NZ241654A

NZ241654A - 2-substituted quinoline derivatives, preparation and pharmaceutical compositions thereof

Info

Publication number: NZ241654A
Application number: NZ241654A
Authority: NZ
Inventors: Siegfried Raddatz; Klaus-Helmut Mohrs; Michael Matzke; Romanis Fruchtmann; Armin Hatzelmann; Christian Kohlsdorfer; Reiner Muller-Peddinghaus; Pia Theisen-Popp
Original assignee: Bayer Ag
Priority date: 1991-02-22
Filing date: 1992-02-19
Publication date: 1994-11-25
Also published as: DE4105551A1; IL101009A; CZ282723B6; HUT67037A; RU2077532C1; DK0499926T3; GR3021014T3; AU1054292A; IL101009A0; PL171026B1; JPH0592957A; FI920732A0; ATE142623T1; IE75728B1; IE920557A1; ZA921268B; PL170726B1; DE59207074D1; HU9200582D0; MY108459A

Abstract

2-substituted quinolines of the general formula <IMAGE> The title compounds are prepared by reacting either the corresponding halomethylquinolines with substituted phenols, then optionally alkylating these and hydrolysing esters to acids, or by reacting phenyl-substituted quinolinecarboxylic acid derivatives with sulphonamides. The novel phenyl-substituted quinolines can be used as active compounds in medicaments, in particular as lipoxygenase inhibitors.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £41 654 241654 Patents Form 5 Piicrity Dsie(s): fit CuiuiJieu: Specification Filsd: Clscq; CQlJKUs/lt*/. CQIimdai... CQtQm/aj- #&te*dn-2 Publication Date: HQV..??! P.O. Journel, No: . ...ysife wo mmm N.Z. No. NEW ZEALAND N2. PATENT OFFICE Patents Act 1953 COMPLETE SPECIFICATION 19 FEB 1992 received 2-SUBSTITUTED OUINOLINES. PROCESSES FOR THEIR PREPARATION AND THEIR USE IN MEDICAMENTS We, BAYER AKTIENGESELLSCHAFT, a company organized under the laws of the Federal Republic of Germany, at Leverkusen, Federal Republic of Germany do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- -1 - (Followed by 1A) 241654 The present invention relates to 2-substituted quino-lines, processes 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)-phenyl acetic acid derivatives have been disclosed in EP 344,519 (US 4,970,215) and EP 339,416. The present invention now relates to 2-substituted quinolines of the general formula (I) a g in which A, B, D, E, 6 and L are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or represent aryl having 6 to 10 carbon atoms, which is co r3 (I) 141654 optionally substituted by halogen, hydroxyl, nitro or cyano, represents halogen, cyano, nitro, azido, trifluoro-methyl, trifluoromethoxy or trifluoromethylthio, or represents straight-chain or branched alkoxy or acyl each having up to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl or alkoxy having up to 6 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents a group of the formula -NR*R5, in which R* and Rs are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl, acetyl or benzoyl, or represents a saturated or unsaturated, optionally substituted 5- or 6-membered heterocycle having up to 3 hetero atoms from the series comprising sulphur, oxygen and nitrogen, represents cycloalkyl or -alkenyl having 3 to 12 carbon atoms, 241654 R3 represents a radical of the formula -OR6 or -NR7-S02-Rs, in which R6 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, R7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R8 denotes aryl having 6 to 10 carbon atoms, which is optionally mono- or disubstituted by identical or different substituents from the series comprising halogen, cyano, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoro-methylthio, or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or denotes straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, which in turn can be substituted by halogen, cyano, nitro, tri-fluoromethyl, trifluoromethoxy, trifluoromethyl thio or hydroxyl, or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms and their physiologically acceptable salts. 241654 5- and 6-membered heterocycles which are mentioned as preferred are those having up to 2 nitrogen atoms such as, for example, pyrryl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl, or furyl or thienyl. 5 In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the 2-substituted guinolines may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly 10 preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluene-sulphonic acid, benzenesulphonic acid, naphthalene-disulphonic acid, acetic acid, propionic acid, lactic 15 acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid. Salts in the context of the present invention are moreover salts of the monovalent metals such as alkali metals and the ammonium salts. Sodium salts, potassium salts and 20 ammonium salts are preferred. The compounds according to the invention exist in stereo-isomeric forms which behave either as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both 25 to the antipodes and to the racemic forms as well as the diastereomer mixtures. The racemic forms, like the diastereomers, can be separated into the 24 1 6 54 stereoisomerically uniform constituents in a known manner [cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962]. Preferred compounds of the general formula (I) are those in which A, B, D, E, 6 and L are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or represent straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or represent phenyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, nitro or cyano, R1 represents fluorine, chlorine, bromine, iodine, cyano, nitro, azido, trifluoromethyl, trifluoromethoxy, or represents straight-chain or branched alkoxy or acyl each having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or alkoxy having up to 4 carbon atoms, or represents straight-chain or branched alkenyl having up-to 4 carbon atoms, or represents a group of the formula -NRAR5, 24 1 6 in which R* and Rs are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or represent pyrryl, pyridyl, furyl or phenyl, represents cycloalkyl having 3 to 12 carbon atoms, reprsents a radical of the formula -OR6 or -NR7-S02-R8, in which R6 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R8 denotes phenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl which can in turn be substituted by fluorine, chlorine, bromine or trifluoromethyl or by straight-chain or 241654 branched alkyl or alkoxy each having up to 4 carbon atoms and their physiologically acceptable salts. Particularly preferred compounds of the general formula 5 (I) are those in which A, B, D, E, 6 and L are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine or straight-chain or branched alkyl having 10 up to 4 carbon atoms, R1 represents fluorine, chlorine, bromine, nitro, azido or trifluoromethoxy, or represents straight-chain or branched alkoxy or acyl each having up to 4 carbon atoms, or 15 represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or methoxy, or represents straight-chain or branched alkenyl having up to 4 carbon atoms, or 20 represents a group of the formula -NR*R5, in which R* and Rs are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, - 7 - 241654 or represents pyrryl, furyl or phenyl, R2 represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, R3 represents a radical of the formula -OR6 or 5 -NR7-S02-R8, in which R6 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R7 denotes hydrogen, methyl or ethyl, 10 R8 denotes phenyl which is optionally substituted by methyl, fluorine, chlorine, bromine, iodine, methoxy or trifluoromethyl, or denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally 15 substituted by phenyl which can in turn be substituted by fluorine, chlorine, bromine, methyl or methoxy and their physiologically acceptable salts. Very particularly preferred compounds of the formula (I) 20 are those in which A, B, D, E, G and L represent hydrogen. Those compounds are also very particularly preferred in which the radical -CHR2-COR3 is in the 4-position ? 416 54 relative to the quinolylmethoxy radical. Processes for the preparation of the compounds of the general formula (I) according to the invention have additionally been found, characterised in that 5 [A] in the case where R3 represents the group -OR6 [A2] either compounds of the general formula (Ila) r1 c02r6' in which Rl and R2 have the abovementioned meaning, 10 W represents a hydroxyl protective group such as benzyl or tert.-butyl, and R6' has the abovementioned meaning of R6 but does not represent hydrogen, 15 are converted, after elimination of the protective group, by etherification with 2-halogenomethylquinolines of the general formula (III) 241654 ch2-y (iii) in which A, B, D, E, G and L have the abovementioned meaning and 5 Y represents halogen, in particular chlorine or bromine, in inert solvents into the compounds of the general formula (IVa) chr2 co#6' (IVa) 10 in which 10 - 241 A, B, D, E, G, L, R1, R2 and R6' have the abovementioned meaning, and the latter in the case of the esters (R6 * H) are then hydrolysed, or [A2] compounds of the general formula (lib) in which R1 and R6' have the abovementioned meaning, are converted, after elimination of the protective group, initially by etherification with 2-halogenomethyl-quinolines of the general formula (III) in inert solvents into compounds of the general formula (IVb) (lib) c02r6' a g (IVb) c02r6' 241654 in which A, B, D, E, G, L, R1 and R6' have the abovementioned meaning, and the latter are then alkylated with compounds of the general formula (V) R2-Z (V) in which R2 has the abovementioned meaning and Z represents chlorine, bromine or iodine, in inert solvents and in the case of the esters (R6 * H) the esters are hydrolysed or [B] in the case where R3 represents the group -NR7-S02RB, compounds of the general formula (IVc) a g (IVc) COOH 2416 54 in which A, B, D, E, G, L, R1 and R2 have the abovementioned meaning, are amidated in inert solvents, if appropriate in the 5 presence of a base, with sulphonamides of the general formula (VI) HNR7-S02R8 (VI) in which R7 and R8 have the abovementioned meaning, 10 and [C] in the case of the enantiomers the corresponding enantiomerically pure acids (IVc) are separated by a customary method and reacted further by the above-mentioned processes, it being possible for the substi-15 tuent R1 to be varied in any of the abovementioned steps, optionally by customary chemical methods. The processes according to the invention can be illustrated by way of example by the following reaction scheme: [a2] CHj-COJCHJ n ch2-ci ?. 4 1 6 5 4 Diazotisation COjCHJ cooh 241654 [B] ch I cojh + NHj-SOJ-CHJ co-nh-so2ch3 - 15 - 41654 The elimination of the protective groups from the corresponding ethers (Ha) and (lib) is carried out by a customary method, for example by hydrogenolytic cleavage of the benzyl ether in the abovementioned inert solvents 5 in the presence of a catalyst with hydrogen gas [cf. additionally Th. Green: "Protective Groups in Organic Synthesis", J. Wiley & Sons, 1981, New York]. The etherification can be carried out in inert solvents, optionally in the presence of a base. Solvents for the 10 etherification can be inert organic solvents which do not change under the reaction conditions. These preferably include ethers such as, for example, dioxane, tetrahydro-furan or diethyl ether, halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 15 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetonitrile, acetone or hexamethylphosphoric triamide. It is also possible to employ mixtures of these solvents. 20 Bases which can be employed for the etherification are 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 25 metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or organic amines (trialkylfCj-Ce)-amines) such as triethylamine, or heterocycles such as - 16 - 241654 pyridine, methylpiperidine, piperidine or morpholine. It is also possible to employ alkali metals such as sodium and its hydrides, such as sodium hydride, as bases. 5 The etherification is in general carried out in a temperature range from 0°C to +150°C, preferably from +10 °C to +100°C. The etherification is in general carried out at normal pressure. However, it is also possible to carry out the 10 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 (III) are employed relative to 1 mol of the reaction component. The base is in general employed in an 15 amount of 0.5 to 5 mol, preferably of 1 to 3 mol, relative to the halide. The compounds of the general formula (Ila) and (lib) are known per se or can be prepared by a customary method [cf. J. Org. Chem. 31, 2658 (1966)]. 20 The compounds of the general formula (III) and their preparation are also known [cf. Chem. Ber. 120. 649 (1987)]. Suitable solvents for the process according to the 241654 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, 5 or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydro-carbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, 10 pyridine, dimethyl sulphoxide, dimethylformamide, hexa-methylphosphoric triamide, 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 08C to +150°C, preferably at room temperature to 100°C, and at normal pressure. The amidation is in general carried out in inert solvents in the presence of a base and of a dehydrating agent. Suitable solvents here are inert organic solvents which 20 do not change under the reaction conditions. These include halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene, 25 xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethyl formamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to 2416 54 employ mixtures of the solvents mentioned. Dichloromethane is particularly preferred. Suitable bases for the amidation are the customary basic compounds. These preferably include alkali metal 5 hydroxides 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 carbonates or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, 10 or alkali metal alkoxides such as, for example, sodium methoxide or ethoxide, potassium methoxide or ethoxide or potassium tert.-butoxide, or organic amines such as benzyl trimethylammonium hydroxide, tetrabutylaxnmonium hydroxide, pyridine, triethylamine or N-methylpiperidine. 15 The amidation is in general carried out in a temperature range from 0°C to 150°C, preferably at 25 °C to 40 °C. The amidation is in general carried out at normal pressure. However, it is also possible to carry out the process at reduced pressure or at elevated pressure (for 20 example in a range from 0.5 to 5 bar). When carrying out the amidation, the base is in general employed in an amount of 1 to 3 mol, preferably of 1 to 1.5 mol, relative to 1 mol of the carboxylic acid (Vic). Suitable dehydrating reagents are carbodiimides 25 such as, for example, diisopropylcarbodiimide, 241654 dicyclohexyl-carbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldimiidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l,2-oxazolium-3-sulphonate or 5 propanephosphonic anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or diphenyl aminophosphonate or methanesulphonyl chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or 10 N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide [cf. J.C. Sheehan, S.L. LEdis, J. Am. Chem. Soc. ££, 875 (1973); F.E. Frerman et al.f J. Biol. Chem. 225. 507 (1982) and N.B. Benoton, K. Kluroda, Int. Pept. Prot. Res. 13, 403 (1979), 12, 187 (1981)]. 15 The compounds of the general formulae (IVa), (IVb) and (IVc) are new and can be prepared by the abovementioned method. The compounds of the general formula (V) are known [cf. Beilstein 5,19/5,24/5,29] or can be prepared from the 20 corresponding alcohols or cycloalkenes by customary methods. The compounds of the general formula (VI) are known [cf., for example, Beilstein 11/104]. The phenyl-substituted quinolines according to the 25 invention can be employed as active substances in medicaments. The substances can act as inhibitors of enzymatic - 20 - 2416 54 reactions in the context of arachidonic acid metabolism, in particular lipoxygenase. They are thus preferred for the treatment and prevention of diseases of the respiratory tract such as 5 allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and oedemas, thromboses and thromboembolisms, ischaemias (peripheral, cardiac, cerebral circulatory disorders), cardiac and cerebral infarcts, angina pectoris, 10 arteriosclerosis, in tissue transplantation, dermatoses such as psoriasis, inflammatory 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 15 veterinary medicine. The pharmacological effects of the substances according to the invention are determined by the following method: As a measure of lipoxygenase inhibition, the release of leukotriene B* (LTB4) in polymorphonuclear human leuco-20 cytes (PMN) was determined after addition of substances and Ca ionophore by means of reverse phase HPLC according to Borgeat, P. et. al., Proc. Nat. Acad. Sci. 76, 2148-2152 (1979). The values obtained by this test for some compounds 25 according to the invention are shown in Table 1 by way of 241654 example: Table 1; Example No. 1 5 27 40 41 The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, 10 pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formula (I) or which consist of one or more active substances of the formula (I), and processes for the production of these preparations. 15 The active substances of the formula (I) should be present in these preparations in a concentration of 0.1 to 99.5 % by weight, preferably of 0.5 to 95 % by weight of the total mixture. In addition to the active substances of the formula (I), 20 the pharmaceutical preparations can also contain other pharmaceutical active substances. The abovementioned pharmaceutical preparations can be prepared in a customary manner by known methods, for example with the auxiliary(ies) or excipient(s). - 22 - 241654 In general it has proved advantageous to administer the active substance(s) of the formula (I) in total amounts of about 0.01 to about 100 mg/kg, preferably in total amounts of about 1 mg/kg to 50 mg/kg of body weight every 5 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. However, it may be advantageous to deviate from the amounts mentioned, in particular depending on the type and the body weight of the subject to be treated, on 10 individual behaviour towards the medicament, the nature and severity of the disease, the type of preparation and administration, and the time or interval at which administration takes place. Startina Compounds 15 Example I Methyl 3-fluoro-5-hydroxyphenylacetate f 19.8 g (0.116 mol) of 3-fluoro-4-hydroxyphenylacetic acid are dissolved in 100 ml of methanol, 1 ml of conc. 20 sulphuric acid is added and the mixture is heated to 241654 boiling for 2 h. After cooling, the solvent is evaporated in vacuo, the residue is taken up in 250 ml of dichloromethane and the solution is extracted twice with saturated NaHC03 solution. After drying, the organic phase is evaporated to dryness in vacuo and a viscous amber-coloured oil is obtained. Yield: 18.4 g (85.8 % of theory) The examples shown in Table I are prepared in analogy to the procedure of Example I: 10 Table Ii w-0 CH-R-2 co2ch3 15 Ex. No. II III W H H Br N02 H H m.p.'C Yield (%) oil 147 82.0 quantitative - 24 - 241654 Example IV Methyl 2-(4-methallyloxyphenyl)-2-cyclopentyl-acetate 10 g (0.043 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclo-pentyl-acetate are dissolved in 200 ml of dimethyl-formamide and 4.1 g (0.043 mol) of methallyl chloride and 5.9 (0.043 mol) of potassium carbonate are added with stirring. The mixture is allowed to react overnight at 100°C. After cooling, the solvent is evaporated in vacuo, the residue is taken up in 200 ml of dichloromethane, the solution is washed twice with 100 ml of water, the organic phase is dried using sodium sulphate and the product from evaporation in vacuo is purified by column chromatography (silica gel 60, eluent: toluene/ethyl acetate = 100:5). Yield: 7.66 g (61.9 % of theory) of pale yellow oil co2ch3 241654 Example V Methyl 2-(4-hydroxy-3-methallylphenyl)-2-cyclopentyl-acetate c02ch3 5 7.6 g (0.026 mol) of the compound from Example IV are dissolved in 50 ml of freshly distilled diethylaniline and the mixture is heated overnight at 200°C (Claisen rearrangement). After cooling, the solvent is distilled off in vacuo, the residue is taken up in 200 ml of 10 dichloromethane and the solution is washed twice with 40 ml of 2N hydrochloric acid in order to extract residues of diethylaniline. It is then washed until neutral, dried with sodium sulphate and concentrated to a small volume. Purification is carried out by column chromato-15 graphy (silica gel 60, eluent: toluene/ethyl acetate = 9:1) . Yield: 4.3 g (57.4 % of theory) of pale yellow oil. A IB LWm - 26 - 241654 Example VI Methyl 2-(4-hydroxy-3-isobutylphenyl)-2-cyclopentyl-acetate ho c02ch: 4 g (0.014 mol) of the compound from Example V are dissolved in 30 ml of methanol and 10 ml of acetic acid and hydrogenated at 5.3 bar using Pd/C as a catalyst. Reaction time: 2.5 h. After filtering off the catalyst, the solvent is evaporated in vacuo and a slightly yellowish oil is obtained. Yield: 3.6 g (88.7 % of theory) Example VII Methyl 4-acetoxy-phenylacetate c02ch3 241654 10 g (0.06 mol) of methyl 4-hydroxyphenylacetate are treated with 18.36 g (0.18 mol) of acetic anhydride (17 ml) and 1 ml of pyridine and the mixture is heated to boiling for 2 hours. The solvents are largely evaporated 5 in vacuo, the residue is taken up in water and the solution is extracted with ethyl acetate. After drying using sodium sulphate, the solvent is distilled off in vacuo and a pale yellow, thin oil is obtained. Yields 12.3 g (98.6 % of theory) 10 Example VIII Methyl 4-hydroxy-3-acetyl-phenylacetate CVCH3 ho. c02ch3 5.3 g of aluminium chloride are introduced under argon, 4 g (0.019 mol) of the compound from Example VII are 15 added and the mixture is heated at 150°C for 2 hours (Fries rearrangement). After cooling, 50 ml of dichloromethane are added, and the mixture is heated briefly to boiling and filtered. Purification is carried out by column chromatography (silica gel 60, eluent: toluene/ 20 ethyl acetate = 8:2). Yield: 2.4 g (60.7 % of theory) of yellow oil. - 28 - 241654 The examples shown in Table II are prepared in analogy to the procedure of Example VIIs Table Hi 5 Ex. No. R1 R2 m.p. °C Yield (%) IX h3c-CO- H oil 86.8 X H H3C-CO- oil 96.0 Example XI 10 Methyl 2- (4-hydroxy-3-nitrophenyl)-2-cyclopentyl-acetate N02 22.9 g (0.1 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclo-pentyl-acetate are dissolved in 50 ml of CH2C12 and added dropwise at 5°C to a solution of 50 ml of conc. 15 HNO3/5O ml of H20. The mixture is stirred for 15 min, then - 29 - 241654 100 ml of H20 are added and the organic phase is separated off. The aqueous phase is extracted three times with 50 ml of CH2C12, and the organic phases are washed 5 times with water, dried, concentrated to a small volume and 5 filtered through silica gel. After concentration, the product is obtained in 71 % yield (20 g). The product is further processed in crude form. Example XII Methyl 2- (3-amino-4-hydroxy-phenyl) -2-cyclopentyl-acetate nh2 co2ch3 10 5.6 g (20 mmol) of the compound from Example XI are hydrogenated at 4 atm. in 100 ml of ethanol with the addition of 0.5 g of palladium/carbon (10 % strength). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is further reacted 15 without further purification (quantitative yield). - 30 - 141654 Example XIII Methyl 2- (3-azido-4-hydroxy-phenyl) -2-cyclopentyl-acetate 5.0 g (20 mmol) of the crude product from Example XII are dissolved in 20 ml of H20, 10 ml of ethanol and 20 ml of conc. HCl and the solution is diazotised at 0°C with 1.8 g (26 mmol) of sodium nitrite in 10 ml of H20. After evolution of N2 has ended, the mixture is extracted three times with 100 ml of CH2C12/ the organic phases are concentrated and the residue is chromatographed on silica gel 60 (CH2Cl2/MeOH = 100:2). Yield: 4.5 g (82 % of theory) M.p.: 59-60°C Example XIV Methyl 2 - [ 3-f luoro-4- (quinolin-2-yl-methoxy) phenyl J -acetate c02ch3 ch2-co2ch3 18.4 g (0.1 mol) of the compound from Example I are 241654 dissolved in 50 ml of DMF and 4 g (0.1 mol) of NaOH in 40 ml of methanol are added. 17.8 g (0.1 mol) of 2-chloromethylquinoline in 50 ml of DMF are added dropwise to this mixture with stirring and it is then 5 heated at 100°C for 5 h. After cooling, the solvent is evaporated in vacuo, the residue is taken up in dichloromethane, and the solution is washed twice with water, dried and concentrated in vacuo to a small volume. Separation is carried out by column chromatography 10 (silica gel 60, eluent: toluene/ethyl acetate = 9:1 to 8:2). Yield: 28 g (86 % of theory) of yellow oil. Example XV 2- [ 3-Fluoro-4- (quinolin-2-yl-methoxy)phenyl]-acetic acid 25 g (0.077 mol) of the compound from Example XIV are dissolved in 300 ml of methanol and 125 ml of 1 molar sodium hydroxide solution are added. The mixture is stirred at the boiling point for 3 h, allowed to cool and 20 neutralised with IN hydrochloric acid. The whole is evaporated to dryness in vacuo, and covered with 50 ml of 241654 water and with 150 ml of dichloromethane. The dichloromethane phase is dried and the solvent is evaporated in vacuo. Colourless crystals remain. Yield: 19.5 g (81.5 % of theory) M.p.: 177-179 °C Example XVI 2 - [3-Fluoro-4-(quinolin-2-yl-methoxy)phenyl]-acetyl-methanesulphonamide 6 g (0.019 mol) of the compound from Example XV, 1.9 g (0.019 mol) of dried methanesulphonamide, 3.8 g (0.019 mol) of N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 2.4 g (0.019 mol) of dimethyl amino -pyridine are dissolved in 40 ml of dichloromethane and the mixture is stirred at room temperature for 60 h. It is then evaporated to dryness in vacuo, the residue is taken up in 40 ml of dichloromethane and the solution is washed twice with 20 ml of water. After drying the organic phase using Na2S0A, it is evaporated in vacuo and the residue is separated by column chromatography (silica gel 60, eluent dichloromethane/ethyl acetate/glacial - 33 - ?.4 1 654 acetic acid = 10:1:1). Yield: 5.2 g (70.5 % of theory) of colourless crystals M.p.: 171°C Example XVII 2- [ 3-Fluoro-4- (quinolin-2-yl-methoxy)phenyl]-acetyl-benzy1sulphonamide In analogy to Example XVI, the title compound is obtained from 4 g (0.013 mol) of the compound from Example XV, 2.22 g (0.013 mol) of dried benzylsulphonamide, 2.49 g (0.013 mol) of N-ethyl-N'-dimethylaminopropyl-carbodi-imide hydrochloride and 1.59 g (0.013 mol) of dimethyl-aminopyridine. Yield: 4.4 g (72.9 % of theory) of colourless crystals M.p.: 156°C - 34 241654 Example XVIII Methyl 2-[3-chloro-4-(quinolin-2-yl-methoxy)phenyl]-acetate CH2-CO2-CH3 The title compound is prepared in analogy to the procedure of Example XIV from 5.3 g (0.03 mol) of 2-chloro-methylguinoline, 6 g (0.03 mol) of methyl 3-chloro-4-hydroxyphenylacetate and 1.2 g (0.03 mol) of sodium hydroxide. Yields 8.7 g (84.9 % of theory) of colourless crystals M.p.s 79°C Example XIX 2- [3-Chloro-4- (quinolin-2-yl-methoxy)phenyl]-acetic acid 241654 In analogy to the procedure of Example XV, the title compound is obtained from 4 g (0.012 mol) of the compound from Example XVIII and 18 ml of IN sodium hydroxide solution. Yield; 3.5 g (89.1 % of theory) of colourless crystals M.p.: 203-205°C Example XX Methyl 2-[ 3-bromo-4- (quinolin-2-yl-methoxy) phenyl ] acetate In analogy to the procedure of Example XIV, the title compound is prepared from 17 g (0.07 mol) of the compound from Example II, 12.32 g (0.07 mol) of 2-chloromethyl-quinoline and 2.8 g (0.07 mol) of sodium hydroxide. Yield: 23.2 g (85.8 % of theory) of slightly yellowish crystals M.p.: 90°C ^V^CH2-C02CH3 241654 Example XXI 2- [ 3-Bromo-4- (quinolin-2-yl-methoxy)phenyl ]acetic acid CH2-COOH In analogy to the procedure of Example XV, the title compound is prepared from 3 g (7.77 mmol) of the compound from Example XX and 12 ml of IN sodium hydroxide solution (12 mmol). Yield: 2.5 g (86.5 % of theory) of colourless crystals M.p.: 206-208°C (dec.) Example XXII 2- [ 3-Bromo-4- (quinolin-2-yl-methoxy)phenyl ]acetyl-methanesulphonamide Br ch2-co-nh-so2ch3 In anology to the procedure of Example XVI, the title 241654 compound is prepared from 2.8 g (7.5 mmol) of the compound from Example XXI, 0.71 g (7.5 mmol) of dried methanesulphonamide, 1.44 g (7.5 mmol) of N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 0.92 g (7.5 mmol) of dimethylaminopyridine. Yield: 0.86 g (25.5 % of theory) of colourless crystals M.p.: 212°C (dec.) Example XXIII Methyl 2-[3-methoxy-4-(quinolin-2-yl-methoxy)phenyl]-acetate In analogy to the procedure of Example XIV, the title compound is prepared from 16 g (0.082 mol) of methyl 3-methoxy-4-hydroxyphenylacetate, 14.5 g (0.082 mol) of 2-chloromethylquinoline and 3.28 g (0.082 mol) of sodium hydroxide. Yield: 20.5 g (74.1 % of theory) of colourless crystals M.p.: 69°C och3 241654 Example XXIV 2-[3-Methoxy-4-(quinolin-2-yl-methoxy)phenyl] -acetic acid The title compound is prepared from 3 g (8.9 mmol) of the compound from Example XXIII and 12 ml of IN sodium hydroxide solution analogously to the procedure of Example XV. Yield: 2.4 g (83.4 % of theory) of colourless crystals M.p.: 168-170°C (dec.) Example XXV Ethyl 2- [3-trif luoromethylthio-4- (quinolin-2-yl-methoxy) -phenyl ] acetate - 39 - 241654 In analogy to the procedure of Example XIV, the title compound is prepared from 10 g (0.036 mol) of ethyl 4-hydroxy-3-trifluoromethylthiophenylacetate, 7.7 g (0.036 mol) of 2-chloromethylquinoline and 2.88 g (0.072 mol) of sodium hydroxide. Yield: 7.55 g (49.8 % of theory) of yellow oil. Example XXVI 2-[3-Trifluoromethylthio-4-(quinolin-2-yl-methoxy)-phenyl]acetic acid In analogy to the procedure of Example XV, the title compound is prepared from 2.1 g (5 mmol) of the compound from Example XXV and 0.4 g (0.01 mol) of sodium hydroxide in dioxane/water. Yield: 1.8 g (91.6 % of theory) of colourless crystals M.p.: 152°C Example XXVII 2- [ 3-Trifluoromethylthio-4-(quinolin-2-yl-methoxy)-phenyl ] acetyl-methanesulphonamide £41654 ch2-co-nh-so2-ch3 In analogy to the procedure of Example XV, the title compound is prepared from 1.2 g (3.1 mmol) of the compound from Example XXVI, 0.38 g (4 mmol) of methane-sulphonamide, 0.77 g (4 mmol) of N-ethyl-N'-dimethyl-aminopropyl-carbodiimide hydrochloride and 0.49 g (4 mmol) of dimethylaminopyridine. Yield: 1.2 g (82.4 % of theory) of colourless crystals M.p.: 183°C (dec.) Example XXVIII Methyl 2-[3-nitro-4-(quinolin-2-yl-methoxy)phenyl]acetate ch2-c02-ch3 In analogy to the procedure of Example XIV, the title compound is prepared from 10.75 g (0.0509 mol) of the 241654 compound from Example III, 10.9 g (0.051 mol) of 2-chloromethylquinoline and 4.32 g (0.11 mol) of sodium hydroxide. Yield: 3.3 g (18.4 % of theory) of yellow crystals M.p.: 177 °C Example XXIX Methyl 2- [ 3-amino-4- (quinolin-2-yl-methoxy)phenyl ] acetate 15 g (0.043 mol) of the compound from Example XXVIII are dissolved in 100 ml of tetrahydrofuran and 100 ml of methanol and 4 g (0.08 mol) of hydrazine monohydrate are added. Raney nickel is added in portions under argon with stirring, the temperature rising to 506C. After the evolution of gas has ended, the mixture is heated to boiling for a further hour and then filtered while hot. The filtrate is concentrated in vacuo and the residual oil is taken up using 250 ml of dichloromethane. After washing twice using water and drying with sodium sulphate, the solvent is evaporated in vacuo and a colourless oil is obtained which crystallises overnight. Yield: 12.5 g (90.3 % of theory) of colourless crystals M.p.: 75°C - 42 - 241114 Example XXX Methyl 2- [ 3- (1-pyrryl) -4- (quinolin-2-yl-methoxy)phenyl ] acetate 5 5 g (0.016 mmol) of the compound from Example XXIX are dissolved in 70 ml of acetic acid, 2.78 g (0.02 mol) of 2,5-dimethoxytetrahydrofuran are added and the mixture is heated to boiling for 2 hours. After distilling off the acetic acid in vacuo, taking up the residue in 200 ml of 10 dichloromethane, extracting with water, drying with sodium sulphate and concentrating in vacuo to a small volume, the brown oil which remains (6 g) is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate = 4:1). 15 Yield: 3.2 g (53.8 % of theory) of colourless crystals M.p.: 102°C Example XXXI 2- [ 3- (1-Pyrryl) -4- (quinolin-2-yl-methoxy) phenyl ] acetic acid 241654 ch2-cooh In analogy to the procedure of Example XV, the title compound is prepared from 0.8 g (2 mmol) of the compound from Example XXX and 0.2 g (5 mmol) of sodium hydroxide in 50 ml of isopropanol. Yield: 0.7 g (97.8 % of theory) of colourless crystals M.p.: 173°C Example XXXII Methyl 2-[ 3-vinyl-4- (quinolin-2-yl-methoxy) phenyl ] acetate ch2-c02-ch3 10 200 mg (0.21 mmol) of the catalyst [P(phenyl)3]<,Pd are weighed into a 50 ml brown glass flask (flushed with argon) and 2 g (5.2 mmol) of the compound from Example XX and 1.4 ml (5.2 mmol) of Bu3SnCH=CH2 (d = 1.086), both nil in - 44 - 241654 dissolved in 10 ml of toluene, are added under argon. The mixture is heated to boiling for 20 hours with stirring in a light-protected apparatus. The solvent is then evaporated in vacuo and the residue is separated by 5 column chromatography (silica gel 60, eluent: toluene/ ethyl acetate = 4:1). Yield: 1.5 g (86.6 % of theory) of colourless crystals M.p.: 69°C Example XXXIII 10 2-[3-Vinyl-4-(quinolin-2-yl-methoxy)phenyl]acetic acid In analogy to the procedure of Example XV, the title compound is prepared from 1.1 g (3.3 mmol) of the compound from Example XXXII and 5 ml (5 mmol) of IN sodium 15 hydroxide solution. Yield: 1.0 g (95.0 % of theory) of colourless crystals M.p.: 173°C Example XXXIV Methyl 2- [ 3-ethyl-4-(quinolin-2-yl-methoxy) phenyl ]acetate - 45 - 241654 co2ch3 14.3 g (0.0429 mol) of the compound from Example XXXII are dissolved in 150 ml of methanol and 15 ml of glacial acetic acid, 1.5 g of 5 % strength Pd-C are added, and the reaction mixture is heated to 30-35 °C and hydrogen-5 ated. It is filtered through silica gel, the filtrate is concentrated in vacuo and the residue is recrystallised from isopropanol. Yields 8.5 g (59.1 % of theory) of colourless crystals M.p. : 72°C 0 Example XXXV The title compound is prepared from 1.5 g (4.48 mmol) of the compound from Example XXXIV and 10 ml (10 mmol) of IN 241654 sodium hydroxide solution analogously to the procedure of Example V. Yield: 1.4 g (97.4 % of theory) of colourless crystals M.p.: 144°C Example XXXVI N- [ 3-Ethyl-4- (quinolin-2-yl-methoxy )phenyl]acetylmethane-sulphonamide Analogously to the procedure of Example XVI, the title compound is prepared from 1.7 g (5.3 mmol) of the compound from Example XXXV, 0.6 g (6 mmol) of methane-sulphonamide, 1.2 g (6 mmol) of N-methyl-N'-dimethyl -aminopropylcarbodiimide hydrochloride and 0.8 g (6 mmol) of dimethylaminopyridine. Yield: 1.4 g (66.3 % of theory) of colourless crystals M.p.: 1708C c0-nh-s02-ch3 241654 Example XXXVII Methyl 2-[3-allyl-4-(quinolin-2-yl-methoxy)phenyl]acetate In analogy to the procedure of Example XXXII, the title compound is prepared from 16.6 g (0.043 mol) of the compound from Example XX, 13.6 g (0.043 mol) of Bu3-Sn-CH2-CH=CH2 and 2.0 g (0.0017 mol) of [P (phenyl )3]4Pd. Yield; 7.6 g (50.9 % of theory) of colourless crystals M.p.; 71°C Example XXXVIII 2-[3-Allyl-4-(quinolin-2-yl-methoxy)phenyl]acetic acid In analogy to the procedure of Example XV, the title c02-ch3 COOH 2416 54 compound is prepared from 2.0 g (5.8 mmol) of the compound from Example XXXVII and 10 ml (10 mmol) of IN sodium hydroxide solution. Yields 1.7 g (88.0 % of theory) of colourless crystals M.p.; 130#C Example XXXIX Methyl 2- [ 3-propyl-4- (quinolin-2-yl-methoxy )phenyl ] -acetate In analogy to the procedure of Example XXXIV, the title compound is prepared from 7.5 g (0.0225 mol) of the compound from Example XXXVII and 0.8 g of Pd/C (5 %) using hydrogen. Yields 6.5 g (82.8 % of theory) of yellowish oil Example XL 2-[3-Propyl-4-(quinolin-2-yl-methoxy)phenyl]acetic acid co2-ch3 241654 cooh In analogy to the procedure of Example XV, the title compound is prepared from 1.5 g (4.3 mmol) of the compound from Example XXXIX and 10 ml (10 mmol) of IN sodium hydroxide solution. Yields 1.4 g (97.2 % of theory) of colourless crystals M.p.s 135°C Example XLI 2-[3-Propyl-4-(qu inol in-2-yl-methoxy) phenyl ] -acetyl-methanesulphonamide o^nh-so2-ch3 In analogy to the procedure of Example XVI, the title compound is prepared from 1.7 g (5.1 mmol) of the 241654 compound from Example XL, 0.6 g (6 mmol) of methane-sulphonamide, 1.2 g (6 mmol) of N-ethyl-N'-dimethylamino-carbodiimide hydrochloride and 0.8 g (6 mmol) of dimethyl aminopyridine . Yield: 1.5 g (71.4 % of theory) of colourless crystals M.p.: 155°C (dec.) Example XLII Methyl 2 -[3-acetyl-4-(quinolin-2-yl-methoxy)-phenyl]acetate In analogy to the procedure of Example XIV, the title compound is prepared from 2.9 g (0.014 mol) of the compound from Example VIII, 2.5 g (0.014 mol) of 2-chloromethylquinoline and 0.56 g (0.014 mol) of sodium hydroxide. Yield: 2.1 g (43.0 % of theory) of colourless oil c02-ch3 241654 Example XLIII 2-[3-Acetyl-4-(quinolin-2-yl-methoxy)phenyl]acetic acid In analogy to the procedure of Example XV, the title compound is prepared from 1 g (2.9 mmol) of the compound from Example XLII and 0.13 g (5.8 mmol) of lithium hydroxide in 10 ml of water. Yield: 0.7 g (72.1 % of theory) of colourless crystals M.p.: 119°C (dec.) Preparation Examples (general formula 1^ Example 1 Methyl 2-[3-fluoro-4-(quinoline-2-methoxy)phenyl]-2-cyclopentylacetate cooh 24 1 6 54 0.45 g (0.015 mol) of 80 % pure NaH is suspended in DMF under argon, and 5 g (0.015 mmol) of the compound from Example XIV in 80 ml of DMF are added to the mixture. After evolution of hydrogen has ended, the mixture is 5 subsequently additionally stirred for 1 h. 2.4 g = 1.61 ml (0.015 mol) of cyclopentyl bromide in 100 ml of DMF are then added dropwise in the course of 1 h and the mixture is allowed to react further overnight. The solvent is evaporated to dryness in vacuo, the residue is 10 taken up in dichloromethane, the solution is extracted with dilute hydrochloric acid and NaHC03 solution, dried and concentrated to a small volume, and the mixture is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate = 9:1). 15 Yield: 3.5 g (59.3 % of theory) of colourless crystals M.p.: 75°C Example 2 Methyl 2-[3-methoxy-4-(quinolin-2-yl-methoxy)phenyl ]-2-cycloocty1acetate 7.68 g (23 mmol) of the compound from Example XXIII and 241654 4.4 g (23 mmol) of cyclooctyl bromide are dissolved in 100 ml of dimethyl formamide. 3.36 g (30 mmol) of potassium tertiary butoxide, dissolved in 30 ml of DMF, are added dropwise to this mixture at 0 - 10°C with stirring. 5 The mixture is subsequently stirred at room temperature for a further two hours and then treated with 30 ml of IN hydrochloric acid. The solvent is then evaporated in vacuo, the residue is taken up in 200 ml of dichloromethane and the dichloromethane solution is washed twice 10 with 100 ml of water. After drying with sodium sulphate, it is concentrated to a small volume in vacuo and the residue is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate = 4:1). Yield: 5.8 g (56.4 % of theory) of yellow oil 15 The compounds shown in Table 1 are prepared in analogy to the procedures of Examples 1 and 2: Table 1 Ex. No. R & X) CI CH co2r3 R1 R2 R3 CH, CH, CI n CH, CI r"! CH-i Br CH, m.p.(°C) yield (% of theory) 95 40.9 85 53.4 oil 43.4 oil 30.8 oil 67 1^3 108-110 28.8 o> an Continuation of Table 1 fix. No. R1 R2 9 Br /O 10 Br 11 och3 j—* 12 och3 jo 13 och3 p ? p m.p.(°C) Yield (% of theory) 19.2 oil 48 oil 23.3 oil 43.5 oil 39.6 oil 82.2 ro o> CJl Continuation of Table 1 Ex. No. Ri R2 R3 r X) is r ch 16 ^ CH r <* r* -o *3 r ja ch3 17 18 ^ CH 19 r r XJ C1I3 I : 1 20 ^ JZ) CH3 m.p.(°C) Yield (% of theory) oil 28.9 oil 60.8 oil 30.5 oil 61.8 oil 50,4 oil 75.6 ro O) Of Ul oo Continuation of Table 1 Ex. No. R1 R2 R3 r" •£> 21 r CH r1 22 S CH 23 -AX CH 24 -CO-CH3 CH3 25 N3 CH, 26 -n02 ch3 m .p.(#C) Yield (% of theory) oil 35.0 oil 86.7 oil 81.7 127 71,9 102-104 77 91-93 71.4 ro on 241654 Example 27 2- [ 3-Fluoro-4- (quiriolin-2-yl-methoxy) phenyl ] -2-cyclo-pentylacetic acid In analogy to the procedure of Example XV, the title compound is prepared from 2.5 g (0.00635 mol) of the compound from Example 1 and 9.35 ml of 1 molar sodium hydroxide solution (0.00935 mol) Yields 1.9 g (78.8 % of theory) of colourless crystals M.p.s 143 - 145#C The compounds shown in Table 2 were prepared in analogy to the procedure of Example 27s COOH Table 2 Ex. No. 28 29 30 31 32 33 CI CI CI Br & X) m.p.(°C) Yield (% of theory) 188-190 62.1 145 90.1 195 94.4 175 97.7 158-160 95.5 108-110 92.1 ro CJl Continuation of Table 2 Ex. No. R1 R2 34 Br 35 Br 36 OCH, 37 OCH3 38 OCH, 39 OCH, jO JO m.p.(°C) Yield (% of theory) 165 58,9 177 74.9 197 66.6 197-199 72.4 174 80.0 167 94.2 ro an Continuation of Table 2 Ex. No. R1 R2 40 ri N 41 42 44 46 I f 43 r 45 C ff f X) r x> 1 : 1 m.p.(°C) Yield (% of theory) 165 96.3 170 99,5 133 98,6 153 90,3 136 89,9 161 95,4 133 97,2 ro CJl Continuation of Table 2 Ex. No. R1 Rz 47 48 49 50 r1 -o r1 JO r1 jz> 51 -CO-CH3 J~} 52 N, XJ m.p.(°C) Yield (% of theory) 136 92.2 159 94.1 129 97,1 120 85.6 210 85,7 i>o 76-79 65 24 16 54 Example 53 { 2 - [ 3 -Fluoro- (4 -quinolin-2 -yl-methoxy) phenyl ] - 2 -eye lo heptylacetyl > -methanesulphonamide In analogy to the procedure of Example XVI, the title compound is prepared from 1.7 g (0.0042 mol) of the compound from Example 29, 0.4 g (0.042 mol) of dried methanesulphonamide, 0.81 g (0.0042 mol) of N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 0.51 g (0.0042 mol) of dimethylaminopyridine. The compounds shown in Table 3 are prepared in analogy to the procedure of Example 53: o^nh-so2-ch3 Table 3 Ex. No. 54 55 56 57 58 59 och, R CI JO CI CI Br '2 co-rj m.p. Yield (% of theory) (°C) -nh-s02-chrc6h5 105 83,3 -nh-s02-ch2-c6h5 184 66,4 -nh-s02-ch3 80 66 -nh-s02-ch2-c6h5 188 77 -nh-so2-ch3 189 63.2 ro -nh-so2-ch3 130 79.7 CJl cr» cn Continuation of table 3 Ex. No. R1 R2 60 61 62 63 64 65 66 67 och3 -O och3 -O o N 1 r r j p p r X V XJ n3 -XJ R3 nh-so2-ch3 nh-s02-ch(ch3)2 nh-so2-ch3 nh-so2-ch3 nh-so2-ch3 nh-so2-ch3 nh-so2-ch3 Nll-S()2-(C6ll5)-p-J m.p. Yield (% of theory) (°C) 123 59.7 103 80.8 196-198 77 157 56.4 143 74»7 147 70.7 97 79.5 63-67 11 ro CJ"t 241654 The compounds shown in Table 4 were prepared in analogy to the procedure of Example 27: Table 4 co2h Ex.No. R 68 69 70 71 72 73 H,C OCH, H,C OH m.p. (°C) 112 Yield (% of theory) 92,7 (-)-Enantiomer (+)-Enantiomer 123 75,1 115 (decomposition) foam 47,9 - 67 - 24 16 54 The compounds shown in Table 5 were prepared in analogy to the procedure of Example 53 s Table 5s Ex. No. R1 m.p. Yield (°C) (% of theory) 74 75 76 77 78 -NH-S02-CH3 140 58,0 -NH-SO2-CH3 amorphous 27 7 ) -NH-S02 -O- CH3 189 89.2 -NH-SO, m Ph0US M -NH-S02-CH3 amorphous 92,3 - 68 - </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 241654 The compounds shown in Table 6 were prepared in analogy to the procedure of Example 2: Table 6: co,r 2^3 5 Ex.No. R1 79 -CH, m.p. Yield (°C) (% of theory) oil 95.2 - 69 - V 241634 WHAT WE CLAIM IS: 1. 2-Substituted quinolines of the general formula A G (I) in which 10 A, B, D, E, 6 and L are identical or different and represent hydrogen, hydroxyl, halogen, cyano,. carboxyl, nitro, trif luoromethyl or trif luoro-methoxy or represent straight-chain or branched alkyl or .alkoxy each having up to 8 carbon atoms, or represent aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, nitro or cyano, 15 20 represents halogen, cyano, nitro, azido, tri-fluoromethyl, trifluoromethoxy or trifluoro-methylthio, or represents straight-chain or branched alkoxy or acyl each having up to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is 24165 A optionally substituted by hydroxyl or alkoxy having up to 6 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents straight-chain or branched alkenyl 5 having up to 6 carbon atoms, or represents a group of the formula -NR4RS, in which R4 and Rs are identical or different and denote hydrogen, straight-chain or 10 branched alkyl having up to 8 carbon atoms, phenyl, acetyl or benzoyl, or together with the nitrogen atom represent a saturated or unsaturated, optionally substituted 5- or 6-membered heterocycle having up to 3 hetero atoms selected from sulphur, oxygen and nitrogen, R2 represents cycloalkyl or alkenyl having 3 to 12 carbon atoms, and R3 represents a radical of the formula -OR6 or 20 -NR7-S02-R8, in which R8 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, 241 6 o 4 R7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, and R8 denotes aryl having 6 to 10 carbon atoms, which is optionally mono- or disubstituted by identical or different substituents selected from halogen, cyano, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or denotes straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, which in turn can be substituted by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or hydroxyl, or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms , and their physiologically acceptable salts. 2-Substituted quinolines according to Claim 1, in which A, B, D, E, 6 emd L are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoro- 2 4 *16 5 4 methyl or trifluoromethoxy or represent straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or represent phenyl which is optionally substi-5 tuted by fluorine, chlorine, bromine, hydroxyl, nitro or cyano, R1 represents fluorine, chlorine, bromine, iodine, cyano, nitro, azido, trifluoromethyl, or trifluoromethoxy, or 10 represents straight-chain or branched alkoxy or acyl each having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or alkoxy having 15 up to 4 carbon atoms, or represents straight-chain or branched alkenyl having up to 4 carbon atoms, or represents a group of the formula -NR*RS, in which 20 R* and Rs are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or represents pyrryl, pyridyl, furyl or phenyl. 25 R2 represents cycloalkyl having 3 to 12 carbon atoms, and 241654 R3 represents a radical of the formula -OR6 or -NR7-S02-R8, in which R6 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and R8 denotes phenyl which is optionally substituted by fluorine, chlorine, bromine,, iodine, or cyano or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl which can in turn be substituted by fluorine, chlorine, bromine or trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms t and their physiologically acceptable salts. - 74 - /Xv"; <N \ 2 1 HAR1994 i I 241654 2-Substituted quinolines according to Claim 1, in which A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 4 carbon atoms, R1 represents fluorine, chlorine, bromine, nitro, azido or trifluoromethoxy, or represents straight-chain or branched alkoxy or acyl each having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or methoxy, or represents straight-chain or branched alkenyl having up to 4 carbon atoms, or represents a group of the formula -NR*R5, in which R* and R5 are identical or different and or represents pyrryl, furyl or phenyl, R2 represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, - 75 - 241 654 R3 represents a radical of the formula -OR6 or -NR7-S02-R8, in which R6 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R7 denotes hydrogen, methyl or ethyl, and R8 denotes phenyl which is optionally substituted by methyl, fluorine, chlorine, bromine, iodine, methoxy or trifluoromethyl, or denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl which can in turn be substituted by fluorine, chlorine, bromine, methyl or methoxy and their physiologically acceptable salts. 2-Substituted quinolines according to Claim 1 for the treatment of diseases. Process for the preparation of a phenyl-substituted quinoline of the general formula 241654 A G D B Coin which A, B, D, E, 6 and L are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxyl, nitro, trifluoromethyl or, trifluoromethoxy or represent straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or represent aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, nitro or cyano, R1 represents halogen, cyano, nitro, azido, trifluoromethyl, trifluoromethoxy or trifluoromethylthio, or represents straight-chain or branched alkoxy or acyl each having up to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl or alkoxy 24165^ having up to 6 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents a group of the formula -NR*R5, in which R* and R5 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl, acetyl or benzoyl, or together with the nitrogen atom represent a saturated or unsaturated, optionally substituted 5- or 6-membered heterocycle having up to 3 hetero atoms selected from sulphur, oxygen and nitrogen, * represents cycloalkyl or alkenyl having 3 to 12 carbon atoms, and represents a radical of the formula -OR6 or -NR7-S02-Rb, in which R8 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, 241654 R7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, and Ra denotes aryl having 6 to 10 carbon atoms, 5 which is optionally mono- or disubstituted by identical or different substituents selected from halogen, cyano, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, or by 10 straight-chain or branched allcyl or alkoxy each having up to 8 carbon atoms, or denotes straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, which in 15 turn can be substituted by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or hydroxyl, or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms , 20 anci a physiologically acceptable salt-Tmstfeop characterised in that [A] in the case where R3 represents the group -OR® [AJ either a compound of the general formula (Ila) 2416 5 4 in which R1 and R2 have the abovementioned meaning, W represents a hydroxyl protective group and R6' has the abovementioned meaning of R6 but does not represent hydrogen, is converted, after elimination of the protective group, by etherification with a 2-halogenomethyl-10 quinoline of the general formula (III) (III) CH2-Y in which A, B, D, E, 6 and L have the abovementioned meaning and 241654 7 represents halogen in an inert solvent into a compound of the general formula (IVa) A G in which A, B, D, E, G, L, R1, R2 and R6' have the above-mentioned meaning, and the latter in the case of the ester (R8 * H) is then optionally hydrolysed, or [Aj] a compound of the general formula (lib) (IVa) C02R6' (lib) COjR6* 241654 in which W, R1 and R8' have the abovementioned meaning, is converted, after elimination of the protective group, initially by etherification with a 2-halogeno-methylguinoline of the general formula (III) as defined above in an inert solvent into a compound of the general formula (IVb) (IVb) CO,R6' in which 10 A, B, D, E, G, L, R1 and R8' have the abovementioned meaning, and the latter is then alkylated with a compound of the general formula (V) R2-Z (V) 15 in which R2 has the abovementioned meaning and 241654 Z represents chlorine, bromine or iodine, in an inert solvent and in tha case of the ester (R* *> B) the estar is then optionally hydrolysed or [B] in the case where R3 represents the group -NR'-SO^R*, a compound of the general formula (IVc) A G (IVc) in which 10 15 A, B, D, E, G, L, R1 and R2 have the abovementioned meaning, i s amidated in an inert solvent, if appropriate in the presence of a base, with a sulphonamide of the general formula (VI) HNR7-S02R8 (VI) in which R7 and R8 have the abovementioned meaning, 83 - and 2! /i r* IF3 [C] in the case of the enantiomers the corresponding enantioxnerically pure acid of the formula (IVc) is separated by a customary method and reacted further 5 by one of the processes as defined above. 6. A process according to claim 5 wherein W is benzyl or tert.-butyl. 7# A process according to claim 5 wherein Y is chlorine or bromine. 10 8. Medicaments containing at least one 2-substituted quinoline according to Claim 1. 9. Process for the production of a medicament according to Claim 8, characterised in that at least one 2-substituted quinoline is formulated into a suitable adminis-15 tration form with, where appropriate, the aid of one or more customary auxiliaries and excipients. 10. Use of at ]east one 2-substituted quinoline according to Claim 1 for the production of medicaments. 11. Use according to Claim 10 for the production of lipoxygenase inhibitors. 12. Use of the 2-substituted quinolines according to Claim 1 for combating diseases in non-human animals. 13. A compound according to claim 1 substantially as herein described or exemplified. 14. a process according to claim 5 substantially as herein described or exemplified. 15. A medicament according to claim 8 substantially as hep^*n ^ described or exemplified. 3 v 9 G WL U',J" - 84 - \" ,0/ 3^ t. 241654 A process according to claim 9 substantially as herein described or exemplified. BAYER AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LTD Per: - 85 - !21MAR!9W£ </div>