SK62293A3 - Substituted (benzothiazolyl and quinaxalyl-methoxy) phenyl-acetic acid derivatives - Google Patents

Abstract

Substituted benzothiazolyl- and quinoxalyl-methoxyphenylacetic acid derivatives are prepared either by reaction of heterocyclylmethyl-halogen compounds with corresponding phenoxy compounds, either directly or with subsequent alkylation, or by reaction of the heterocyclylmethyl-halogen compound with phenoxy compounds and subsequent reaction with suitable Grignard compounds. The substituted benzothiazolyl- and quinoxalyl-methoxyphenylacetic acid derivatives can be employed as active compounds in medicaments.

Description

The compounds of the present invention may exist in stereoisomeric forms which behave either as an image and a mirror image (enantiomers) or not as an image and a mirror image (diastereomers) .The present invention relates to both andipodes and racemic forms, and Racemic forms, like the diastereomers, can be resolved into known stereoisomerically uniform constituents (see EL Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962) by known methods.

Preferred are compounds of formula I wherein:

A. B, D, E and L are the same or different and are hydrogen, fluorine, chlorine or bromine, tri fluoromethoxy or carboxyl, straight or branched alkyl of up to 8 carbon atoms optionally substituted by hydroxy or atom fluorine, chlorine or bromine, a straight or branched alkoxy or alkoxycarbonyl group of up to 8 carbon atoms, or a phenyl group. which is optionally substituted by a fluorine, bromine or chlorine atom, a nitro group, a cyano group or a straight or branched alkyl or alkoxy group having up to 6 carbon atoms.

G is S or N = CH-,

R ¹ represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group or a straight or branched alkyl group having up to 8 carbon atoms optionally substituted by a phenyl group or a naphthyl group,

R ² represents hydrogen or a group -OR ^4, wherein

R ⁴ represents a hydrogen atom, a straight or branched alkyl group having up to 6 carbon atoms, a benzyl group or a phenyl group,

R ³ is hydroxy, straight or branched alkoxy having up to 6 carbon atoms or a group -NHSO 2 R ^5,

Why?

R ⁵ represents a wish or branched alkyl group having up to carbon atoms optionally substituted by a phenyl group which may itself be substituted by a straight or branched alkyl group having up to 6 carbon atoms or a fluorine, chlorine or bromine atom, or a phenyl group optionally substituted salts thereof.

a fluorine, chlorine or bromine atom, or a branched alkyl group of up to atoms, straight or carbon

Particularly preferred are the compounds of formula I wherein

A.

B.

D, E and L are the same or different and represent a hydrogen atom, a fluorine, chlorine or bromine atom, or a straight or branched alkyl or alkoxy group

R < ¹ & gt ^; in each case represents up to 6 carbon atoms.

sulfur or a cyclopentyl group

N = CH, cyclohexyl.

cycloheptyl or a straight or branched alkyl group of up to 6 carbon atoms optionally substituted by a phenyl group

R ² represents hydrogen or -OR ^"4 wherein

R ' ⁴ represents a hydrogen atom, a straight or branched alkyl group up to carbon atoms, or a phenyl group,

R ³ represents a hydroxy group, a straight or branched alkoxy group having up to 4 carbon atoms, or a group of the formula -NHSO 2 -R ⁵ .

while

R ⁵ represents a straight or branched alkyl group having up to carbon atoms optionally substituted by a phenyl group which may itself be substituted by a straight or branched alkyl group having up to 4 carbon atoms or a fluorine, chlorine atom or a phenyl group optionally substituted by an atom fluorine, chlorine, or methyl, and salts thereof.

Very preferred are compounds in which the -CR ¹ R ² -CO ³ radical is in the 3- or 4-position of the heterocyclylmethoxy radical.

The present invention further provides a process for the preparation of the compounds of formula (I). wherein (A) is a compound of formula Ia

A

(la) in which they have:

A, B, D, E, G, L, R ^{1 and} R ³ as defined above.

is prepared by producing a compound of formula II

ch ₂ -m (II), wherein A, B, D, E and G are as defined above and a

M represents a halogen atom, preferably bromine.

either directly etherifying with a compound of formula III

(III) in which:

R ⁶ represents a typical hydroxy protecting group, such as benzyl or tert-butyl, preferably benzyl, and

R ^'7 represents a C 1 to 8 carbon atoms, in inert solvents, optionally in the presence of a base, the removal of the protective group, or in a first step initially etherified with a compound of formula IIIa

(Hla), wherein R ⁶ and R ^{7 are} as defined above.

in inert solvents, optionally in the presence of a base, after cleavage of the protecting group, and then in the second step of alkyl, the compound of formula IV

R ^{@ 1} - T (IV).

wherein R ^{1 is} as defined above and

T represents a halogen atom, preferably chlorine or bromine, in inert solvents. optionally in the presence of a base, and in the case of acids (R ³ = OH), the ester is saponified by conventional methods, and in the case of sulfonamides (R ³ = NHSO ² R ⁵ ). starting from the corresponding acids, followed by their possible prior activation, amidation by reaction with the corresponding sulfonamide of formula VIII

Hz N - SO ² R ⁵ (VIII).

wherein R ⁵ has the abovementioned meaning, in inert solvents, optionally in the presence of a base and / or auxiliary agents, and also in case of different esters based esterification is carried out, optionally, the activated carboxylic acid.

and in the case of pure enantiomers, the corresponding acids are separated.

D, L, and L are optionally introduced or changed using conventional methods.

or be

CB) a compound of formula 11b

A

(IIb) in which they have A, B, D, E. G, L, R ¹ ,

R ³ and R ⁴ are as defined above.

they make it.

wherein the compound of formula (II) is first reacted with a compound of formula (V)

(V), in which L, R ⁶ and R ⁷ are as defined above, is converted by etherification of merging and not the

VI (VI), ιό in which A, B, D, E, G, L, and R ⁷ as defined above, and in a second step by reaction with a Grignard compound of the formula VII

R ¹ -V (VII), wherein R ^{1 is} as defined above and a

V is a typical Grignard residue V - Z, where

V means magnesium or zinc; and

Z is a chlorine, bromine or iodine atom, or is lithium, sodium, magnesium, aluminum or zinc, is reduced in an inert solvent, optionally in the presence of a base, by cleavage of the group V, and in case R ^{4 is} not hydrogen, ! ikuje.

and in case of (R ³ = OH) the esters by customary methods saponified, and in case of sulfonamide (R ³ = · NH-SO 2 R ^5), starting from the corresponding acid, and after a possible previous activation, followed by amidation reaction with the corresponding sulfonamide of formula VIII

H ₂ N-SO 2 -R ⁵ (VIII), wherein R ^{5 is} as defined above.

in inert solvents, optionally in the presence of a base and / or an auxiliary agent, and, for the various esters, optionally esterification, also starting from activated carboxylic acids, and for pure enantiomers, the corresponding acids, and the substituents A, B, D, E and L are optionally introduced by conventional methods or alternatively the process of the present invention can be illustrated by way of example by the following reaction scheme:

[A]

co ₂ ch ₃

οο ₂ οη,

COjH

HO

The cleavage of the protecting groups from the corresponding ethers is carried out by customary methods, for example by hydrogenolytic cleavage of benzyl ether in the above inert solvent in the presence of a catalyst with hydrogen gas. Greene ^: Protective Groups in Clrganic Synthesis, J. Viley / Sons, 1981, New York).

The solvents for the etherification include inert organic solvents which do not change under the reaction conditions. These include, in particular, 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, toluene, xylene, hexane, cyclohexane or the like. petroleum fractions; and nitromethane, dimethylformamide, acetonitrile, acetone or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents mentioned.

As bases for etherification, inorganic or organic bases can be used. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as carbonate calcium or organic amines (triethyl (C1-C6) -amines), such as triethylamine, or heterocycles, such as pyridine, methylpiperidine, piperidine or morpholine.

It is also possible to use alkali metals such as sodium or their hydrides such as sodium hydride as bases.

The etherification is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably in the range of 10 ° C to 100 ° C.

The esterification is generally carried out under normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

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

The saponification of carboxylic acid esters is carried out by conventional methods by treating the ester in an inert solvent with a conventional base.

Suitable bases for saponification are conventional inorganic bases. These preferably include alkali or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate, potassium carbonate and sodium bicarbonate. Sodium hydroxide or potassium hydroxide is particularly preferred.

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethyl alcohol, propyl alcohol, isopropyl alcohol or butyl alcohol, or ethers such as tetrahydrofuran or dioxane, or also dimethylformamide and dimethylsulfoxide. Alcohols such as methanol are particularly preferred. ethyl alcohol, propyl alcohol or isopropyl alcohol. It is also possible to use mixtures of the solvents mentioned.

The saponification is generally carried out at a temperature in the range of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C.

In general, the saponification is carried out at normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

In carrying out the saponification, the base or acid is generally used in an amount of 1 to 5 mol, preferably 1 to 1.5 mol, based on 1 mol of esters. Molar amounts of the reactants are particularly preferably used.

Suitable solvents for the reduction are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane. tetrahydrofuran and glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions. or also dimethylformamide. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran and diethyl ether are preferred.

The reduction is generally carried out at a temperature in the range of -80 ° C to 30 ° C, preferably -40 ° C to 25 ° C.

The reduction is generally carried out under normal pressure, but it is also possible to work under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

ft

The cleavage of the group V is carried out by methods customary for Grignard reactions with an aqueous solution of ammonium chloride Cvd. J. March, Advanced Organic Chemistry, Second Edition. 836).

In general, 1 to 3 mol, preferably 1.1 mol, of a Grignard compound or an organometallic compound of the formula VI is used, based on 1 mol of the glycoxy ester of the formula V.

Suitable solvents here are the customary organic solvents which do not change under the reaction conditions. These preferably include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, carbon tetrachloride, 1,2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, toluene, xylene, hexane, hexane, hexane, hexane, hexane, hexane, petroleum fractions, or else nitromethane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents mentioned. Particular preference is given to dichloromethane.

Suitable bases for sulfamidation are the customary basic compounds. These include in particular alkali or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrides such as sodium hydride, alkali metal or alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, or alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert -butyl, or organic amines. such as benzyltriammonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiperidine.

Sulfamidation is generally carried out at a temperature in the range of 0 ° C to 150 ° C. preferably 25 ° C to 40 ° C.

Sulfamidation is generally carried out under normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

In carrying out the sulfamidation, the bases are generally used in an amount of 1 mol to 3 mol, preferably 1 mol to 1.5 mol. based on one mole of the corresponding carboxylic acid.

Suitable dehydrating agents are carbodiimides, such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N ' -ethylcarbodiimide hydrochloride, carbonyl compounds such as carborimide imidazole. 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate, propanephosphoric anhydride, isoborformate, benzotriazolyloxy-tris-Cd imethylamino) phosphonium -hexafluorophosphate, diphenyl ester phosphonic acid or methanesulfonic acid chloride, optionally in the presence of a base. such as triethylamine, N-ethylmorpholine,

- 1 ° Im

N-methyl1 per perid, d 1 kexyl 1 carbodi m i d or

N-hydroxy-succinimide (see J. C. Sheehan. S.L. Ledis, J. Am. Cliem. Soc. 95, <375 (1973); F. L. Freeman et al., J. Biol. Chem.

225. 507 (1.982) and N. B. Benoton, K. Kluroda, Int. Peptidase. Prot.

Res. 13, 403 (1979). 17, 187 (1981)).

The compounds of the general formula can, for example, be produced in a halogen function such as in one, preferably in carbon tetrachloride, preferably AIBN, preferably N-bromosuccinimide, at ° C, preferably 60 ° C to 80 ° C, and

II are for the most part known or that the corresponding methylene of the abovementioned solvents, optionally in the presence of halogenating agents, is at a temperature in the range of 20 ° C to 100 normal pressure.

The compounds of formulas III, IIIa and V are for the most part known or can be prepared by known methods (see Chem. Commun, 1972 (11), 668).

Compounds of formula IV are also known (see Beilstein 5.19 / 5.24 / 5.29) or can be prepared from the corresponding alcohols or cycloalkanes by conventional methods.

The compounds of formula (VI) are novel and can be prepared by the above process.

The compounds of formula (VII) are known per se or can be prepared by customary methods (see K. Niitzel Houben-Veyl, Methoden der Organischen Chemie, 4th edition, Vol. 13 / 2a, 53 et seq. (Thieme Verlag, Stuttgart) (1973). S-Kharash, 0 Reinmuth, Grignard Reactions of Nonmetallic Compounds Prentice Halí, Nev York, 1974; Uhlman XII, 370; Houben-Veyl XIII / 2a, 289-302; RI Trust, RE Ireland, Org. 116, (1973); 0. Grummitt, EI Becker, Org. Syrith, Coll., Vol. IV, 771 (1963); H. Adkins, V. Zartman, Org., Synth, Coll., Vol. II, 606 (1943). ).

The sullonamides of formula VIII are known or can be prepared by known methods.

For example, the pure enantiomers of the compounds of formula (I) of the present invention can be prepared by resolving the corresponding enantiomerically pure acids by conventional methods and then reacting further as described above.

The compounds of formula I exhibit surprisingly high activity as leukotriene inhibitors, especially after oral administration.

The compounds of the present invention can be used as active ingredients in medicaments. These substances may act as inhibitors of enzymatic reactions in the metabolism of arachidonic acid j, in particular 5-1-lipoxygenase.

They are thus advantageous for the treatment and prevention of respiratory diseases such as allergic asthma, bronchitis, empphysema, shock lung, pulmonary hypertonia, inflammatory rheumatism and edema, gout.

thrombosis and thromboembolism, ischemia (peripheral, cardiac and cerebral blood flow disorders), heart and brain infarctions, heart rhythm disorders.

angina pectoris, arteriosclerosis, in tissue transplants.

dermatoses such as psoriasis, inflammatory dermatoses such as eczema, dermatophyte infections of the skin by bacteria, metastases, and also for cytoprotection in the gastrointestinal tract.

Substituted (benzothiazolyl-quinoxalinyl-2-yl-methoxy) phenyl-acetic acid derivatives can be used in both human and veterinary medicine.

The pharmacological effect values of the compounds of the invention are determined by the following method:

The release rate of leukotriene B-4 from polymorphic granular human leukocytes (PMN) upon addition of substance and Ca ⁴ '-lonophore A 23187 by reversed phase IIPLC according to P. Borgeata is determined as a measure for the inhibition of 5- 1 ipoxygenase of the present (LOI) and kol-. Proc.

Nat. Acad-Sc i 76, 2148-2152 (1979). The results are shown in the following table.

table

Example

LOI IC50 (mol / l)

9 5.4 x 10 ^-6 10 2.8 x 10-7 11 3.1 x 10- ⁷ 15 1.8 x 10 ⁷ 17 1.2 x io- ⁷ 18 2.8 x 10 ~ ⁷ 19 1.3 x 10- ⁷ 20 4.4 x 10 ~ ⁷ 23 3.0 x 10- ⁷ 24 2.4 x 10 ⁷

The present invention also provides pharmaceutical compositions which, in addition to inert, nontoxic and pharmaceutically acceptable carriers or solvents, contain one or more compounds of the formula I or consist of one or more active compounds of the formula I. Furthermore, the present invention also relates to a process for the manufacture of such compositions.

The therapeutically active compounds of formula I are to be present in these preparations in a concentration of about 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight of the total mixture.

In addition to the active compounds of the formula I, these pharmaceutical preparations can also contain other pharmaceutical active compounds.

The above pharmaceutical preparations may be prepared by conventional methods according to known methods, for example with a carrier or carriers or excipients or excipients.

In general, it has proven advantageous to administer the active compound (s) of the formula I in an amount of about 0.01 to about 100 mg / kg, preferably about 1 to 50 mg / kg of body weight per 24 hours, optionally in the form of several individual doses.

Nevertheless, it may be necessary to dispense with the abovementioned amounts. depending on the body weight or the type of application, but also on the individual tolerance to the medicament, the type and type of the preparation and the moment or the interval at which the application takes place.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example I

4-Benzyloxyphenylacetic acid methyl ester

397 g (2.39 mol) of 4-hydroxyphenyl acetic acid methyl ester and 330 g (2.39 mol) of potassium carbonate are stirred in 2 liters of dimethylformamide for one hour at 25 ° C. Then, 302 g (2.39 mol) of benzyl chloride is added and heated at 50 ° C for hours. After concentration in vacuo, the residue is partitioned between water and ethyl acetate, the organic phase is dried over sodium sulphate and concentrated. The product is crystallized from methanol.

Yield: 511 g (83% of theory)

Freezing point: 60 ° C.

The compounds listed in Table I were prepared analogously to Example I.

Table I

Example L 1.1. <C) yield (¾) II -C1 72 - 74 98 II Br 40 91

Example IV

2-C4-Benzyloxyphenyl) -2-cyclopentyl-acetic acid methyl ester

CO ₂ CH ₃

256.3 g (1 mol) of the compound of Example I are dissolved in one liter of dimethylformamide and under a protective gas atmosphere, a suspension of 24 g (1 mol) of sodium hydride in 100 ml of dimethylformamide is added dropwise at 0 ° C. After the evolution of hydrogen was complete, the reaction mixture was stirred for 2 hours at 0 ° C. 149 g (1 mol) of cyclopentyl bromide dissolved in 400 ml of dimethylformamide are then added dropwise at this temperature. After the addition was complete, the reaction mixture was stirred for 15 hours at room temperature. The solvent is then removed by rotary evaporation and the residue is mixed with hot water (80 ° C). After stirring, the mixture was slowly cooled.

The crystalline product is filtered off with suction, washed well with water, dried and recrystallized from methanol.

Yield - 276 g (85% of theory)

Pour point: 77 - 78 ° C (methanol)

Analogously to that described above. listed in Table II.

of Example IV, the mergers are produced. Table II

Example L R ¹ R 2 t. t. b.p.. (° C) yield (¾) IN H - (CH ₂ ) 3 -CH ₃ H 145-150 0.2 mm 87 VI H H 59 76 VII C1 H 165-170 0.2 mm 74

Example VIII

2-Cyclopentyl-2- (4-hydroxyphenyl) acetic acid methyl ester

HO

CO ₂ CH ₃ g (0.2 mol) of the compound of Example IV are dissolved in 100 ml of tetrahydrofuran, 200 ml of ethyl alcohol and 100 ml of triethylamine, and after addition of 1.5 g of palladium catalyst (10¾ on carbon) hydrogenated for 2 hours at hydrogen pressure 0.3 MPa. The catalyst is then filtered off, the filtrate is concentrated and chromatographed on silica gel using methylene chloride).

Yield - 43.7 g (93% of theory) Boiling point - 150 - 153 ° C / 0.2 mm.

The compounds listed in Table III were prepared analogously to Example VIII.

Table III

L

HO

CO ₂ CH ₃

Example L R ¹ R ² t.t./t,v. (° C) yield (¾) IX H - (CH 2) 3 -CH 3 H 134-138 0.2 mm 81 X H H 80 79 XI C1 H 155-160 0.2 mm 74

Example XII

2- [3- (Benzothiazol-2-yl-methoxy) -phenyl] -acetic acid methyl ester

14.9 g (0.1 mol) of 2-methylbenzothiazole in 250 ml of bromine carbon tetrachloride are treated with 19.6 g (0.11 mol) of NBS and 0.5 g ΛΙΒΝ. After the reaction, the precipitated succinimide is filtered off, the filtrate is concentrated, taken up in 100 ml of dimethyl formamide and a solution of 16.6 g (0.1 mol) of ethyl ester is added to this solution.

3-hydroxyphenyl ether and 13.8 g (0.1 mol) of potassium carbonate in 250 ml of dimethylformamide. The reaction mixture was heated at 50 ° C for 10 hours. After cooling, the solvent is evaporated, the residue is partitioned between water and ethyl acetate, the organic phase is concentrated and the residue is chromatographed on silica gel 60 using dichloroethane.

Yield 11.7 g (37.3% of theory)

Freezing point 58 - 61 ° C (diisopropyl ether).

Example XIII

Acetic acid 2- [3-bromo-4- (quinoxalinyl-2-yl-methoxy) -phenyl] -acetic acid methyl ester

CO ₂ CH ₃

The title compound is prepared analogously to Example XII.

Yield - 4.7 g (94.2% of theory)

Pour point: 120-122 ° C (ethyl acetate).

Example XIV

4- (Quinoxyl-2-yl-1-ethoxy) -phenylglyoxyl methyl ester

CO ₂ CH ₃

The title compound is prepared analogously to Example I.

yield : 8.0 g (37.7% of theory) temperature solidification 125 ° C (methanol). Example 1 a d XV

5- (Benzothiazol-2-yl-methoxy) -phenylglyoxylic acid methyl ester

CO ₂ CH ₃

The title compound is prepared analogously to Example XIV.

Yield: 10.3 g (31.4% of theory) Freezing point · 114 ° C (methanol).

Production examples

Example 1

2- [4-Benzothiazol-2-yl-methoxy) -phenyl] -2-cyclopentylacetic acid methyl ester

CO ₂ CH ₃

3.0 g (20 minol) of 2-methylbenzothiazole is brominated in 50 ml of carbon tetrachloride with 4.0 g <22.5 mmol) of N-bromosuccinimide and 0.3 g of AIBN. After the reaction, the precipitated succinimide is filtered off, the filtrate is concentrated, taken up in 50 ml of dimethylformamide and added to a solution of 4.7 g (20 mmol) of methyl acid ester.

2-cyclopentyl-2- (4-hydroxyphenyl) acetic acid and 2.8 g (20 mmol) of potassium carbonate in 100 ml of dimethylformamide. The reaction mixture is heated at 50 ° C for 10 hours. After cooling, the solvent is evaporated, the residue is partitioned between water and ethyl acetate, the organic phase is concentrated and the residue is chromatographed on silica gel 60 using cyclohexane / ethyl acetate (3 = 1).

Yield - 1.7 g <22.3% of theory) Freezing point - 97 - 98 ° C (diisopropyl ether).

Analogously to Example 1, the compounds listed in the following Table 1 were prepared.

Table 1

co-r ₃

Ex. G L R ² R ¹ R ³ t. t. (° C) (Rozp-) yields. (g) (¾ theory) 2 S H H ~ _(CH2> 3Cll3 -0CI13 65-66 (Di isopro- pyléter) 2.6 (14.1) 3 -N = CH- H H -OCH3 95-97 (Di isopropyl ether) 5.7 (68) 4 -N = CH- C1 H -00,113 98-100 (Di isopropyl ether) 2.3 (90) 5 -N = CH- H H -OCH3 108-110 (Di isopropyl ether) 1.7 (93)

Example 6

2- [3-Benzothiazol-2-ylmethoxy) phenyl] caproic acid methyl ester

The title compound was prepared analogously to Example IV from 10.9 g (0.035 mol) of the compound of Example IX. Yield ^: 6.4 g <50% of theory)

Pour Point: 108 ° C (Guetanol)

Example 7

2- [3-Bromo-4- (quinoxalin-2-ylmethoxy) phenyl] methyl ester

2-cyklohepty1octovéj

The title compound was prepared analogously to Example 6 of the compound of Example IX.

Yield ^: 2.1 g <40% of theory)

Freezing point 1132 ° C (metariol).

Example 8

2- [4-Benzothiazol-2-yl-methoxy) -phenyl] -2-cyclopentyl-acetic acid every ₂ h

1.5 g (3.9 mmol) of 2- [4-benzothiazol-2-ylmethoxy] phenyl-2-cyclopentylacetic acid methyl ester are refluxed in 50 ml of methanol and 20 ml of sodium hydroxide (1N). After cooling, 20 ml of 1N hydrochloric acid are added to the mixture, whereupon the product precipitates. After suction, it is washed with water, dried and recrystallized from methanol.

Yield - 1.3 g (97% of theory)

Pour point 152 - 154 ° C (methanol)

The compounds listed in Table 2 are prepared analogously to Example 8.

Table 2

Ex. G L R ² R ³ m.p. (° C) (NC.) vyťaž- (g) (% theor.) 9 -N = CH- H OH 173-175 (Diéty1 ether) 3.2 (60) 10 -N = CH- C1 OH 101-103 (Diéty1- ether) 1.7 (78.4) 11 -N = CH- H OH 163-165 (CH ₂ C1 ₂₎ 1.2 (87) 12 WITH H - (CH ₂ ) ₃ CH ₃ OH 117-118 (Methanol) 2.1 (67.8) 13 -N = CH- br OH 149 (CH 3 OH) 1.3 (51.5) 14 WITH H - (CH ₂ ) ₃ CH ₃ OH 99-102 (CH ₃ 0H) 1.9 (95)

Example 15

2- [3- (Benzothiazol-2-yl-methoxy) -phenyl] -caproic acid N-methylsulfonylamide

Phenyl I] (2.8 mmol) 2- (3- (benzothiazol-2-yl-methoxy) caproic acid, 0.267 g (2.8 mmol) of methanesulfonamide, 0.54 (2.8 mmol)

N '-ethyl - N' - (3-dimethylene and propyl 1) carbodi im idu

0.45 (3.7 mmol) of DMAP is dissolved in 30 ml of dichloromethane and the reaction mixture is stirred for 15 hours at 25 ° C.

The solvent was then evaporated and the residue was chromatographed on silica gel 60 using dichloromethane / methanol (100: 5).

Yield 0.42 g (34.7% of theory)

Freezing temperature

- 101 ° C (methanol)

Analogously to Example 15, the compounds shown in Table 3 are obtained.

Table 3

co-r ₃

Example 1. L R ¹ R ³ m.p. (° C) (dec.) yields. (g) (% theor.) 16 C1 -NHSO2CH3 163-165 (Diéty1éter) 0.3 (34) 17 C1 -NHSO2CH2-C6H5 150-152 (Diéty1- ether) 0.7 (53.6) 18 H -NHSO2CH3 160-162 (DiétyΙ- ό ter) 0.5 (51.4) 19 H -NHSO 2 CH 2 -C 6 h ₅ 148-150 (Diets I- ether) 0.6 (57) 20 H -NHSO 2 - CC ₆ IN> p - CH 3 137 (Diets 1 Ether) 1.3 (92.5)

Example 21

Methyl 2- [4- (quinoxolin-2-yl-methoxy) -phenyl] -phenyl ester 11-2-cyclopentylhydroxyacetic acid methyl ester

To a cooled solution (0 ° C) of 5 g (1.55 mmol) of 2- [4- (quinoxyl-2-yl-methoxy) -phenyl] -glyoxylic acid methyl ester in 50 mL of tetrahydrofuran was added dropwise freshly prepared ethereal ether under a protective gas atmosphere. Grignard reagent solution from 5.49 g (3.1 mmol) cyclopentyl bromide and 0.75 g (3.1 mmol) magnesium. After warming to 25 ° C, the reaction mixture was stirred overnight. then poured into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The residue obtained after evaporation is chromatographed on silica gel 60 using a mixture of cyclohexane and ethyl acetate (3 = 1).

Yield = 2.26 g (34% of theory)

Freezing point - 121 ° C (methanol).

The compounds listed in Table 4 were prepared analogously to Example 21.

Table 4

Ex. GR ¹ R ³ m.p. (° C) (NC.) yields. (g) (% theor.) 22 WITH -OCH3 101 (CH 3 OH) 2.56 (39.4) 23 -N = CH- OH 160 (CH 3 OH) 1.1 (50.7) 24 WITH OH 190 (CH 3 OH) 1.8 (86.5)

Claims (9)

1. Substituted (benzothiazoles-1- and quinoxaly-1-methoxy) -phenyl-acetic acid derivatives of the general formula I And in which A. B, D. E and L are the same or different and represent a hydrogen atom, a hydroxy group, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group or a carboxyl group. a straight or branched alkyl group having up to 10 carbon atoms optionally substituted by a hydroxy or halogen atom, a straight or branched alkoxy or a 1-alkoxycarbonyl group having up to 10 carbon atoms; 10 carbon atoms. (C až-Cry) aryl group optionally substituted by halogen, nitro, cyano, or straight or branched (C 8-C alky) alkyl or alkoxy. G is S or N = CH-, R ¹ represents a cycloalkyl group having 3 to 12 carbon atoms or a straight or branched alkyl group having up to 10 carbon atoms, which is optionally substituted with an aryl group having G to 10 carbon atoms. R ² represents hydrogen or a group -OR ^'5th Why? R ⁴ represents a hydrogen atom, a straight or branched alkyl group having up to 8 carbon atoms, a benzyl group or a phenyl group, R ³ is hydroxy. a straight or branched alkoxy group having up to 8 carbon atoms or a phenoxy group or a group of the formula -NHSO 2 -R ⁵ , wherein: R ⁵ represents a straight or branched alkyl group having from 1 to ⁵ carbon atoms; Is optionally substituted by a phenyl group, which may itself be substituted by a straight or branched alkyl group of up to 6 carbon atoms or a halogen atom, or a phenyl group optionally substituted by a halogen atom. three fluoromethyl or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each, and salts thereof. Substituted (benzothiazolyl-quinoxalyl-methoxy) -phenyl-acetic acid derivatives according to claim 1, in which: A, B, D, E and L are the same or different and represent a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a trifluoromethoxy group or a carboxy group of a straight, branched or alkyl group having up to 8 carbon atoms which is optionally substituted by a hydroxy or fluorine, chlorine or bromine atom, a straight or branched alkoxy or alkoxycarbonyl group of up to 8 carbon atoms, or a phenyl group. which is optionally substituted by fluorine, bromine or chlorine, nitro, cyano or straight or branched and 1-alkyl or alkoxy G R ^{1 is a} group of up to 6 carbon atoms. represents a sulfur atom or a group of the formula - N = CH-, represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. cyclohexyl, cycloheptyl or cyclooctyl or a straight or branched alkyl group of up to 8 carbon atoms optionally substituted by phenyl or naphthyl means a hydrogen atom or -OR ⁴ , wherein: R ⁴ represents a hydrogen atom, a straight or branched alkyl group having up to 6 carbon atoms, a benzyl group or a phenyl group, R ³ is hydroxy, straight or branched alkoxy having up to 6 carbon atoms and one group of the formula -NHSO 2 EBO-R ^5, wherein R ^a represents straight or branched alkyl having up to G carbon atoms, optionally substituted by phenyl, which in turn may be substituted by a straight chain or branched alkyl having up to 6 carbon atoms or by fluorine. chlorine or bromine, or a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, or a straight or branched alkyl group having up to 4 carbon atoms, and salts thereof. Substituted (benzothiazoles-1- and quinoxaly-1-methoxy) -phenyl-acetic acid derivatives according to claim 1 of the general formula I: A. B D, L, and L are the same or different and are hydrogen. fluorine atom. chlorine or bromine, or a straight or branched alkyl or alkoxy group In each case, R &lt; ¹ &gt; means up to 6 carbon atoms, sulfur or cyclopentyl N = CH-, cyclohexyl. cycloheptyl is alkyl with up to or straight or branched chain 6 is a hydrogen atom R ² optionally substituted by phenyl or -OR ⁴ , wherein R ⁴ represents a hydrogen atom, a straight or branched alkyl group having up to 4 carbon atoms, or a phenyl group, R ³ represents a hydroxy group, a straight or branched alkoxy group having up to 4 carbon atoms, or a group of the formula -NHSO 2 -R ⁵ , wherein: R ⁵ represents a straight or branched alkyl group having from 1 to ⁵ carbon atoms; 4 carbon atoms optionally substituted by a phenyl group, which may itself be substituted by a straight or branched and 1 keel group with up to 4 carbon atoms or a fluorine, chlorine, or phenyl group, optionally substituted by a fluorine, chlorine or methyl group , and salts thereof. 4. A compound according to claim 1, wherein the -CR &lt; ¹ &gt; R &lt; ² &gt; residue is in the 3- or 4-position of the heterocyclomethoxy radical. 5. Substituted (benzothiazolyl- and quinoxalyl-methoxy) phenyl-acetic acid derivatives for therapeutic use. A process for the preparation of substituted (benzothiazolyl- and quinoxalyl-methoxy) phenyl-acetic acid derivatives according to claim 1, characterized in that (A) is a compound of the formula Ia Wherein A, B, D, E, G, L, R ¹ and R ^{3 are} as defined above, are prepared by producing a compound of formula II E --G ^x n ^ ch ₂ -m (II), in which they have A. B, D, E and G as defined above, and M represents a halogen atom, preferably bromine. either directly etherifies using a compound of formula III in which R ⁶ represents a typical hydroxy protecting group, such as benzyl or tert-butyl, preferably benzyl, and R ⁷ represents an alkoxy group having 1 to 8 carbon atoms, in inert solvents, optionally in the presence of a base, after deprotection. and / or in the first step, it is first purified by the compound of formula (IIa) CH ₂ —C — R ₇ Wherein R ⁶ and R ^{y are} as defined above. in inert solvents, optionally in the presence of a base, after cleavage of the protecting group and then in a second step alkylated with a compound of formula IV R ¹ - T (IV), wherein R ¹ has the abovementioned meaning and represents halogen. preferably chlorine or bromine. in inert solvents, if appropriate in the presence and in the case of acids (R ³ = OH) the esters by customary methods saponified, and in case of sulfonamides (R ³ = NHSO 2 R ^5), starting from the corresponding acid, followed by their possible with prior activation, amidation by reaction with the corresponding sulfonamide of formula VIII H 2 N - SO 2 R ⁵ (VIII). in which he has R ⁵ as defined above, and rozpúšťad1ách means of an inert, optionally in the presence of a base and / or auxiliary, and in case of the different esters is carried out by esterification, optionally, also based on the activated carboxylic acids, and in the case of the pure enantiomers of the corresponding sharing. and the substituents A, B, D, E and L are optionally introduced or changed by conventional methods, or (B) a compound of formula IIb (Hb) in which they have A, B, D, E, G, L, R ¹ , R ³ and R ⁴ have the same meaning as previously defined; The method according to claim 1, wherein the compound of formula II is first reacted with a compound of formula V (V) in which L, R ⁶ and R ⁷ are as defined above. by etherification to a compound of formula VI and in a second step by reaction with a Grignard compound of formula VII R ¹ -V (VII). wherein R ^{1 is} as defined above and V is a typical Grignard residue V - Z, where V means magnesium or zinc; and Z is a chlorine, bromine or iodine atom, or is lithium, sodium, magnesium, aluminum or zinc. It is reduced in an inert solvent, optionally in the presence of a base, by cleavage of the group V, and in case R ^{4 is} not hydrogen, it is etherified in a conventional manner. and in case of (R ³ = OH) the esters by customary methods saponified, and in case of sulfonamide (R ³ -NH-SO 2 R ^5), starting from the corresponding acid, and after a possible previous activation, followed by amidation reaction with the corresponding sulfonamides of formula VIII 112 N-SO 2 -R ⁵ (VIII), wherein R ^{5 is} as defined above. in inert solvents, optionally in the presence of a base and / or auxiliary agent, and for the various esters optionally esterification, also starting from activated carboxylic acids, is carried out, and for pure enantiomers the corresponding acids are separated. and substituents A, B, D. E and L are optionally introduced or changed by conventional methods. A medicament comprising at least one substituted (benzothiazolyl- or quinoxalylmethoxy) phenyl-acetic acid derivative according to claim 1. n • A process for the manufacture of medicaments according to claim 7, characterized in that. The process according to claim 1, characterized in that the substituted (benzothiazolyl) and quinoxalyl-methoxy) -phenyl-acetic acid derivatives are converted, if appropriate with the aid of conventional carriers and auxiliaries, into a suitable dosage form. Use of the substituted (benzothiazolyl-quinoxalyl-methoxy) phenyl-acetic acid derivatives according to claim 1 for the production of