Substituted quinol-2-yl-methoxy-phenylacetic acid derivatives

AU9344253 (12) PATENT ABRIDGMENT (11) Document no AU-B-44253/93 (19) AUSTRALIAN PATENT OFFICE (10) Accop.ance No 668574 (54) Title SUBSTITUTED QUINOL-2-YL-METHOXY-PHENYLACETIC ACID DERIVATIVES (51)⁵ (21) (30) (31) (43) (44) (71) (72) (74) (56) International Patent Classification(s) C07D 215/14 A61K 031/47 Application No. : 44253/93 Priority Data (22) Application Date: 28.07.93 Number (32) D (33) Country 11.08.92 DE GERMANY Publication Date : 17.02,94 Publication Date of Accepted Application : 09.05.96 Applicant(s) BAYER AKTIENGESELLSCHAFT Inventor(s) VSSRiSSS^^S^lffXSSSSS?^nADDATZ;R0MA'"^S ™^CHMANN: Attorney or Agent DAVIES COLLISON CAVE , GPO Box 3876, SYDNEY NSW 2001 Prior Art Documents AU 29799/92 C07D215 14 AU 61084/90 C07D215 14 US 5310744 Claim Substituted quinol-2-yX-methoxy-phenylac6tic acid, derivatives of the general forroula (I) (57) 1.

I) CO-R³ in which A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxyl, nitro, trifluoromethyl, trifluoro-methoxy or represent straight-chain or branched alkyl or alkoxy with in each case up to 8 carbon atoms, or ./2 (11)AU-B-44253/93.₂.(10)668574 represent aryl with 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, nitro or cyano, R⁴ represents halogen, cyano, nitro, azido, hydroxyl, carboxyl, trifluoromethyl, trifluoro-methoxy or trifluoromethylthio, or represents straight-chain or branched alkyl, alkenyl or alkinyl with in each case up to 8 carbon atoms, which are optionally substituted by phenyl or cycloalkyl with 3 to 8 carbon atoms, or represents cycloalkyl with 3 to 8 carbon atoms or phenyl, or represents straight-chain or branched alkoxy or alkoxycarbonyl with in each case up to 6 carbon atoms, R² represents hydrogen or represents straight-chain or branched alkyl with up to 6 carbon atoms, or represents cycloalkyl with 3 to 12 carbon atoms, represents hydroxyl, or represents straight-chain or branched alkoxy with up to 8 carbon atoms or phenyl, or represents a group of the formula -NR'S0₂R⁵ or -NR⁶R⁷, in which R\ R⁶ and R⁷ are identical or different and represent hydrogen, straight-chain or branched alkyl with up to 6 carbon atoms, phenyl or benzyl, R represents trifluoromethyl or phenyl, R³ .../3 (11) AU-B-44253/93.₃_(10)668574 which is optionally substituted by halo­gen, cyano, hydroxyl, nitro, trifluoro-methyl, trifluoromethoxy or trifluoro-methylthio, or by straight-chain or branched alkyl or alkoxy with in each case up to 6 carbon atoms, or represents straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or hydroxyl or by straight-chain or branched alkyl or alkoxy with in each case up to 6 carbon atoms, and their salts. 8. A method for ,he treatment and/or prevention of inflanunanons, pulmonary hypertension, rheumatism, oedemas, thromboses and thrombo-emboiisms, ischaemias myocardtal and cerebral infarcts, disturbances of cardiac rhythm, angina pectoris artenosclcrosis, dermatoses, inflammatory dermatoses, dermatophyte infection, infections of the skm by bacteria and metastases whtch comprises administering to a subject in need of such treatment a therapeu.icaily effective amount of a compound according to any one of claims 1 to 5 or a saU thereof optionally in association with a pharmaceutically acceptable carrier.

Our Ref: 475872 P/OO/Oll Regulation 3:2 AUSTRALIA Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT •%J • • • • • • • •• • • • • Applicant(s):Bayer Aktiengesellschaft D-5090 Leverkusen Bayerwerk GEfiMANY • # • • «« « • • • •» Address for Service: DAVIES COLLISON CAVE Patent S> Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Invention Title:Substituted quinol-2-yl-methoxy-phenylacetic acid derivatives The following statement is a full description of this invention, including the best method of performing it known to me:- The present invention relates to substituted quinol-2-yl-methoxy-phenylacetic acid derivatives, processes for their preparation and their use in medicaments. Substituted 4-(quinol-2-yl-methoxy)phenylacetic acid derivatives and a-substituted 4-(quinol-2-yl-methoxy)-phenylacetic acid derivatives are known from EP 344 519 (US 4 970 215) and EP 339 416.

The present invention now relates to substituted quinol-2-yl-methoxy-phenylac#tic acid derivatives of the general formula (I) A G ••« • • (I) • •• « in which CO-R^J • ••« • •• « A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or represent straight-chain or branched alkyl or alkoxy with in each case up to & carbon atoms, or • • * • •• « 11 • • • •• Le A 29 237. 1 - represent aryl with 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, nitro or cyano.

R¹ represents halogen, cyano, nitro, azido, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy or trifluoromethylthio, or represents straight-chain or branched alkyl, alkenyl or alkinyl with in each case up to 8 carbon atoms, which are optionally substituted by phenyl or • • • • • • t • cycloalkyl with 3 to 8 carbon atoms, or represents cycloalkyl with 3 to 8 carbon atoms or phenyl, or represents straight-chain or branched alkoxy or alkoxycarbonyl with in each case up to 6 carbon 15atoms, • • • • *• R represents hydrogen or represents straight-chain or branched alkyl with up to 6 carbon atoms, or represents cycloalkyl with 3 to 12 carbon atoms, R³ represents hydroxyl, or represents straight-chain or * •• I I • •• a branched alkoxy with up to 8 carbon atoms or phenyl, or represents a group of the formula -NR*S0₂R⁵ or -NR⁶R⁷, in which R*, R⁶ and R⁷ are identical or different and repres-²⁵ent hydrogen, straight-chain or branched alkyl t& A 29 227- 2 - with up to 6 carbon atoms, phenyl or benzyl, R⁵ represents trifluoromethyl or phenyl, which is optionally substituted by halogen, cyano, hydroxyl, nitro, trifluoromethyl, trifluoro-5methoxy or trif luoromethyl thio, or by straight- chain or branched alkyl or alkoxy with in each case up to 6 carbon atoms, or represents straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally iOsubstituted by phenyl, which in turn may be substituted by halogen, cyano, nitro, tri-fluoromethyl, trifluoromethoxy, trifluoro-methylthio or hydroxyl or by straight-chain or • •• • * • • •• • branched alkyl or alkoxy with in each case up **. : 15to 6 carbon atoms.

• • • • •• and their salts. Within the scope of the present invention, physiologi­cally acceptable salts are preferred. Physiologically acceptable salts of the (quinol-2-ylmethoxy)-phenylacetic acid derivatives may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are those, for example, with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzene-sulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid,, Le A 29 227- 3 - fumaric acid, maleic acid or benzoic acid. Salts within the scope of the present invention are additionally salts of the monovalent metals, such as alkali metals, and the ammonium salts. Sodium, potassium and ammonium salts are preferred. The compounds according to the invention exist in stereo-isomeric forms (*) which either do (enantiomers) or do not (diastereomers) relate to each other as image to mirror image. The invention relates to both the antipodes • •• • •• and the racemic forms as well as to the diastereomeric mixtures. The racemic forms as well as the diastereomeric mixtures can be separated in a known manner into the stereoisomerically uniform components [cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962]. Compounds of the general formula (I) are preferred, in which A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoromethyl or tri- 20fluoromethoxy or represent straight-chain or branched alkyl or alkoxy with in each case up to 6 carbon atoms, or represent phenyl, which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, nitro or cyano.

Le A 29 227» 4 - ••» •• ft- • *• • • • • • •• R¹ represents fluorine, chlorine, bromine, iodine, cyano, nitro, azido, hydroxyl, carboxyl, trifluoro-methyl or trifluoromethoxy, or represents straight-chain or branched alkyl, alkenyl or alkinyl with in each case up to 6 carbon atoms, which are optionally substituted by phenyl, cyclo-propyl, cyclopentyl or cyclohexyl, or represents cyclopropyl, cyelobutyl, cyclopentyl, cyclohexyl or cycloheptyl or phenyl, or 10represents straight-chain or branched alkoxy or alkoxycarbonyl with in each case up to 4 carbon atoms, R² represents hydrogen or represents straight-chain or branched alkyl with up to 4 carbon atoms, or represents cyclopropyl, cyelobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyelooctyl, R³ represents hydroxyl, or represents straight-chain or branched alkoxy with up to 6 carbon atoms or phenyl, or represents a group of the formula -NR^SC^R⁵ or -NR⁶R⁷, in which R*, R^s and R⁷ are identical or different and repres­ent hydrogen or straight-chain ot branched alkyl with up to 4 carbon atoms, R⁵ represents trifluoromethyl e>r phenyl, which is • • • • » 1 Le h 29.-221- 5 - • • optionally substituted by fluorine, chlorine, bromine, iodine or cyano, or by straight-chain or branched alkyl or alkoxy with in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by fluorine, chlorine, bromine or trifluoromethyl or by straight-chain or branched alkyl or alkoxy with in each case up to 4 carbon atoms, and their salts. Compounds of the general formula (I) are particularly preferred.

• ••• 1 in which A, B, D, E, G and L are identical or different and represent hydrogen, hydroxy1, fluorine, chlorine or bromine, or straight-chaim or branched alkyl with up to 4 carbon atoms,^20r1represents fluorine, chlorine, bromine, nitro, azido or trifluoromethoxy, or represents straight-chain or branched alkyl, alkenyl or alkinyl with in each case up to 4 carbon atoms, which are optionally substituted by phenyl or cyclo- propyl, or • •• • •-•a » «« *• LQ A 29 227 B •• • represents cyclopropyl, cyclopentyl or cyclohexyl, R² represents hydrogen, or represents straight-chain or branched alkyl with up to 3 carbon atoms, or represents cyclopentyl, cyclohexyl or cycloheptyl, R³ represents hydroxyl, or represents straight-chain or branched alkoxy with up to 4 carbon atoms, or represents a group of the formula -NR^SC^R or -NR⁶R⁷, in which 10R⁴, R⁶ and R⁷ are identical or different and repres- ent hydrogen or methyl, R^s represents trifluoromethyl or phenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, methoxy, methyl or trifluoro- 15methyl, or represents straight-chain or branched alkyl with up to 4 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by fluorine, chlorine, bromine, 20methyl or methoxy, and their salts. Compounds of the general formula (I) are very particu­larly preferred in which A, B, O, E, G and L represent hydrogen. Those compounds are also very particularly • ••• •«•• Le A 29 227- 7 - preferred in which the residue -CHR²-CO-R⁰ is located in the 4-position in relation to the quinolylmethoxy resi­due. In addition, processes have been found for preparing the compounds according to the invention of the general formula (I), characterised in that phenols of the general formula (II) HO R¹ R²' ^^ (II) CO-vR⁰ in which % • » Rhas the abovementioned meaning.

c c« • t ft * R² has the abovementioned meaning of R² but does not represent hydrogen, and R⁸ represents Cj-C^-alkyl, • »# ♦ l • are etherified in inert solvents with 2-halogenomethyl-quinolines of the general formula (III) (III) Le A,29 227 - 8 in which A, B_f D, E, G and L have the abovementioned meaning and T represents halogen/ preferably chlorine or bromine, or phenols of the general formula (Ha) HO CH, (Ila) CO,-R⁰ in which R¹ and R⁸ have the abovementioned meaning, are first converted, by reaction with the compounds of the general formula (III) in inert solvents, into the compounds of the general formula (la) A G B. 1 JL .L • ••< (la) • *• • • • I • * • •• CO-R^aLQ A 29 221 - 9 - in which A, B, D, E, G, L, R¹ and R⁸ have the abovementioned meaning, and the latter are subsequently alkylated in inert solvents with compounds of the general formula (IV) R²'-W(IV) in which R²' has the abovementioned meaning and W represents chlorine, bromine or iodine, and in the case of the acids (R³ = OH) the esters are hydrolysed, and, in the case that R³ represents the group of the formula -NR'^,S0₂R^s or -NR⁶R⁷, the acids (R³- OH), optionally 15 with prior activation, are sulphoamidated or amidated, respectively, with the corresponding sulphonamides of the formula (V) or the amines or ammonia of the formula (VI) NHR^SOz-R⁵ (V) or HNR⁶R⁷ (VI) • • • ««« Le A 29 22?- 10 • • • • •• • in which R'', R⁵, R⁶ and R⁷ have the aboveraentioned meaning, and, in the case that R¹ represents alkenyl or alkinyl, reaction is carried out, starting from the corresponding halogeno compounds of the general formula (la / R¹ = halogen, preferably bromine), with compounds of the general formula (VII) <C«H₉)3Sn-R^r(VII) in which R¹' represents (Cj-Cs) -alkenyl or alkinyl, in the presence of palladium(O) catalysts, preferably tetrakis(triphenylphosphine)palladium(0), and, in the case that R¹ = (Ci-CgJ-alkyl, hydrogenation is optionally carried out subsequently according to custom-ary methods, and, in the case of the enantiomers, the corresponding enantiomerically pure acids (I/R³ - OH) are separated by a customary method, and the substituents A, B, D, E, G, L and R¹ are option-ally introduced or modified by further customary methods at each of the above-listed stages.

••* • • • • • ••• I m » •« •*• • « ** • • c • • • Lq A 29 227- 11 - The processes according to the invention may be exemplified by the following formula diagrams: • « • * * • NaOH 0«««< t • • ••» • •• • •• * * •• *• • It » • I* A 29 227 12 « • * * + NH-jSCCH, CO-NH-S0₂-CH₃ B • * »•»HOBr^^ C0₂CH3 V « t > • ••«»»•••»»••••« »»«•Br-COjCH,LQ A 29 227•»• X J <M+ (C₄H₉)₃Sn / [Pd⁰] H₂/Pd-C NaOH • ••••••• • » ••»•• * • i • • • •• La A 23 22? - 14 9« • » • « • • • The etherification can be carried out in. inert organic solvents, optionally in the presence of a base. Solvents for the etherification can be inert organic solvents which are not altered under the reaction conditions. Among these are, preferably, ethers such as, for example, dioxane, tetrahydrofuran or diethyl ether, ha loge no hydro­carbons such as dichloromethane, trichloromethane, tetra-chloromethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetonitrile, acetone or hexamethyl-phosphoric acid triamide. It is also possible to employ mixtures of the solvents. Inorganic or organic bases may be employed as bases for the etherification. Among these are, preferably, 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 carbon-ate, alkaline earth metal carbonates such as calcium carbonate, or organic amines (trial]cyl(C_x-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 generally takes place in a temperature •••« I « • •-• • • • • Le A 29 22?- 15 - • ••• I 4 range from 0^oC to +150^oC, preferably from +10^oC to +100^oC. The etherification is generally carried out under atmos­pheric pressure. It is, however, also possible to carry out the process under reduced pressure or under elevated pressure {e.g. in a range from 0.5 to 5 bar). In general/ 0.5 to 5 mol, preferably 1 to 2 mol, of halide (III), based on 1 mol of the reaction partner, are employed. The base is generally employed in a quantity of 0.5 to 5 mol, preferably of 1 to 3 mol, based on the halide. Suitable solvents for the alkylation are customary organic solvents which are not altered under the reaction conditions. Among these are, preferably, ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons such as diehioromethane, trichloro-methane, tetrachloromethane, dichloroethylene, trichloro- ethylene or chlorobenzene, or ethyl acetate, or triethyl-amine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the said solvents. Dichloromethane is preferred. The alkylation is carried out in the above-listed sol­vents at temperatures of 0°C to +150⁹C, preferably at Le A 29 227- 16 room temperature up to +100^aC, and under atmospheric pressure. The amidation and the sulphoamidation generally take place in inert solvents in the presence of a base and a dehydrating agent. Suitable solvents in this context are inert organic solvents which are not altered under the reaction condi­tions. Among these are halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, • • • • • • ••« 1,2-dichloroethane, trichloiroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Dichloromethane is particularly preferred. Suitable bases for the amidation and the sulphoamidation are the customary basic compounds. Among these are, for example, alkali metal and alkaline earth metal hydrox- ides, such, as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrides such as sodium hydride, alkali metjal or alkaline earth metal carbonates, such as sodium carbonate or potassium carbonate, or alkali m^tal alcoholates such as, for example, sodium methanolate or ethanolate, potassium methanolate o£ ethanolate or potassium tert-butylate, or Organic amines such as benzyltrimethylammonium hydroxide, •••« * « • **• heA 29 227« 17 - tetrabutylaimnoniuni hydroxide, pyridine, triethylamine or N-methylpiperidine. The amidation and the sulphoamidation are generally carried out in a temperature range from 0^oC to 150'c, 5 preferably at 25"C to 40⁰C. The amidation and the sulphoamidation are generally carried out under atmospheric pressure. It is, however, also possible to carry out the process under reduced pressure or under elevated pressure (e.g. in a range from 10 0.5 to 5 bar). In carrying out the amidation and the sulphoamidation, the base is generally employed in a quantity of 1 to 3 mol, preferably of 1 to 1.5 mol, based on 1 mol of the particular carboxylic acid.

Suitable dehydrating reagents are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbo-diimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, or carbonyl compounds such as carbonyl-diimidazole, or 1,2-oxazolium compounds such as 2-ethyl-S-phenyl-l^-oxazolium 3-sulpftonate, or propanephosphonic anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phasphoniura hexafluorophosphate or diphenylphosphoryl azide or methanesulphonyl chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclo-hexylcarbodiimide and N-hydroxysuccinimide.

• < • ••• • •• ••« • • *• *• • • • * • •• Le A 29 32?„ _lB.

It has, in particular, been found expedient to carry out the reaction in a stream of ammonia (R⁶R⁷=H) at slight excess pressure. Hydrolysis of the carboxylic acid esters takes place according to customary methods by treating the esters in inert solvents with customary bases. Suitable bases for the hydrolysis are the customary inorganic bases. Preferred among these are, for example, alkali metal hydroxides or alkaline earth metal hydrox- ides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen .. ..carbonate. It is particularly preferred for sodium I ..*hydroxide or potassium hydroxide to be employed. •• • • • • .*" 15 Suitable solvents for the hydrolysis are water or the ""Jorganic solvents which are customary for a hydrolysis. Among these are, preferably, alcohols such as methanol, _tittethanol, propanol, isopropanol or butanol, or ethers,_pI*j._#such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. It is particularly preferred that •,'_ffm,alcohols such as methanol, ethanol, propanol or isopro- ,«•••,panol are used. It is also possible to employ mixtures of »••• the said solvents. The hydrolysis is generally carried out in a temperature range from 0*G to +100^oC_f preferably from +20"C to +80^,'C.

Le A 2§ 227* 19 - »•• • In general, the hydrolysis is carried out under atmos­pheric pressure. It is, however, also possible to use reduced pressure or elevated pressure (e.g. from 0.5 to bar). In carrying out the hydrolysis, the base is generally employed in a quantity of 1 to 3 mol, preferably of 1 to 1.5 mol, based on 1 mol of the ester. It is particularly preferred to use molar quantities of the reactants. The hydrogenation generally takes place in inert solvents such as alcohols, such as, for example, methanol, ethan-ol, propanol or isopropanol, preferably in methanol, in the presence of a noble metal catalyst such as platinum, palladium, palladium on animal charcoal or Raney nickel, in a temperature range from 0^oC to +150⁰C, preferably from room temperature to +100"C, and under atmospheric pressure or under elevated pressure. The pure enantiomers of the compounds according to the invention of the general formula (I) may be prepared, for example, by separating the corresponding acid racemates into the enantiomers according to a customary method and subsequently further reacting the enantiomers as indi­cated above. The phenols of the general formulae (II) and (Ha) are known or_/ in particular in the case where R¹ represents alkyl, are_/ as concrete substance representatives, novel and may be prepared, for exaittple, either by, in the case * • •• • •- * •••# ♦ •• I** • * •* • • • I • * > • * Le A 29 22?- 20 - of the compounds of the general formula (Ila/R² = H) , initially carrying out a ring opening on compounds of the general formula (VIII) x-o (VIII) in which X represents a hydroxyl-protective group such as, for example, benzyl or tert-butyl or else represents methyl, and R represents straight-chain or branched alkyl with up to 7 carbon atoms, • ••• • • • either by hydrogenation, preferably by reaction with hydrogen/Pd-C, and subsequently liberating the hydroxyl functionality by customary methods, for example with HBr, and in a fimal step esterifying with the corresponding alcohol, in the presence of an acid, preferably sulphuric acid, or by, in the case of the compounds of the general formula (II/R²' .* H), initially converting the compounds of the general formula (VIII), by alkylation with com­pounds of the abovementioned general formula (IV), into •• • • • • • •• Le A 29 227 - 21 - the compounds of the general formula (IX) (IX) • ••• r • «** *• • *•• » in which X, R and R have the abovementioned meaning, and subsequently carrying out the ring opening, removal of the protective group and esterification as described above. The alkylation and the hydrogenation take place under the conditions which have already been described above.

• • * The reaction with hydrogen/Pd-C generally takes place in one of the solvents listed above, preferably methanol, in a temperature range from O'C to 70⁰C, preferably from 10"C to 50"C, and under a pressure of 1 bar. The esterification generally takes place with the corres-ponding alcohols in the presence of acids, preferably sulphuric acid, in a temperature range from O'C to 150"c, preferably from 50"C to 100⁹C, and under atmospheric pressure.

••••>••*•»• •• •• • *Le A 29 227- 22 - • • The compounds of the general formula (VIII) are known in some cases or may be prepared according to known methods by, for example, starting from the protected 4-hydroxy-benzyldialkylamines and carrying out a reaction of these with the corresponding aldehydes in the presence of bases, preferably butyllithium, in one of the above-mentioned solvents, preferably diethyl ether, to give the corresponding substituted 2-hydroxymethylbenzyldialkyl compounds and subsequently cyclising with chloroformic acid ester, potassium cyanide and potassium hydroxide to the corresponding 1-substituted ispchromanone compounds. The compounds of the general formula (IX) are mostly novel and may be prepared, for example, according to the abovementioned process. The removal of the protective groups from the correspond­ing ethers (VIII) and (IX) takes place according to a customary method, for example by hydrogenolytic cleavage of the benzyl ether in the abovementioned inert solvents in the presence of a catalyst with hydrogen gas. The compounds of the general formula (III) are known or may be prepared according to known methods. The compounds of the general formula (la) are novel and may be prepared as described above. The compounds of the general formulae (IV), (V), (VI) and (VII) are known per se« «««i ► t » •» * » • Le A 29 227- 23 - • ••» » • • mm » The compounds according to the invention can be employed as active substances in medicaments. The substances can act as inhibitors of enzymatic reactions within the scope of arachidonic acid metabolism, in particular of 5-lipoxygenase. The compounds of the general formula (I) surprisingly demonstrate high in vitro activity as inhibitors of leukotriene synthesis, and a stron«, in vivo effect following oral administration. They are consequently suitable, in a preferred manner, for the treatment and prevention of inflammations, in particular of disorders of the respiratory tract, such as allergies/asthma, bronchitis, emphysema, shock lung and pulmonary hypertension, inflammations/rheumatism and oedemas, thromboses and thrombo-embolisms, ischaemias (disturbances of peripheral, cardiac and cerebral blood flow), myocardial and cerebral infarcts, disturbances of cardiac rhythm, angina pectoris, arteriosclerosis, in tissue transplantations, dermatoses such as psoriasis, inflammatory dermatoses, e.g. eczema, dermatophyte infection, infections of the skin by bacteria, and metastases, and for eytoprotection in the gastro­intestinal tract. The compounds according to the invention can be employed both in human medicine and in veterinary medicine.

• • # • » » Le A ^9 227- 24 The data on the pharmacological activity of the substan­ces according to the invention are determined by the following method: As a measure of the inhibition of 5-lipoxygenase in vitro, the liberation of leukotriene b, (LTBJ was deter­mined in polymorphonuclear human leukocytes (PMN) follow­ing addition of substances and Ca ionophore by means of reverse-phase HPLC using the method of Borgeat, P. et al., Proc. Nat. Acad. Sci. 76, 2148-2152 (1979).

• * *« • ••• Phaxmaceutical compositions which, besides inert, non­toxic, pharmaceutically suitable adjuvants and excipi-ents, contain one or more compounds of the general formula (I), or which are composed of one or more active substances of the formula (I), as well as processes for 15 preparing these compositions, also belong to the present invention. The active substances of the formula (I) should be present in the compositions at a concentration of 0.1 to 99.5% by weight-, preferably of 0.5 to 95% by weight, of 20 the. complete mixture. Besides the active substances of the formula (I), the pharmaceutical compositions may also contain other pharmaceutical active substances.

• •• *• • • t # • • • • The abovemention@d pharmaceutical compositions may be prepared in a customary manner according to known Le.Jt.29[/a] 22?- 25 - methods, for example with the adjuvant(s) or excipient(s). in general, it has been found advantageous, in order to achieve the desired result, to administer the active 5_Substance(_S) of the formula (I) in total quantities of about 0.01 to about 100 mg/kg, preferably in total quantities of about 1 mg/kg to 50 mg/kg, of body weight every 24 hours, optionally in the form of several indivx-dual doses. It can, however, where appropriate be advantageous to deviate from the said quantities, specifically depending on the nature and the body weight of the subject under treatment, on the individual response to the medicament, on the nature and severity of the disorder and on the nature of the formulation and its administration, as well as on the time or interval over which administration takes place. Starting compoundsExample I 20 Methyl 2-bromo-4-hydroxyphenylacetate CO2CH3 _f* A 29 22?- 26 A solution of 70 g (0.303 mol) of 2-bromo-4-hydroxy-phenylacetic acid in 560 ml of methanol and 14 ml of sulphuric acid is stirred at 80^oC for 3 h. Subsequently the mixture is concentrated in vacuo and the residue is 5 taken up in dichloromethane. The organic phase is washed successively with water, saturated sodium hydrogen carbonate solution and water, dried over sodium sulphate and concentrated in vacuo. The crude product is purified by column chromatography (dichloromethane/methanol, 20si) 10 Yields 54.3 g (73.1% of theory) Example II N-[2-(1-Hydroxyisobutyl)-4-methoxybenzyl]dimethylamine H₃CO • • •« •••• »< •••• 140 ml of a 1.6 molar solution of butyllithium in hexane (0.224 mol) are added dropwise at 0^oC and under an argon atmosphere to a mixture of 12.5 g (0.075 mol) of p-methoxybenzyldimethy1amine in 60 ml of analytical grade diethyl ether. The mixture is stirred at room temperature for 24 h. Then 21.5 g (0.298 mol) of iso-butyraldehyde are added dropwise such that the reaction mixture boils under reflux. Subsequently the mixture is stirred at room temperature for 2 h and mixed with 150 ml of water, and the organic phase is extracted with half-concentrated « • « • •• Le A 29 227- 27 - hydrochloric acid. The product is extracted with ether from the aqueous phase following addition of 2 N NaOH to pH 12. The organic phase is dried over sodium sulphate and concentrated in vacuo, and the residue is purified on silica gel 60 (dichloromethane/methanol, 9sl). Yield: 13.7 g (77% of theory), oil. Example III l-Isopropyl-7-methQxy-3-isochromanone H3CO • ••• » • A solution of 148 ml (1.55 mol) of ethyl chloroformate in ml of analytical grade toluene is added dropwise at room temperature to a mixture of 23.7 g (0.1 mol) of the compound from Example II and 60 g of sodium hydrogen carbonate in 375 ml of analytical grade toluene. The mixture is stirred at room temperature for 1 h. Subse­quently it is filtered and the filtrate is concentrated in vacuo. The residue is mixed with 90 ml of analytical grade DHF and 20 g (0.3 mol) of potassium cyanide, and the reaction mixture is stirred at room temperature for 6 h. Subsequently water is added and extraction with ether is carried out, and the organic phase is dried over Na₂SO_Mand concentrated in vacuo. A mixture of the residue in 45 ml of methanol, 15 g of potassium hydroxide and 100 * • V • • • Le A 29 22?- 28 ml of water is heated under reflux for 8 h. After removal of the solvent by distillation in vacuo, water is added and the mixture is washed with ether. The aqueous phase is acidified with half-concentrated hydrochloric acid, and the product is extracted with ether. The organic phase is dried over sodium sulphate and concentrated in vacuo. The product is purified by colunm chromatography over silica gel 60 (petroleum ether/ether, 1:1). Yield: 12.3 g (55.8% of theory), oil.

Example IV 4-,Cycloheptyl-l-isopropyl-7-methoxy-3-isochromanone •• • • • • H₃CO • • « •» • 5.3 g (0.024 mol) of the compound from Example III and 8.5 g (0.048 mol) of cycloheptyl bromide are dissolved in 25 ml of analytical grade DMF. A solution of 5.9 g (0.053 mol) of potassium tert-butylate is added dropwise at 0⁸C and under an argon atmosphere. The reaction mixture is stirred for 20 h and subsequently mixed with ice-water and acidified with half-concentrated hydrochloric acid to pH 5-6. The mixture is extracted with ethyl acetate and > ••» • •• • • •• •• * • » • t* & 39 227 29 - the organic phase is dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel 6 0 (petroleum ether/ether, 1:1) Yield; 3.5 g (46% of theory), oil. Example V 2-Isobutyl-4-methoxyphenylacetic acid H3CO C0₂H 4.6 g (0.02 mol) of the compound from Example III are hydrogenated for 5 h at 1 bar in 200 ml of analytical • » • » • • grade methanol following addition of 1 g of Pd-carbon (10%). The catalyst Is removed by filtration and the filtrate is concentrated in vacuo. The residue is taken up in ether and the organic phase is extracted with 3% strength sodium hydroxide. The alkaline aqueous phase is acidified with concentrated hydrochloric acid while cooling, and the product is extracted with ether. After drying over sodium sulphate, the organic product phase is concentrated in vacuo. Yield: 2.8 g (64% of theory), oil.

• ••• ► • « «... • ••• * *♦ • •• • ••« •» • • • • *•» Le A 29 22?, 30 * Example vt 2-Cycloheptyl-2-(2-isobutyl-4-methoxyphenyl)acetic acid H^CO ' TT .COpH • ••• • •• •• • In analogy with the instructions for Example V, the title compound is prepared by hydrogenation of 4.3 g (0.014 mol) of the compound from Example IV in the presence of 1 g of palladium-carbon (10%). Yields 1.8 g (41.6% of theory) M.p.: 119⁰C Example VII 4-Hydroxy-2-isobutylphenylacetic acid I • ••• ••• •• *• •• A mixture of 2.6 g (0.012 mol) of the compound from Example V and 50 ml of 8.8 N (48% strength) hydrobromic Le A 2f 227. 3! .

acid is heated under reflux for 1 h. After cooling, the mixture is diluted with water and the product is extrac­ted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated in vacuo. Yield: 2.4 g of crude product which is used directly for the next reaction. Example VIII 2-Cycloheptyl-2-(4-hydroxy-2-isobutylphenyl)acetic acid •• • » • • • •• CO2H A mixture of 3.9 g (0.012 mol) of the compound from Example vi, 25 ml of 8.8 N (48% strength) hydrobromic acid and 25 ml of glacial acetic acid is heated under reflux for 3 h. Subsequently the mixture is diluted with water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo. The product is purified by column chromatography on silica gel 60 (petroleum ether/ether l!l) Yield: 3.4 g (91.2% of theory), oil • • •• > • • •• • t «• • • • La.A 29 22?Example IX Methyl 4-hydroxy-2-isobutylphenylacetate C0₉CH, After addition of 30 ml of analytical grade methanol and 0.7 ml of cone, sulphuric acid, 2.4 g of the crude product of the compound from Example VII are heated under reflux for 3 h. After diluting with water and extracting with ethyl acetate, the organic phase is dried and concentrated in vacuo. The residue is chromatographed on silica gel 60 (dichloromethane/methanol, 50:1). Yield: 1.7 g (65.4% of theory, based on the compound from Example V).

Example X • ••• Methyl acetate 2-cycloheptyl-2-(4-hydroxy-2-isobutylphenyl)- • » « »• » C0₂CH₃9*9 9*«« #9mLe A 29 227 - 33 - In analogy with the instructions for Example IX, the title compound is prepared from 2 g (7 mmol) of the compound from Example VIII. Yield: 1.8 g (86% of theory), oil Preparation ExamplesExample 1 Methyl 2-bromo-4-(quinol-2-yl-methoxy)phenylacetate • • * • • • • •• CO2CH3 A mixture of 14.7 g (0.06 mol) of methyl 2-brorao-4-hydroxy-phenylacetate and 20.7 g (0.15 mol) of potassium carbonate in 150 ml of analytical grade DMT is stirred at 100"C for 1.5 h. After adding 12.8 g (0.06 mol) of 2-chloromethylquinoline hydrochloride, the mixture is stirred at 100⁰C for a further 8 h. Most of the solvent is subsequently distilled off in vacuo. The residue is taken up in ethyl acetate, and the organic phase is extracted with water, dried over sodium sulphate and concentrated in vacuo. The crude product is purified by column chromatography (dichloromethane/methanol, 50:1). Yield: 14.8 g (63.9% of theory) • ••• » m * • 0• •• I^-,A 29 327 - 34 - M.p.j 90^oC Example 2 Methyl2-[2-bromo-4-(quinol-2-yl-methoxy)phenyl]-2- cyclopentyl-acetate C0₂CH3 • •• • ••• A solution of 3.77 g (0.034 mol) of potassium tert-butylate is added dropwise at 0^oC and under an argon atmosphere to a solution of 5.9 g (0.015 mol) of the compound from Example 1 and 4.6 g (0.031 mol) of cyclo- pentyl bromide in 20. ml of dime thy Iformamide. Subse­quently, the mixture is stirred at room temperature for h. The reaction mixture is poured into ice-water. Extraction with ethyl acetate is carried out, and the organic phase is dried over sodium sulphate and con- centrated in vacuo. The residue is chromatographed over silica gel 60 (petroleum ether/ether, 1:1). Yield: 5.6 g (80.6% of theory), oil • ••• » 4 •»* • Le A 29 227 - 35 - Example 3 and Example 4 Methyl 2-[2-allyl-4-(quinol-2-yl-methoxy)phenyl]-2-cyclopentylacetate (Example 3) CO2CH3 • • • •• • « Methyl 2-[4-(quinol-2-y1-methoxy)-2-eyelopropyIpheny1] 2-cyclopentylacetate (Example 4) • • • • C0₂CH3 A reaction mixture of 16 g (0.035 mol) of methyl 2-[2-bromo-4-(qtiinol-2-yl-methoxy)phenyl]-2-cyclopentyl­acetate, 13.2 g (0.039 mol) of allyltributyltin and 1.6 g (1.4 mmol) of tetrakis(triphenylphosphine)palladium(0) Le A29 227 - 36 - in 160 ml of analytical grade toluene is stirred at 120"C under argon and with the exclusion of light for 19 h. Subsequently, the solid is filtered off and the filtrate is concentrated in vacuo. The product mixture is purified by column chromatography (petroleum ether/ether 1:1); the products are not separated at this stage. Yield: 11.1 g ((3) allyl/(4) cyclopropyl, 7:3) (73.5% of theory) Example 5 Methyl 2-allyl-4-(quinol-2-yl-methoxy)phe£*ylacetate • •*•• • C0₂CH3 • •••• #**• •••* • •• * a In analogy with the instructions in Example 3, the title compound is prepared from 15.2 g (0.040 mol) of the compound from Example 1 and 14.4 g (0.044 mol) of allyl-tributyltin in the presence of 1.8 § (1.6 mmol) of tetrakis(triphenylphosphine)-palladium(0). Yield: 8.7 g (62.'5% of theory), oil • ••'a # • t+,A.z$aii - 37 - Example 6 and Example 4 Methyl 2-[4-(quinol-2-yl-methoxy)-2-propylphenyl]-2-cyclopentylacetate (Example 6) C0₂CH3 • • • • # Methyl 2- [ 4-(quinol-2-».yl-methoxy) -2-cyclopropylphenyl ] 2-cyclopentylacetate (Example 4) C0₂CH₃ •#• • •• • • •• • • • a • • •• 11.1 g of the product mixture from Examples 3 and 4 are dissolved in 190 ml of methanol and hydrogenated in the presence of 1*5 g of palladium/carbon (10%) for 4 h under Le A 29 227 38 - 1.5 bar. The catalyst is filtered off, the filtrate is concentrated in vacuo and the product mixture is chroma- tographed on silica gel 60 (petroleum ether/ethyl acetate, 10:1). Yield: 5.9 g (Example 6) Yield: 2.5 g (Example 4) Example 7 Methyl 4-(quinol-2-yl-methoxy)-2-propyl-phenylacetate COgCHjj 8.7 g (0.025 mol) of the compound from Example 5 are hydrogenated in analogy with the instructions in Examples 6 and 4 in the presence of 1.3 g of palladium/carbon (10%). Yield: 3.6 g (42.3% of theory), oil Le A 29 217 39 - Example 8 Methyl2-[2-brorao-4-(quinol-2-yl-methoxY)phenyl]-2- cycloheptylacetate CO2CH3 In analogy with the instructions in Example 2, the title compound is prepared from 23.6 g (0.061 mol) of the compound from Example 1, 21.6 g (0.122 mol) of cyclo-heptyl bromide and 15 g (0.122 mol) of potassium tert-butylate. Yield: 16.4 g (55,6% of theory) Example 9 Methyl2-[4-(quinol-2-yl-methoxy)-2-vinylphenyl]-2- eyclopentylacetate • •• ••• •# * C0₂CH3 he A 29 22?- 40 - A mixture of 2.3 g (5 mmol) of the compound from Example 2, 1.6 g (5 mmol) of tributylvinyltin and 223 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0) in 40 ml of analytical grade toluene is heated under reflux for 15 h under an argon atmosphere and with exclusion of light. Subsequently, the solid is filtered off and the filtrate is concentrated in vacuo. Purification by column chromatography on silica gel 60 with petroleum ether/ ether (1:1) follows. The resulting product is contamin­ated with tin salts and is used directly for further reaction. Yield: 2.5 g of crude product, oil Example 10 Methyl 2-[4-(quinol-2-yl-methbxy)-2-ethylphenyl]-2-eyelopenty1ac etate •••• > « C0₂CH3 • •• • «* * 4 g (0.01 raol) of the compound from Example 9 are dis­solved in 10 ml of dichlororaethane p.a. and 70 ml of analytical grade methanol and hydrogenated for 6 h under Le A 29 22? • 41 •» 2 bar in the presence of 800 mg of Pd-carbon (10%), The catalyst is filtered off and the filtrate is concentrated to 70 ml volume and hydrogenated once more for 4 h under 2 bar in the presence of 800 mg of Pd-carbon (10%). After filtration to remove the catalyst, the mixture is con­centrated in vacuo and the residue is chromatographed on silica gel 60. Yield: 1.1 g (27.4% of theory), oil Example 11 Methyl 2-[4-(quinol-2-yl-methoxy)-2-vinylphenyl]-2" eyelohepty1acetate • * • • •• • CQ₂CH₃ •• •• In analogy with the instructions in Example 9, the title compound is prepared from 7.2 g (0.015 mol) of the compound from Example 8 and 4.8 g (0.015 mol) of tri-butylvinyltin in the presence of 670 mg (0.006 mol) of tetrakis(triphenylphosphine)-palladium(0). Yields 6.8 g of crude product (contaminated With tin salts). The crude product is directly used for further reaction.

•»• •»• •• a Le A 29 227 - 42 - Example 12 Methyl 2-[4-(quinol-2-yl-methoxy)-2-phenylethinylphenyl 2-cyclopentylacetate A mixture of 9.8 g (0.022 mol) of the compound from Example 2, g (0.054 mol) of phenylethinyltributyltin and 2.3 g (2 mmol) of tetrakis(triphenylphosphine)-palladium(O) in 80 ml of analytical grade toluene is heated under reflux for 36 h under an argon atmosphere and with exclusion of light. The mixture is concentrated in vacuo and the residue is purified by column chromatography (petroleum ether/ether, 1:1). Yield: 9.0 g (87,7% of theory), oil • • *• • •>• Le A 29 22? - 43 - Example 13 Methyl 4-(quinol-2-yl-raethoxy)-2-.isobutylphenylacetate C0₂CH3 • > • 4«» « In analogy with the instructions in Example 1, the title compound is prepared from 1.7 g (7.7 mmol) of methyl 4-hydroxy-2-isobutylphenylacetate, 2.64 g (0.019 mol) of potassium carbonate and 1.63 g (7.7 mmol) of 2-chloro-methylquinoline hydrochloride. Yield: 2.17 g (78% of theory), oil Example 14 » • » Methyl 2-[4-(quinol-2-yl-methoxy)-2-isobutylphenyl]-2-cycloheptylacetate * * « « COgwH^ • •• • •• « •« » • Le A 29 227 - 44 - In analogy with the instructions in Example 1, the title compound is prepared from 1.59 g (S mmol) of methyl 2-(4-hydroxy-2-isobutylphenyl)-2-cycloheptylacetate_/ 1.66 g (12 mmol) of potassium carbonate and 1.07 g (5 mmol) of 2-chloromethylquinoline hydrochloride. Yields 2 g (89% of theory), oil Example 15 2-[2-Bromo-4-(quihol-2-yl-methoxy)phenyl]-2-cyclopentyl-acetic acid •••« •*•< 50 ml of methanol and 8 ml of 1 N NaOH are added to 2.2 g (4.8 mmol) of the compound from Example 2. The reaction mixture is heated under reflux for 20 h and subsequently concentrated in vacuo and the residue is taken up in water/diethyl ether and washed with diethyl ether. The aqueous phase is acidified with 2 N hydrochloric acid and extracted with diethyl ether. After evaporating the solvent in vacuo, the crude product is chromatographed on silica gel 60 (dichloromethane/methanol, 9:1). Yield: 1.85 g (86.8% of theory) Le A 29 227- 45 - M.p.: 73-75⁰C Example 16 2-[4-(Quinol-2-yl-methoxy)-2-isobutylphenyl]-2-cyclo-heptylacetic acid C0₂H • ••• • •• •• • A mixture of 2 g (4.3 mmol) of the compound from Example 14, 12 ml of isopropanol and 12 ml of 1 N NaOH is heated under reflux for 12 h. Subsequently, the mixture is concentrated in vacuo, water and diethyl ether are added and this mixture is extracted with diethyl ether. The organic phatse is concentrated in vacuo and the recovered starting compound id hydrqlysed once again. The combined aqueous phases are acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated in vacuo. The crude product is recrystallised in methanol. 3 reaction cycles are carried out to achieve complete hydrolysis. Yield: 1.45 g (76.7% of theory) M.p.: 178-180^oC • • ♦te A 29 m 46 - The compounds listed in Table l are prepared in analogy with the instructions in Examples 15 and 16. Table ItIL^Y^C0*^H EX. NO.

R¹ M.p. {'C)Yield (solvent)(% of theory) H 176-178 (CH3OH) 83.5 • • • • • • • • 129-131 (CH₂C1₂) 73.1 H 138-140 (CH3OH) • ••. • ••• ^ 152-153 (diethyl ether) J 129-131 (ethyl acetate) 86.2 he k 29 221 - 47 ~n 145-147 (diethyl ether) 67.2 115-117 (ethyl acetate) 25.8 215-217 (ethyl acetate) Example 25 N-{2-[2-Bromo-4-(quinol-2-yl-methoxy) phenyl] -2 -cyclo-pentylacety1}-methanesulphonamide CO-NH-S0₂-CH3 •*•« • * A solution of 1.2 g (2,64 mmol) of the compound from Example 15, 280 mg (2.9 mmol) of methanesulphonamide, 0.76 g (3.96 mmol) of N-(3-dimethylamino-propyl)-N'-ethylcarbodiimide hydrochloride and 0.35 g (2.9 mmol) of 4-dimethylaminopyridine in 60 ml of analytical grade dichloromethane is stirred at room temperature for 20 h.

0 •• Le A 29 221 48 - Subsequently, the organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is purified by column chromatography on silica gel 60 (dichloromethane/methanol, 50:1). Yield: 0.9 g (65.9% of theory), oil Example 26 N-{ 2- [ 4- (quinol-2 -yl-methoxy) -2-propyl,phenyl J acetyl} -N-methyl-trifluoromethanesulphonamide CO— N-SO_?-CF, I CH₃ 0.37 ml (4.8 mmol) of methanesulphonyl chloride are added dropwise at 0^oC to a suspension of 0.67 g (2 mmol) of 2-[4-(quinol-2-yl-methoxy)-2-propylphenyl]acetic acid and 0.55 ml (4 mmol) of triethylamine in 20 ml of analytical grade tetrahydrofuran. After 15 min, a solution of 0.59 g (3.6 mmol) of N-methyltrifluoromethanesulphonamide and 0.49 g (4 mmol) of 4-dimethylaminopyridine in 5 ml of analytical grade tetrahydrofuran is added dropwise at 0^OC. The reaction mixture is stirred at room temperature for 20 h and subsequently poured into ice-water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated in vacuo.

• •• 4 IS Le A 29 22? - 49 - • Purification of the residue by column chromatography on silica gel 60 (dichloromethane/methanol, 20:1) follows. Yield: 0.73 g (76% of theory) M.p.: 111-112⁰C The compounds listed in Table 2 are prepared in analogy with the instructions in Examples 25 and 26. Table 2: Ex.No. R¹R²R³M.p. ("C) Yield (solvent) (% of theory) Br\J-NHS0₂-CH₂C₆H₅72-7470.2 • ••• •• •• • •• • •• • • (CH₂C1₂)^28Br}—/-NHS0₂-C_eH₄-p.CH3oil38.3¹⁵,nf^„155-15789.5²⁹JH-mS0₂CH₃(CH₂C1₂) r' (/133-13462.4 30^J\_y-NHS0₂CH3(diethyl ether) Lq A 29 227* 50 - Continuation of Table 2; Ex. No. R^x R^J -NHS0₂CH3 -N(CH₃)S02CF3 -NHS0₂CH3 -NHS0₂CH3 M.p. (⁰C) (solvent) Yield (% of theory) 130-132 (CH₂C1₂) 40.4 93-95 (CH₂C1₂) 62. 7 97-99 (CH₂C1₂) 55.4 88-90 (diethyl ether) 44.1 M.p. (⁰C) (solvent) Yield (% of theory) 130-132 (CH₂C1₂) 40.4 93-95 (CH₂C1₂) 62. 7 97-99 (CH₂C1₂) 55.4 88-90 (diethyl ether) 44.1 H H j p • * -NHS0₂CH3 amorphous48.8 -NHS0₂CH3 110-120 (CH₂C1₂) 89.9 •••• « • • • • • -NH, 119-121 (diethyl ether) 38.7 -NH, 109-111 (CH₂C1₂) 63.1 • • •*' •«• »•• • #«# mm • • * • - 51 - 51a COMPARATIVE ACTIVITY EXAMPLE EXAMPLE A Liberation of LTB₄ in human PMNL - test method according to the description Compound of 5-lipoxygenase-inhibition ICjo [/xmol] Example 1 of US-P 5,091,392 0.29 Example 9 of US-P 4,970,215 0.49 Example 16 of invention 0.10 • Example 18 of invention 0.21 Example 22 of invention 0.09 Example 30 of invention 0.22 Example 33 of invention 0.17 Example 35 of invention 0,08 Compound of 5-lipoxygenase-inhibition ICjo [/xmol] Example 1 of US-P 5,091,392 0.29 Example 9 of US-P 4,970,215 0.49 Example 16 of invention 0.10 • Example 18 of invention 0.21 Example 22 of invention 0.09 Example 30 of invention 0.22 Example 33 of invention 0.17 Example 35 of invention 0,08 • ••• • •• • •• •• •*• •• • •• • •• • *• •••• «#• • The Claims defining the invention are as follows Substituted quinol-2-yl-methaxy-phenylacetic acid derivatives of the general formula (I) (I) CO-R^J in which • • •• • *a t «• •• A, B, D, E, G and L are identical or different and represent hydrogen, hydroxy1, halogen, cyano, carboxyl, nitro, trifluoromethyl, trifluoro-methoxy or represent Straight-chain or branched alkyl or alkoxy with in each case up to 8 carbon atoms, or represent aryl with 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxy!, nitro or cyano.

• • * ••* « • •• ••• * •»• •• • • • • R represents halogen, cyano_rnitro, azido, hydroxyl, carboxyl, trifluoromethyl, trifluoro-methoxy or trifluoromethylthio, or represents straight-chain or branched alkyl, te A 29 227 52 - alkenyl or alkinyl with in each case up to 8 carbon atoms, which are optionally substituted by phenyl or cycloalkyl with 3 to 8 carbon atoms, or represents cycloalkyl with 3 to 8 carbon atoms or phenyl, or represents straight-chain or branched alkoxy or alkoxycarbonyl with in each case up to 6. carbon atoms, represents hydrogen or represents straight-chain or branched alkyl with up to 6 carbon atoms, or represents cycloalkyl with 3 to 12 carbon atoms, represents hydroxyl, or represents straight-chain op branched alkoxy with up to 8 carbon atoms or phenyl, or represents a group of the formula -NR^SC^R⁵ or -NR⁶R⁷, in which R^A, R⁶ and R⁷ are identical or different and represent hydrogen, straight-chain or branched alkyl with up to 6 carbon atoms, phenyl or benzyl.

R *• * R³ » • • *•» ••• # •*' # « »• R⁵ represents trifluoromethyl or phenyl, Le A 29 227- 53 - •« -«-*•• • «» • ** », which is optionally substituted by halo­gen, cyano, hydroxyl, nitro, trifluoro-methyl, trifluoromethoxy or trifluoro-methylthio, or by straight-chain or branched alkyl or alkoxy with in each case up to 6 carbon atoms, or represents straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthid or hydroxyl or by straight-chain or branched alkyl or alkoxy with in each case up to 6 carbon atoms, and their salts. 2. Substituted guinol-2-yl-methoxy-phenylacetic acid derivatives according to Claim 1, where A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, fluorine, chlor­ine, bromine, carboxyl, nitro, trifluoromethyl or trifluoromethoxy or represent straight-chain or branched alkyl or alkoxy with in each case up to 6 carbon atoms, or represent phenyl, which is optionally substi­tuted by fluorine, chlorine, bromine, hydroxyl, nitro or cyano, mm-** I t • v* « ► < r •* t»» * • «• • • • ta A 19 22-?- S4 - il represents fluorine, chlorine, bromine, iodine, cyano, nitro, azido, hydroxyl, carboxyl, trifluoromethyl or trifluoromethoxy, or represents straight-chain or branched alkyl, alkenyl or alkinyl with in each case up to 6 carbon atoms, which are optionally substituted by phenyl, cyclopropyl, cyclopentyl or cyclo-hexyl, or represents cyclopropyl, cyclobutyl, cyclo­pentyl, cyclohexyl or cycloheptyl or phenyl, or represents straight-chain or branched alkoxy or alkoxycarbonyl with in each case up to 4 carbon atoms, R² • •• ? • • ♦ •• • represents hydrogen or represents straight-chaia or branched alkyl with up to 4 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclo­pentyl, cyclohexyl, cycloheptyl or cyclooctyl, R represents hydroxyl, or represents straight-chain or branched alkoxy with up to 6 carbon atoms or phenyl, or represents a group of the formula -NR*S0₂R⁵ or -NR^eR⁷, in which R⁴, R⁶ and R⁷ are identical or different and > • • •• ••»' • • •• •< • • * ♦ Le A 29 22?. 55 •« • • • R⁵ represent hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms, represents trifluoromethyl or phenyl, which is optionally substituted by fluor­ine, chlorine, bromine, iodine or cyano, or by straight-chain or branched alkyl or alkoxy with in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by fluorine, chlorine, bromine or trifluoromethyl, or by straight-chain or branched alkyl or alkoxy with in each case up to 4 carbon atoms, • •• and their salts. 3. Substituted guinol-2-yl-methoxy-phenylacetic acid derivatives according to Claim 1, where A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, fluorine, chlor­ine or bromine, or straight-chain or branched alkyl with up to 4 carbon atoms, R¹ represents fluorine, chlorine, bromine, nitro, azido or trifluoromethoxy, or t ••• • ••• » • « • #•♦ » tAj^^aai - sg R² represents straight-chain or branched alkyl, alkenyl or alkinyl with in each case up to 4 carbon atoms, which are optionally substituted by phenyl or cyclopropyl, or represents cyclopropyl, cyclopentyl or cyclo-hexyl, represents hydrogen, or represents straight-chain or branched alkyl with up to 3 carbon atoms, or represents cyclopentyl, cyclohexyl or cyclo-heptyl, R³ represents hydroxyl, or represents straight-chain or branched alkoxy with up to 4 carbon atoms, or represents a group of the formula -NR*S0₂R⁵ or -NR⁶R⁷, in which R⁴, R⁶ and R⁷ are identical or different and represent hydrogen or methyl, R represents trifluorofttethyl or phenyl, which is optionally substituted by fluor­ •«•• • ••• •• a •• a ••«» a • ••* ine, chlorine, bromine, iodine, methoxy, methyl or trifluoromethyl, or •••"•represents straight-chain or branched •"*•.:alkyl with up to 4 carbon atoms, which is optionally substituted by phenyl, which in te A 29 23¹?- 57 - 58 - turn may be substituted by fluorine, chlorine, bromine, methyl or methoxy.

and their salts.

4,Substituted qmnol-2-yl-methoxy-phenylacetic acid derivatives according to Cl aim 1, in which A, B, D, E, G and L represent hydrogen, and their salts.

Substituted quinoI-2-yl-methoxy-phenylacetic acid derivatives according to Claim 1, in which the residue -CHR²-COR³ is located in the 4-position to the quinolyhnethoxy residue, and their salts.

• • • • i • •• • •• • • • •• •• * •••• * ••• •»•«•• 6. Process for preparing substituted qumol-2-yl-methoxy-phenylacetic acid 15 derivatives according to Claim 1, characterised in that phenols of the general formula (II) R¹r2 (II) C0₂-R⁸• * in which F_Tfd ' 951123.p:iwpdocs\amd,475872.58 R has the abovementioned meaning, R²' has the abovementioned meaning of R² but does not represent hydrogen, and R⁸ represents C^-alkyl, are etherified in inert solvents with 2-halogeno-methylquindlines of the general formula (III) A G (III) in which • • • • • * • A, B, D, E, G and L have the abovementioned meaning and T represents halogen., preferably chlorine or bromine, or phenols of the general formula (Ila) ••• • •• « ••• •• • < • • •«• (Ila) COj-R⁸L<S A 23 227- 59 - in which R and R⁸ have the abovementioned meaning, are first converted, by reaction with the compounds of the general formula (III) in inert solvents, into the compounds of the general formula (la) • •• • • • in which (la) CO-R⁸ A, B, D, E, G, L, R and R⁸ have the abovementioned meaning, and the latter are subsequently alkylated in inert solvents with compounds of the general foritula (IV) R^2,-W (IV) in which **« • mm a * •• R has the abovementioned meaning US A 29 221 - 60 - and ••« • • • ••• • W represents chlorine, bromine or iodine, and in the case of the acids (R³ - OH) the esters are hydrolysed, and, in the case that R³ represents the group of the formula -NR*S0₂R^S or -NR⁶R⁷, ttie acids (R³ = OH), optionally with prior activation, are sulphoamidated or amidated, respectively, with the corresponding sulphonamides of the formula (V) or the amines or ammonia of the formula (VI) NHR*S0₂-R⁵ (V) or HNR⁶R⁷ (VI) in which R , R , R and R have the abovementioned meaning, and, in the case that R¹ represents alkenyl or alk-inyl, reaction is carried out, starting from the corresponding halogeno compounds of the general formula {la / R¹ - halogen, preferably bromine), with compounds of the general formula (VII) (C^Hg^Sn-R¹*(vil) in which ••• • • •• »** Le A 29 221- 61 - -62 R^r represents (C^C^-alkenyl or alkinyl, • • *•m •• • • in the presence of palladium(O) catalysts, preferably tetrakis(triphenylphosphine)-palladium(O), 5 and, in the case that R^! = (C.-C^-alkyl, hydrogenation is optionally carried out subsequently according to customary methods, and, in the case of the enantiomers, the corresponding enantiomerically pure acids (I/R³ 10 = OH) are separated by a customary method, and the substituents A, B, D, E, G, L and R¹ are optionally introduced or modified by further customary methods at each of the above-listed stages. 7. A pharmaceutical or veterinary composition comprising a substituted quinol-2-yl-methoxy-phenylacetic acid derivative and salts thereof as claimed in any one of claims 1 to 5 in association with a pharmaceutically or veterinarilly acceptable carrier. 8.A method for the treatment and/or prevention of inflammations, pulmonary hypertension, rheumatism, oedemas, thromboses and thrombo-embolisms, ischaemias, myocardial and cerebral infarcts, disturbances of cardiac rhythm, angina pectoris, arteriosclerosis, dermatoses, inflammatory dermatoses, dermatophyte infection, infections of the skin by bacteria and metastases which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to 25 any one of claims I to 5 or a salt thereof optionally in association with a pharmaceutically acceptable carrier. 9.A method according to claim 8 for the treatment and/or prevention of allergies, asthma, bronchitis, emphysema, shock lung, psoriasis or eczema.

**«••••• •••« •••ft *• * • • 951 \l\p \'«T«kics\amtl.47.'i872.6J - 63 10. A method for the maintenance of tissue transplants or eryoprotection in the gastrointestinal tract which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of 5 claims 1 to 5 optionally in association with a pharmaceulicaily acceptable carrier. DATED this 22nd day of November, 1995 BAYER AKTIENGESELLSCHAFT 10 By Its Patent Attorneys DAVIES COLLISON CAVE •»•• • •• * •••• «•« »• ••• • ••«* • •• • •. . . « « • »«• #*» •*««A'^;%* 9S1 l23.p\wpdocswtr!d.47>S7:.h'!Substituted cruinol-2-vl-meth[/strike]oxv-_Phenvlacetic acid deriva­tives Abstract Substituted quinol-2-yl-methoxy-phenylacetic acid deriva­tives are prepared by reacting correspondingly substi­tuted phenols with quinolylmethyl halides or by reacting unsubstituted phenols with quinolylmethyl halides and subsequent alkylation, The substituted quinol-2-yl-methoxy-phenylacetic acid derivatives may be employed as active substances in medicaments.

• • *»••• ••• •• • »• ••4 • ••• • •** * • • • *•♦ • •« •• • • • « te A M 257