DD283812A5 - MEASURING CIRCUIT FOR WEAK MEDIA STROMEME - Google Patents

Abstract

The invention relates to a process for the preparation of 4- (quinolin-2-yl-methoxy) phenyl-acetic acid derivatives. According to the invention compounds of the formula are prepared, wherein the substituents R1, A, B, Y and Z have the meaning given in the description and in the claims. Formula {novel (quinolin-2-yl-methoxy) phenylacetic acid derivatives; leucotriene synthesis inhibitors; Use as a medicine}

Description

-1-

Process for the preparation of substituted 4- (quinolin-2-yl-ethoxy) -phenyl-acetic acid derivatives

Field of application of the invention

The invention relates to a process for the preparation of novel substituted 4- (quinolin-2-yl-methoxy) phenylacetic acids, their esters and amides and their use in medicaments.

Characteristic of the known state of the art

It is known that 3- (quinolin-2-yl-methoxy) phenylacetic acid and 2- / _l ~ "3- (öhinolin-2-yl-methoxy) phenyl_7propionsäμre and their methyl and ethyl esters possess anti-inflammatory and anti-allergic action /" see. EP-A 181 568__7

Object of the invention

The aim of the invention is to provide novel (quinolin-2-ylmethoxy) phenylacetic acid derivatives having an improved spectrum of activity.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

There have been new substituted 4- (quinolin-2-yl-methoxy) -phenylacetic acids, their esters and amides of general formula (I)

-1a-

Y Z

in which 5

R ¹ - ilir a group of the formula

-OR ² or -N looks, where

No. ³

R ^ and R ^{3 are the} same or different and

- represents hydrogen, alkyl, aryl, aralkyl, or a group of the formula

15 R ⁴ R ^{4 r4}

Il

-CH-CO ₂ R ⁵ , -CH-CH ₂ -OR ⁵ , -CH-OR ⁶

R ⁴ 20 or | | stand, where

Ύ ⁰

R ⁴ - represents hydrogen, alkyl, aralkyl or aryl, dns optionally sub

may be substituted by hydroxyl, carboxyl, alkoxycarbonyl, alkylthio, heteroaryl or carbamoyl,

30 R ⁵ - represents hydrogen, alkyl, aryl or aralkyl

stands,

Le A 26

20

2838

R ^{6 represents} a group of the formula -COR ⁵ or -CO ₂ R ⁵ , where

R ^{5 has} the meaning given above,

R ⁷ - is hydrogen, alkyl or aryl, 10

Y - for a group of the formula

R ⁸

(-CH) _n , where I

R ⁸ - is hydrogen, alkyl or aryl, and η - is a number from 0 to 5,

Z - stands for norbornyl or

for a group of the formula

- = 10 ^ iI- "10

^R 9 ^ t ^R 9

R ⁹ or -Cs ^ ΓΗ R ⁹ ,

(C) ₁

> m

in which

30

R ⁹ and R ^{10 are the} same or different and are hydrogen, alkyl or aryl, or

R ⁹ and R ¹⁰ together represent a saturated carbocyclic ring having up to 6 carbon atoms

can form and

Le A 26 119

m - a number from 1 to 6 means 5

A and B are the same or different and denote hydrogen, lower alkyl or halogen. «

and their salts »10

found"

In comparison to the compounds known from EP-A 181 568, the quinolines according to the invention of the formula I surprisingly have a higher in vitro activity than leukotriene synthesis inhibitors and a stronger in vivo action after oral administration,

Alkyl is in general a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Preferred is lower alkyl having 1 to about 6 carbon atoms. Examples being methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, isopentyl, hexyl, Isohexyl, heptyl, isoheptyl "octyl and isooctyl"

Halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Halogen is particularly preferably fluorine or chlorine

Arvl generally represents an aromatic radical having from 6 to about 12 carbon atoms Preferred aryl radicals are phenyl-naphthyl and biphenyl.

-

Le A 26 119

Aralkvl is generally an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain. Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. For example, the following aralkyl radicals may be mentioned: benzyl naphthylmethyl Phenethyl and phenylpropyl ♦

Alkylthio generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via a sulfur atom. Preference is given to lower alkylthio having 1 to about 6 carbon atoms.

Particular preference is given to an alkylthio radical having 1 to 4 carbon atoms, for example methylthio, ethylthio-propylthio, isopropylthio, butylthio-isobutylthio, pentylthio, isopentylthio, hexylthio, hexohexylthio, hep-

"tylthio, isoheptylthio" called octylthio or isooctylthio

Alkoxycarbonyl may, for example, be represented by the formula

C-Oalkyl are displayed «

Alkyl is in this case a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Preferred is lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl moiety. Particularly preferred is an alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety. For example, the following alkoxycarbonyl radicals may be mentioned: methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl or isobutoxycarbonyl «

Le A 26 119

Heteroarvl within the given above definition in general represents a 5- to 6-membered aromatic ring "of the heteroatoms oxygen," Sulfur may contain nitrogen and to which a further aromatic ring can be fused, are preferred and / or 5- and 6 -membered aromatic rings, the

* 0 contains an oxygen "a sulfur and / or up to 2 nitrogen atoms and which are optionally benzo-fused" as particularly preferred heteroaryl radicals may be mentioned: thienyl, furyl, pyridyl »pyrimidyl» pyrazinyl, pyridazinyl »quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thiazolyl» Benzothiazolyl »isothiazolyl» oxazolyl »benzoxazolyl» isoxazolyl »imidazolyl» benzimidazolyl, pyrazolyl »indolyl and isoindolyl.

In the context of the present invention, physiologically acceptable salts are preferred. "Physiologically acceptable salts of the substituted 4- (quinolin-2-ylmethoxy) phenylacetic acids, esters and amides can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Salts with hydrochloric, hydrobromic, sulfuric »phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic» benzenesulfonic, naphthalenedisulfonic, acetic, propionic »lactic, tartaric» citric acid »fumaric, maleic or benzoic acid«

Salts in the context of the present invention are also salts of monovalent metals such as alkali metals and the ammonium salts. Preference is given to sodium, potassium and ammonium salts.

Le A 26 119

Ee compounds of the general formula (I) are preferably in which

R ¹ - for a group of the formula

"*

-OR * ⁵ or -N, where

N3

R ² and r ^{3 are the} same or different and

- for hydrogen, lower alkyl, benzyl, phenyl

or a group of formula 15

R ⁴ R ⁴ R ⁴

R ⁴

I ₇ -CITs ^ ⁷

or I | stand, where

R ⁴ - for hydrogen, lower alkyl, benzyl

or phenyl which may optionally be substituted by hydroxy, lower alkoxycarbonyl, carboxyl, lower alkylthio, heteroaryl or carbamoyl,

R ⁵ - represents waxy, lower alkyl, phenyl or benzyl,

R ⁶ - is a group of the formula -COR ⁵ or -CO ₂ R ⁵ , where R ^{5 is} the abovementioned

has meaning, and

Le A 26 119

R ⁷ - is hydrogen, lower alkyl or phenyl.

Y - for a group of the formula

F ^{8 (} " ^CH) n, where

R ⁸ - for hydrogen. Lower alkyl or phenyl

is, 15

and

η - a number from 0 to 5 means

Z - stands for norbornyl or

for a group of the formula

* "I ~ * 9 *"<· Ι "" 9 -C ^ TR or -C>. ή R stands, where

_R 10 / il "10

R ⁹ and R ^{10 are the} same or different and are hydrogen, lower alkyl or phenyl, or

R and R ^ may together form a saturated carbocyclic ring of up to 6 carbon atoms and

Le A 26 119

m - a number from 1 to 6 means «

A and B are the same or different and are hydrogen, methyl ι ethyl, fluorine, chlorine or bromine,

and their salts.

Particularly preferred compounds of general formula (I) are those in which

R * - for a group of the formula

or -N

stands, where

R and R 1 are the same or different and represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, phenyl or benzyl, or a group of the formula

or

-CH-CH ₂ -OR ⁵

R ⁴ -CH-OR ⁶

stand, where '

Le A 26 119

- 10 -

R ⁴ - represents hydrogen, methyl, ethyl, propyl, Isopropyl, butyl, tert, butyl, benzyl or

Phenyl which may optionally be substituted by hydroxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, carboxyl, methylthio, ethylthio, propylthio, imidazolyl or carbamoyl,

R ⁵ - represents hydrogen, methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, phenyl or

Benzyl, 15

R ⁶ - represents a group of the formula -COR ⁵ or -CO ₂ R ⁵ , where

R ^{5 has} the meaning given above 20

and

R ⁷ - represents hydrogen, methyl, ethyl, propyl,

Isopropyl, butyl, tert-butyl or phenyl,

Y - for a group of the formula

R ⁸

⁽ " ^CH) n, where

Le A 26 119

- 11 -

R ⁸ - represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or phenyl

stands,

and η is a number from 0 to 5,

Z - stands for norbornyl or

for a group of the formula

»10

.j. J

R ⁷ or -Cs ^ λ R ⁷ ,

(C) ₁

> m ^ C) _n ,

where 20

R ⁹ and R * ^ are the same or different and are hydrogen, methyl, ethyl, n-propyl, iso-propyl, butyl or tert-butyl, or

R ⁹ and R * ^ may together form a saturated carbocyclic ring of up to 6 carbon atoms, and

m - a number from 1 to 6 means 30

Le A 26

- 12 -

A and B are identical or different and ⁵ methyl "ethyl" hydrogen "is fluorine or chlorine,

and their salts «

Very particularly preferred compounds of the general ¹⁰ formula (I) are those "where

R ¹ - for a group of the formula

2 **

-OR ^ or -N, where

15 years ago

R ² and R ^{3 are the} same or different and

- stand for hydrogen or methyl "or:

- for a group of the formula

²⁰ R ⁴ R ⁴ R ⁴

-CH-CO ₂ R ⁵ , -CH-CH ₂ -OR ⁵ -CH-OR ⁶

R ⁴

HN., ^ R ⁷

²⁵ -C ^

or I I stand «- where

⁰ Y ⁰

R ⁴ - represents hydrogen, methyl or phenyl 30

stands"

R ^{5 is} hydrogen, methyl, ethyl, tert-butyl or benzyl,

35, u

R ° - represents a group of the formula -COR ',

wherein R ^{5 has} the meaning given above, and

Le A 2 6 119

- 13 -

F ⁷ - is methyl, 5

Y - for a group of the formula

(-CH) _n , where I

R ^{8 is} hydrogen or methyl.,

and

η - a number 0 or 1 means

Z - is norbornyl, or a group of the formula

10 ^ YY-R ¹⁰

-R or -C _n ^ r | R ⁹ stands,

< ^c > m -m

in which

R and R are the same or different and Mean hydrogen or methyl, or R ⁹ and R ¹⁰ together form a cyclohexyl ring,

and 30

m is a number 1, 2, 3, 4 or 5,

A and B are hydrogen or fluorine,

and their salts.

Le A 2 6

- 14 -

2838Ί2

The compounds according to the invention can exist in ethereal forms which are either like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers). The invention relates to both the antipodes and racemic forms and the mixtures of diastereomers Racem forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform constituents (cf. "E * L, Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962)."

For example, the following active ingredients may be mentioned in detail:

He teaches 2- [4- (quinolin-2-yl-methoxy) -phenyl3-3-cyelopropylpropionic acid methyl ester 2-C4- (quinol-2-yl-methoxy) -phenyl] -3-cyclohexylpropionic acid

2- [4- (Quinolin-2-yl-methoxy) phenyl 3-2-eye. \ OpentyI-acetic acid methyl ester

2-C4- (quinol-2-yl-methoxy) -phenyl 3-2-cyclohexyl-acetic acid methyl ester

2- [4- (quinolin-2-yl-methoxy) pheny13-2-cycloheptylpojigsauremethylester

2- [4- (Quinolir-2-yl-methoxy) phenyl-3,3'-ylpropyl-propionic acid 2-t4- (quinolin-2-yl-methoxy) -phenyl3-3-cyclohexylpropionic acid

2-C4- (quinolin-2-yl-inethoxy) phenyl 3-2-eye 1 open-ty 1-acetic acid

Le A 26 119

- 15 -

2-C4- (quinolin-2-yl-methoxy) phenyl] -2-cyclohexylacetic acid

2- [4- (quinolin-2-yl-methoxy) phenyl3-2-cycloheptylessigsaure

2- (4- (Quinolin-2-yl-methoxy) -phenyl] -2- (cyclohex-2-enyl) -acetic acid methyl ester 2-) 4- (Quinolin-2-yl-methoxy) -phenyl3-2-cyclopropyl-propionic acid benzyloxycarbonyl-naphthylene ether

2 - £ 4- (Quinolin-2-yl-methoxy) phenyl] -2-cyclopentylbenzene urebenzyloxycarbonylmethyl ester

2-C4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentylessigsäuremethyloxycarbonylmethylamid

2- £ 4- (quinolin-2-yl-methoxy) phenyl] -2- (1-dekalinyl) -essigsaureniethylester

2-C4- (quinolin-2-yl-methoxy) -phenyl 3-2-eye 1-penty1-acetic acid tert -butyloxycarbonylmethyl ester 2-C4- (quinolin-2-yl-methoxy) -phenyl 3-2-cy r. lopentylessigsäurepivBloyloxymethylester

2- [4- (Quinolin-2-yl-methoxy) -phenyl 3-2-eyelpentylacetic acid methoxycarbonylmethyl ester

2- [4- (Quinolin-2-yl-methoxy) phenyl 3-2- (1-dekalinyl) -acetic acid

2-C4- (quinolin-2-yl-methoxy) -phenyl 3-2-eyelpentyl-acetic acid carboxymethyl-amide

2- (4- (Quinolin-2-yl-methoxy) phenyl) 3-2-eyelpentyl-acid-sodium salt 2-E4- (quinolin-2-yl-methoxy / phenyl3-3-cyclopentyl-propionic acid, methyl ester

2-C4- (quinolin-2-yl-methoxy) -phenyl 3-3-eyepropentyl-propionic acid

Le A 26 11 9

2 - / "" 4- (2-yinolin-2-yl-methoxy) -phenyl-7-2- (cyclohex-2-enyl) -acetic acid 2 - / "" 4- (2-chloro-2-yl-methoxy) -phenyl _> _7-2- cyolopentyl easigBäurecarboxymethyleater-2- / ~ 4- (6-Pluoi * ohinolin-2-yl-methoxy) phenyl-2-cyolopentylessigaäuremetfhylester 2 - / "" 4- (6-i ^l luorohinolin-2-yl-methoxy) phenyl-2 -oyclopentylesaigaic acid 2 - / "" 4- (ghinolin-2-yl-methoxy) phenyl__7-2 ~ norbornyl ~ eaaigaoic acid methyl 2- / ~ 4- (quinolin-2-yl-methoxy) phenyl__7-2-norbornyl-eaaic acid 2- / "" 4- (Quinolin-2-yl-methoxy) phenyl "7-2-cyclopentylacetic acid / (L) -2-hydroxy-1-phenylethyl_7amide (both diastereomers) (+) - 4- / 2- (Ohinolin-2 -yl-methoxy) phenyl_7-2-cyclopentylacetic acid (-) - 4- [2- (2-chloro-2-yl-methoxy) -phenyl-7-2-oyclopentylacetic acid

Daa process according to the invention for the preparation of the compounds of general formula (I)

in which

A, B, R, Y and Z have the abovementioned meaning, iat characterized in that

-17-

A_7 4- (Ohlnolin-2-yl-methoxy) phenylacetic acid ester of general formula (Ia)

(Ia)

in which

R ¹¹ - is alkyl and

A and B have the abovementioned meaning, with compounds of the general formula (II)

(II)

in v / elcher

Y and Z are as defined above, and

X - for chlorine "bromine or iodine" 5

alkylated and in the case of Δ @ γ acids the esters saponified »or by [B] the acids of the general formula (Ib)

CO ₂ H

in which 20

λ »Β» Y and Z have the abovementioned meaning »with compounds of the general formula (III) XR ¹² (III)

in which

r12 _ fo _re i _ne group of the formula _R 4-r4 '· _r4

-CH-CO ₂ R ⁵ , -CH-CH ₂ -OR ⁵ »-CH-OR ⁶

-CHN. ⁷

or I I stands »where

Ύ °

Le A 2 6

- 19 -

R ⁴ '- is alkyl, aralkyl or aryl, which may optionally be substituted by

Hydroxy, carboxyl, alkoxycarbonyl, alkylthio, heteroaryl or aminocarbonyl,

R ⁵ '- is alkyl, aryl or aralkyl, 10

R ^ '- is a group of the formula -COR ^ or -CO ₂ R ⁵ ', where

R ^ has the meaning given above, 15

R ⁷ '- is alkyl or aryl,

and

X has the meaning given above,

esterified and, in the case of acids, subject the esters to a hydrogenolytic cleavage,

or by

CC] the acids of the general formula (Ib) with amines of the general formula (IV)

HN (IV)

\ ³

in which 35

Le A 2 6

- 20 -

R ² and R ^{3 have} the abovementioned meaning ι. 5

with the proviso "that R ⁵ does not signify hydrogen" if R ^ or R ^ for the group

R ^{4 is} -CH-CO ₂ R ⁵

in which

R ⁴ and R ^{5 have} the abovementioned meaning »

in the presence of common Aktivierungsreagentien amidated and saponified in the case of acids, the esters

or by 20

[D] Phenols of the general formula (V)

(V) Y-Z

R ι Y and Z have the meaning given ubrn

With

2-halomethylquinolines of the formula (VI)

(VI)

Le A 26

- 21 -

2838] 2

in which

λ, B and X have the abovementioned meaning, etherified and, in the case of the acids, the esters are saponified,

10

the processes according to the invention can be illustrated by the following equation schemes:

20 25 30

[A]

CO ₂ CH ₃

alkylation

CO ₂ CH ₃

saponification

CO ₂ H

Le A 26 119

- 22 -

[B]

CC]

CO ₂ H + Br-CH ₂ -CO ₂ -CH ₂ esterification

CO ₂ -CH ₂ -CO ₂ CH ₂ hydrogenolysis

CO ₂ -CH ₂ -CO ₂ H

CO ₂ H + H ₂ N-CH ₂ -CO ₂ -CH ₃ Aniidierung CONH-CH ₂ -CO ₂ -CH ₃

CONH-CH ₂ -CO ₂ H

Le A 26

- 23 -

CO ₂ -CH ₃

0-alkylation

CO ₂ -CH ₃

saponification

CO ₂ H

The alkylation of the C-acidic compounds (formula Ia) with alkyl halides is generally carried out in inert solvents in the presence of a base.

Suitable solvents here are, depending on the nature of the alkylating agent, all inert organic solvents. These include preferably ethers such as diethyl ether "dioxane or tetrahydrofuran" or hydrocarbons such as benzene, toluene or xylene "or dimethylformamide or Hexamethylphosphorsauretriamid" or mixtures of said solvents.

Suitable bases are the usual basic compounds "These include preferably alkali metal hydrides such as sodium hydride" alkali metal amides such as sodium amide or Lithiumdiieo-

Le A 26 119

- 24 -

833 12

propylamide, Alkal! alcoholates such Natriununethanolat, Na ° triumethanolat, at potassium methanol, potassium ethoxide or potassium tert-butoxide, "or organic amines such as trialkylamines, for example triethylamine, or organolithium compounds such as phenyllithium or butyl 1ithium"

The alkylation of the CH-acidic compounds is generally carried out in a temperature range vein O ⁰ C to 150 ⁰ C, preferably from 10 ⁰ C to 100 ⁰ C ₄

The alkylation of the CH-acidic compounds is generally carried out at atmospheric pressure "but it is also possible" to carry out the process at reduced pressure or overpressure (z "B" in a range of 0.5 to 5 bar).

2 "in general, 0.5 to 5, preferably 1 to 2 mol of halide, based on 1 mol of the reactant, is used. The base is generally obtained in an amount of from 0.5 to 5 mol, preferably from 1 to 3 mol on the

Halide used «25

The saponification of the carboxylic acid esters is carried out by customary methods, by treating the esters in inert solvents with customary bases, it being possible to convert the salts initially formed by treatment with acid into the free carboxylic acids.

Le A 26 119

/ ils bases are suitable for saponification the usual inorganic bases "These include preferably alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide or alkali metal carbonates such as sodium or potassium carbonate or Natriumhydrogencarbonatι or alkali metal such as sodium" sodium , sodium , potassium methoxide or potassium tert "Butanolate" Particularly preferred are sodium hydroxide or potassium hydroxide. «

As lots agent suitable for the hydrolysis are water or the customary for hydrolysis organic loose means "These preferably include alcohols such as methanol, ethanol ι propanols isopropanol or Butar.ol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide," are particularly preferably alcohols such as Methanol »Ethanol ι Propanol or Isopropanol used« It is also possible »to use mixtures of the mentioned solvents«

^uO The hydrolysis "is generally used in a temperature range from ⁰ ° C to + 100 ° C preferably from +20 ⁰ C to +80 ⁰ C.

In general, the saponification is carried out at atmospheric pressure 3 "but it is also possible to work under reduced pressure or overpressure (for example, from 0.5 to 5 bar).

Le A 26 119

- 26 -

In carrying out the saponification, the base is generally used in an amount of from 1 to 3 mol, preferably from 1 to 1.5 mol, based on 1 mol of the ester or of the lactones. Particular preference is given to using molar amounts of the reactants.

In carrying out the saponification, the salts of the compounds according to the invention are obtained in the first step as intermediates which can be isolated. The acids according to the invention are obtained by treating the salts with customary inorganic acids. These preferably include mineral acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid or Phosphoric acid "It has proved to be advantageous in the production of carboxylic acids, the basic Rbaktionsmiechung the saponification in a second

To acidify the step without isolating the salts, the acids can then be isolated in the usual way.

The esterification of the carboxylic acids is carried out by conventional methods by treating the acids in inert solvents, optionally in the presence of a base, with alkyl halides.

Suitable bases are the customary organic amines. These preferably include alkylamines such as triethylamine, diisopropylamine, dicyclohexylamine and ethyldiisopropylamine.

Suitable solvents here are all inert organic solvents. These include preferably ethers such as 35

Le A 26 119

- 27 -

Diethyl ether * dioxane or tetrahydrofuran or hydrocarbons such as benzene «toluene or xylene» or dimethylformamide or mixtures of said solvents,

The esterification of the carboxylic acids is generally carried out in a temperature range from ⁰ ° C. to 150 ^° C., preferably from 10 ^° C. to 100 ^° C.

The esterification of the carboxylic acids is generally carried out at atmospheric pressure. However, it is also possible to carry out the process under reduced pressure or overpressure (for example in a range from 0.5 to 5 bar).

In general, from 0.5 to S _1, preferably 1 to 2 mol of halide, based on 1 mol of the reactant, the base is in ellgmeinen in an amount of 0.5 to 5 mol, preferably from 1 to 3 mol based on the Halide used.

In general, 0.01 to 1 "preferably 0.0 ^c > to 0.5 mol of catalyst" based on 1 mol of reactants.

The hydrolytic cleavage of the benzyl esters is carried out by customary methods "by hydrogenating the benzyl ethers in an inert solvent in the presence of a catalyst with hydrogen fluoride gas."

Le A 2 <j 119

- 28 -

Ale catalysts are the usual metal catalysts, which are optionally applied to an inert support such as Kuhle in variable concentrations. These include preferably palladium "nickel, platinum" particularly preferably 5 to 15% palladium

activated carbon

 10

The solvents used here are all inert organic solvents. These preferably include ethers, such as diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons, such as benzene, toluene or xylene, or alcohols, such as methanol, ethanol or propanol, or low-boiling esters such as ethyl acetate, or amines such as triethylamine, or mixtures of these solvents «

The hydrogenolytic cleavage is generally carried out in a temperature range from ⁰ ° C. to 150 ^° C., preferably from 10 ^° C. to 100 ^° C.

The hydrogenolytic cleavage is generally carried out with hydrogen at atmospheric pressure. However, it is also possible to carry out the process under overpressure (for example in a range from 1 to 10 bar).

In general, from 0.01 to 1, preferably 0.05 to 0.5 mol of catalyst, based on 1 mol of reactants.

Le A 26 119

- 29 -

The amidation of the compounds (Ib) with amines is carried ° generally in inert solvents in the presence of a base "

Depending on the nature of the amine, inert inert organic solvents are suitable as solvents. These preferably include ethers, such as diethyl ether, dioxane or tetrahydrofuran, hydrocarbons, such as benzene, toluene or xylene, or dimethylformamide or mixtures of the solvents mentioned. "Dimethylformamide is particularly preferred."

¹ ^ The bases the ordinary basic compounds "Suitable for this are preferably include organic amines such as trialkylamines," B. triethylamine "

As Aminkomponenten are in addition to the usual Ami- ^ O NEN such as propylamine dimethylamine or diethylamine and optically active amino acid esters such as the esters of alanine, leucine, methionine, threonine, tyrosine, cystine, glycine, isoleucine, lysine, phenylalanine, phenylglycine or valine , or amino alcohols such as 2-aminoethanol or phenylglycinol / alamine, the latter can be prepared in optically pure form by reduction of the corresponding amino acid according to known methods (see <G ₄ C

 Barrett, Chemistry and Biochemistry of the Amino Acids, Chapman and Hall, 1985),

By using the above-mentioned amine components can thus in analogy to the method described above

CC] the diastereomeric amides of the compounds of formula 35

Le A 26 119

- 30 -

(I) "After separation of the diastereomers according to the abovementioned customary methods and subsequent saponification, the pure enantiomers of the compounds of the formula (I) according to the invention are obtained.

As activating agents, the usual peptide coupling reagents are generally used. These include preferably carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1-oxazolium compounds such as 2-ethyl-5 -phenyl-l, 2-oxazolium-3-sulfonate or propanephosphonic anhydride or isobutylchloroformate or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or phosphoric acid diphenylesteramide or methanesulphonic chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccin

imid «25

The hydrolysis generally takes place with inorganic or organic acids such as hydrochloric acid "hydrobromic acid" sulfuric acid "phosphoric acid" formic acid "acetic acid" propionic acid "methanesulfonic acid or trifluoroacetic acid or mixtures of said acids"

The amidation of the compounds of the general formula (I) is generally carried out in a temperature range from ⁰ ° C to +150 ⁰ C, preferably from ⁰ ° C to +50 ⁰ C.

Le A 26 119

- 31 -

The amidation is generally carried out at atmospheric pressure "but it is also possible" to carry out the process under reduced pressure or overpressure (for example in a range from 0.5 to 5 bar).

The esters of the general formula (Ia) used as starting compounds are also prepared from the known 4-hydroxyphenylsigsäuren by etherification with 2-halomethylquinolines of the general formula (VI) analogously to process D.

The etherification can be carried out in inert organic solvents, if appropriate in the presence of a base.

Solvents for the etherification may be inert organic solvents which do not change under the conditions of Keatkions These include preferably ethers such as dioxane, tetrahydrofuran or diethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane or trichlorethylene, hydrocarbons such as benzene, Xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetonitrile, acetone or hexamethylphosphoric triamide "It is likewise possible to use mixtures of the solvents" 30

As bases for the etherification it is possible to use inorganic or organic bases. "These include, preferably, alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as, for example, Bei-35

Le A 26 119

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barium hydroxide «alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonates or organic amines (trialkyl (Cj-C ₆ ) amines) such as triethylamine« or heterocycles such as pyridine, methylpiperidine, piperidine or morpholine.

It is also possible to use alkali metals, such as sodium, and their hydrides, such as sodium hydroxides, as bases. "

The etherification for the preparation of the compounds of the formula (Ia) is generally carried out in a temperature range from ⁰ ° C. to 150 ^° C., preferably from 10 ^° C. to 100 ^° C., and generally at normal pressure. However, it is also possible to carry out the process under reduced pressure or overpressure (for example in a range from 0.5 to 5 bar).

In general, from 0.5 to 5, preferably 1 to 2 mol of halide, based on 1 mol of the reactants. The base is generally used in an amount of from 0.5 to 5 mol, preferably from 1 to 3 mol, based on the halide.

4-Hydroxyphenylessig8Buree8ter are known or can be prepared by conventional methods from the corresponding phenols 3 "with elimination of suitable protecting groups [see H. Beyer, textbook of organic chemistry, S. Hirzel Verlag, Stuttgart, Protective Groups in Organic Synthesis, J. Wiley t Sons, 1981, New York].

·

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The substituted 4-hydroxyphenylacetic esters of the general formula (V) are largely new and can be prepared from the abovementioned 4-hydroxyphenylacetic acid esters by alkylation by a known method (cf. "ferrite reactions of organic synthesis,

Georg Thieme Verlag «Stuttgart, 1978). 10

2-Halomethylquinolines of the formula (VI), for example 2-chloromethylquinoline, are known and can be prepared by customary methods [cf. Chem.

Reports. 12fi, 649, 1987], 15

The compounds of the formula (II) and (III) are known or can be prepared by customary halogenationmelodies [cf. Organikum VEB German publishing house of the

Sciences, Berlin 1977]

 20

The acids, esters and ai.iide according to the invention can be used as active ingredients in medicaments. The substances are particularly effective as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism, in particular 5-lipoxygenase.

The compounds according to the invention show good oral administration in lipoxygenase-sensitive test models

effect

 30

They are thus preferred for the treatment and prevention of respiratory diseases such as allergies / asthma, bronchitis, emphysema, shock lung, pulmonary hypertension.

Le A 26 119

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never «inflammation / rheumatism and edema, thrombosis and thromboembolism, ischaemia (peripheral» cardiac, cerebral circulatory disorders), heart and brain infarcts, cardiac arrhythmia, angina pectoris, arteriosclerosis, in tissue transplants, dermatoses such as psoriasis, metastases and for cytoprotection in the gastrointestinal tract suitable.

The novel active compounds can be converted into the customary formulations in a manner known per se using inert non-toxic, pharmaceutically suitable carriers or solvents, such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions. Here, the therapeutically active compound in each case in a concentration of about 0.5 to 90 wt .-%, preferably of up to 70 wt. X, in the total mixture, that is. in amounts sufficient to achieve the stated dosage margin.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of using water as the diluent, organic solvents may optionally be used as auxiliary solvents.

Examples of adjuvants include: water, non-toxic organic solvents such as paraffins

Le A 26 119

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(ζ, B, petroleum fractions) ι vegetable oils (eg peanut / sesamol), alcohols (eg ethyl alcohol, glycerol), glycols (eg propylene glycol polyethylene glycol), solid carriers, such as natural minerals (eg Kao-Ιίηβι clays »talc, chalk) , ground synthetic minerals (eg highly disperse silicic acid, silicates), sugars (eg cane, milk and dextrose), emulsifying agents (eg polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohols ethers, alkyl sulfonates and arylsulfonates), dispersing agents (eg lignin-sulphite liquors, methylcellulose, Starch and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, talc, stearic acid and sodium lauryl sulfate.

The application can be carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, of course, apart from the abovementioned carriers, tablets may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used for tableting. In the case of aqueous suspensions and / or elixirs, which are intended for oral applications, the active ingredients can be added to the abovementioned excipients with various flavor enhancers or dyes.

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In the case of parenteral applications, "solutions of the active substances may be used using suitable liquid carrier materials"

In general, it has been found to be advantageous to administer amounts of about 0.01 to 10 mg / kg when administered intravenously, preferably from ₁ to 5 mg per kg of body weight, to achieve effective results. In the case of oral administration, the dosage is generally about 0.1 to 200 mg / kg, preferably 1 to 100 mg / kg

Body weight · 15

Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or the route of administration, on the individual behavior towards the drug, the nature of its formulation and on the time or interval at which it is administered he follows. Thus, in some cases, it may be sufficient to come up with less than the aforementioned minimum amount, while in other cases, the above upper limit must be exceeded. "In the case of the application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

The acids and esters according to the invention can be used both in human medicine and in veterinary medicine. "

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Embodiment

The invention is explained in more detail below with reference to some examples.

HerBtellunasbeiBDJele Example 1 (output connection)

4- (quinolin-2-y1-methoxy) methyl phenylacetate

^C0 2 ^CH3

200 g (1.2 mol) of 4-hydroxyphenylacetic acid methyl ester and 166 g (1.2 mol) of potassium carbonate are stirred in 2 l of dimethylformamide for 1 h at 25 ° C. After addition of 214 g (1.2 mol) of 2-chloromethylquinoline is warmed to 50 ° C for 15 h «After concentration in vacuo, the residue is partitioned between water and ethyl acetate, the organic phase dried over sodium sulfate and concentrated. The remaining product is recrystallized from methanol.

Yield: 293 g (79% of theory) Melting point: 71-73 ⁰ C

Le A 26

- 38 -

BeJBDJel 5

2- [4- (Quinolin-2-yl-methoxy) phenyl-3-cyclopropyl-propionic acid methyleetor

CO ₂ CH ₃

To a suspension of 1.5 g (55 mmol) of sodium hydride in

60 »1 of dimethylformamide are added dropwise under protective gas at ⁰ ° C. 15.4 g (50 mmol) of 4- (quinolin-2-ylmethoxy) phenylacetic acid methyl ester. After the evolution of hydrogen has ended, the mixture is stirred at 25 ° C. for 1 h, with eie cooling 7. 4 g (55 mmol) (bromomethyl) -cyclopropane in 60 ml of dimethylformamide was added dropwise and stirred at 25 ° C for 16 h. After evaporation of the solvent in vacuo, the residue is partitioned between ethyl acetate and water, the organic phase is dried over sodium sulfate and concentrated. The residue is recrystallized from methanol. Yield: 15 g (83% of theory) of fixed point 47 ° C.

Example 3 30

2-C4- (quinolin-2-yl-methoxy) -phenyl 3-3-cyclohexyl-propionic acid methyl ester

Le A 26

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H ₃ CO ₂ C

The representation is made from 15.4 g (50 nunol) of 4- (chino

lin-2-yl-methoxy) phenyl methylacrylate and 9.74 g (55 mmol) (bromomethyl) -eyelohexane analogously to the instructions

of example 2.

Yield: 15.9 g (79% of theory) Fixed point! 69 ⁰ C Example 4

2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentylessigsäuremethylester

CO ₂ CH ₃

Method a) The representation is made from 15.4 g (50 nunol) of 4- (chino

lin-2 * -yl-methoxy) phenylacetic acid diethoxylate and 8.2 g (55 mmol) cyclopentylbromide analogously to the procedure of

Example 2 « Yield: 12.8 g (68% of theory) Fixed point: 94 ⁰ C

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Method b) 5

2.3 g (10 mmol) of methyl 2- (cyclopentyl-2 (4-hydroxyphenyl) acetate are dissolved in 30 ml of dimethylformamide. After addition of 1.4 g (10 mmol) of potassium carbonate, the mixture is stirred at 60 ^° C. for 1 h, a Solution of 2.3 g (10 mmol) of 2-chloromethylquinoline in 20 ml of dimethylformamide is added dropwise and stirred at 60 ° C for 15 h After cooling, the mixture is concentrated, the residue taken up in ethyl acetate and washed twice with water After drying over sodium sulfate is concentrated and the residue is recrystallised from methanol,

Yield? 3, lfl g (85 '/. Of theory) Example 5

2- [4- (Chino1in-2-yl-methoxy) phenyl] -2-cyclohexylessigsauremethylester

CO ₂ CH ₃

The preparation is carried out bus 15.4 g (50 mmol) 4- (quinolin-2-yl-methoxy) phenylacetic acid methyl ester and 11.55 g (55 mmol) cyclohexyl iodide analogously to the procedure of Example 2.

Yield: 11.74 g (60X theory) Fixed point: 92 ° C 35

Le A 26 119

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Example 6

2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl acetic acid methyl ether

CO ₂ CH ₃

The preparation is carried out from 15.4 g (50 mmol) of 4- (quinoline).

lin-2-yl-methoxy) phenyl methylate and 9.07 g (55 mmol) of cycloheptylbromide analogously to the instructions of

example Yield: 16 g (80% of theory) Fixed point! 81 ⁰ C Example 7

2- [4- (Quinolin-2-yl-methoxy) -phenyl] -3-cyclopropyl-propionic acid

Le A 26

- 42 -

13.33 g (37 mmol) of 2- [4- (quinolin-2-yl-methoxy) phenyl] -3-cyclopropyl-propionic acid methyl ester are refluxed in 200 ml of methanol and 55 ml of 1 molar sodium hydroxide solution for 10 h. After cooling, it is acidified with concentrated hydrochloric acid, the precipitated product is filtered off with suction and dried. Yield? 12.5 g (98% of theory) fixed point 146 ⁰ C.

Example 8

2- [4- (quinolin-2-yl-methoxy) phenyl] -3-cyclohexylpropionic acid

CO ₂ H

The preparation is carried out from 6.25 g (15.5 mmol) 2- [4- (quinolin-2-yl-methoxy) phenyl] -3-cyclohexyl-propionsauremethylester analogous to the procedure of Example Yield: 5 g (83% of Theory) fixed point: 148 - 151 ⁰ C

Example 9

2-C4- (quinolin-2-yl-methoxy) phenyl3-2-cyclopentylacetic acid

CO ₂ H Le A 26 119

- 43 -

The preparation is carried out from 10.87 g (29 mmol) of 2-C4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentyl-acetic acid methyl ester analogously to the procedure of Example 7, yield. 8.8 g (84X theory) Fixed point: 183-185 ⁰ C

example

2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cyclohexyl-

acetic acid 15

CO ₂ H

The preparation is carried out from 10 g (26 mmol) 2- [4- (Chi no 1-in-2-yl-methoxy) phenyl 3-2-cyclohexyl-acetic acid methyl ester analogously to the procedure of Example 7 «Yield: 8.7 g (9OX der Theory) Fixed point: 201 - 207 ° C

example

2- [4- (quinolin-2-yl-nsethoxy) phenyl] -2-cycloheptylessigsaure

L e A 26

- 44 -

The preparation is carried out from 11 g (27 mmol) of 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl-acetic acid methyl ester analogously to the procedure of Example 7.

Yield: 9.3 g (87% of theory). Fix point: 176 ^° C.

example

2- [4- (quinolin-2-yl-methoxy) phenyl] -2- (eyelohex-2-enyl) essigsauremethylester

CO ₂ CH ₃

The preparation is carried out from 15.4 g (50 romol) of 4- (quinolin-2-yl-methoxy) phenylessig6äuremethylester and 8.86 g (55 mmol) of 3-bromocyclohexene analogous to the procedure of

Example 2 Yield: 14.74 g (76% of theory) Benchmark: 102 - 104 ⁰ C

Le A 26

- 45 -

example

2- [4- (Quinolin-2-yl-methoxy) -phenyl] -3-cyclopropyl-propionicbenzyloxycarbony! Methyl ester

7 g of 2-C4- (quinolin-2-yl-methoxy) phenyl3-3-cyclopropylpropionic acid * 5 g of bromoacetic acid benzyl ester and 4 g of dicyclohexylamine are refluxed in 100 ml of tetrahydrofuran for 15 hours. After cooling to ⁰ ° C., the precipitated salt is filtered off and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel with methylene chloride. An oil is obtained. Yield: 9.27 g (93% of theory)

R ₁ (HPLC) = 4.30 min (RP 8, 7 mmol acetonitrile / water (70:30)).

example

2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentyl-essigsäurebenzyloxycarbony! Methylester

Le A 26

- 46 -

The preparation is carried out from 7.22 g (20 mmol) of 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-eyelpentyl-acetic acid and 5 g (22 mmol) of bromoacetic acid benzyl ester analogously to the procedure of Example 13,

Yield! 8.03 g (79% of theory)

Fixed point? 63-65 ° C (hydrochloride) 10

Beispje 15

2- [4- (quinolin-2-yl-methoxy) phenyl] -2-eyelopentyl-

acetic acid methyl oxycarbonylmethylamide 15

7.22 g (20 mmol) of 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentylacetic acid and 3.0 g (24 mmol) of glycine methyl ester hydrochloride are dissolved in 75 ml of dimethylformamide. After cooling to ⁰ C, 6.6 g (24 mmol) Phosphoreaurediphenylesterazid dissolved in 25 ml of dimethylformamide, added dropwise and 30 min'nachgeriihrt, then 7.3 g (72 mmol) of triethylamine are added dropwise and 4 h at ^{0 0} C and Stirring for 15 h at 25 ° C · The reaction solution is poured onto 300 g of egg and extracted 3 times with ethyl acetate · The organic phases are washed 1 time with 1 normal hydrochloric acid, 1 time with water, dried over sodium sulfate and concentrated The product is from Methanol recrystallized.

Yield: 5.34 g (62X of theory) fixed point; 134 - 136 ⁰ C

Le A 26 119

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example

2-C4- (quinolin-2-yl-methoxy) -phenyl] -2- (1-dekalinyl-eicacetic acid methyl ester

H ₃ CO ₂ C

The representation is made from 15.4 g (50 nunol) of 4- (Chi-

methyl nolin-2-yl-methoxy) -phenyl acetate and 9.55 g (55 mmol) of 1-chloro-decalin analogously to the procedure of Example 2,

Yield: 3.11 g (14% of theory) Benchmark: 118 ⁰ C example

2- [4- (quinolin-2-yl-methoxy) phenyl) -2-tert-cyclopentylesεigsäure, butyloxycarbony! Methylester

Le A 26

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The preparation is carried out from 3 g (8.3 mmol) 2- [4- (quinolin-2-yl-methoxy) -phenyl] -2-cyclopentyl-acetic acid and 1.77 g (9.1 mmol) Bromesbigsaure-tert. butyl ester analogous to the procedure of example 13 «yield: 3.18 g (80.5K of theory)

Fixed point 88 - 91 ⁰ C 10

example

2- [4- (quinolin-2-yl-methoxy) -phenyl] -2-cyclopentyl-

acetic acid pivaloyloxymethyl ester 15

9 ^H 3 20

- CO-J-CH ₃

The preparation is carried out from 3 g (8.3 mmol) 2- [4- (Chino-1in-2-yl-methoxy) -phenyl] -2-cyclopehtyl-acetic acid and 1.37 g (9.1 mmol) Pivalinsiurechlormethylester analog the procedure of Example 13 «Yield: 1.38 g (35% of theory)

Fixed point: 30 - 32 ° C 30

Example

2- [4- (quinolin-2-yl-methoxy) phenyl3-2-cyclopenyl-essigsäuremethoxycarbony methylester!

Lc A 26

- 49 -

CO ₂ N ₂ CO ₂ CH ₃

The preparation is carried out from 3 g (8.3 mmol) of 2- [4- (quinoline-2-yl-methoxy) phenyl) 3-eyero-pentyl-acetic acid and 1.39 g (9.1 mmol) of methyl bromoacetate analogously to Example 13 "Yield: 3.37 g (94% of theory). Fix point: 90-93 ° C

example

2- [4- (quinolin-2-yl-methoxy) phenyl] -2- (1-dekalinyl) -acetic acid

CO ₂ H

The preparation is carried out from 610 mg (1.37 mmol) of 2- [4- (quinolin-2-yl-methoxy) phenyl] -2- (ld "kalynyl) acetic acid methyl ester analogously to the procedure of Example 7. Yield: 470 mg. 80% of theory) Fixed point: 200 - 207 ° C

Le A 26

- 50 -

example

2-14- (Quinolin-2-yl-methoxy) -phenyl3-2-cyclopentylacetic acid carboxymethylamide

The preparation is carried out from 3 g (69 mmol) of 2- [4- (quinoline)

1-in-2-yl-methoxy) -phenyl] -2-cyclop9ntyl-Essi "gsäuremethyloxycarbonyl-methylamide analogous to the procedure of

Example 7 Yield: 2.47 g (85% of theory) Fixed point: 182 - 185 ⁰ C example

2-C4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentylacetic acid sodium salt

CO ₂ Na

Le A 26

283612

10 g (27.7 mmol) 2- [4- (quinolin-2-yl-methoxy) phenyl] -2- ^ cyclopentyleesigsaure are dissolved in 100 ml of water After Z'igabe of 27 * 7 ml 1-normal sodium hydroxide solution is Stirred at 25 ⁰ C for 1 h, then concentrated and dried at 100 ⁰ C in vacuo. Yield: quantitative. Fixed point:> 230 ° C.

Example 23

Methyl 2- [4- (quinolin-2-ylmethoxy) phenyl] -3-cyclopentyl propionate

CO ₂ CH ₃

The preparation is carried out from 6.2 g (20 mmol) of 4- (quinoline

Methyl 2-yl-methoxy-1-butylphenolate and 3.3 g (20 mmol) of bromomethyl-cyclopentane analogously to the procedure of Example 2.

Yield: 5.1 g (65.5 X of theory) Melting point: 66-68 ⁰ C

Le A 26 119

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2838 I 2

example

2-C4- (quino1-in-2-yl-methoxy) -phenyl] -3-cyclopentyl-propionic acid

CO ₂ H

The preparation is carried out from 5 g (12.8 mmol) of 2- [4- (quino-1-in-2-yl-methoxy) phenylJ-S-cyclopentyl-propibanoic acid methyl ester analogously to the procedure of Example Yield: 2.5 g (52 %). theory) fixed point 126 - 128 ⁰ C

example

2- [4- (Chino1-in-2-yl-methoxy) phenyl 3-2-eyelohex-2-enyl) acetic acid

CO ₂ H

Ls A 26

20

- 53 -

The preparation is prepared from 24.34 g (62 × 8 mmol) of 2- [4- (quinolin-2-yl-methoxy) -phanyl] -2- (cyclohex-2-enyl) -acetic acid methyl ester analogously to the procedure of Example 7

Yield: 18.3 g (78 % of theory)

Fixed point! 188 - 192 ⁰ C 10

Example 26

2- [4- (quinolin-2-yl-methoxy) phenyl3-3-cyclopentyl-

acetic acid carboxymethyl ester 15

6.91 g (13.5 mmol) of 2-C4- (quinolin-2-yl-methoxy) -phenyl 3 2-cyclopentyl-acetic acid benzyloxycarbonylmethyl ester are dissolved in 100 ml of ethyl acetate and 10 ml of triethylamine, 0.5 g of palladium catalyst After addition of the theoretical amount of hydrogen, the catalyst is filtered off and concentrated by evaporation in vacuo, the residue is recrystallized from methanol. Yield: 3.15 g (55%), and the mixture is hydrogenated at normal pressure at 25.degree. 6 X of the theory.) Fixed point: 168 - 171 ⁰ C

Le A 26 119

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838

example

2-C4- (6-Fluoroquinolin-2-yl-inethoxy) phenyl] -2-cyclopentylacetic acid methyl ester

CO ₂ CH ₃

4.68 g (20.4 mmol) of 2- [4- (hydroxyphenyl) -2-cyclopentylessigsauremethylester are dissolved in 50 ml of dimethylformamide »After addition of 2.82 g (20.4 mmol) of potassium carbonate is at 50 ⁰ C for 1 h stirred, 4 g (20.4 mmol) of 2-chloroethyl-6-fluoro-quinoline added and stirred for a further 15 h at 50 ⁰ C »After concentration in vacuo, the residue is partitioned between water and ethyl acetate, the organic phase dried over sodium sulfate _t concentrated and the residue recrystallized from methanol · Yield: 7.36 g (91.6% of theory) fixed point! 117 - 119 ⁰ C

example

2- [4- (6-Fluoquinoquinolin-2-yl-methoxy) phenyl 3-2-eye 1-opentylacetic acid

CO ₂ H

Le A 26

- 55 -

The preparation is carried out from 7 g (17.8 mmol) 2- [4- (fluoroquinolin-2-yl-methoxy) phenyl] -2-eye 1 openty1-acetic acid methyl ester analogously to the procedure of Example 7, yield! 4.51 g (67 % of theory) fixed point: 182-184 ⁰ C.

Example 29

2- [4- (quinolin-2-yl-methoxy) -phenyl] -2-norbornyl-sssig acid methyl ester

CO ₂ CH ₃

The preparation is carried out from 6.2 g (20 mmol) 2- [4- (Chino · 1-yl-methoxy) phenyl] acetic acid methyl ester and 3.5 g (20 mmol) of exo-2-norbornyl chloride analogously to the procedure of Example 2. For the purpose of saturation, silica gel 60 (eluent toluene / acetic acid 9: 1) is chromatographed. Yield: 0.2 g (2.5 Ά of theory) Melting point: 123-125 ⁰ C.

Example 30

2- [4- (quinolin-2-yl-methoxy) phenyl] -2-norbornyl acetate

CO ₉ H

Le A 26 119

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The preparation is carried out from 0.4 g (1 mmol) 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-norbornyl-acetic acid methyl ester analogous to the procedure of Example Yield: 0.36 g (93 X of theory, fixed point: 158 - 160 ⁰ C

Example 31

4-BenzyloxyphenyleBsigsauremethylester

Il J

'CO ₂ CH ₃

397 g of methyl 4-hydroxyphenylacetate and 330 g of potassium carbonate are stirred in 2 l of dimethylformamide at 25 ° C. for 1 h. Thereafter, 302 g of benzylchloria are added and heated to 50 ° C for 15 h. After concentration in vacuo, the residue is partitioned between water and ethyl acetate, the organic phase dried over sodium sulfate and concentrated. The product is recrystallized from methanol. Yield: 511 g (83 % of theory). Fix point: 60 ° C

Example 32

2- (4-benzyloxyphenyl) -2-cyclopentylessigsäurtmethylester

CO ₂ CH ₃ Le A 26 119

- 57 -

256.3 g (1 mol) of 4-Benzyloxyphenyleeaigeäuremethyle8ter are dissolved in 1 1 dimethylformamide and added dropwise under protective gae (argon) at ^{0 0} C in a suspension of 24 g (1 mol) of sodium hydride in 100 ml of dimethylformamide After completion of ^ -Devicklung becomes 2 h bsi O ⁰ C stirred, then at the same temperature 149 g (1 mol)

Cyclopentyl bromide, in 400 ml of dimethylformamide gelabt,

added dropwise "After complete addition, 15 h at room temperature stirring. The solvent is concentrated in vacuo and the residue with hot water (80 ⁰ C) was added. While stirring (KPG stirrer) is cooled slowly. "The crystallized product is filtered off, washed well with water, dried and recrystallized from methanol. Yield: 276 g (85% of theory) Melting point: 77-78 ⁰ C (methanol)

2-Cyclopentyl-2- (4-hydroxyphenyl)

CO ₂ CH ₃

65 g (0.2 ml / l) of 2- (4-benzyloxyphenyl) -2-cyclopentylsuccinate are dissolved in 100 ml of tetrahydrofuran, 200 ml of ethanol and 100 ml of triethylamine. Mach addition of 1.5 g of palladium catalyst (lOxig au / coal) is hydrogenated for 2 h at 3 bar hydrogen. The catalyst is filtered off, the filtrate is concentrated and chromatographed on silica gel (eluant: methylene chloride). This gives a tough oil.

Yield: 43.7 g (93 % of theory)

Le A 26 119

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Examples 34 A and 34 B

Diastereomers of 2- [4-quinolin-2-yl-methoxy) phenyl 3-2-cyclopentylacetic acid C (L) -2-hydroxy-1-phenylethyl] emide

(L) 15

7.2 g (20 mmol) of 2- [4-quinolin-2-yl-methoxy) phenyl] -2-cyclopentylacetic acid and 3.3 g (24 mmol) of (L) -phenylglycinol are dissolved in 100 ml of dimethylformamide to -10 ⁰ C cooled solution 6.6 g (24 nunol) Phosphorsäurediphenylesterazid is added dropwise in 25 ml of dimethylformamide slowly, followed by 4.8 g (48 mmo!) of triethylamine was added and stirred for 15 h at -10 ⁰ C «The reaction mixture Ice is added, the crude product is filtered off, washed with water and dried. "Three times the recrystallization from ethanol gives diastereomer 34 A" Diastereomer 34 B is obtained by three-fold recrystallization of the combined mother liquors from dichloromethane.

Example 34 A: Yield: 1.93 g (20.1 % of theory)

Benchmark: 201 - 203 ° C (EtOH)

Example 34 B: Yield: 1.52 g (15.8 X of theory)

Bold point: 158-159 ⁰ C (CH ₂ Cl ₂ ) 35

Le A 26 119

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Example 35

(+) - 4- (2-quinolin-2-yl-methoxy) -phenyl] -2-eye-1-pentyl-acetic acid

(+) - enantiomer

CO ₂ H

4.8 g (10 mmol) of diastereomer A from Example 34 are heated in 50 ml of dioxane and 50 ml of 5 normal sulfuric acid under F. for 10 h. After cooling to ⁰ ° C., pH 3 is obtained with normal sodium hydroxide "The product is filtered off with suction and recrystallised from ethanol. Yield: 2.38 g (65.8 V, of theory) <x _D ²⁵ - +40.9 (c = I ₁ CHCl ₃ ) Melting point! 170-172 ⁰ C

Example 36

(-) - 4- [2-quinolin-2-yl-methoxy) phenyl] -2-cyclopentylacetic

(-) - enantiomer

COOH

Le A 26 119

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The preparation of the compound 36 is carried out analogously to the procedure of Example 35 using 4.8 g (10 itunol) of the diastereomer B from Example 34 «yield: 2.28 g (63.2 × of theory)

Melting point 170-172 ⁰ C Example 37 (Application example)

As a measure of a lipoxygenase inhibition, the release of leukotriene B ^ (LTB ^) from polymorphonuclear rat leucocytes (PMN) after addition of substances and Ca ionophore by reverse phase HPLC according to Borgest, P, et al, Proc. Nat, Acad, Sei. (USA) 76, 2148-2152 (1979).

Table 1 shows, by way of example, the values of some of the compounds according to the invention obtained by this test:

Table 1 Lipoxygenase inhibition Expl LO inhibition

7 0.14

8 0.01

9 0.04

(ΜΜ)

Le A 26 119

Claims (2)

claims A process for the preparation of substituted 4- (quinolin-2-yl-methoxy) phenylacetic acid derivatives of the formula in which R ¹ - for a group of the formula 2 ^ -OR ^ or -N is »where No. ³ R ² and R ^{3 are} identical or different and, for hydrogen, alkyl, aryl, aralkyl, or a group of the formula , 7 R ⁴ R ⁴ R ⁴ -CH-CO ₂ R ⁵ , -CH-CH ₂ -OR ⁵ , -CH-OR ⁶ R ⁴ or I I stand, where ., R ⁴ - represents hydrogen, alkyl, aralkyl or aryl which may be optionally substituted by hydroxy, carboxyl, alkoxycarbonyl, alkylthio, heteroaryl or carbamoyl. R ⁵ - represents hydrogen, alkyl, aryl or aralkyl, Le KsU b / R ⁶ - for a / m / group of the formula -COR ^{5 5} 'or -CO ₂ F ⁵ , wherein R ^{5 is} the above given meaning » and
¹⁰ R ⁷ - for hydrogen, alkyl or aryl, Y - for a group of the formula R ^{8 1
15 (} " ^CH) n, where R ⁸ - is hydrogen, alkyl or aryl, 20 and η - a number from 0 to 5 means Z is norbornyl or 25 is a group of the formula R ⁹ or -C ^ ä-R ⁹ , where 'm 30 R ⁹ and R are the same or different and are hydrogen, alkyl or aryl, or Le A 2t 119 ^ 838 R ⁹ and R ¹⁰ together form a saturated carbo- ⁵ cyclic ring with up to 6 carbon atoms atoms can form «and m - a number from 1 to 6 means « ¹⁰ A and B are the same or different and denote hydrogen "lower alkyl or halogen" as well as their salts, "^ d ¹ ABy in 'that CA] 4- (quinoi in-2-yl-m9thoxy) phenylessi'gsäureeste of the general formula (Ia) (Ia) in which COOR ¹¹ R ¹¹ - is alkyl and A and B have the meaning given above "30 with compounds of the general formula (II) Y-Z-X (II) 35 Le A / 26 ⁶⁵ 2 83 β 1 in which 5 Y and Z have the meaning given above »and X - represents chlorine» bromine or iodine » alkylated and in the case of the acids, the ester saponified »or indan man [B] the acids of the general formula (Ib) in which 25 A "B" Y and Z have the abovementioned meaning, with compounds of the general formula (III) XR ¹² (III) in which R ¹² - for a group of the formula _R 4 P ⁴ R ⁴ -CH-CO ₂ R ⁵ »-CH-CH ₂ -OR ⁵ , -CH-OR ⁶ Le A 26 R ^{4 5} I -CHv.i. ^ R '
or I j, where ⁰ Y ⁰ R ⁴ - is alkyl, aralkyl or aryl, dsB may be optionally substituted by hydroxy, carboxyl, alkoxycarbonyl, alkylthio, heteroaryl or carbo moyl, and
15 R ⁵ '- is alkyl, aryl or hralkyl, R ⁶ '- for a group of the formula -COR ⁵ or -CO * rx ⁵ ', where> 20 * Pr has the meaning given above, R ⁷ '- is alkyl or aryl, X has the meaning given above, esterified and, in the case of acids, subject the esters to a hydrogenolytic cleavage, or by [C] the acids of the general formula (Ib) Le A 26 119 in which λ "Bi Y and Z have the abovementioned meaning» with amines of the general formula (IV) HN (IV) N ³ in which 20 and R ^{3 have} the meaning given above » with the proviso "that R ^{5 is} not hydrogen" when R ² or R ^{3 is} the group R ⁴ -CH-CO ₂ R ⁵ Bteht »where R ⁴ and Br have the abovementioned meaning hf.bon, amidated in the presence of customary activating reagents and, in the case of acids, saponifying the esters, or by [D] Phenols of general formula (V) Le A Zi Y Z (V) COR in which R, Y and Z have the abovementioned meaning, with 2-halomethylquinolines of the formula (VI) (VI) in which A, B and X have the abovementioned meaning, etherified and saponified in the Pail of the acid esters. 2. The method according to claim 1, characterized in that it is carried out in the l'emperaturbereich from 0 to 150 ⁰ O.