CA2103600A1

CA2103600A1 - Isobutyl-substituted methanesulphonyl- quinolyl-methoxyphenyl-cycloalkylacetamides

Info

Publication number: CA2103600A1
Application number: CA002103600A
Authority: CA
Inventors: Siegfried Raddatz; Klaus-Helmut Mohrs; Michael Matzke; Romanis Fruchtmann; Reiner Muller-Peddinghaus; Armin Hatzelmann
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1992-08-12
Filing date: 1993-08-09
Publication date: 1994-02-13
Also published as: AU669913B2; DE4226649A1; IL106623A0; NO179948C; FI933529A0; MX9304608A; PL174102B1; RU2103261C1; CZ163693A3; NZ248350A; MY108716A; SK86693A3; FI933529A; NO932731D0; HU9302320D0; CN1087084A; NO179948B; JPH06157462A; AU4425593A; ZA935828B

Abstract

New isobutyl-substituted methanesulphonyl-quinolylmethoxyphenyl-cycloalkylacetamides A b s t r a c t The new isobutyl-substituted methanesulphonylquinolyl-methoxyphenyl-cycloalkylacetamides can be prepared by reaction of the corresponding racemic or enantiomeric acids with methanesulphonamide, it being possible to resolve the racemic final products into the enantiomers by customary methods. The isobutyl-substituted methane-sulphonyl-quinolylmethoxyphenyl-cycloacetamides can be employed as active compounds in medicaments.

Description

2103~

The invention relates to new isobutyl-substituted meth-anesulphonyl-quinolylmethoxyphenyl-cycloalkylacetamides, a process for their preparation and their use in medica-ments.

Substituted 4-(quinolin-2-yl-methoxy)phenylacetic acid derivatives and ~-substituted 4-(quinolin-2-yl-methoxy)-phenylacetic acid derivatives have been di~closed in EP
344,519 (US 4,970,215) and EP 339,416.

The pre~ent invention relates to new isobutyl-substituted methanesulphonyl-quinolylmethoxyphenyl-cycloalkylacet-amides of the general formula (I) ~''1~ ~
O ~ (I) Rl in which Rl represents cyclohexyl, in the form of the racemate and of the enantiomers as well as the two enantiomers of the compounds of the Le A 29 239 - 1 -~1 ~3~0~J

formula (I) in which R1 represents cyclopentyl or cyclo-heptyl and their salts.

In the context of the present invention, physiologically acceptable salts are preferred. Physiologically accept-able salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids.
Particularly preferred salts, for example, are those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane~ulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts in the context of the present invention are addi-tionally metal salts, preferably of the univalent metals, and the ammonium salts. Preferred alkali metal salts are those such as, for example, sodium, potassium and ammo-nium salts.

The compounds of the general formula (I) according to theinvention are prepared by reacting the carboxylic acids of the general formula (II3 Le A 29 239 - 2 -21~3 ~ Rl in which C02H

R1 has the abovementioned meaning, if appropriate with prior activation, with methanesul-phonamide of the formula (III) H2N-S02-CH3 (III) in inert solvents, in the presence of a base and/or catalyst, and in the case of the enantiomers, either employing the enantiomerically pure acids (II) directly or resolving the racemates (I) according to customary methods.

The enantiomers are preferably resolved by column chroma-tography.

The process according to the invention can be illustrated by way of example by the following reaction scheme:

Le A 29 239 - 3 -21 ~3~

esyl chloride Tr iéthylamlne ~ CH DMAp I

S ~`CI~
CO-NH^SO2-CH3 The sulphoamidation iR in general carried out in inert solvents in the presence of a base and of a dehydrating agent.

Suitable solvents in this connection are inert organic solvents which do not change under the reaction condi-tions. These include halogenohydrocarbons such as dichlo-romethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane or mineral oil fractions, nitromethane, d i m e t h y l f o r m a m i d e , a c e t o n i t r i l e o r Le A 29 239 - 4 -21~3~0~
hexamethylphosphoramide. It is also possible to employ mixtures of the solvents. Dichloromethane is particularly preferred.

Suitable ba~es for the sulphoamidation are the customary basic compound~. The~e preferably include alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, pota~sium hydroxide or barium hydroxide, alkali metal hydrides such as sodium hydride, alkali metal or alkaline earth metal carbonates such a~ sodium carbonate or potassium carbonate, or alkali metal alkoxides such as, for example, sodium methoxide or sodium ethoxide, potas~ium methoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as benzyltrimethylammonium hydroxide, tetra-butylammonium hydroxide, dimethylaminopyridine, pyridine,triethylamine or N-methylpiperidine.

Suitable dehydrating reagents are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcar-bodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodi-imide hydrochloride or carbonyl compounds such as car-bonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-~ulphonate or propanephosphonic anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or diphenyl phosphoramidate or methanesulphonyl chloride, if appropriate in the presence of ba~es such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and Le A 29 239 - 5 -210360~
N-hydroxysuccinimide.

When carrying out the sulphoamidation, the base is in general employed in an amount from 1 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the carboxylic acid (II).

In the case of reaction via the mixed anhydride, di-methylaminopyridine is preferably employed as the cata-lyst.

The cataly~t is in general employed in catalytic to equimolar amounts, preferably equimolar amount~.

The ~ulphoamidation i8 in general carried out in a temperature range from 0C to 150C, preferably at 25C
to 40C.

The sulphoamidation is in general carried out at normal pre~sure. However, it is also possible to carry out the process at reduced pressure or at elevated pre~sure (for example in a range from 0.5 to 5 bar).

With the exception of the case Rl = cycloheptyl, the carboxylic acid~ of the general formula (II) are, as actual substance representatives, in particular in enantiomerically pure form, new and can be prepared, for example, by either converting compound~ of the general formula (IV) ~e A 29 239 - 6 -210360~
or (IVa) T-O

CH-RI
IO2R2 (IV) or T'-O ~

CH2 (IVa) C2R2' in which R1 ha~ the abovementioned meaning, T and T' are identical or different and represent a hydroxyl protective group ~uch a~ benzyl or tert-butyl and R2 and RZ are identical or different and denote Cl-C4- -Le ~ 29 239 - 7 -210360~
alkyl, after removal of the protective group with 2-halogenomethylquinoline of the formula (v) ~ ~ ~CH2-v (V) in which V represents halogen, preferably chlorine or bromine, in inert ~olvents by etherification into the compounds of the general formula ~VI) or (VIa) ~ 1 ~ (VI) or CH-RI

Le A 29 239 - 8 -2~0360 -,~, ~ (VIa~

~CH2 C2R2 ' in which R1, R2 and R2 have the abovementioned meaning, and in the ca~e of the compounds of the general formula (VIa), subjecting these in a 2nd step to an alkylation with compounds of the general formula (VII) Rl-w (VII) in which R1 has the abovementioned meaning and W represents chlorine, bromine or iodine, in inert solvents, and then hydrolysing the esters by customary methods, Le A 29 ~39 - 9 -~3~00 and in the case of the enantiomers, resolving the racemic acids by column chromatography on chiral acids according to a customary method.

The protectlve groups are removed from the corresponding ethers (IV) and (IVa) by a customary method, for example by hydrogenolytic cleavage of the benzyl ethers in the abovementioned inert solvents in the presence of a catalyst using hydrogen gas.

The etherification can be carried out in inert organic solvents, if appropriate in the presence of a base.
Solvents for the etherification can be inert organic solvents which do not change under the reaction condi-tions. These preferably include ethers such as, for example, dioxane, tetrahydrofuran or diethyl ether, halogenohydrocarbons such as dichloromethane, trichloro-methane, tetrachloromethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, nitromethane, dimethylformamide, acetonitrile, acetone or hexamethylphosphoramide. It is also possible to employ mixtures of the solvents.

Bases employed for the etherification can be inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium Le A 29 239 - 10 -21~3SQ~

carbonate, alkaline earth metal carbonates such as calcium carbonate, or organic amines (trialkyl(C1-C6)amines) such as triethylamine, or heterocycles such as pyridine, methylpiperidine, piperidine or morpholine.

It is also possible to employ as bases alkali metals such as sodium and their hydrides, such as sodium hydride.

The etherification i~ in general carried out in a tem-perature range from 0C to +150C, preferably from +10C
to +100C.

The etherification is in general carried out at normal pressure. However, it is also possible to carry out the process at reduced pressure or elevated pressure (for example in a range from 0.5 to 5 bar).

In general, 0.5 to 5 mol, preferably 1 to 2 mol of halide (V) are employed, relative to 1 mol of the reactant. The base i8 in general employed in an amount from 0.5 to 5 mol, preferably from 1 to 3 mol, relative to the halide.

The compounds of the general formulae (IV) and (IVa) are known per se or can be prepared by a customary method.

The compounds of the general formula ~V) and their preparation are also known.

Suitable solvents for the processes according to the Le A 29 239 - 11 -21Q36~0 invention and for the alkylation are customary organic solvents which do not change under the reaction condi-tions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenohydro-carbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexa-methylphosphoramide, acetonitrile, acetone or nitrometh-ane. It is also possible to use mix~ures of the solvents mentioned. Dichloromethane is preferred.

The alkylation is carried out in the abovementioned solvents at temperatures from 0C to +150C, preferably at room temperature to +100C, and at normal pressure.

The compounds of the general formula (III) are known per se.

As actual substance representatives, the compounds of the general formula (VI) are new in ~ome cases and can be prepared as described above.

The racemates are in general resolved by column chromato-graphy on chiral HPLC columns using solvent mixtures such as, for example, n-heptane/2-propanol or via diastereo-meric e~ters.

Le A 29 23g - 12 -2~3~0~
The new N-methanesulphonyl-2-[3-isobutyl-3-(quinolin-2-yl-methoxy)phenyl]-2-cycloalkylacetamides according to the invention can be employed as active compounds in medicaments. The substances can act as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism, in particular of lipoxygenase.

They are thus preferably suited to the treatment of and prevention of diseases of the airways such a~ aller-gies/asthma, bronchitis, emphysema, shock lung, pulmonary hyperten~ion, inflammations/rheumatism and oedemas, thrombose~ and thromboembolisms, ischaemia (peripheral, cardiac and cerebral circulatory disorders), cardiac and cerebral infarcts, angina pectori~, arteriosclerosis, in tissue transplants, dermatoses such as psoriasis, inflam-matory dermatoses and for cytoprotection in the gastro-intestinal tract.

The phenyl-~ubstituted quinolines according to the invention can be used both in human medicine and in veterinary medicine.

The pharmacological actions of the substances according to the invention are determined by the following method:

As a measure of lipoxygenase inhibition, the release of leucotriene B4 (LTB4) in polymorphonuclear human leuco-cytes (PMN) was determined after addition of substances and Ca ionophore by means of reverse pha~e HPLG according to Borgeat, P. et al., Proc. Nat. Acad. Sci., 76, Le A 29 239 - 13 -2103~0~
2148-2152 ~lg79).

Lipoxygenase inhibition (human PMNL) Ex. No. IC50[mol/l]
1 5.2 x 10-8 6 5.8 x 10 7 7.0 x 10-~

The present invention also includes pharmaceutical preparations which, apart from inert, non-toxic, phar-maceut cally suitable auxiliaries and excipients, contain one or more compounds of the general formula (I), or which consist of one or more active compounds of the formula (I), as well as processes for the production of these preparations.

The active compounds of the formula (I) should be present in these preparations in a concentration from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight of the total mixture.

Apart from the active compounds of the formula (I), the pharmaceutical preparations can also contain other pharmaceutical active compounds.

The abovementioned pharmaceutical preparations can be prepared by known methods in a customary manner, for example using the auxiliary(ies) or excipient(-s).

Le A 29 23g - 14 -2i ~3~0~

In general, it has proven advantageous to administer the active compound(s) of the formula (I) in total amounts from about 0.01 to about 100 mg/kg, preferably in total amounts from about 1 mg/kg to 50 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired result.

However, it may 60metimes be advantageous to deviate from the amounts mentioned, mainly depending on the type and on the body weight of the subject to be treated, on individual behaviour towards the medicament, the nature and severity of the disease, the method of preparation and admini~tration, and the time or interval at which administration takes place.

Startina Compounds ExamPle I

Methyl 2-[3-i~obutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexyl-acetate O~

Le A 29 239 - lS -~l03~0a 12 g (0.033 mol) of methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenylacetate and 6.52 g (0.04 mol) = 4.9 ml of cyclohexyl bromide are dissolved in 36 ml of DMF and cooled to 0C under an argon atmosphere. 4.8~ g (0.04 mol) of potassium tertiary butoxide, dissolved in 80 ml of DMF, are added dropwise to this mixture with stirring.
After a reaction time of about 2 h, the temperature i8 allowed to rise to RT, and the mixture is acidified with 2N hydrochloric acid and concentrated to dryness in vacuo. The residue which remains i8 stirred with 100 ml of dichloromethane and 50 ml of water, the organic phase is separated of f, dried using Na2SO4 and concentrated to a small volume in vacuo, and the residue which remains is separated by column chromatography (silica gel 60, eluent: dichloromethane/ethyl acetate = 100:2).
Yield: 13 g (88.4% of theory), slightly yellowish oil Example II

2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclo-hexyl-acetic acid ~, ~ N
O
~02H

Le A 29 23~ - 16 -210~00 10.2 g (0.0236 mol) of the compound from Example I are taken up in 70 ml of 2-propanol and heated to boiling overnight with 50 ml of lN sodium hydroxide solution.
After cooling, the mixture is neutralised using 50 ml of lN hydrochloric acid. The precipitate obtained is fil-tered off with suction, washed and dried, and then recrystallised from diisopropyl ether.
Yield: 9.5 g (96.3% of theory), colourless crystals M.p.: 130C

Example III and ExamDle IV

(+)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexyl-acetic acid (Example III) (-)-2-t3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexyl-acetic acid (Example IV) ~J

The title compounds are obtained by resolution of the racemate (Example II) by means of chromatographic resolution on chiral columns.

Le A 29 239 - 17 -210360~
(+)-Enantiomer: spec. rotn.: 17.96 (CHCl3) (Example III) mol. rotn.: 77.41 Enantiomer: spec. rotn.: -18.86 (CHC13) (Example IV) mol. rotn.: -81.28 Example V

Methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptyl acetate ~ ~ ' 10 g (0.0275 mol) of methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenylacetate are reacted with 10.04 g (0.055 mol) of cycloheptyl bromide and 6.17 g (0.055 mol) of potassium tertiary butoxide to give the title compound in analogy to the procedure of Example I.
Yield: quantitative, yellow-brown oil lS Example VI

2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclo-heptylacetic acid Le A 29 23~ - 18 -21û~0~

N ~

COOH

The title compound is prepared from the compound of Example V and 30 ml of lN sodium hydroxide solution with sub~equent acidification in analogy to the procedure of Example II.
Yield: 11.3 g (92.3% of theory~, colourless crystals M.p.: 112C

Example VII and Exam~le VIII

(+)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptylacetic acid (Example VII) (-)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptylacetic acid (Example VIII) Le A 29 239 - 19 -21~3~

''"`'~J~

The title compounds are prepared from the racemate (Example VI) by chromatographic resolution on HPLC-H 1050 Chiralpak AS in a solvent mixture of 96% n-heptane and 4%
of a mixture of 2-propanol which contains 1% water and 0.2% trifluoroacetic acid.

(+)-Enantiomer: spec. rotn.: 15.72, solvent CHCl3, Example VII
mol. rotn.: 69.96 0 (-)-Enantiomer: spec. rotn.: -18.7, solvent CHCl3, Example VIII
mol. rotn.: -86.19 Le A 29 239 - 20 -21036~0 Example IX

Methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptylacetate 0~

The title compound is prepared from 10 g ~0.0275 mol) of methyl 2-t3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-acetate, 8.2 g (0.055 mol) of cyclopentyl bromide and 6.17 g (0.055 mol) of potassium tertiary butoxide in analogy to the procedure~ of Example~ I and V.
Yield: quantitative, yellow-brown oil Exam~le X

2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl)-2-cyclo-pentylacetic acid Le A 29 239 - 21 -2~03~

b N'~ ~
O~

The title compound i~ prepared from the compound of Example IX by hydroly~i~ using 30 ml of sodium hydroxide solution and ~ubsequent acidification in analogy to the procedure~ of Examples II and VI.
Yield: 10.5 g (91.S~ of theory), slightly yellowish crystals M.p.: 120C

Examples XI and XII

(+)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentylacetic acid (Example XI) (-)-2-[3-Isobutyl-4-lquinolin-2-yl-methoxy)phenyl]-2-cyclopentylacetic acid (Example XII) Le A 29 239 - 22 -. .

2 ~ 0 ~

~`r~
O J~

In analogy to the procedure of Example~ VII and VIII, the title compound~ are obtained by chromatographic resolu-tion of the compound of Example X. (+)-Enantiomer: spec. rotn.: 44.56 (THF), Example XI
mol. rotn.: 185.84 (-)-Enantiomer: spec. rotn.: -41.07 (THF), Example XII
mol. rotn.: -171.28 Example XIII

N-Methanesulphonyl-2-[3-isobutyl-4-(quinolin-2-yl-meth-oxy~phenyl]-2-cycloheptylacetamide 0~

o NH-SO2CH3 Le A 29 239 - 23 -2~0360~

2 g (0.0045 mol) of the compound from Example VI are suspended in 20 ml of dried THF under argon and treated with 1.82 g (0.018 mol) of triethylamine (d = 0.73). A
clear solution is formed. 1.14 g (0.01 mol) of mesyl chloride (d = 1.48) are added dropwise with cooling in an ice bath, the mixture is stirred at this temperature for a further 15 min and 1.52 g (0.016 mol) of methanesul-phonamide and 1.1 g (0.009 mol) of dimethylaminopyridine, dissolved in 10 ml of dry T~F, are then added dropwise with stirring. The mixture is allowed to react overnight, during the course of which the temperature rises to RT.
The mixture is poured into toluene and extracted with water and dilute acetic acid. The organic phase is separated off, dried using Na2SO4 and concentrated in vacuo to a small volume, and the pale brown oil which remains (2.42 g) is subjected to column chromatography (silica gel 60, eluent: toluene/ethyl acetate/glacial acetic acid = 8:2:1).
1.75 g (74.6% of theory) of a colourless product (amor-phous) are obtained.

Preparation Examples Example 1 N-Methanesulphonyl-2-[3-isobutyl-4-(quinolin-2-yl-meth-oxy)phenyl]-cyclohexylacetamide Le A 29 239 - 24 -21Q3^50 - ,~
o~

o ~ NH-SO,-CH~
In analogy to the procedure of Example XIII, the title compound is prepared from 3.5 g (0.008 mol) of the compound from Example II, 1 g (0.008 mol) of mesyl chloride, 0.912 g of methanesulphonamide, 1.62 g (0.016 mol) of triethylamine and 0.98 g (0.008 mol) of dimethyl-aminopyridine.
Yield: 3.48 g (84.9~ of theory), colourless amorphous powder M.p.: 163-170C

Exam~le 2 and Example 3 (+)-N-Methanesulphonyl-2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexylacetamide (Example 2) (-)-N-Methanesulphonyl-2-[3-isobutyl-4-(quinolin-2-yl-methoxy~phenyl]-2-cyclohexylacetamide (Example 3) Le A 2g 239 - 25 -2~3~00 '~ ,1 o~
o~ NH-SO2-CH3 The two enantiomers are obtained by col-lmn chromato-graphic resolution of the compound from Example 1 on HPLC-HP lOSO Chiralcel OD in an eluent mixture of 86%
n-heptane and 14% of a 2-propanol mixture which contains 1% water + 0.2% trifluoroacetic acid.
(+)-Enantiomer: spec. rotn.: +32.15 (CHCl3) Example 2 mol. rotn.: +163.32 (-)-Enantiomer: spec. rotn.: -28.96 (CHC13) Example 3 mol. rotn.: -147.12 The pure enantiomers shown in Table 1 can either be prepared in analogy to the procedures of Examples 2 and 3 via resolution of the racemate or by use of the corresponding enantiomerically pure carboxylic acidsO

Le A 29 239 - 26 -2~ ~3~0~
Ta~le 1:

O~
~CH-R, Ex. No. Rl Enantiomer mol. rotn. spec. rotn.

4 ~ (+) ~ (~) 6 ~ (+) +147.99 +28.35 ~ (CHCl3) (CHCl3) 1~
7 ~ (-) -169.91 -32.55 ,~\~ ~ (CHCl3) (CHCl3) Le A 29 239 - 27 -

Claims

1. New isobutyl-substituted methanesulphonyl-quinolyl-methoxyphenyl-cycloalkylacetamides of the formula in which R1 represents cyclohexyl in the form of the racemate and of the enantiomers as well as the enantiomers if R1 represents cyclopentyl or cycloheptyl and their salts.

2. Racemate, (+)-enantiomer and (-)-enantiomer of the compound of the formula and its salts.

3. (+)-Enantiomer and (-)-enantiomer of the compound of the formula and its salts.

4. (+)-Enantiomer and (-)-enantiomer of the compound of the formula and its salts.

5. A process for the preparation of the isobutyl-substituted methanesulphonyl-quinolylmethoxy-cycloalkylphenylacetamide according to Claim 1, which comprises:
reacting a carboxylic acid of the general formula:

(II) (in which R1 has the meaning given in claim 1) which has optionally been activated, with methanesulphonamide of the formula:
H2N-SO2-CH3 (III) in an inert solvent in the presence of a base or a catalyst, wherein when the enantiomer is required, either the acid of the formula (II) is enantiomerically pure or an obtained racemate of the formula (I) is resolved into its enantiomers.

6. The process according to Claim 5, wherein the racemate is resolved into the enantiomers by column chromatography.

7. A medicament for the treatment or prevention of disease related to lipoxygenase, which comprises an effective amount of at least one isobutyl-substituted methanesulphonyl-quinolylmethoxyphenyl-cycloalkylacetamide according to any one of Claims 1 to 4 or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable auxiliary or excipient.

8. Use of the isobutyl-substituted methanesulphonyl-quinolylmethoxyphenyl-cycloalkylacetamide according to any one of Claims 1 to 4 for the production of a medicament for the prevention or treatment of disease related to lipoxygenase.