AU669913B2

AU669913B2 - New isobutyl-substituted methanesulphonyl-quinolylmethoxyphenyl-cycloalkylacetamides

Info

Publication number: AU669913B2
Application number: AU44255/93A
Authority: AU
Inventors: Romanis Fruchtmann; Armin Dr Hatzelmann; Michael Dr Matzke; Klaus-Helmut Dr Mohrs; Reiner Prof Dr Muller-Peddinghaus; Siegfried Dr Raddatz
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1992-08-12
Filing date: 1993-07-28
Publication date: 1996-06-27
Anticipated expiration: 2013-07-28
Also published as: IL106623A0; FI933529A; KR940003937A; NO179948C; NZ248350A; HU9302320D0; PL174102B1; EP0582916A1; FI933529A0; MX9304608A; CA2103600A1; NO932731L; NO179948B; PL300025A1; ZA935828B; AU4425593A; JPH06157462A; RU2103261C1; CN1087084A; NO932731D0

Description

Our Ref: 476256 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Address for Service: Bayer Aktiengesellschaft D-5090 Leverkusen Bayerwerk

GERMANY

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 New isobutyl-substituted methanesulphonyl-quinolylmethoxyphenyl-cycloalkylacet amides e k Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 The invention relates to new isobutyl-substituted methanesulphonyl-quinolylmethoxyphenylcycloalkylacetamides, a process for their preparation and their use in medicaments.

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

The present invention relates to new racemate, (+)-enantiomer and (-)-enantiomer of the compound of the formula (1) 6 0 NH-S0 2

-CH

3 and its salts.

In the context of the present invention, physiologically acceptable salts are preferred.

Physiologically acceptable 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, methanesulphonic 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 additionally metal salts, preferably of the univalent metals, and the ammonium salts. Preferred alkali metal salts are those such as, for example, sodium, potassium and ammonium salts.

example, sodium, potassium and ammonium salts.

The compounds of tie general formula according to the invention are prepared by reacting the carboxylic, acids of the general formula (11)

N.

*100

CO

2

H

if appropriate with prior activation, with methanesulphonamide of the formula (III) H2N-SO,-CH (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 (11) directly or resolving the racemates according to customary methods.

The anantiomers are preferably resolved by column chromatography.

The process according to the invention can be illustrated by way of example by the following reaction scheme: a I N' *1 0lsy'l chlo CH I) N AP J Tr ithylamrain;.

I

DNA

CO

2

H

CO-NII-SO,-CH1 4.

The sulphoamidation is 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 conditions. These include halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, S1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane or mineral oil fractions, nitromethane, dimethylformamide, acetonitrile or r Le A 29 239 4 hexamethylphosphoramide. It is also possible to employ mixtures of the solvents. Dichloromethane is particularly preferred.

Suitable bases for the sulphoamidation are the customary basic compounds. These preferably include alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrides such as sodium hydride, alkali metal or alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, or alkali metal alkoxides such as, for example, sodium methoxide or sodium ethoxide, potassium methoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as benzyltrimethylammonium hydroxide, tetra- 15 butylammonium hydroxide, dimethylaminopyridine, pyridine, ."triethylamine or N-methylpiperidine.

Suitable dehydrating reagents are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodi- 20 imide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphonic anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or diphenyl phosphoramidate or methanesulphonyl chloride, if appropriate in the presence of bases such as triethylamine or N-ethylmorpholine or Nmethylpiperidine or dicyclohexylcarbodiimide and Le A 29 239 5 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, dimethylaminopyridine is preferably employed as the catalyst.

The catalyst is in general employed in catalytic to equimolar amounts, preferably equimrlar amounts.

The sulphoamidation is in general carried out in a temperature range from 0 C to 150 0 C, preferably at to 40 0

C.

The sulphoamidation is in general carried out at normal 15 pressure. However, it is also possible to carry out the process at reduced pressure or at elevated pressure (for example in a range from 0.5 to 5 bar).

With the exception of the case R 1 cycloheptyl, the carboxylic acids of the general formula (II) are, as 20 actual substance representatives, in particular in enantiomerically pure form, new and can be prepared, for example, by either converting compounds of the general formula (IV) Le A 29 239 6 or (IVa)

T-OR

CEI-

M0R,

(IV)

T'-O

(IVa)

CH-I

C0 2

R

2 in which

R

1 has the aboveinentioned meaning, T and T' are identical or different and represent a hydroxyl protective group such as benzyl or t'-3rtbutyl and R 2 and R 2 are identical or different and denote CI-C 4

S.

Le A 29 239-7 7 alkyl, after removal of the protective group with 2-halogenomethylquinoline of the formula (V)

(V)

N CH 2

-V

in which V represents halogen, preferably chlorine or bromine, in inert solvents by etherification into the compounds of the general formula (VI) or (VIa)

S..N

N

0 (VI) or CH-R I C0 2

R

2 •Y V

H-R

i :I .co Le A 29 239 8 0 (VIa)

CH,

in whi-ch

COR'

R

1

R

2 and R 2 havPe ne abovementioned meaning, and in the case of the compounds of the general formula (VIa), subjecting these in a 2nd step to an alkylation with compounds of the general formula (VII) R-W (VII) in which

R

1 has the abovementioned meaning 10 and W represents chlorine, bromine or iodine, in inert solvents, siee and then hydrolysing the esters by customary methods, Le A 29 239 9 anr in the case of the enantiomers, resolving the racemic acids by column chromatography on chiral acids according to a customary method.

The protective 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 conditions. These preferably include ethers such as, for example, dioxane, tetrahydrofuran or diethyl ether, 15 halogenohydrocarbons such as dichloromethaiie, trichloromethane, 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 smploy mixtures of the solvents.

Bases employed for the etherification can be inorganic o, organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or 25 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 j carbonate, alkaline earth metal ci nates such as calcium carbonate, or organic amities (trialkyl(C 1 Ce)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 is in general carried out in a temperature range from 0 C to +150C, preferably from to +100°C.

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 15 are employed, relative to 1 mol of the reactant. The base is in general employed in an amount from 0.5 to mol, preferably from 1 to 3 mol, relative to the halide.

The compounds of the general formulae (IV) and (IVa) are 20 known per se or can be prepared by a customary method.

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

Suitable solvents for the processes according to the Suitable solvents for the processes according to the Le A 29 239 11 invention and for the alkylation are customary organic solvents which do not change under the reaction conditions. 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 halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane is preferred.

The alkylation is carried out in the abovementioned 15 solvents at temperatures from 0 C to +150 0 C, preferably at room temperature to +100°C, and at normal pressure.

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

As actual substance representatives, the compounds of the 20 general formula (VI) are new in some cases and can be prepared as described above.

The racemates are in general resolved by column chromatography on chiral HPLC columns using solvent mixtures such as, for example, n-heptane/2-propanol or via diastereo- 25 meric esters. I 2 Le A 29 239 12 The new N-methanesulphonyl-2- 3-isobutyl-3-(quinolin-2yl-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 as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and oedemas, thromboses and thromboembolisms, ischaemia (peripheral, cardiac and cerebral circulatory disorders), cardiac and cerebral infarcts, angina pectoris, arteriosclerosis, in tissue transplants, dermatoses such as psoriasis, inflam- 15 matory dermatoses and for cytoprotection in the gastrointestinal tract.

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

20 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 B 4 (LTB,) in polymorphonuclear human leucocytes (PMN) was determined after addition of substances 25 and Ca ionophore by means of reverse phase HPLC according to Borgeat, P. et al., Proc. Nat. Acad. Sci., 76, Le A 29 239 13 2148-2152 (1979).

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

B

7 7.0 x 10 The present invention also includes pharmaceutical preparations which, apart from inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formula or which consist of one or more active compounds of the formula as well as processes for the production of these preparations.

The active compounds of the formula should be present 15 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 the pharmaceutical preparations can also contain other 20 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 29 239 14

C

In general, it has proven advantageous to administer the active compound(s) of the formula 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 sometimes 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 administration, and the time or interval at which administration takes place.

Starting Compounds 15 Example I Methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2cyclohexyl-acetate

N

*l ego•

O

o tol o go o Le A 29 239 15 12 g (0.033 mol) of methyl 2-[3-isobutyl-4-(quinolin-2yl-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 0 C under an argon atmosphere. 4.88 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 is allowed to rise to RT, and the mixture is acidified with 2N hydrochloric acid and concentrated to dryness in vacuo. The residue which remains is stirred with 100 ml of dichloromethane and 50 ml of water, the organic phase is separated off, dried using Na 2

SO

4 and concentrated to a small volume in vacuo, and the residue which remains is separated by column chromatography (silica gel 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-cyclohexyl-acetic acid 20

O

N

C02H Le A 29 239 16 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 IN hydrochloric acid. The precipitate obtained is filtered off with suction, washed and dried, and then recrystallised from diisopropyl ether.

Yield: 9.5 g (96.3% of theory), colourless crystals 130°C Example III and Example IV (+)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2cyclohexyl-acetic acid (Example III) (-)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2cyclohexyl-acetic acid (Example IV)

O

o* 0 CO H 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 (+)-Enantiomer: spec. rotn.: 17.960 (CHCl 3 (Example III) mol. rotn.: 77.410 (-)-Enantiomer: spec. rotn.: -18.86' (CHCl 3 (Example IV) mol. rotn.: -81.280 Example V Methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2cycloheptyl acetate

S

55 S

S

.555 5*5

CO

2

CH

3 10 g (0.0275 mol) of methyl 2-[3-isobutyl-4-(quinolin-2- 10 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 15 Example VI 2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptylacetic acid I See

S.

*.006 Le A 29 239 18

N

0

COOH

The title compound is prepareO f rom the compound of Example V and 30 ml of 1N sodium hydroxide solution with :subsequent acidification in analogy to the procedure of Example II.

Yield: 11.3 g (92.3% of theory), colourless crystals 112'C Example VII and Example VIII (+)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)pheny.L]-2cycloheptylacetic acid (Example VII) (-)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2cycloheptylacetic acid (Example VIII) Le A 29 239 19

N

0 CO2H 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.: 15.720, solvent CHCl 3 Example VII mol. rotn.: 69.960 spec. rotn.: -18.70, solvent CHCl 3 Example VIII mol. rotn.: -86.190 (-)-Enantiomer: Le A 29 239 20 Example IX Methyl 2-[3-isobutyl-4-(quinolii-2-yl--methoxy)phenyl]-2cycloheptylacetate

ON

0

CO,CF

3 5 The title compound is prepared from 10 g (0.0275 mol) of ~:methyl 2-[3-isobutyl-4- (quinolin-2-yl-methoxy) phenylli- :acetate, 8.2 g (0.055 mol) of cyclopentyl bromide and .:6.17 g (0.055 mo.1) of potassium tertiary butoxide in analogy to the procedures of Examples I and V.

10 Yield: quantitative, yellow-brown oil Example X 2-[3-Isobutyl-4- (quinolin-2-yl-methoxy)phenyl] 2 cyclopentylacetic acid Le A 29 239 -2 21

CO

2

H

The title compound is prepared from the compound of Example IX by hydrolysis using 30 ml of sodiu.a hydroxide solution and subsequent acidification in analogy to the procedures of Examples II and VI.

Yield: 10.5 g (91.5% of theory), slightly yellowish crystals 120°C Examples XI and XII 10 (+)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2cyclopentylacetic acid (Example XI) (-)-2-[3-Isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2cyclopentylacetic acid (Example XII) *e es Le A 29 239 22

N

C0 2

H-

In analogy to the procedure of Examples VII and VIII, the title compounds are obtained by chromatographic resolution of the compound of Example X.

(+)-Enantiomer: spec. rotn.: 44.560 (THF), Example XI moi. rotn.: 185.840 (-)-Enantiomer: spec. rotn.: -41.070 (THF), Example XII mol. rotn.: -171.280 Examle XIII N-Methanesulphonyl-2- [3-isobutyl-4- (quinolin-2-yl--methoxy) phenyl]I-2--cycloheptylacetamide

N

0 0 NH--SU 2

,-CH

3 Le A 29 239,-2 23 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 cooliqn in an ice bath, the mixture is stirred at this temperature for a further 15 min and 1.52 g (0.016 mol) of methanesulphonamide and 1.1 g (0.009 mol) of dimethylaminopyridine, dissolved in 10 ml of dry THF, 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 Na 2 SO, 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- 20 phous) are obtained.

Preparation Examples Example 1 N-Methanesulphonyl-2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-cyclohexylacetamide Le A 29 239 24 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 1I, 1 g (0.008 mol) of mesyl chloride, 0.912 g of methane sulphonamide, 1.62 g (0.016 mol) of triethylamine and 0.98 g (0.008 mol) of dimethylaminopyridine.

Yield: 3.48 g (84.9% of theory), colourless amorphous powder 163-170 0

C

Example 2 and Example 3 -N-Methanesulphonyl-2- 3-isobutyl-4- (quinolin-2-ylmethoxy) phenyl]-2-cyclohiexylacetamide (Example 2) methoxy)phenyl] '2-cyclohexylacetamide (Example 3) Le A 29 239 25 0' 'NH-SO 2

-CH

3 The two enantiomers are obtained by column chromatographic resolution of the compound from Example 1 on HPLC-HP 1050 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.: +32.150 (CHC13) Example 2 mol. rotn.: +163.320 (-)-Enantiomer: spec. rotn.: -28.96° (CHC1 3 Example 3 10 mol. rotn.: -147.120 The pure enanti mers 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 acids.

Le A 29 239 26 Table 1: Ex. No. R 1 Enantiomer mol. rotn. spec. rotn.

4(+y

Y

+147.990 (CHCl 3 -169.910 (CHCl 3 +28. 350 (CHC133) -32.*550 CHC1 3 Le A 29 239 27

Claims

1. Racemate, (+)-enantiomer and (-)-enantiomer of the compound of the formula (I) 0' NH-S0 2 -CH 3 and its salts. 9 .9

2. Process for the preparation of new isobutyl-substituted methanesulphonyl- quinolylmethoxy-cyclo-alkylphenylacetamides according to formula of Claim 1, characterised in that carboxylic acids of the general formula (II) n 'N (II) CO 2 H are reacted, if appropriate with prior activation, with methanesulphonamide of the formula (III) H 2 N-SO-CH 3 (III) in inert solvents, in the presence of a base and/or catalyst, and in the case of the enantiomers, either the enantiomerically pure acids (II) are employed directly or the racemates are resolved according to customary methods.

3. Process according to Claim 2, characterised in that the enantiomers are resolved by column chromatography.

4. Medicaments containing at least one compound according to Claim 1 in association with one or more pharmaceutically acceptable carriers and/or excipients.

Process of manufacture of a medicament which comprises mixing one or more compounds which accord with Claim 1 with one or more pharmaceutically acceptable carriers and/or excipients.

6. A method for the treatment or prevention of diseases of the airways, shock lung, pulmonary hypertension, inflammations/rheumatism, oedemas, thromboses and thromboembolisms, ischaemia, cardiac and cerebral infarcts, angina pectoris, arteriosclerosis, dermatoses and inflammatory dermatoses which comprises S"administering to a subject in need of such treatment a therapeutically effective amount of a compound according to Claim 1 or salts thereof, optionally in association with a S* pharmaceutically acceptable carrier.

7. A method according to Claim 6 which is a method for the treatment of allergies, asthma, bronchitis, emphysema, peripheral, cardiac and cerebral infarcts, or psoriasis.

8. A method for the treatment of tissue transplants or cytoprotection in the gastro- intestinal tract which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to Claim 1 or salts thereof, optionally in association with a pharmaceutically acceptable carrier. DATED this 1st day of May 1996 BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys DAVIES COLLISON CAVE w New isobutyl-substituted iethanesuiphonyl- cuinolylmethoxvphenyl-cycloalkvlacetamide s A bs t ra ct The new isobutyl- substituted methane sulphonylguino lyl methoxyphenyl-cycloalkylacetamideS can be prepared by reaction of the corresponding racemic or enantiomeric acids with methane su lphonamide, 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. Le A 29 239