according to Example 1 are dissolved under argon in 30 ml of tetrahydrofuran, then 6.3 ml of 0.2N sodium hydroxide solution are added at 0° and the mixture is stirred for 1 hour at 0 to 5°. The reaction mixture is freed of tetrahydrofuran in a rotary evaporator and taken up in 20 ml of water and 50 ml of methylene chloride. The mixture is acidified to pH 1 with 2N hydrochloric acid and extracted three times using 50 ml of methylene chloride each time. The combined organic phases are dried over sodium sulfate and concentrated by evaporation. The residue is purified over a column of silica gel using methylene chloride/methanol (4:1) as eluant, yielding the title compound in the form of a viscous resin.

Example 6: In a manner analogous to that described in Examples 1 to 5 it is also possible to prepare: 7-[(6R,7S)-13-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-l, 1,1,2,2-pentafluoro-6-hydroxytrideca-8(E),10(Z)-dien-7-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl -23IE 903376 ester and the sodium salt thereof; 7-[(5R,6S)-14-(4-ace tyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-5-hydroxytetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(5R,6S)-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-l,l,l,2,2-pentafluoro-5-hydroxydodeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(4R,5S)-13-(4-ace tyl-3-hydroxy-2-propyl-phenoxy)-l, 1,1,2,2-pentafluoro-4-hydroxytrideca-6(E),8(Z)-dien-5-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(4R,5S)-11 -(4-acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-4-hydroxyundeca-6(E),8(Z)-dien-5-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(3R,4S)-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-l,l,l-tri fluoro3-hydroxy-l-dodeca-7(E),9(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(5R,6S)- 14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro5-hydroxy-tetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(3R,4S)-10-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1-tri fluoro3-hydroxy-deca-5(E),7(Z)-dien-4-yl-thio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(3R,4S)-11 -(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichIoro-1,1,1 -trifluoro3-hydroxy-undeca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(3R,4S)-13-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-l,l,l-trifluoro3-hydroxy-trideca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, -24IE 903376 the methyl ester and the sodium salt thereof; 7- [(3R,4S)- 14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-tetradeca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(5R,6S)- 14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1-trifluoro5-hydroxy-tetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof; 7-[(5R,6S)-13-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1-trifluoro5-hydroxy-trideca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof, and 7-[(5R,6S)-12-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro5-hydroxy-dodeca-(7E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, the methyl ester and the sodium salt thereof.

Example 7: An inhalation suspension, containing propellant and forming a solid aerosol, containing 0.1 % by weight active ingredient, for example the sodium salt of 7-[(6R,7S)15-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-6-hydroxypentadeca-8(E),10(Z)-dien-7-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, can be prepared, for example, as follows: Composition: active ingredient, micronised sorbitan trioleate propellant A (trichlorotrifluoroethane) 4.4 propellant B (dichlorodifluoromethane 15.0 and 1,2-dichlorotetrafluoroethane) 80.0 % by weight 0.1 0.5 Preparation: In the absence of moisture, the active ingredient is suspended in the trichlorotrifluoroethane using a customary homogeniser and with the addition of the sorbitan trioleate, and the suspension is introduced into an aerosol container provided with a metering valve; the container is sealed and filled up with propellant B under pressure. -25IE 903376 Example 8: An approximately 2 % aqueous solution, suitable for inhalation, of an active ingredient in the form of its sodium salt, for example the sodium salt of 7-[(6R,7S)15-(4-acetyl-3-hydroxy-2-propyI-phenoxy)-l, 1,1,2,2-pentafluoro-6-hydroxypentadeca-8(E),10(Z)-dien-7-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid, can be prepared, for example, as follows: Composition active ingredient (K or Na salt) 2000 mg disodium salt of ethylenediaminetetraacetic acid 10 mg benzalkonium chloride water, freshly distilled ad 100 mg ml Preparation: The active ingredient is dissolved in about 60 ml of freshly distilled water, and the stabiliser (disodium salt of ethylenediaminetetraacetic acid) and the preservative (benzalkonium chloride) are added. When all the components have completely dissolved, the resulting solution is made up to 100 ml and introduced into small pressurised bottles which are then sealed in gas-tight manner. The propellant is added, as required, in gaseous form under pressure or in liquid form.

Claims

What is claimed is:

1. Novel p-substituted alkanophenones of the general formula (I), wherein Rj is unsubstituted or fluorinated lower alkyl, R 2 is hydrogen, unsubstituted or 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 unsubstituted or chlorinated polyfluoro-lower alkyl, R 4 is free, esterified or amidated carboxy or 5-tetrazolyl, and R 5 is hydrogen or lower alkyl, and their salts.

2. Compounds according to claim 1 wherein Rj is lower alkyl or mono-, di- or polyfluoro-lower alkyl, R 2 is hydrogen, lower alkyl, lower alkenyl or mono-, di- or poly-fluoro-lower alkyl, X is lower alkylene, oxy or thio, alk is lower alkylene, R 3 is polyfluoro-lower alkyl having from 5 to 9 fluorine atoms or chlorinated polyfluoro-lower alkyl having from 3 to 7 fluorine atoms and from 2 to 5 chlorine atoms, R 4 is carboxy, lower alkoxycarbonyl, 5-tetrazolyl, carbamoyl, N-mono- or Ν,Ν-di-lower alkylcarbamoyl, or N-(benzenesulfonyl)-carbamoyl that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl, and R 5 is hydrogen or lower alkyl, and their salts.

3. Compounds according to claim 1 wherein Rj is C r C 4 alkyl or ω,ω,ω-trifluoro-Cj-C^ alkyl, R 2 is hydrogen, C r C 4 alkyl, C 2 -C 4 alkenyl or (o, 4 alkyl, X is C r C 3 alkylene, oxy or thio, alk is straight-chain C 2 -C 6 alkylene, n is 1 or 2, R 3 is a>,(0,co,a)-l,(o-l-pentafluoro-C 3 -C7alkyl, R 4 is carboxy or N-(benzenesulfonyl)carbamoyl, and R5 is hydrogen, and their salts. -27IE 903376

4. Compounds according to any one of claims 1 to 3 wherein the group X is bonded in the para-position to the Rj-C^O) group, and their salts.

5. Compounds according to claim 1 of the formula O wherein Rj is Cj-C 4 alkyl, R 2 is Ci-C 4 alkyl, X is oxy, alk is C 2 -C 6 alkylene, n is 1 or 2, R 3 is (i},(o,0),a>-l,(0-l-pentafluoro-C 3 -C7alkyl, R 4 is carboxy and R 5 is hydrogen, and their salts.

6. Compounds according to claim 5, of formula Ia, wherein Rj is C 1 -C 4 alkyl, R 2 is Cj-C 4 alkyl, X is oxy, alk is C 2 -C5alkylene, n is 2, R 3 is ω,ω,ω,ω-Ι,ω-1-pentafluoroC 3 -C 5 alkyl, R 4 is carboxy, and R 5 is hydrogen, and their salts.

7. A compound according to any one of claims 1 to 6 wherein the double bond joined to the radical alk is in the (Z)-, that is to say the cis-configuration, and the additional double bond which may be present is in the (E)-, that is to say the trans-configuration.

8. A compound according to any one of claims 1 to 7 wherein the chain carbon atom bonded to the sulfur atom has the (S)-configuration and the chain carbon atom carrying the hydroxy group has the (R)-configuration.

9. 7-[(6R,7S)-2,2,3,3,3-Pentafluoro-6-hydroxy-14-(4-acetyl-3hydroxy-2-propylphenoxy)-tetradeca-8(E),10(Z)-dien-7-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester. -28VE 9033 76

10. 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-l-benzopyrane-2-carboxylic acid or a salt thereof.

11. 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-l-benzopyrane-2-carboxylic acid methyl ester.

12. 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-l-benzopyrane-2-carboxylic acid or a salt thereof.

13. 7-[(6R,7S)-13-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-l, 1,1,2,2-pentafluoro-6hydroxy-trideca-8(E),10(Z)-dien-7-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

14. 7-[(6R,7S)-13-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-l, 1,1,2,2-pentafluoro-6hydroxy-trideca-8(E),10(Z)-dien-7-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

15. 7-[(5R,6S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-5hydroxy-tetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-1 -benzopyrane-2-carboxylic acid methyl ester.

16.7- [(5R,6S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pen tafluoro-5hydroxy-tetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

17. 7-[(5R,6S)-12-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-l, 1,1,2,2-pentafluoro-5hydroxy-dodeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

18. 7-[(5R,6S)-12-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-5hydroxy-dodeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof. -29IE 903376

19. 7-[(4R,5S)-13-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-4hydroxy-trideca-6(E),8(Z)-dien-5-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

20. 7-[(4R,5S)-l 3-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-4hydroxy-trideca-6(E),8(Z)-dien-5-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

21.7 - [(4R,5S)-11 -(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-4hydroxy-undeca-6(E),8(Z)-dien-5-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

22. 7-[(4R,5S)-11 -(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-pentafluoro-4hydroxy-undeca-6(E),8(Z)-dien-5-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

23. 7-[(3R,4S)-12-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-l-dodeca-7(E),9(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

24. 7-[(3R,4S)-12-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-l,l,l-trifluoro3-hydroxy-l-dodeca-7(E),9(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

25. 7-[(5R,6S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-l, 1,1-trifluoro5-hydroxy-tetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxyIic acid methyl ester.

26. 7-[(5R,6S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro5-hydroxy-tetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid and the sodium salt thereof.

27. 7-[(3R,4S)-10-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-deca-5(E),7(Z)-dien-4-yl-thio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester. -30IE 903376

28. 7-[(3R,4S)-10-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-deca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

29. 7-[(3R,4S)-11 -(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-undeca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

30. 7-[(3R,4S)-11-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-undeca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

31. 7-[(3R,4S)-13-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-trideca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

32. 7-[(3R,4S)-13-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro3-hydroxy-trideca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

33. 7-[(3R,4S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1-trifluoro3-hydroxy-tetradeca-5(E),7(Z)-dien-4-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

34. 7-[(3R,4S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-l,l,l-trifluoro3-hydroxy-tetradeca-5(E),7(Z)-dien-4-yIthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

35. 7-[(5R,6S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro5-hydroxy-tetradeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

36. 7-[(5R,6S)-14-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-l, 1,1-trifluoro5-hydroxy-tetradeca-7 (E),9(Z)-dien-6-ylthio]-4-oxo-4H-1 -benzopyrane-2-carboxyIic acid or a salt thereof. -31

37. 7-[(5R,6S)-13-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro5-hydroxy-trideca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

38. 7-[(5R,6S)-13-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-l,l,l-trifluoro5-hydroxy-trideca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

39. 7-[(5R,6S)-12-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro5-hydroxy-dodeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid methyl ester.

40. 7-[(5R,6S)-12-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2,2-dichloro-1,1,1 -trifluoro5-hydroxy-dodeca-7(E),9(Z)-dien-6-ylthio]-4-oxo-4H-l-benzopyrane-2-carboxylic acid or a salt thereof.

41. A compound according to claim 1 as described in the Examples.

42. A compound according to any one of claims 27 to 40 for use in a method for the therapeutic treatment of the human or animal body.

43. A compound according to any one of claims 1 to 26 and 41 for use in a method for the therapeutic treatment of the human or animal body.

44. Pharmaceutical preparations containing as pharmaceutical active ingredient a compound according to any one of claims 27 to 40 and 42.

45. Pharmaceutical preparations containing as pharmaceutical active ingredient a compound according to any one of claims 1 to 26, 41 and 43.

46. A process for the preparation of a p-substituted alkanophenone of the general formula -32•Ε 903376 Ο OH Φ, wherein Rj is unsubstituted or fluorinated lower alkyl, R 2 is hydrogen, unsubstituted or 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 unsubstituted or chlorinated polyfluoro-lower alkyl, R 4 is free, esterified or amidated carboxy or 5-tetrazolyl, and R 5 is hydrogen or lower alkyl, and their salts, which process comprises: reacting an epoxide of formula O O / \ X -alk -(CH= CH)— CH CH- R 3 n (II), wherein R b R 2 , X, alk, n and R 3 are as defined above, with a thiol of formula (ΙΠ), wherein R 4 and R 5 are as defined above, or with a salt thereof, and, if desired, converting a compound obtainable in accordance with the process into a different compound of formula I, separating a stereoisomeric mixture obtainable in accordance with the process into the components and/or converting a free compound obtainable in accordance with the process into a salt, or converting a salt obtainable in accordance with the process into the free -33 Ιε 903376 compound or into a different salt.

47. A method of treating allergic disorders, wherein a compound according to any one of claims 1 to 41 or a pharmaceutical preparation according to claim 44 or 45 is administered.

48. The use of compounds according to any one of claims 1 to 43 for the manufacture of an anti-allergic medicament.

49. A p-substituted alkanophenone of the general formula (I) given and defined in claim 1., or a salt thereof, substantially as hereinbefore described and exemplified.

50. A pharmaceutical preparation according to claim 44 or 45, substantially as hereinbefore described and exemplified.

51. A process for the preparation of a p-substituted alkanophenone of the general formula (I) given and defined in claim 1, or a salt thereof, substantially as hereinbefore described and exemplified.

52. A p-substituted alkanophenone of the general formula (I) given and defined in claim 1, or a salt thereof, whenever prepared by a process claimed in claim 46 or 51.

53. Use according to claim 48, substantially as hereinbefore described.