CZ390392A3 - Benzofuranyl- and thiophenylmethylthio alkanecarboxylic acid derivatives, process of their preparation and use - Google Patents

Abstract

A method of transferring excess heat from coolant in a primary vessel (1) of a nuclear reactor through a space (5) between the wall of the primary vessel and the wall of a secondary vessel (3) containing the primary vessel, comprises disposing in the space pieces of a heat transfer medium which is solid at temperatures at and below the normal operating temperature of the coolant but which melts if the coolant temperature becomes excessive, the medium thereby making good heat transferring contact with both of the walls. The medium may be, for example, particles of aluminium. <IMAGE>

Description

Technical field

The present invention relates to benzofuranyl- and thiophenylmethylthioalkanecarboxylic acid derivatives, to a process for the preparation of these compounds and to their use as medicaments.

BACKGROUND OF THE INVENTION

With respect to the prior art, the benzofuran and benzothiophene derivatives which exhibit lipoxygenase inhibitory activity are described in European Patent No. 146 243. The compounds of formula I of the present invention are partially included within the broadest scope of the compounds in this patent, but without In this patent, concrete examples of active ingredients are given. In addition, NADPH phagocyte oxidase is known to be a physiological source of the hyperoxide anion (O ₂ ") and reactive oxygen moieties derived from this anion, which are very important in protecting against pathogens. However, uncontrolled formation leads to tissue damage in inflammatory processes, many NADPH oxidase inhibitors are known in the prior art, but do not have a selective effect (see, for example, Free Radicals in Biology and Medicine, Vol. 8, pp. 71-93, 1990).

SUMMARY OF THE INVENTION

The present invention relates to benzofuranyl- and thenylthioalkanecarboxylic acid derivatives of the general formula I:

in which it means':

R @ ¹ , R @ ² and R @ ^{3 are the} same or different substituents which represent a hydrogen atom, a hydroxyl group, a straight or branched chain alkoxy group containing up to 8 carbon atoms or a benzyloxy group;

n is 1, 2, 3, 4, 5 or 6;

R ⁴ is hydrogen, a straight- or branched chain containing up to 8 carbon atoms or phenyl,

A is a direct bond or -CO- or -CH ₂ -,

B represents an aryl group having 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocyclic group containing up to 3 heteroatoms from the group consisting of nitrogen, sulfur or oxygen, optionally monosubstituted to trisubstituted with the same or different substituents selected from carboxyl, atoms halogen, cyano, phenyl, tetrazolyl, thiazolyl and alkyl, straight or branched chain alkoxy or alkoxycarbonyl, each of which contains up to 8 carbon atoms, or

-co-nr ⁵ -so ₂ -r ⁶ where:

R @ ⁵ is hydrogen or a straight or branched chain alkyl group containing up to 4 carbon atoms, and

R ⁶ represents a straight or branched chain perfluoroalkyl group containing up to 6 carbon atoms, or an alkyl group or a straight or branched chain alkyl group having up to 6 carbon atoms, each of which may be optionally substituted by phenyl. wherein the phenyl radical may be monosubstituted to trisubstituted by the same or different substituents from the group consisting of halogens, carboxyl, cyano and nitro, or a straight or branched chain alkyl group of up to 6 carbon atoms, or a cycloalkyl group of 3 to 7 atoms or is an aryl group of 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocyclic group containing up to 3 heteroatoms from the group consisting of nitrogen, sulfur or oxygen, which are optionally monosubstituted to trisubstituted by the same or different substituents from

- 4 groups comprising halogens, carboxyl, cyano and nitro, or a straight or branched chain alkyl group containing up to 6 carbon atoms, and

D represents an oxygen or sulfur atom, and salts derived therefrom.

The benzofuranyl- and thiophenyimethylthioalkanecarboxylic acid derivatives of the present invention may also be used in the form of their salts. In general, the compounds may be in the form of salts with organic or inorganic bases.

In the context of the present invention, physiologically acceptable salts derived from the compounds of the present invention are preferred compounds. The physiologically acceptable salts of the benzofuranyl thiophenylmethylthioalkanecarboxylic acid derivatives may be metal salts or ammonium salts derived from said compounds of the invention which contain a free carboxyl group. Particularly preferred compounds include, for example, sodium salts, potassium salts, magnesium salts or calcium salts derived from these compounds of the invention, as well as ammonium salts derived from ammonia or organic amines such as ethylamine, diethylamine or triethylamine, diethanolamine or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

These physiologically acceptable salts can also be salts of the compounds of the invention with inorganic or organic acids. Preferably, the salts of the above compounds of the invention are salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or they may be salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and naphthalenedisulfonic acid.

The compounds of the present invention may exist in stereoisomeric forms which appear either as image forms and mirror forms (enantiomers) or which do not represent image or mirror forms (diastereoisomers). The present invention includes both these antipodes and racemate forms as well as diastereomeric mixtures. Racemate forms, like diastereomers, can be separated into their individual stereoisomeric homogeneous components by conventional techniques (see, for example, E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Said heterocyclic group is generally a 5- to 7-membered saturated or unsaturated ring, preferably a 5- to 6-membered ring, which may contain up to 2 oxygen, sulfur and / or nitrogen atoms as heteroatoms. Preferred heterocyclic groups are five- and six-membered rings containing oxygen, sulfur and / or up to 2 nitrogen atoms. Particularly preferred heterocyclic groups are: thienyl, furyl, pyrrolyl, pyrazolyl, pyridyl , pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl and tetrazolyl.

Preferred compounds of formula (I) of the present invention are those wherein:

R @ ¹ , R @ ² and R @ ^{3 represent the} same or different substituents which represent a hydrogen atom, a hydroxyl group, a straight or branched chain alkoxy group containing up to 6 carbon atoms or a benzyloxy group; n is 1, 2, 3, 4 or 5;

R ⁴ is hydrogen, a straight- or branched chain containing up to 6 carbon atoms or phenyl,

A is a direct bond or -CO- or -CH ₂ -,

B is phenyl, pyridyl, thienyl or furyl, which are optionally monosubstituted to trisubstituted with the same or different substituents selected from the group consisting of carboxyl, fluorine, chlorine, bromine, cyano, phenyl, tetrazolyl and thiazolyl, straight chained or branched chain alkyl, alkoxy or alkoxycarbonyl, each containing up to 6 carbon atoms or a group of formula

-co-nr ⁵ -so ₂ r ⁶ in which it means:

R 5 is hydrogen, methyl or ethyl, and

R ⁶ represents an alkyl group having a straight or lower alkyl group;

a branched chain or a perfluoroalkyl group, each of which contains up to 4 carbon atoms, or is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, or a benzyl group, a phenyl group or a pyridyl group which are optionally monosubstituted or disubstituted by the same or different substituents selected from the group consisting of fluorine, chlorine, bromine, carboxyl, cyano and nitro, or a straight or branched chain alkyl group containing up to 4 carbon atoms, wherein:

D represents an oxygen or sulfur atom, and salts derived therefrom.

Particularly preferred compounds of formula (I) of the present invention are those wherein:

R @ ¹ , R @ ² and R @ ^{3 represent the} same or different substituents which represent a hydrogen atom, a hydroxyl group, a straight or branched chain alkoxy group containing up to 4 carbon atoms or a benzyloxy group; n represents 1, 2, 3 or 4;

R ⁴ represents a hydrogen atom or an alkyl group with straight or branched chain containing up to 4 carbon atoms,

A is a direct bond or -CO- or -CH ₂ -,

B represents a phenyl or "yridyl" group, which are optionally monosubstituted to trisubstituted by the same or different substituents selected from the group consisting of carboxyl, cyano, chloro, bromo and alkyl, alkoxy or straight or branched chain alkoxycarbonyl of up to 4 carbon atoms or a group of formula

-co-nr ⁵ -so ₂ r ⁶ in which: c

R is hydrogen or methyl, and R is methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, or cyclohexyl, or is benzyl or phenyl, each of which is optionally monosubstituted or disubstituted by the same or different substituents selected from the group consisting of fluorine, chlorine, bromine, carboxyl, methyl and ethyl, and

D represents an oxygen or sulfur atom, and salts derived therefrom.

The present invention also relates to a process for the preparation of a compound of the formula (I) which comprises the preparation of a compound of the formula (II)

in which they mean:

R ¹ , R ² , R ³ , A, B and D have the same symbols as above, when R ¹ , R ² and / or R ^{3 do} not represent a hydroxyl group, by reaction with N-bromosuccinimide in the presence of a catalyst and in an inert solvent to the compound of formula III below;

and in the case where R ¹ , R ² and / or R ³ represent a hydroxyl group, this compound is first protected by conventional hydroxy protecting groups and then converted with boron tribromide or hydrobromic acid in glacial acetic acid in an inert solvent to a compound of formula III

in which they mean:

R @ ¹ , R @ ² , R @ ³ , A, B and D by the same symbols as above, in the next step, this compound is reacted with a compound of formula IV:

HS- (CH ₂ ) _n -CO ₂ R ⁷ (IV) wherein:

n the same symbol as above, and R ⁷ has the same meaning as above for R ⁴ , but does not represent a hydrogen atom, in an inert solvent, optionally in the presence of a base, and under a protective gas atmosphere; ί resulting esters are hydrolysed, and in the preparation of compounds with free hydroxyl functional groups (-this is R ¹ 'R ² and / or R ³ represent a hydroxyl group), the protecting groups are removed by conventional methods, and in the case where B represents one of the above said cyclic residues which are substituted by a group of the formula -NR ^ R ^ -SC ⁹ apply the sulfonamide compound of formula V

HNR ⁵ -SO ₂ -R ⁶ (V) in which they mean:

R ⁵ and R ^{6 have the} same substituents as mentioned above starting from the free carboxylic acid and optionally carrying out the reaction in the presence of a base and / or an additive, followed by amidation.

The process of the present invention can be illustrated by one of the following examples:

CN

The hydroxyl protecting groups mentioned in the context of the above description of the process for preparing the compounds of the invention generally represent protecting groups selected from the group consisting of trimethylsilyl, tert-butyl-dimethylsilyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, acetyl , tetrahydropyranyl and benzoyl.

Suitable solvents for carrying out the thioeterification are the customary organic solvents which do not change under the reaction conditions. Suitable solvents include, preferably, ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, acetone, dimethylformamide and methyl isobutyl ketone.

Suitable solvents for bromination are halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene and chlorobenzene. Carbon tetrachloride is preferably used for N-bromosuccinimide bromination, dichloromethane is preferably used for boron tribromide bromination, and glacial acetic acid is preferably used for hydrobromic acid bromination. Acetone and methyl isobutyl ketone are preferred solvents for performing thioeterification.

Suitable catalysts for carrying out bromination are the free radical reagents used, such as dibenzoyl peroxide or azobisisobutyronitrile. Preferably dibenzoyl peroxide is used.

The catalyst is used in an amount ranging from 0.001 mole to 0.2 mole of the compound of formula (II), preferably from 0.1 to 0.05 mole per mole of the compound of formula (II).

Suitable bases for performing thioeterification are the commonly used and known inorganic or organic bases. Preferred 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 and potassium carbonate, carbonates alkaline earth metals such as calcium carbonate or alkali or alkaline earth metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines, trialkylamines containing 1 to 6 atoms carbon, such as triethylamine, or heterocyclic materials, such as e.g.

1,4-diazabicyclo [2.2.2] octane (DABCO),

1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine or methylpiperidine. It is also possible to use alkali metals such as sodium or metal hydrides such as sodium hydride as bases. Preferably potassium carbonate is used.

The base is used in an amount ranging from mole to 10 moles per mole of the compound of formula III, preferably from 2.0 moles to 2.1 moles per mole of the compound of formula III.

Bromination is generally carried out at a temperature in the range of -30 ° C to +150 ° C, preferably in the range of -20 to +50 ° C.

The bromination is generally carried out at normal pressure. However, it is also possible to carry out the bromination at elevated pressures or at reduced pressures (such as pressures ranging from 0.05 to 0.5 MPa).

The thioeterification is usually carried out at a temperature in the range of +10 to +150 CC, preferably at a temperature in the range of +20 to +100 ’C.

Said thioeterification is usually carried out at normal pressure. However, it is also possible to carry out this etherification at elevated pressure or at reduced pressure (such as at a pressure in the range from 5 to 5 bar).

Generally, from 0.5 mole to 5 moles of halide (III), preferably from 1 mole to 2 moles of halide (III) per mole of reagent is used in the reaction. The base is generally used in an amount ranging from 0.5 mol to 5 mol, preferably from 1 mol to 3 mol, based on the amount of said halide.

The deprotection is carried out by conventional methods known in the art, for example, by hydrogenolytic cleavage of the above mentioned benzyl ethers in the inert solvents mentioned above, in the presence of a catalyst and using hydrogen gas (see in more detail Th. Green: Protective Groups in Organic).

Synthesis, J. Wiley & Sons, 1981, New York).

The tertiary butyl group is preferably removed by treatment with trifluoroacetic acid in dichloromethane and the methyl ester groups are removed by treatment with methanolic sodium hydroxide solution in tetrahydrofuran.

The compounds of formula II above are known in several variants (see, for example, European Patent No. 399 773; European Patent No. 146 243 and J. Med. Chem. 1978, Vol. 21, No. 4, pp. 348-352) Wherein when A is -CO-, the compound may be prepared by reacting a compound of formula VI

in which they mean:

R ¹ , R ² , R ³ and D have the same symbols as above with the compound of formula VII

(VII)

X in which means:

A '-CO-,

B is as defined above, and

X represents a typical leaving group such as chlorine, bromine, iodine, tosylate or mesylate in an inert solvent, optionally in the presence of a basic compound, and when A is a bond, the compound of formula VI is converted by reaction with a compound of formula (VIII) b-ch ₂ -y (VIII) wherein:

B is the same as above, and Y has the same meaning as X, preferably being a chlorine atom, in an inert solvent and in the presence of a basic compound to form a compound of formula IX

in which they mean:

R @ ¹ , R @ ² , R @ ³ , B, and D with the same symbols as above, followed by cyclization in a manner known per se, preferably using acetic anhydride, and when A is -CH ₂ ', then the compound of formula (VI) is first reacted with a compound of formula (VII) as described above, followed by reduction of the keto group (A' = -CO) by a conventional method.

Suitable solvents for the above reactions of the compounds of formulas VI, VII, VIII and IX are the abovementioned solvents and bases, preferably acetone and potassium carbonate.

The base is used in an amount ranging from 1 mol to 10 mol, preferably 1.0 mol to 2.1 mol, per 1 mol of the compound of formula (VI).

The above reaction is usually carried out at a temperature in the range of +30 ° C to +100 ° C, preferably in the range of +40 ° C to +80 ° C, and at normal pressure.

The cyclization is generally carried out at a temperature in the range of +30 ° C to 180 ° C, preferably in the range of +60 ° C to 120 ° C, and at normal pressure.

The reduction of the keto group is usually carried out using conventional reducing agents such as hydrides such as sodium cyanoborohydride or sodium borohydride, preferably sodium cyanoborohydride is used in an inert solvent such as ethers, hydrocarbons or alcohols or mixtures thereof preferably, the reduction is carried out in an ether such as diethyl ether, tetrahydrofuran or dioxane, or in an alcohol such as ethanol at a temperature in the range of 0 ° C to +150 ° C, preferably in the range of + 20 ° C to +50 ° C

The process according to the invention is usually carried out at normal pressure. However, it is also possible to carry out the process at elevated pressure or at reduced pressure (for example at a pressure in the range from 5 to 5 bar).

The compounds of formulas V, VI, VII, VIII and IX are known per se or can be prepared by conventional methods known in the art [cf. Beilstein 7,271; Beilstein 8, 85; Helv. Chim. Acta 50, (1967) 628, 637, 2233; 52 (1969) 887,888; J. Org.

Chem. 5 (1940), 54, 56; European Patent No. 165,810; Hoube-Weyl, Vol. IX-p. 407 et seq.].

Compounds of formula III are known in some variations (see, for example, U.S. Patent Nos. 4,137,414, 413,424; J. Med. Chem. 1978, Vol.

4) or represent new substances which can be prepared by the above process.

Compounds of formula IV are known (see, for example, Beilstein 3, 255, MSD Book, 2,2447 B).

Suitable bases for carrying out the above hydrolysis are commonly used inorganic bases.

These include, but are not limited to, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium bicarbonate, or alkali alkoxides metals such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or a target. potassium butoxide. Particularly preferred materials for this purpose include sodium hydroxide or potassium hydroxide.

Suitable solvents for carrying out the hydrolysis are water or organic solvents which are commonly used for carrying out the hydrolysis. These solvents are preferably alcohols such as methanol, ethanol, propanol, isopropanol or butanol, ethers such as tetrahydrofuran or dioxane, and dimethylformamide and dimethylsulfoxide. Especially preferred is the use of alcohols such as methanol, ethanol, propanol or isopropanol. Mixtures of the solvents mentioned above may also be used.

The hydrolysis can also be carried out with acids such as trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid, with trifluoroacetic acid being preferred.

This hydrolysis is typically carried according to the invention is carried out at temperatures ranging from 0 C to +100 ° C, preferably carried out at a temperature ranging from +20 DEG C. to +80 DEG C. ^e Usually, the hydrolysis is carried out normal pressure. However, it is also possible to operate at reduced pressure or at elevated pressure (such as at a pressure in the range of 0.5 bar to 0.5 bar).

In carrying out the hydrolysis, the base is usually used in an amount ranging from 1 mole to 3 moles, preferably from 1 mole to 3 moles.

1.5 mol, per 1 mol of ester. It is particularly preferred to use the reactants in a molar ratio to each other.

In the process for the preparation of the compounds of the formula I according to the invention, in the first step, the carboxylates of the compounds of the invention are formed as intermediates which can be separated. The acids of the invention are obtained by treating these carboxylates with commonly used inorganic acids for this purpose. These acids are preferably mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

In this context, it has been noted that it has proven advantageous in the preparation of these carboxylic acids to carry out the acidification of the basic reaction mixture obtained in the hydrolysis in one step without separating the carboxylate. The acids can then be isolated in a manner known per se. In the case of basic heterocyclic compounds, it is also possible to treat the carboxylate solutions with the above acids to obtain salts of the heterocyclic compounds with inorganic acids.

Said amidation / sulfoamidation is usually carried out in one of the abovementioned solvents, preferably in the dichloromethane. It is also possible to proceed by starting from the free carboxylic acid, which is converted to an activated form, for example the corresponding acid halide, which can be prepared from the corresponding acid by reaction with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride. In a preferred embodiment of the invention, the activated form is prepared from the corresponding acid using dicyclohexylcarbodiimide hydrochloride

N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide or carbonyldiimidazole and this activated form reacts in situ with the sulfonamide.

Said amidation and sulfoamidation is generally carried out at a temperature in the range of -20 to +80 ° C, preferably at a temperature in the range of -10 to +30 ° C, and at normal pressure.

In addition to the aforementioned bases, suitable bases for the above reactions are preferred

4.

according to the invention triethylamine and / or dimethylaminopyridine, DBU and DABCO.

The base is used in an amount ranging from 0.5 to 10 moles, preferably from 1 mol to 2 moles, per 1 mol of the above-mentioned compound of formula (V).

Acid binding agents can be used for the sulfoamidation, for example alkali metal carbonates or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide; potassium hydroxide, or as a substance; using acidic bases such as pyridine, triethylamine, N-methylpiperidine, or bicyclic amines such as

1,5-diazabicyclo [3.4.0] non-5-ene (DBN) or

1,5-diazabicyclo [3.4.0] undec-5-ene (DBU). Potassium carbonate is preferred in this context.

Suitable dehydrating reagents are, for example, carbodiroids such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole compounds or 1,2-oxazole compounds such as 2-ethyl compounds -5-phenyl-1,2-oxazolium-3-sulfonate or propanephosphonic anhydride or isobutyl chloroformate or benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate or diphenylphosphoramidate or methanesulfonyl chloride, optionally used in the presence of a base such as methyl-triethylamine or N-triethylamine or N-ethylamine dicyclohexylcarbodiimide and N-hydroxysuccinimide [cf. for example, J.C. Sheehan, S.L. Ledis, J. Amer. Chem. Soc. 95, 875 (1973); F.E. Frerman et al., J. Biol. Chem. 225, 507 (1982) and N.B. Benoton, K. Klurod, Int. Pept. Prot. Res.

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

These acid binding agents and dehydrating reagents are generally used in an amount of from 0.5 to 3 moles, preferably in an amount of from 1 mole to 1.5 moles, per 1 mol of the corresponding carboxylic acid.

The benzofuranyl- and thenylthioalkanecarboxylic acid derivatives of the present invention exhibit an unexpected variety of pharmacological effects, which can be used in medical practice.

Specifically, the compounds of the present invention inhibit NADPH phagocyte oxidase without impairing other cell functions such as degranulation or respiratory chain phosphorylation.

Thus, these compounds can be used as medicaments for controlling acute and chronic inflammatory processes.

Thus, the compounds of the present invention are preferably used to treat and prevent acute and chronic airway inflammations such as emphysema, alveolitis, shock lung, asthma, bronchitis, joint inflammation such as rheumatism, and vascular inflammation such as arteriosclerosis , arthrosis, inflammations of the gastrointestinal tract, and myocarditis. In addition, the compounds of the present invention are useful for reducing damage to infarcted tissue after reoxidation. In this case, it is appropriate to co-administer allopurinol to inhibit xanthine oxidase. Combination therapy using peroxide dismutase is also suitable. The compounds of the present invention are novel oxygen radical scavengers.

Description of the test performed.

1. Preparation of human PMN

Blood was collected from healthy subjects by venous puncture, with neutrophils purified by dextran sedimentation and then resuspended in buffer.

2. Inhibition of FMLP-stimulated formation of hyperoxide radical anions.

Neutrophils (2.5 χ 10 ⁵ ml ^-1 ) were mixed with the compounds of the present invention in dimethylsulfoxide (DMSO), with a final concentration of 10 µ vynálezu and a DMSO concentration of 1% by weight based on the total mass. After addition of luminol, final concentration about 10 M, and 33 [g / ml cytochalasin B, the cells were stimulated with FMLP at a final concentration of about 5 x 1O M ^_S peak chemiluminescence measurement was performed using an LKB luminometer 1251. In a similar manner was measured and inhibition of superoxide reducing cytochrome C levels by FMLP stimulated cells.

Neutrophils (2.6 χ 10 ⁵ ml ^-1 ) were mixed with the compounds of the invention in the same manner as in the chemiluminescence assay. Cytochrome C at a concentration of 3.8 x 10 ^-8 M FMLP was also present. The hyperoxide-dependent decrease in cytochrome C levels was measured using a Molecular Devices Thermomax plate recorder.

The inhibition of hyperoxide formation was calculated as follows:

^E x

- (—-) X 100 ^E 0 where:

_Ε χ emission cuvette containing the compound according to the invention, and

Εθ emission of cuvette with control sample.

FMLP induced cheminoluminescence of polymorphonuclear granulocytes: inhibition rate in% after administration of 10 μΜ test compound and IC ₅₀ (μΜ) values are given in Table A below:

Table A

Example # % inhibition ^IC 50 17 96 ± 2 0.7 18 77 ± 8 19 Dec 43 ± 15 20 May 59 ± 18 21 ‘51 ± 7 22nd 4.0 23 2.5 24 5.8

3. Inhibition of myeloperoxidase.

The compounds of this invention were tested for their effect on human neutrophil myeloperoxidase by the procedure of A.J. Bose et al., See Infection and Immunity, 1981, 32 (2), 427-431.

4. Test for xanthine oxidase.

According to this assay, equal portions of the substrate (7.5 mM hypoxanthine) were incubated at 25 ° C with the compounds according to the invention or carrier, wherein immediately prior to luminescence measurement was added 10 ^"5 luminol and xanthine oxidase. Hyperoxide formation was then determined for 140 seconds using the above LKB.1251 luminometer The activity was determined in each case against xanthine oxidase in the presence or absence of the compounds of the invention by monitoring increasing absorption at 292 nm due to the formation of uric acid.

5. Determination of specificity of effect.

When neutrophils are activated by PMA or FMLP. then release the lysosomal enzyme beta-glucuronidase. Preliminary experiments have shown that in the presence of cytochalasin B, FMLP exerts a stronger stimulatory effect. than PMA. The compounds of this invention were tested in parallel using a cell preparation and at a cell concentration of 10 ⁶ ml ^-1 to determine their ability to inhibit FMLP-induced hyperoxide formation and FMLP-induced beta-glucuronidase release.

6. NADPH oxidase assay.

Neutrophils were stimulated with PMA and then sonicated to prepare a membrane fraction. Oxidation of exogenous NADPH by this fraction was observed spectrophotometrically from a decrease in absorption at 340 nm. Compounds were tested at a final concentration of 33 μΜ.

The percent inhibition of NADPH oxidase in membrane fractions, measured at a final test compound concentration of 33 μΜ, is given in Table B.

- 27 Table B

Example # % inhibition of NADPH oxidase 17 21 ± 7 31 20 May

7. Oxidation test with mitochondrial substrate.

The mitochondrial fraction was prepared from finely cut guinea pig hearts. Oxidation of both nicotinamide adenine dinucleotides attributed to NADH was observed using an oxygen electrode in a Clandon Scientific Model 53. The compounds of the invention were tested for their ability to inhibit cell respiration by detecting their effect on oxidation of the two at concentrations up to 100 pg / ml. .

The percent inhibition of NADPH oxidation by mitochondria at the final test compound concentration of 300 μΜ is given in Table C.

Table C

Example # % inhibition (mitochondrial respiration) 17 24 + 2 31 0 ± 7

The novel active compounds according to the invention can be converted into conventional pharmaceutical preparations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using conventional means. known inert, non-toxic, pharmaceutically acceptable carriers or solvents. In this context, the therapeutically active compound should in each case be used in a concentration in the range of about 0.5 to 90% by weight based on the total weight of the composition, i.e. in an amount sufficient to of this range.

The compositions of the invention are prepared, for example, by combining the active compound with a solvent and / or vehicle, optionally using emulsifying agents and / or dispersing agents, for example, when water is used as a diluent, organic solvents may be suitably used as co-solvents.

Administration of these compositions is carried out in a conventional manner, preferably orally or parenterally, in particular orally or intravenously.

For parenteral administration, solutions of the active compound using suitable liquid carriers can be used.

In general, it has been found to be advantageous for the intravenous administration of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight, at a dosage level of about 0.001 to 10 mg / kg. to administer the active ingredient in an amount ranging from about 0.01 to 25 mg / kg body weight, preferably from 0.1 to 10 mg / kg body weight.

Notwithstanding the foregoing, it may be necessary in some cases to use amounts other than those indicated, particularly depending on body weight and the mode of administration of the composition, the individual response to the drug being administered, the manner in which the composition is formulated and the time or administration interval. Thus, in some cases, it may be sufficient to use smaller doses than those mentioned above as minimum doses, and in other cases situations may need to be used in which higher doses than those indicated above are required. In the case of administration of relatively high amounts, it is desirable to divide these into several individual doses and to administer these doses throughout the day.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention and their preparation will be illustrated by the following non-limiting examples.

Solvents:

A = CH ₂ C1 ₂

Al = CH ₂ Cl ₂ / CH ₃ OH 99: 1

A5 - CH ₂ Cl ₂ / CH ₃ OH 95: 5

A10 = CH ₂ Cl ₂ / CH ₃ OH 9: 1

B = ether / petroleum ether 1: 1

Without details:

RP-HPLC (C18 column) 10-90% acetonitrile in phosphate buffer (0.01 M, pH = 7.5).

The following is a basic structure of the compounds of the present invention with numerical designation of positions to illustrate sites where substituents are attached.

7a D

Starting compounds

Example

2- (4-Bromobenzoyl) -3-methylbenzo [b] furan.

The starting materials used in an equivalent amount of 10.8 grams (0.079 moles) of 2-hydroxyacetophenone and 22.1 grams (0.079 moles) of < &gt; -bromoacetopheone were dissolved in 50 ml. acetone, and then 22.0 grams (equivalent to 0.159 mol) of potassium carbonate was added. The suspension thus obtained was heated to reflux for 16 hours. The mixture was hot filtered and washed with hot acetone and the combined extracts were freed from solvent under vacuum. The crude product was then recrystallized from methanol or optionally purified by chromatography (silica gel 60).

Yield: 17.2 g (69%)

Melting point: 113 ° C

_Rf: 0.84 (A).

The compounds of Table I below were prepared in an analogous manner

TABLE I

X

Example DR ¹

C.

Y X Z

II

III

IV v

VI

VII

VIII

IX

X

XI

XII

XIII

XIV

XV

XVI

O H

O H

O H

O H

O H

O 4 -OH

O 6 -OCH ₂ C ₆ H ₅

O 6-OCH ₃

O 6-OCH ₃

O p-OCH ₃

O H

O 4 -O-CH ₂ C ₆ H ₅

O 5-OCH ₃

O 6-OCH ₃

H

H

-CN

- about ₂ ch ₃

Η

H

H

-ch ₃

H

H

H

H

H

H

H

H

CN

H and ₃ co ₂ ch ₃ ch ₃ ch ₃

₃ och ₃

Br

Cl

CH ^CH :

I WANT

Η

H

H

H

H

H

H

H

Cl

H

H

H

H

H

H

Table I (continued)

Example • « C. ^R f Melting point CC) Yield (% theoretical values) II 0.83 (A) 95 III 0.27 (A) 19 Dec IV 0.26 (A) 15 Dec in 0.47 (A) 79 VI 0.57 (A.) 47 VII 0.62 (A) 29 VIII 0.70 (A) 28 IX 0.64 (A) 55 X 0.71 (A) 66 XI 107 56 XII 0.82 (A) XIII 0.67 (B) XV 0.78 (A) 57 XVI 0.85 (A) 101 89

HPLC residence time, SiO ₂ 60 (CH ₃ / CN) / H ₂ O gradient / * benzo [b] thiophene

Example XVII

2- (4-bromobenzoyl) -3-bromomethylbenzo [b] furan.

Br

Br

16.9 g (0.054 mol) of the compound of Example I were dissolved in 100 ml of carbon tetrachloride, 9.5 g (0.054 mol) of N-bromosuccinimide were added and the mixture was treated with 0.3 g g of dibenzoyl peroxide and then refluxed for 8 hours. The mixture was hot filtered, and the solvent was distilled off under vacuum, whereupon the residue was optionally chromatographed.

R _f = 0.91 (CH ₂ C1 ₂ SiO ₂₎

M.p .: 133 ° C

Yield: 14.7 g (69% of theory).

Example XVIII

3-Bromomethyl-2- (4-methylbenzoyl) -6-hydroxybenzo [b] furan.

Br

CH ₃

and)

14.6 g (0.041 mol) of the compound of Example XV were dissolved in 50 ml of dichloromethane, cooled to -20 ° C, and 203 ml (0.203 mol) were added dropwise. boron tribromide BBr-j (1 M solution in CH ₂ C1 _2). After warming the solution to room temperature overnight, the mixture was poured onto ice and extracted three times with ethyl acetate. The combined organic phases were dried over Na ₂ SO ₄ and the solvent was removed under vacuum and the residue was crystallized from CH ₂ Cl ₂ .

Yield: 10.5 g (75% of theory)

_{F f} = σ, 16 ()).

(b)

...., -. The title compound can also be prepared by adding 20 ml (33%) of glacial acetic acid solution to 1.75 g of the compound of Example VIII which was dissolved in 150 ml of warmed glacial acetic acid. . The solution was heated to 60 ° C for 2 hours and then concentrated in vacuo. Dilution with cold water gives a solid product which is then filtered off, washed with water and dried using P ₂ O 5 by applying a vacuum.

Yield: quantitative.

Table II lists compounds which can be prepared by a method analogous to that described in Examples XVII and XVIII.

TABLE II

Br

, 0

O

OF,

X

Example C. ^R 1 Y X of XIX H H H H XX H H CN H XXI H CN H H XXII H co ₂ ch ₃ och ₃ H XXIII H H co ₂ ch ₃ H XIV 4-OH H ch ₃ H XXV 6-OH H ch ₃ H XXVI 5-OH H ch ₃ H XXVII 6-0-CH ₂ C ₆ H ₅ H ch ₃ H XXVIII 6-OH ch ₃ H H XXIX 6-OH H och ₃ ch ₃ XXX H H Cl H XXXI 4-OCH ₂ C ₆ H ₅ H ch ₃ H

Table II (continued)

Example C. ^R 1 Y X XXXII 6-OCH ₃ H CH. XXXIII 5-OCH ₃ H CH. XXXIV 6-OCH ₃ H Br XXXV 6-OCH ₃ ch ₃ H XXXVI 6-OCH ₃ H H

Table II (continued)

Example R _f (*)

C.

Yield ( ^a C) (% of theoretical)

XIX 0.92 102 37 XX 0.64 (AND) 58 XXI 0.64 (AND) 40 XXII 0.24 (AND) 57 XXIII 0.60 (AND) 38 XXIV 0.56 (Al). . 20 May XXV 0.28 (AND) 41 XXVI 0.22 (AND) 52 XXVII 0.74 (AND) 28 XXVIII 0.32 (Al) 66 XXIX 0.20 (AND) 78 XXX 0.85 128 41 XXXI 0.91 (B) 19 Dec XXXII 0.78 (AND) 39 XXXIII 0.86 (AND) 31 XXXIV 0.87 (AND) 8.0 XXXV 0.85 (Al) 48 XXXVI 0.82 (AND) 67

Examples of preparation procedures

Example 1

Preparation of 2- (4-bromobenzoyl) -3- [1- (2-methoxycarbonylethyl) thiomethyl] benzo [b] furan.

In this embodiment, 5.0 grams (equivalent to 0.013 mol) of the compound of Example XVII, 1.7 grams (equivalent to 0.014 mol) of methyl 3-mercaptopropionate, and 1.8 grams (equivalent to 0.013 mol) of potassium carbonate K ₂ The CO _{3 was} suspended in 50 ml of acetone or MIBK, after which 0.5 grams of potassium iodide was added and the mixture was refluxed under argon for eight hours. After cooling, the mixture was filtered, the solid was washed with acetone and the combined extracts were concentrated. The residue was taken up in dichloromethane CH ₂ C1 ₂ and the solution was washed several times with bicarbonate solution, dried over magnesium sulfate, '\ SO ₄ and concentrated by rotary evaporation. The product is purified or chromatographed (silica gel 60).

Yield: quantitative _Rf = 0.51 (A).

Table 1 below lists the compounds prepared in an analogous manner to the compounds of Example 1.

TABLE 1

Example R ¹ n Y X of R ⁴ C.

2 H 2 H H H -ch ₃ 3 H 2 H CN H . -ch ₃ 4 H 2 -CN H H -ch ₃ 5 H 2 - about ₂ ch ₃ -OCH ₃ H -C _{(CH3) 3} 6 H 2 H - about ₂ ch ₃ H -ch ₃ 7 4-OH 2 H ch ₃ H -0 (CH3) ₃ 8 6-OH 2 H ch ₃ H -C _{(CH3) 3} 9 5-OH 2 H ch ₃ H -ch ₃ 10 o-ch ₂ -c ₆ h ₅ 2 H ch ₃ H -ch ₃ 11 6-OH 2 -ch ₃ H H -ch ₃ 12 6-OH 2 H H ch ₃ -ch ₃ 13 6-OH 1 H ch ₃ H -C ₂ ^H 5

Table 1 (continued)

Example # Yield (% of theoretical value) R _f (*) 2 90 0.53 (A) 3 66 0.42 (A) 4 90 0.34 (A) 5 85 0.15 (A) 6 68 0.18 (A) 7 76 0.27 (A) 8 45 0.28 (A) 9 34 0.58 (A5) 10 quantitative 0.38 (A) 11 77 0.12 (A) 12 81 0.31 (Al) 13 49 0.09 (A)

- 44 Example 14

Preparation of 2- [3-carboxy-4-methoxybenzoyl] -3 - [(2 tert-butoxycarbonylethyl) thiomethyl] benzo [b] furan.

Example 15

Preparation of 2- [3-carboxy-4-methoxybenzoyl] -3 - [(2 carboxyethyl) thiomethyl] benzo [b] furan.

In carrying out the procedure of these two examples was

49.2 g (corresponding to 0.1100 mol) of the ester of Example 5 was dissolved in 400 ml of a 5: 3 mixture of methanol and tetrahydrofuran, and the mixture was cooled to 0 DEG C. and treated with 55.9 ml of 2N NaOH. After stirring at room temperature for 24 hours, the mixture was concentrated under vacuum, the residue dissolved in water and the solution separated from the undissolved material on diatomaceous earth and adjusted to pH 7 1.0 using phosphate buffer and 0.1N hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate several times and the organic extracts were washed with a buffer solution, wherein ^one then by drying the product over magnesium sulfate MgSO ₄ and concentrated. The residue was then recrystallized from isopropyl ether. 26.1 g (55% of theory) of the monoesters (Example 14) and a small amount (4 grams, corresponding to a yield of 9.6%) of the dicarboxylic acid (Example 15), which was obtained in pure form from the aqueous mother lye after acidification (pH <3).

Example 14: Yield = 58% of theoretical _Rf = 0.24 (CH ₂ Cl / CH ₃ OH 99: 1)

Example 15: Yield = 10% of theoretical Rf = 0.78.

Example 16

Preparation of 2- [4-methoxy-3- (2-tolylsulfonamidecarbonyl) benzoyl] -3 - [(2-tert-butoxycarbonylethyl) thiomethyl] benzo [b] furan.

For example, 1.8 grams (0.011 mol) of tolylsulfonamide, 5.0 grams (0.011 mol) of the carboxylic acid of Example 11, 1.3 grams (corresponding to 0.011 mol) of dimethylaminopyridine and 2.4 grams (0.013 mol) of N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride dissolved in CH ₂ Cl ₂ dichloromethane. The solution was stirred for 12 hours to exclude moisture. To work up the solution, the solution was shaken successively twice with 1N hydrochloric acid solution and then with water, and the organic phase was dried over sodium sulphate Na ₂ SO ₄ and concentrated in vacuo. The residue was recrystallized from methanol and dichloromethane, CH ₂ Cl _second

Yield: 99% of theory

R _f = 0.39 (CH ₂ C1 ₂ / CH ₃ OH 99: 1)

Example 17

Preparation of 2- [4-methoxy-3- (2-tolylsulfonamidecarbonyl) benzoyl] -3 - [(2-carboxyethyl) thiomethyl] benzo [b] furan.

4.8 g (0.008 mol) of t-butyl ester (Example 16) was dissolved in 50 ml of pure trifluoroacetic acid and the solution was allowed to stand at room temperature for 2 hours. The trifluoroacetic acid was distilled off under vacuum and the residue was crystallized from a mixture of dichloromethane and ethyl acetate. The resulting product was then carefully washed with water and dried over P ₂ O ₅ ⁱⁿ vacuo.

The methyl esters were dissolved in THF in an analogous manner to that of Example 14, followed by treatment with 1.1 equivalents of 1 N NaOH in methanol (2.2 equivalents for hydroxybenzo [b] furan) and stirred. overnight. The resulting solution was concentrated under vacuum and the residue was dissolved in water. The solution was washed several times with diethyl ether and then acidified with hydrochloric acid (1N solution). The prepared product was filtered or it may be optionally extracted with ethyl acetate, dried over magnesium sulfate MgSO _4, and then freed from the solvent in vacuo.

Yield: 76%

R _f = 0.46 (CH ₂ C1 _2).

The following Table 2 lists the compounds prepared from the carboxylic acid esters listed above (see Examples 1-17) by hydrolysis (see General Procedure).

TABLE 2

X

Example C. Ř ¹ n γ X ' OF 18 H 2 H -CN Η 19 Dec H 2 -CN H H 20 May H 2 H H H 21 H 2 H - after ₂ h H 22nd 4-OH 2 H ch ₃ H 23 6-OH 2 H ch ₃ H 24 5-OH 2 H ch ₃ H 25 6-OCH ₂ -C ₆ H ₅ 2 H ch ₃ H 26 6-OH 2 -ch ₃ Η H 27 Mar: 6-OH 2 H H ch ₃ 28 OH 2 H -Br H 29 H 2 H -Cl H 30 6-OH 1 H -ch ₃ H 31 H 2 - after ₂ h -och ₃ H 32 H 2 H Br H 33 6-OH 2 - after ₂ ^h -och ₃ H

Table 2 (continued)

Example # Yield (% of theoretical value) R _f (*) 18 50 6,281 19 Dec 52 6,208 20 May 38 0.49 (A5) 21 quantitative 5,973 22nd 62 0.38 (A10) / 6.690 23 76 0.26 (A5) / 6.271 24 5-4 0.31 (A10) / 6.414 25 76 0.21 (A5) 26 77 0.39 (A10) / 6.252 27 Mar: 81 0.44 (A10) / 5.981 28 48 6.64 29 18 7.66 30 84 0.07 (Al) / 6.030 31 10 5.73 32 70 0.51 (A5) 33 64 5,001

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Claims

Li1ío oc o o ^f czx ςχ 'Τ' *

Claims (10)

PATENTOVÉ 1. Benzofuranyl and thiophenylmethylthioalkanecarboxylic acid derivatives of the general formula I in which: R @ ¹ , R @ ² and R @ ^{3 are the} same or different substituents which represent a hydrogen atom, a hydroxyl group, a straight or branched chain alkoxy group containing up to 8 carbon atoms or a benzyloxy group; n is 1, 2, 3, 4, 5 or 6; R ⁴ is hydrogen, a straight- or branched chain containing up to 8 carbon atoms or phenyl, A is a direct bond or -CO- or -CH ₂ -, B represents an aryl group having 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocyclic group containing up to 3 heteroatoms from the group consisting of nitrogen, sulfur or oxygen, which are optionally monosubstituted to trisubstituted with the same or different substituents selected from carboxyl, atoms halogen, cyano, phenyl, tetrazolyl, thiazolyl and alkyl, straight or branched alkoxy or alkoxycarbonyl 52 chain, each of which contains up to 8 carbon atoms, or -co-nr ⁵ -so ₂ -r ⁶ where: R is a hydrogen atom or a straight or branched chain alkyl group containing up to 4 carbon atoms, and g R represents a straight or branched chain perfluoroalkyl group containing up to 6 carbon atoms, or an alkyl group or a straight or branched chain alkenyl group containing up to 6 carbon atoms, each of which may be optionally substituted by a phenyl group, wherein said phenyl radical it may be monosubstituted to trisubstituted by the same or different substituents from the group consisting of halogens, carboxyl, cyano and nitro, or straight or branched chain alkyl of up to 6 carbon atoms, or a cycloalkyl group of 3 to 7 carbon atoms, or an aryl group containing 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocyclic group containing up to 3 heteroatoms from the group consisting of nitrogen, sulfur or oxygen, which are optionally monosubstituted substituted to trisubstituted by the same or different substituents from the group consisting of halogens, carboxyl, cyano and nitro, or straight or branched alkyl. and D represents an oxygen or sulfur atom, and salts derived therefrom. Benzofuranyl- and thiophenylmethylthioalkanecarboxylic acid derivatives according to claim 1, in which: R ¹ , R ² and R ³ represent the same or different substituents which represent a hydrogen atom, a hydroxyl group, a straight or branched chain alkoxy group containing up to 6 carbon atoms or a benzyloxy group, n represents 1, 2, 3, 4 or 5, R ⁴ is hydrogen, a straight- or branched chain containing up to 6 carbon atoms or phenyl, A is a direct bond or -CO- or -CH ₂ -, B represents a phenyl, pyridyl, thienyl or furyl group, which are optionally monosubstituted to trisubstituted with the same or different substituents selected from the group consisting of carboxyl, fluorine, chlorine, bromine, cyano, phenyl, tetrazolyl and thiazolyl, alkyl a straight, branched, alkoxy or alkoxycarbonyl group, each of which contains up to 6 carbon atoms or a group of the formula -co-nr ⁵ -so ₂ r ⁶ in which it means: R is hydrogen, methyl or ethyl, and R ⁶ represents a straight or branched chain alkyl group or a perfluoroalkyl group, each of which contains up to 4 carbon atoms, or is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group,. or is a benzyl, phenyl or pyridyl group, which are optionally monosubstituted or disubstituted with the same or different substituents selected from the group consisting of fluorine, chlorine, bromine, carboxyl, cyano and nitro, or straight or branched chain alkyl of up to 4 carbon atoms, wherein D represents an oxygen or sulfur atom, and salts derived therefrom. 3. Benzofuranyl- and thiophenylmethylthioalkanecarboxylic acid derivatives according to claim 1, in which: R ^1, R ² and R ³ represent identical or different substituents which are hydrogen, hydroxy, alkoxy, straight or branched chain group containing up to 4 carbon atoms or benzyloxy, n represents a number 1, 2, 3 or 4, R ^ represents a hydrogen atom or a straight or branched chain alkyl group containing up to 4 carbon atoms, A is a direct bond or -CO- or -CH ₂ -, B represents a phenyl or pyridyl group, which are optionally monosubstituted to trisubstituted by the same or different substituents selected from the group consisting of carboxyl, cyano, chloro, bromo and alkyl, alkoxy or straight or branched chain alkoxycarbonyl of up to 4 carbon atoms, or a group of the general formula -CO-NR ⁵ -SO ₂ R ⁶ wherein: R ⁵ is hydrogen or methyl, and R is methyl, ethyl, propyl, trifluoromethyl, cyclopropyl or cyclohexyl, or is benzyl or phenyl, each of which is optionally monosubstituted or disubstituted by the same or different substituents selected from the group consisting of fluorine, chlorine, bromine, carboxyl, methyl and ethyl, and D represents an oxygen or sulfur atom, and salts derived therefrom. Benzofuranyl- and thiophenylmethylthioalkanecarboxylic acid derivatives according to claim 1 for disease control. 56 A process for the preparation of benzofuranyl thiophenylmethylthioalkanecarboxylic acid derivatives of the general formula I in which: R @ ¹ , R @ ² and R @ ^{3 are the} same or different substituents which represent a hydrogen atom, a hydroxyl group, a straight or branched chain alkoxy group containing up to 8 carbon atoms or a benzyloxy group; n is 1, 2, 3, 4, 5 or 6; R ⁴ is hydrogen, a straight- or branched chain containing up to 8 carbon atoms or phenyl, A is a direct bond or -CO- or -CH ₂ -, B represents an aryl group having 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocyclic group containing up to 3 heteroatoms from the group consisting of nitrogen, sulfur or oxygen, which are optionally monosubstituted to trisubstituted with the same or different substituents selected from carboxyl, atoms halogen, cyano, phenyl, tetrazolyl, thiazolyl and alkyl, straight or branched alkoxy or alkoxycarbonyl, each containing up to 8 carbon atoms, or -co-nr ⁵ -so ₂ -r ⁵ where: R @ ⁵ is hydrogen or a straight or branched chain alkyl group containing up to 4 carbon atoms, and R ⁶ represents a straight or branched chain perfluoralkyl group containing up to 6 carbon atoms, or an alkyl group or a straight or branched chain alkenyl group having up to 6 carbon atoms, each of which may be optionally substituted by a phenyl group, wherein said phenyl the radical may be substituted in the same manner as below for an aryl group, or a cycloalkyl group containing 3 to 7 carbon atoms, or an aryl group having 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocyclic group containing up to 3 heteroatoms from the group including nitrogen, sulfur or oxygen, which are optionally monosubstituted to trisubstituted by the same or different substituents from the group consisting of halogens, carboxyl, cyano and nitro, or alkyl sp a straight or branched chain containing up to 6 carbon atoms, and D represents an oxygen or sulfur atom, and salts derived therefrom, - 58, characterized in that the compound of formula (II): R ¹ , R ² , R ³ , A, B and D have the same symbols as above, when R ¹ , R ² and / or R ^{3 do} not represent a hydroxyl group, by reaction with N-bromosuccinimide in the presence of and in the case where R ¹ , R ² and / or R ³ represent a hydroxyl group, the compound is first protected by conventional hydroxy protecting groups and then converted with boron tribromide or acid hydrobromic acid in glacial acetic acid in an inert solvent to the compound of formula III in which: R ¹ , R ² , R ³ , k, B and D with the same symbols as above 59 from above, in which the following compound is reacted with a compound of formula IV: MS (CH ₂ ) _n -CO ₂ R ⁷ (IV). in which it means: n the same symbol as above, and R is as defined above for R &lt; ⁴ &gt; but does not represent a hydrogen atom, in an inert solvent, optionally in the presence of a base, and under a protective gas atmosphere, where the esters obtained are hydrolyzed in the preparation of acids; free hydroxyl functional groups (i.e., R ¹ , R ² and / or R ³ represent a hydroxyl group) are deprotected by conventional methods, and in the case where B represents one of the aforementioned cyclic radicals which are substituted with -NR ^ -SO ₂ R ^6, are used sulfonamide compounds of general formula V HNR @ ⁵ -SO ₂ -R ⁶ (V), wherein in R ⁵ and R ^{6 have the} same substituents as mentioned above starting from the free carboxylic acid and the reaction optionally carried out in the presence of a base and / or an additive, followed by amidation. A medicament comprising at least one benzofuranyl- or thiophenylmethylthio-alkanecarboxylic acid derivative according to claim 1. The medicament of claim 6 for controlling acute and chronic inflammatory processes. The medicament of claim 6 for reducing damage to infarcted tissue after reoxidation. A process for preparing a pharmaceutical composition according to claim 6, wherein the benzofuranyl or thiophenylmethylthio-alkanecarboxylic acid derivative is converted into a suitable dosage form, optionally combined with a conventional adjuvant and a vehicle. Use of the benzofuranyl thenylthioalkanecarboxylic acid derivatives according to claim 1 for the preparation of medicaments. Represented by: Dr. Miloš Všetečka Annotation (general formula I)