AU641585B2 - 2-substituted quinolines, process for their preparation and their use in medicaments - Google Patents

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

Our Ref: 419226 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT oil o **l see *00.

*o **oo Applicant(s): Address for Service: Invention Title: Bayer Aktiengesellschaft D-5090 Leverkusen Bayerwerk

GERMANY

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 2-Substituted quinolines, processes for their preparation and their use in medicaments The following statement is a full description of this invention, icluding the best method of performing it known to me:- 5020 The present invention relates to 2-substituted quinolines, 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)phenylacetic 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) *o.

A G *o oo o CO- R 3 in which A, B, D, E, Q and L are identical or different and represent ihydrogen, 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 Le A 28 177 1

I

optionally substituted by halogen, hydroxyl, nitro or cyano,

R

1 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 having up to 6 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or O represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents a group of the formula -NR 4

R

5 15 in which

R

4 and R 5 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, e 2

R

2 represents cycloalkyl or -alkenyl having 3 to 12 carbon atoms, Le A 28 177 2

R

3 represents a radical of the formula -OR 6 or -NR'-SOz-R 8 in which

R

6 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl,

R

7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R

8 denotes aryl having 6 to 10 carbon atoms, which is optionally mono- or disubstituted by identi- O 10 cal or different substituents from the series comprising halogen, cyano, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or by straight-chain or bzanched alkyl or alkoxy .ach having up to 8 carbon 15 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 jr hydroxyl, or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms and their physiologically acceptable salts.

Le A 28 177 3 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.

In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the 2-substituted quinolines may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluene- S sulphonic acid, benzenesulphonic acid, naphthalenedisulphonic 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 stereoisomeric 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 t* i diastereomer mixtures. The racemic forms, like the diastereomers, can be separated into the Le A 28 177 4 stereoisomerically uniform constituents in a known manner [cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962].

Preferred compounds of the general formula are those in which A, B, D, E, G 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, 6 6 R 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 20 represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substi- Stuted by hydroxyl or alkoxy having up to 4 carbon atoms, or represents straight-chain oz branched alkenyl having up*to 4 carbon atoms, or represents a group of the formula -NRR 5 Le A 28 177 5 in which

R

4 and R 5 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,

R

2 represents cycloalkyl having 3 to 12 carbon atoms,

R

3 reprsents a radical of the formula -OR 6 or -NR-S0 2 Sin which 10 R 8 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R

7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, 0

R

8 denotes phenyl which is optionally substituted 0 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 0 substituted by phenyl which can in turn be substituted by fluorine, chlorine, bromine or trifluoromethyl or by straight-chain or Le A 28 177 6 branched alkyl or alkoxy each having up to 4 carbon atoms and their physiologically acceptable salts.

Particularly preferred compounds of the general formula are those 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, R 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 20 represents a group of the formula -NR 4

R',

in which

R

4 and R 5 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, alkyl having up to 3 carbon atoms, Le A 28 177 7

I

or represents pyrryl, furyl or phenyl,

R

2 represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,

R

3 represents a radical of the formula -OR 6 or

-NR

7

-SO-R

8 in which

R

6 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, O R 7 denotes hydrogen, methyl or ethyl, 10 R 8 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 to. 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 -CHR 2

-COR

3 is in the 4-position Le A 28 177 8 relative to the quinolylmethoxy radical.

Processes for the preparation of the compounds of the general formula according to the invention have additionally been found, characterised in that in the case where R 3 represents the group -OR 6 [Ai] either compounds of the general formula (IIa)

W-O

(lIa) CH- R CO 2R6' ft.

ft.f.

fft

*J

ooeo oo oooo ooooo in which ft. ft left ee

R

1 and R 2 have the abovementioned meaning, W represents a hydroxyl protective group such as benzyl or tert.-butyl, and

R

6 has the abovementioned meaning of R 6 but does not represent hydrogen, 15 are converted, after elimination of the protective group, by etherification with 2-halogenomethylquinolines of the general formula (III) f f ot Le A 28 177 9 I t I

(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 gerneral formula (M) 0

SO

00

S

*SSS

0 S*S S *550

C

S

0 S S 944VO (Iva) C HR 2 C0 2

R"

in which Le A 28 177 10 A, B,0 D, E, G, L, R 1 R 2 and R 6 have the abovementioned meaning, and the latter in the case of the esters (R6 H) are then hydrolysed, or [A~j compounds of the general formula (lIb) W-0 (lIb)

CH

2 (Mi), C0 2

R'

in which

R

1 and RG' have the abovementioned meaning, are converted, after elimination of the protective group, initially by etherification with 2-halogenomethylquinolines of the general formula (III) in inert solvents into compounds of the general formzila (IVb)

G

B

-IZ

:R0 D:I N-L E 0 (IVb)

CH-

2 .C96.

C0 2

P

6 Le A 28 177 11 t 1 l in which A, B, D, E, G, L, R 1 and R 6 have the abovementioned meaning, and the latter are then alkylated with compounds of the general formula (V)

R

2 -Z

(V)

in which

R

2 has the abovementioned meaning and Z represents chlorine, bromine or iodine, in inert solvents and in the case of the esters (R 6 o H) the esters are hydrolysed or a a a.

a a oooo in the case where R 3 compounds of the general a.

*o°°o A G represents the group -NR 7

-SO

2

R

8 formula (IVc)

,L

R

I

I (IVc) a a a

CHR

2

COOH

Le A 28 177 12 in which A, B, D, E, G, L, R 1 and R 2 have the abovementioned meaning, are amidated in inert solvents, if appropriate in the presence of a base, with sulphonamides of the general formula (VI) HNR'-SOzR 8

(VI)

in which

R

7 and R 8 have the abovementioned meaning, 10 and in the case of the enantiomers the corresponding enantiomerically pure acids (IVc) are separated by a customary method and reacted further by the abovementioned processes, it being possible for the substituent R 1 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]

F

H

H

2

-CO

2

CH

3

CH,-CI

Le A 28 177 13

Y

Br

N-F

0 CH--C0 2

CH

3 Hydrolysis 0 CH-CO 2

H.

4**4 a.

C

Ct..

[All Diazotisation B. B

C*

4* C C C. C Hydrolysis

C

BC j a.

Le A 28 177, 14 4., .4 t 4 -7 N F 0

OH

CO

2

H

NH

2 -S0 2 -0H, C N' F C0.NH-SO 2 CH3 .4 9 9 9**4 9 S 4* 9 9 9*99 9* 49 9 9. 9 9 99 4 99 Le A 28 177 15

S'

The elimination of the protective groups from the corresponding ethers (IIa) and (IIb) is carried out by 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 [cf.

additionally Th. Green: "Protective Groups in Organic Synchesis", 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 etherification can be inert organic solvents which do not change under the reaction conditions. These preferably Sinclude ethers such as, for example, dioxane, tetrahydrofuran 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.

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 (trialkyl(C3-C,)- :amines) such as triethylamine, or heterocycles such as e• Le A 28 177 16 A 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.

The etherification is in general carried out in a temperature range from 0°C to +150 0 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 process at reduced pressure or elevated pressure (for j 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 (IIa) and (IIb) are known per se or can be prepared by a customary method [cf. J. Org. Chem. 31, 2658 (1966)].

The compounds of the general formula (III) and their preparation are also kno'm [cf. Chem. Ber. 120, 649 (1987)].

Suitable solvents for the process according to the Le A 28 177 17 1 invention and for the alkylation are customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons such as dichlrorethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitr,ie acetone or nitromethane. It is also possible to use mixtures of the Ssolvents mentioned. Dichloromethane is preferred.

The alkylation is carried out in the abovementioned solvents at temperatures from 0°C to +150*C, preferably at room temperature to 100 0 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 do not change under the reaction conditions. These include halogenohydrocarbons such as dichloromethane, trichloromethane, tetrchloromethane, 1,2-dichloroethane "trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to a Le A 28 177 18 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 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, or alkali metal alkoxides such as, for example, sodium methoxide or ethoxide, potassium methoxide or ethoxide or Spotassium tert.-butoxide, or organic amines such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiperidine.

*9 15 The amidation is in general carried out in a temperature range from 0"C to 150 0 C, preferably at 25°C to 40 0

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).

9 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 carbodi aides 25 such as, for example, diisopropylcarbodiimide, Le A 28 177 19 dicyclohexyl-carbodiimide or N- (3-dimethyai~opropyl) N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldimiidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulphonate or propanephosphonic anhydride or isobutyl chioroformate or benzotriazolyloxy-tris- (dimethylamino )phosphonium hexafluorophosphate or diphenyl aminophosphonate or methanesuiphonyl chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methy).piperidine or dicyclohexylcarbodiinide and 11hydroxysuccinimide [cf. J.C. Sheehan, S.L. LEd4Is, J, Amn.

Chem. Soc. 95, 875 (1973); F.E. Frerman et al., Biol.

Chem. 225, 507 (1982) and N.B. Benoton, K. Rluroda, Int.

Pept. Prot. Res. L3, 403 (1979)r J1, 187 (1981)).

The compounds of the general formulae (IVa), (IVb) and (IVc) are new anld can be prepared by the abovementioned method.

6 6460 The compounds of the general formula are known [cf.

9601 0 0 Beiletein 5,19/5,24/5,29] or can be prepared from the corresponiding 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 invention can be employed as active substances in medica- :ments. The substances can act as inhibitors of enzymatic Le A 28 177 20 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 allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and aedemas, thromboses and thromboembolisms, ischaemias (peripheral, cardiac, cerebral circulatory disorders), cardiac and cerebral infarcts, angina pectoris, arteriosclerosis, in tissue transplantation, dermaLoses 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 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 4 (LTB4) in polymorphonuclear human leuco- 20 cytes (PMN) was determined after addition of substances and Ca ionophore by means of reverse phase HPLC according "I tQo orgeat, P. et. al., Proc. Nat. Acad. Sci. 76, 2148- 2152 (1979).

S" The values obtained by this test for some compounds 25 according to the invention are shown in Table 1 by way of

S**

Le A 28 177 21 Y example: Table 1: Example No. 5-LO IC 50 (umol/l) 1 2.50 27 0.69 0.79 41 0.56 The present invention also includes pharmacetical preparations which, in addition to inert, non-toxic, 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 and processes for the production of these preparations.

The active substances of the formula should be present in these prepar~tions 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 S* 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).

Le A 28 177 22 In general it has proved advantageous to administer the active substance(s) of the formula in total amounts of about 0.01 to about 100 mg/kg, preferably in total amounts of about i mg/kg to 50 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results.

However, it may be advantageous to deviate from the amounts mentiored, in particular depending on the type and the body weight of the subject to be treated, on individual behaviour towards the medicament, the nature and severity of the disease, the type of preparation and A administration, and the time or interval at which administration takes place.

Starting Compounds 15 Example I Methyl

F

HO

CH

2 -C2CH3 19.8 g (0.116 mol) of 3-fluoro-4-hydroxyphenyla'etic acid are dissolved in 100 ml of methanol, 1 ml of conc.

sulphuric acid is added ond the mixture is heated to Le A 28 177 3 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 NaHCO 3 solution. After drying, the organic phase is evaporated to dryness in vacuo and a viscous ambercoloured 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: Table

R

s

CH-R

2 C0 2

CH

3 Ex. No. W R 1

R

2 m.p.aC Yield 4* S II H Br H oil 82.0 III H NO 2 H 147 quantitative Le A 28 177 24 Example IV Methyl 2-(4-methallyloxyphenyl)-2-cyclopentyl-acetate O0

COCH

3 g (0.043 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclopentyl-acetate are dissolved in 200 ml of dimethylformamide and 4.1 g (0.043 mol) of methallyl chloride and i 5.9 (0.043 mol) of potassium carbonate are added with stirring. The mixture is allowed to react overnight at 100 0 C. After cooling, the solvent is evaporated in vacuo, 10 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 S' 15 acetate 100:5).

Yield: 7.66 g (61.9 of theory) of pale yellow oil oo .004~ Le A 28 177 25 'S 1 I Example V Methyl 2-(4-hydroxy-3-methallylphenyl)-2-cyclopentylacetate

HO

C0 2

CH

3 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 0 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.

C

C. S Le A 28 177 25 Example VI Methyl acetate 2- (4-hyd :oxy-3-isobutylphenyl) -2-cyclopentyl-

CO

2

CH

3

C

n.e

C

9 4 .4 4* 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 of f the catalyst, the solvent is evaporated in vacuo and a slightly yellow- 10 ish oil is obtained.

Yield: 3.6 g (88.7 of theory) Example VII Methyl 4 -acetoxy-phenylacetate

H

3 C

CQ

2

CH

3 Le A 28 177 27 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 in vacuo, the residue is taken up in water and the solution is extracted with ethyl acetate. After drying using sodiuza sulphate, the solvent is distilled off in vacuo and a pale yellow, thin oil is obtained.

Yield: 12.3 g (98.6 of theory) Example VIII Methyl 4-hydroxy-3-acetyl-phenylacetate O CH 3

*H

CO

2

CH

3 :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 0 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/ ethyl acetate 8:2).

Yield: 2.4 g (60.7 of theory) of yellow oil.

Le A 28 177 28 The examples shown in Table 11 are prepared in analogy to the procedure of Example VII: Table II: W-0

CO

2

CH

3 .0* 9* 90*0 0000 9**000 0 Ex. No.

IX

x RI R m.p.OC Yield Ii 3 C-CO- H oil H H 3 C-CQ- oil 86.8 96.0 Example XI Methyl 2 (4 -hydroxy-3 -nitrophenyl) 2-cyc lopentyl- acetate 00 0000 0 0 **0000 0 0000 *0* *0 0 0 ~0 N0 2 22.9 g (0.1 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclopeuityl-acetate are dissolved in 50 ml of CH 2 C1 2 and added dropwise at 5*C to a solution of 50 ml of conc.

HN0 3 /50 ml of H 2 0. The mixture is stirred for 15 min, then Le A 28 11.7 29 100 ml of HO0 are added and the organic phase is separated off. The aqueous phase is extr:acted three times with ml of CHCl 2 and the organic phases are washed 5 times with water, dried, concentrated to a small volume and filtered through silica gel. After concentration, the product is obtained in 71 yield (20 The product is further processed in crude form.

Example XII Methyl 2- (3-amino-4-hydroxy-phenyl)-2-cyclopentyl-acetate

NH

2

HO

CO

2

CH

3 10 5.6 g (20 mmol) of the compound from tfxample XI are hydrogenated at 4 atm. in 100 ml of et lanol with the addition of 0.5 g of palladium/carbon 0 strength),, The catalyst is filtered off with suction, the filtrate is concentrated and the residue is further reacted w without further purification (quantitative yield), 6** 6. S S Se Le A 28 177 30 \4 Example XIII Methyl 2- (3-azido-4-hydroxy-phenyl) -2-cyclopentyl-acetate

N

3

S.

i .5 S S

S

S

.5.5

*,*SSS

S

do 2 Cll 3 g (20 mrnol) of the crude product from Example XII are dissolved in 20 ml of H201 10 ml of ethanol and 20 ml of conc. HCl and the solution is diazotised at 0 0 C with 1.8 g (26 mmol) of sodium nitrite in 10 ml of H 2 0. After evolution of N 2 has ended, the mixture is extracted three times with 100 ml of CH 2 C1 2 the organic phases are 10 concentrated and the residue is chromatographed on silica gel 60 (Cf1 2 C1 2 /MeOH 100:2).

Yield: 4.5 g (82 of theory) 59.,60*C Example XIV S. S S S

SS

555.

S S S. S

S

*.SS

S

*SS!*

S

S. S 0S

S.

15 Methyl acetate 2-[3-fluoro-4-(quinolin-2-yl-methoxy)phenyl]- 0

CH

2

-CO

2

CH

3 18.4 g (0.1 mol) of the compound from Example I are Le-A 28 177-3.- 31 dissolved in 50 ml of DMF and 4 g (0.1 mol) of NaOH in ml of methanol are added. 17.8 g (0.1 mol) of 2-chloromethylguinoline in 50 ml of DMF are added dropwise to this mixture with stirring and it is then 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 (silica gel 60, eluent: toluene/ethyl acetate 9:1 to 8:2).

Yield: 28 g (86 of theory) of yellow oil.

_Example XV a.

a* .s 2-[3-Fluoro-4-(quinolin-2-yl-methoxy)phenyl]-acetic acid N F 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 neutralised with IN hydrochloric acid. The whole is evaporated to dryness in vacuo, and covered with 50 ml of Le A 28 177 32 water and with 150 ml of dichioromethane. The dichioromethane phase i~s dried and the solvent is evaporated in vacuo. Colovirless crystals remain.

Yield: 19.5 g (81.5 of theory) 177-179*C Example XVI 2 3 -Fluoro-4- (quinoin2ylmethoxy Nhzyl3...acetyl.

methanesulphonamide

F

0

CH

2 .C0-N1{-SO 2

-CH

3 6 g (0.019 mol) of the compound from Example XV, 1.9 g (0.019 mol) of dried methanesuiphonamide, 3.8 g 019 mol) of N'tylNI-dime,.hylaminopropylcarbodiimide hydrochloride and 2.4 g (0.01P mol) of dimethylaxuinopyridine are dissolved in 40 mi of dichioromethane and S 15 the mixture is stirred at room temperature for 60 h. It is then evaporated to dryness in vacuo, the residue is ta3~en up in 40 ml of dJichloromethane and the solution is washed twice with 20 ml of water. Aftel: drying the organic phase using NaSO 4 it is evaporated in vacna and the residue is separated by column chromatography (silica gel 60, eluent dichloromethane/athy! acetate/glacial Le A 28 177 33 acetic acid 10:1:1).

Yield: 5.2 g (70.5 of theory) of colourless crystals 1716C Example XVII 2-[3-Fluoro-4-(quinolin-2-yl-methoxy)phentyi]-acetylbenizyl1suiphonamide

~F

In analogy to Example XVI, the title compound is obtained :from 4 g (0.013 mol) of the compound from Example AV, 2.22 g (0.013 mol) of dried, benzyloulphonamide, 2.49 g 10 (0.013 mol) of N-ethyviL-N' -dimethyiazninopropyl-carbodiimide hydrochloride and 1.59 g /~003 mol) of dimethylaminopyridine.

Yield: 4.4 g (72.9 of theory) of colourless crystals 156*C 6 a Le A R8 177 34 Example XVTII Methyl 2- 3-chloro-4- (qu4;nolin-2-yl-1vethoxy) phenyl] acetate N C1

CH

2 -C0 2

-CFI

3 The title cordpound is prepared in analogy to the procedure of Ejcample XIV from 5.3 g (0.03 mol) of 2-chioromethy.quiproline, 6 g (0.03 mol) of methyl 3-chloro-4- 0.0 h y dro vheylacetate and 1. 2 g 03 mol) of sodium *Soo Go*# S hydroxidr;,, 10 Yield-. 8.7 q (84.9 of theory) of colourless cryd,;als M.p.s 79*C S Example XIX 0 2- (3-ChJloro-4- (quinolin-2-yl-methoxy)phenyll -acetic acid boo 4~ 000C 2 -CQ O

H

Le A 28 177 35 In analogy to the procedur~e 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.z 203-205*C Example XX Methyl 2- [3-bromo-4- (quinolin-2-yl-methoxy)phenyl Jacetate N Br

CHI

2

-CO

2

CH

3 In analogy to the procedure of Example XIV, the title compound is prepared from, 17 g (0,07 mol) of the compound from Example 1I, 12.32 g (0.07 mol) of 2-chloromethylquinoline and 2.8 g (0.07 niol) of sodium hydroxide.

Soo$*:Yield: 23.2 g (85.8 of theory) of slightly yellowish 15 crystals MX.P.: 5 0.0 Le A 2 8 177 36 Example XXI 2-'(3-Bromo-4- (quinolin-2-yl-methoxy)phenyl]acetic acid N Br 0 N CH 2

-COOH

In analogy to the procedure of Example xv, the ti-'tle compound is prepared from 3 g (7.77 mmol) of the compound from Example XX and 12 ml of 1N sodium hydroxide solution (12 mmol).

Yield: 2.5 g (86.5l- of theory) of colourless Y.-rys'iAs *999M.P.: 2O6-208*c' (dec.) 10 Example XXII 2-(3-Bromo-4-(guinolin-2-yl-methoxy)phenyl]acetyl X2 methanesuiphonamide C(N N Br .0.

C14 2

-CO-NH-SO

2

CH

3 in anology to the procedure of Example XVI, the title Le A 28 177 37 compound is prepared from 2.8 g (7.5 mmol) of the compound from Example XXI, 0.71 g (7.5 mmol) of dried methanesuiphonamide, 1.44 g (7.5 mniol) of N-ethyl-N'dimethylaminopropylcarbodiimide hydrochloride and 0.92 g mmol) of dimethylaminopyridine.

Yield: 0.86 g (25.5 of theory) of colourless crystals Np.: 212"C (dec.) Exaniole XXIII Methyl 2- (3-methoxy-4- (quinolin-2-yl-methoxy) phenyl) acetate N OCH 3 0

CH

2

-CO-OCH

3 :In analogy to the procedure of' Example XIV, the title compound is prepared from 16 g (0.082 mol) of methyl 3 -methoxy- 4-hydroxyphenyl acetate, 14.5 g (0.082 mol) of 15 2-chioromethylguinoline and 3.28 g (0.082 mol) of sodium hydroxide.

Yield: 20.5 g (74.1 0 theory) of colourless crystals 69 0

C

LeA.28 177 38 Ex~imple XXIV 2- 3-Methoxy-4- (quinolin-2-yl-methoxy)phenyl] -acetic acid N

QCH

3 N. C1 2

-COOII

The title compound is prepared from 3 g (8.9 mmol) of the 5 compound from Example XXIII and 12 ml of IN sodium hydroxide solution analogously to the procedure of 00% Example

XV.

Seto Yield: 2.4 g (83.4 of theory) of colourless crystals 168-170*C (dec.) Example XXV Ethyl 2- [3-trifluoromethylthio-4- (quinolin-2-yl-methoxy) phenyl ]acetate N s~CF3 07 L. CH 2

-CQ

2

'CH

2

-CH

3 Le A 28 177 39 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-chloromethylguinoline 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-(quinolin2-ylmethoxy)phenyl 3acetic acid S I

CI'C

0 In analogy to the procedure of Example XV, the title compound is prepared from 2.1 g (5 nimol) 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 *5 Example XXVII 2-[(3-Trifluoromethylthio-4- (quinolin-2-yl-methoxy) phenyl 3acetyl-methanesulphonamide Le A 28 177 40

~CF

3 N S 07 I N LCH 2 -CO-NH-S0 2

-CH

3 In analogy to the p~rocedure 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 methanesulpho..I.i~ide, 0.77 g (4 mmol) of N-ethyl-N'-dimethylaminopropyl-carbodiimide hydrochloride and 0.49 g (4 mmol) of dimethylaminopyridine.

Yield: 1.2 g (82.4 of theory) of colourless crystals 1830C (dec.) Example XXVIII Methyl 2- 3-nitro-4- (quinolin-2-yl-methoxy) phenyl acetate

S.-CH

CH

2 -C0 2

-C

3 In analogy to the procedure of Example XIV, the title ****compound is prepared from 10.75 g (0.0509 mol) of the

S*

Le A 28 177 41 A I 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 177C Example XXIX Methyl 2-[3-amino-4-(quinolin-2-yl-methoxy)phenyl]acetate N NH 2

S-CH

2 -C0 2

-CH

3 g (0.043 mol) of the compound from Example XXVIII are dissolved in 100 ml of tetrahydrofuran and 100 ml of Smethanol 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 50 0 C. After the evolution of gas has ended, the mixture is heated to 15 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 Le A 28 177 42 Example XXX Methyl 1-pyrryl)-4-(quinolin-2-yl-methoxy)phenyl]acetate N

(N

0 N CH 2 -C0 2

-CH

3 -9 5 g (0.016 nimol) of the compound from Example XXIX are dissolved in 70 ml of acetic acid, 2.78 g (0.02 mol) of 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 dichioromethane, 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).

Yield: 3.2 g (53.8 of the~ory) of colourless crystals Mop.: 102 0

C

:J6 Example XXXT 2-[3-(l-Pyrryl)-4-(quinolin-2-yl-methoxy)phenyl~acetic acid Le A 28 177 43 N N

CH

2

-COOH

In analogy to the procedure of Example XV, the citle compound is prepared from 0. 8 g (2 mmol) of the compound from Example XXX and 0.2 g (5 inmol) of sodium hydroxide in 50 ml of isopropanol.

Yield: 0.7 g (97.8 %of theory) of colourless crystals 173 0

C

Example XXXII Methyl 2- [3-.vinyl-4- (quinolin-2-yl-methoxy) pheny.1 acetate

N

N. CH 2 -C0 2

-CH

3 00mg(021mml)of tecatalyst [Ppey)1P 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 BU 3 SnCH=CH 2 (d 1.086), both Le A 28 177 4 44 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 column chromatography (silica gel 60, eluent: toluene/ ethyl acetate 4:1).

Yield: 1.5 g (86.6 of theory) of colourless crystals 69 0

C

Example XXXIII 2-[3-Vinyl-4-(quinolin-2-yl-methoxy)phenyl]acetic acid 0

SCH

2

-COOH

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 173 0

C

Example XXXIV Methyl 2- 3-ethyl-4-(quinolin-2-yl-,methoxy) phenyl] acetate Le A 28 177 45

CO

2

CH

3 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 0 C and hydrogenated. It is filtered through silica gel, the filtrate is concentrated in vacuo and the residue is recrystallised from isopropanol.

Yield: 8.5 g (59.1 of theory) of colourless crystals Map.: 72 0

C

46 10 Example XXXV ***~*2-j3-Ethyl-4- (quinolin-2-yl-methoxy)phenyl3 acetic acid Oates* 6.0007 0000 COGH 0 The title compou~d is prepared from 1.5 g (4.48 mmol) of the compound from Example XXXIV and 10 ml (10 mmol) of 1N Le A 28 177 46 1 r sodium hydroxide solution analogously to the procedure of Example V.

Yield: 1.4 g (97.4 of theory) of colourless crystals I4.p.: 144 0

C

Examtle XXXVI 3 -Ethyl 4- (quinolin-2 -yl-methoxy) phenyl Jacetylmethanesuiphonamide

N

CO-NH.S0 2

-CH

3 **Analogously to the procedure of Example XVI, the title 10 compound is prepared from 1.7 q (5.3 mmol) of the cornpound from Example XXXV, 0. 6 g (6 mmol) of methanesulphonamide, 1.2 g (6 mmol) of N-methyl-N'-dimethylazinopropylcarbodiimide hydrochloride and 0.8 g (6 nunol) of dimethylaminopyridine.

Yield: 1.4 g (66.3 of theory) of colourless crystals 1700C *6* Le A 28 177 47

I

Example XXXVII M~ethyl 2- 3-allyl-4- (quinolin-2-yl-methoxy) phenyl ]acetate C0 2

-CH

3 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 BU 3 -Sn-

CH

2

-CH=CH

2 and 2.0 g (0.0017 mol) of [P(phenyl) 3 4 Pd.

Yield: 7.6 g (50.9 of theory) of colourless crystals 14.p.: 710C Examle XXXVIII 10 2-[3-Allyl-4-(qtixiolin-2-yl-methoxy)phenyl~acetic acid

S

S S

SS

5* S S

S

S

S

S

In analogy to the procedure of Example XV, the title S S S. S *5 S S S 5 55 Le A 28 177 48 compound is prepared f rom 2. 0 g 8 rnmol) of the compound from Example XXXVII and 10 mil (10 mmol) of 1N sodium hydroxide solution.

Yield: 1.7 g (88.0 of theory) of colourless crystals 130 0

C

Example XXXIX Methyl 2- 3-propyl.-4- (quinolin-2-yl-xnethoxy) pheinyljacetate 7 N 07 00 0 0: 0 In analogy to, the procedure of Example XXXIV, the title 4:06 compound is prepared from 7.5 g (0.0225 mol) of the *00% compound from Example XXXVII and 0.8 g of Pd/C (5 'Go** using hydrogen.

Yield: 6.5 q (82.8 of theory) of yellowlsh oil Exatple XL a0 .0 2-[3-Propyl-4-(qinolin-2-yl-methoxy)phenyl~acetic acid *0 0 00 0 00 Le A 28 177 49

I

1

COOH

In analogy to the procedure of Example XV, the title compound is prepared from 1.9 g (4.3 mmol) of the comnpound~ from Example XXXIX and 10 ml (10 nimol) of IN sodium hydroxide solution.

Yield: 1.4 q (97.2 of theory) of colourless crystals 135 0

C

Example XLI 2-[3-Propyl-4-(quinolin-2-yl-methoxflphenyl]-acety..

methanesulphom\mide 0**0 0 NH-S0 2

-CH

3 6 In analogy to the procedure of Examrple XVI, the title compound is prepared from 1.7 g (5.1 mmol) of the Le A 2B 177 50 f f compound from Example XL, 0.6 g (6 mmo~,) of methanesuiphonamide, 1.2 g (6 mmol) of N-ethyl -N I-dimethyl aminocarbodjmide hydrochloride and 0.8 g (6 namol) of dimethyl~wrinopyridine.

Yield: 1.5 g (71.4 of theory) of colourless crystals 155 0 C (dec.) Example XLII Methyl 2-f3-acetyl-4-(cluinolin-2-yl-methoxy)phenyl) acetate 0 CH 3 0 9 C0 2

-CH

3 ~10 In analogy to the procedure of Example XIV, the title compound is preparedA from 2.9 g (0.014 mol) of the compound from Example VIII, 2.5 g (0.01.4 mol) of 2-chloromethylquinoline and 0.56 g (0.014 mol) of sodium hydroxide.

Yield: 2.1.q (43.0 of theory) of colourless oil see# Le A 28 177. 51 Examp~le XLII 2- C 3-Acetyl-4- (quinolin-2-yl-vnethoxy) phenyl acetic acid a N clI

COOR

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 Inmol) of lithium hydroxide in 10 ml of water.

Yield: 0.7 g (72.1 of theory) of colourless crystals 119 0 C (dec.) Preparation Examnles (general formula I) Exapl 1 Mehy 2Se ur q.in 1ie-2-etox)pey 0 **ccopnyactt ~p~F C..0 *so *so$C Le A 28 177 52 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 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 taken up in dichloromethane, the solution is extracted with dilute hydrochloric acid and NaHCO 3 solution, dried and concentrated to a small volume, and the mixture is separated by column chromatography (silica gel eluent: toluene/ethyl acetate 9:1).

Yield: 3.5 g (59.3 of theory) of colourless crystals Example 2 Methyl 2-[3-methoxy-4-(quino "n-2<-yl-methoxy)phenyl]-2cyclooctylacetate

SOCH

3 0 COCH3 7 7.68 g (23 mmol) of the compound from Example XXIII and Le A 28 177 53 1 1 4.4 g (23 mmol) of cyclooctyl bromide are dissolved in 100 ml of dimethylformamide. 3.36 g (30 mmol) of potassium tertiary butoxide, dissolved in 30 ml of DMF, are added dropwise to this mixture at 0 10 0 C with stirring.

The mixture is subsequently stirred at room temperature for a further two hours and then treated with 30 ml of 1N 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 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 eluent: toluene/ethyl acetate 4:1).

Yield: 5.8 g (56.4 of theory) of yellow oil The compounds shown in Table 1 are prepared in analogy to the procedures of Examples 1 and 2:

O

l

**S

Le A 28 177 54

C

C

CC C. C

C

C C Table 1 Ex. No.

9

CH

3

CH

3

CH

3

CH

3

CH

3 M.P. (OC) 95 85 oil oil oil Yield of theory) 40.9 53.4 43.4 30.8 67 8 Br 8 rCH 3 108-110 28.8

S

S

S S S *S

S

S

0 Continuation of Table 1 Ex. No.

CH

3

CH

3 m-p. 0

C)

oil oil oil oil Yield of theory) 19.2 48 23.3 43.5 39.6

OCH

3

CH

3

OCH

3

CH

3 OCI1 3

N

CH

3

CH

3 oil 8.

82.2

S

*5 S. S *S S S S S S S 555 *5 h1~ 1 Continuation of Ta ble Ex. No.-

CH

3

CH

3

K

K

rurP 1:1

CH

3 M.P. C) oil oil oil oil oil oil Yield of theory) 28.9 60.8 30.5 61.8 50.4 75.6

CH-

3 C'1 3 (7

CH

3

S.

S

S

a *5 a C S Continuation of Table 1, Ex. No.

'~0 CH 3

CH

3 m-p. 0

C)

oil ol Oil 127 Yield of theory) 35.0 86.7 81.7 71,9

CH

3

-CO-CH

3 -IJ7: CH 3

CH

3 102-104 77 26 -N02 IQ17 2-N 2

CH

3 91-93 71.4 I I Elrnl1e 27 2- [3-Fluoro-4- (quinolin-2-yl-methoxy) phenyl -2-cyclopentylacetic acid

COOH

In analogy to the procedure of Example XV, the title compound is prepared from 2.5 g (0.00635 mol) of thecompound from Example 1 and 9.35 ml of 1 molar sodium h,'droxide solution (0.00935 mol) Yield: 1.9 g (18.8 of theory) of colourless crystals 143 145 0

C

The compounds shown in Table 2 were prepared in analogy to the procedure of Example 27: S p*e S

S

S~

*5 *t.Sfl.

S S S. S

SS

Le A 28 177 59 t

S

COH

Table 2 Ex. No. m-p. 0 C) Yield of theory) 9 188-190 62.1 90.1 94A4 9737 158-160 95.5 108-110 92.1 a.

S.

S

.rz* a

S

S S

SSS

a a

S..

a. 0 0 Continuation of Table 2 Ex. No.

M.P. (CC) 165 177 197 Yield of theory) 58,9 74.9 66-6 _I OCH 3

OCH

3 197-199 72.4

OCH

3 80.0 94.2 OCH 3 p 0** C. a

C.

a C C C a. C. C Continuation of Table 2 Ex. No.

m-p. (CC) 112

N

,,G

9, Yield of themrjl 96,3 99.5 98.6 90.3 89.9 95,4 97,2 p a a.

a.

a a .a a a.

a a a. a a a a a t Continuation of Table 2 Ex.* No.

m-p. (OC) Yield of theory) 92.2 94.1 97.1 85.6 85,7 -CO-CH 3 I 1191 210 52

N.

3 -9 6 76-79 [3-Fluoro- (4-quinolin-2-yl-methoxy) phenyl]3-2-cycloheptylacetyl }-methanesulphonamide aN

F

0- 0 NH-S0 2

-C-T-

3 In analogy tcu the procedure of Exampl~e XVI, the title compound is prepared from 1.7 g (0.0042 mol) of the compo,?und from Example 29, 0.4 g (0.042 mol) of dried methanesuiphonamide, 0.81 g (0.0042 mol) of N-ethyl-N'diniethylaminopropylcarbodiimide hydrochloride and 0.51 g (0.0042 mol) of dimethylaminopyridine.

S 0" The compounds shown in Table 3 are prepared in analogy to the procedure of Example 53: :00.* 0:0 .00. Le A 28 177 64 p p. p p p pp p pp.

p p p p *p p p Table ~3

RI

CO-Fl 3 Ex. No. R

M.-P.

0 c) Yield of theory) p -NH-S0 2

-CH

2

-C

6

HS

-NH-S0 2

CH

2

-C

6 1{ 5 -NV-S0 2

-CH

3

-NH-SO

2

-CH

2

-C

6

H

5 -NH-S0 2

-CH

3 105 83.3 184 66.4 80 66 188 77 189 63.2 130 79.7 p OCH3 OCH 3 -NH-,90 2

-CH

3 Continuation of table 3 Ex. No. R 1

OCH

3

OCH

3 M.P. Yield of theory) -NH-S0 2

-CH

3 1232 :59.7 80.8 -NH-S0 2

-CH(CH

3 2

N

-NHi-S0 2

-CH

3 -NH--S0 2

-CH

3 196-198 77 1 63 56.4 -NH-S0 2

-CH

3 -NH-S0 2

-CH

3 -NH-S,0 2

-CH

3 70.7 97 79.5 63-67 11 67 N 3 j The coinpoindo shown in Table 4 were prepared in analogy to the procedure of Example 27: TIable4 C02H Ex. No. R' M.P.

C)

Yield of theory) 68 69 7 7., .000 *40.0 000* 0 0 112 (,)-Enantiomer (+)-Enanfiomer 123 115 (decomposi tioni) f oam 9Zd7 71 72 H 3 C TOCH 3 ~7 73H 3 C TOH 47,9 Le A-28 1'77 67 The compounds shown in Table 5 were prepared in analogy to the procedure of Example 53: Table

CO-R

3 Ex. No. R1 99 9 99 o *9 9 9 999 9 *999 9 99.9.,- 9 i.

*9 9**9 9* 74 76 77

W

3 -NH-S0 2

-CH

3 -NHi-S0 2

-CH

3 m~p. Yield Of thcry) 58,,O amorphous -NH-S -a CR 3 189 89.2 se*.:

-NH-SO

2

CR

3 -NH-S0 2

-CH

3 amorphous 115 amorphous 9Z3 78 A7 Le A 28 177 68 'a a The compounds shown in Table 6 were prepared in analogy to the procedure of Example 2: Table 6: t.

5 Ex. No. R 1 79 r m~p. Yield (t of thery) oil 95.2 ,J 7

-CH

3 C C

C.

*CC#

C C C.

C

C

C. C 'C C

C

C.

Le A28 177 69

Claims (7)

1. 2-Substituted quinolines of the general formula A G BA L 3R(I E 0 4: CO-R 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 10 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, RIrepr~esent~s halogen, cyano, nitro, azido, tri- f 15 foromethyl trif luoromethoxy or trif luoro- 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 Le A 28 177 70 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 4 R in which R 4 and R 5 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, S.I optionally substituted 5- or 6-membered heterocycle having up to 3 hetero atoms 15 from the series comprising sulphur, oxygen and nitrogen, R 2 represents cycloalkyl or -alkenyl having 3 to 12 carbon atoms, SR represents a radical of the formula -OR or -NR 7 -SO 2 -R, in which SR denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, Le A 28 177 71- ii I R 7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R 8 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, tri- fluoromethoxy, trifluoromethylthio, or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or b« 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 and their physiologically acceptable salts.

2. 2-Substituted quinolines according to Claim 1, Oin which SA. A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoro- Le A 28 177 72 'I ii methyl, trifluoromethoxy or represent straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or represent phenyl which is optionally substi- tuted by fluorine, chlorine, bromine, hydroxyl, nitro or cyano, R 1 represents fluorine, chlorine, bromine, iodine, cyano, nitro, azido, trifluoromethyl, tri- fluoromethoxy, or represents straight-chain or branched alkoxy or acyl each having up to 6 carbon atoms, or represents straight-chain or branched alkyl Shaving up to 6 carbon atoms, which is option- ally 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 .to. represents a group of the formula -NR R 5 Sin which R 4 and R 5 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, 25 R 2 represents cycloalkyl having 3 to 12 carbon atoms, Le A 28 177 73 .IL i E R3 represents a radical of the formula -ORO or -NR 7 -SO 2 -R 8 in which RB denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R 7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, Ra denotes phenyl which is optionally sub- stituted by fluorine, chlorine, bromine,. iodine, cyano or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or 15 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 and their physiologically acceptable salts. Le A 28 177 74

3. 2-Substituted quinolines accordi'lg 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, R 1 represents fluorine, chlorine, bromine, nitro, azido or trifluoromethoxy, or represents straight-chain or branched alkoxy or 10 acyl each having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is option- ally 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 4 R 5 in which R and R 5 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or represents pyrryl, furyl or phenyl, R 2 represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, Le A 28 177 75 R 3 represents a radical of the formula -OR 6 or -NR'-SO 2 -R in which R" denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R 7 denotes phenyl which is optionally substituted by methyl, fluorine, chlorine, bromine, iodine, methoxy or trifluoromethyl, or denotes stright-chain or brnched 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.

4. A method for the treatment of diseases of the respiratory tract, shock lung, pulmonary hypertension, inflammations/rheumatism, oedemas, thromboses and thromboembolisms, ischaemias, cardiac and cerebral infarcts, angina pectoris, arteriosclerosis, dermatoses and inflammatory dermatoses, tissue transplantation, and for cytoprotection in the gastrointestinal tract, which comprises administering *.o to a subject in need of such treatment a therapeutically effective amount of a compound of the Formula I, optionally in association with the pharmaceutically acceptable carrier.

5. A method for the inhibition of lipoxygenase which comprises administering to a subject a lipoxygenase inhibitory effective amount of a compound of the Formula I optionally in association with a pharmaceutically acceptable carrier.

6. Process for the preparation of phenyl-substituted quinolines of the general formula: *I I I A G B L D N 3 R2 (I) E O) CO---R 3 in which A, B, D, E, G and L are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxyl, nitro, trifluoromethyl, trifluoro- 5 methoxy or see 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, R 1 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 optionally substituted by hydroxyl or alkoxy Le A 28 177 77 \t 1 1 I 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 4 R s in which R 4 and R 5 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 15 and nitrogen, R 2 represents cycloalkyl or -alkenyl having 3 to 12 carbon atoms, *r R 3 represents a radical of the formula -OR 6 or -NR-SO 2 -R 8 20 in which R 6 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, Le A 28 177 78 \a R 7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R 8 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, tri- fluoromethoxy, trifluoromethylthio, or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or denotes straight-chain or branched alkyl 9 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 S 20 and their physiologically acceptable salts, characterised in that in the case where R 3 represents the group -OR 6 d: either compounds of the general formula (IIa) (IIa) CH- R 2 CO 2 R 6 Le A 28 177 79 1 L in which R 1 and R 2 have the abovementioned meaning, W represents a hydroxyl protective group such as benzyl or tert.-butyl, and afl. S. a. RG has the abovementioned meaning of R8 but does not represent hydrogen, are converted, after elimination of the protective group, by etherification with 2-halogenomethyl- quinolines of the general formula (III) A G (III) CH 2 -Y a. a. a a. a in which A, B, D, El G and L have the abovementioned meaning and S a. a. a a. Le A 28 177 80 1~i~ Y represents halogen, in particular chlorine or bromine, in inert solvents into the compounds of the general formula (IVa) A G E 0 (Iva) CHR 2 9 9~ 9 9. 9 ~9*9 09 9 9 9999 i 9 C0 2 R' R 8 have the above- i.n which A, B, D, Er G, L, R' 1 R 2 and mentioned meaning, 99 9 9* 9999

9. 9 and the latter in the case of the esters (R 6 o H) are then hydrolysed, or compounds of the general formula (Ib) So W-0 (Ib) CH 2 C0 2 R 6 Le A 28 177 81 in which R' and R 6 have the abovementioned meaning, are converted, after elimination of the protective group, initially by etherification with 2-halogeno- methyiquinolines of the general formula (III) in inert solvents into compounds of the general formula (IVb) A G B L CH 2 (IVb) 46:: C 2 R 6 in which s 10 A, B, D, E, G, L, R' and R6' have the abovementioned meaning, and the latter are then alkylated with compounds of so. the general formula (V) ses:R 2 -Z MV in which oo.o R 2 has th-. abovementioned meaning ee se and Le A28 177 82 Z represents chlorine, bromine or iodine, in inert solvents and in the case of the esters (R 6 o' H) the esters are hydrolysed or in -the case where R 3 represents the group -NR 7 S0 2 R%, compounds of the general formula (IVc) A G 6* 6 SO *000 0* 6 6 66* S 6 en. S 0 (IVC) CHR 2 COOH in which A, B, D, E, G, L, R 1 and R 2 have the abovementioned meaning, are amidated in inert solvents, i.f appropriate in the presence of a baso, with sulphonamides of the general formula (VI) 6g *6 ek.. 6 0 06 S0~e S 0006 0006 "hli'-S0 2 R' in which R 7 and R" have the abovementioned meaning, (VI) Le A28.177 83 and in the case of the enantiomers the corresponding enantiomerically pure acids are separated by a customary method and reacted further by the abovementioned processes. 7. A pharmaceutical composition comprising at least one 2-substituted quinoline according to Claim 1 in association with a pharmaceutically acceptable carrier. 8, Process for the production of a medicament according to Claim 6, characterised in that the 2-substituted quinolines are brought into a suitable administration form, if appropriate with the aid of customary auxiliaries and excipients. DATED this 22nd day of July, 1993 BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys DAVIES COLLISON CAVE