WO1998050373A1

WO1998050373A1 - Substituted aminothiazoles and the use thereof as active antimicrobial substances

Info

Publication number: WO1998050373A1
Application number: PCT/EP1998/002378
Authority: WO
Inventors: Bernd Baasner; Michael Matzke; Hans-Christian Militzer; Klaus Schaller; Harald Labischinski; Rainer Endermann; Hans-Otto Werling
Original assignee: Bayer Aktiengesellschaft
Priority date: 1997-05-06
Filing date: 1998-04-22
Publication date: 1998-11-12
Also published as: DE19719053A1; AU7646598A

Abstract

The invention relates to substituted aminothiazoles, a method for the production and the use thereof as medicaments, specially as active antimicrobial substances.

Description

SUBSTITUTED AMINOTHIAZOLES AND THEIR USE AS ANTIMICROBIAL ACTIVE SUBSTANCES

The present invention relates to substituted aminothiazoles, a process for their preparation and their use as medicaments, in particular as antimicrobial active substances.

From the publications DE-38 36 184 and DE-38 36 167 2-aminothiazoles with an antimycotic effect are already known. In addition, 1 - (thiazol-2-yl) -2- (arylimino) -5-triazolo [5, l-b] thiazoles and triazolylguanidines have been described as antibacterial agents and with an insecticidal action [cf. PCT WO 91/18 882; Indian J. Heterocycl. Chem. (1994), 4 (1), 5-8; J. Indian Chem. Soc. (1979), 56 (9), 937-8; Curr. Sei (1969), 38 (22), 538-9].

The present invention now relates to substituted aminothiazoles of the general formula (I)

in which

A, D and E are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 5 carbon atoms, cyano, halogen or the rest SCF ₃ ,

R ^{1 represents} phenyl, which is optionally up to 5 times the same or different by halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, trifluoromethyl sulfide, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms , Hydroxy or substituted by trifiuormethyl, R ² , R ³ R ⁴ and R ^{5 are the} same or different and are hydrogen or a radical of the formula

stand, or for a 5- to 6-membered, saturated or unsaturated heterocycle with up to 4 heteroatoms from the series S, N or O, or for cycloalkyl with 3 to 11 carbon atoms or for aryl with 6 to 10 carbon atoms, where all ring systems optionally up to 5 times the same or different by cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkoxycarbonyl or alkoxy each having up to 6 carbon atoms, straight-chain or branched alkyl or hydroxy-substituted alkyl each having up to 6 carbon atoms, trifiuormethyl, carboxy, Hydroxy, halogen or are substituted by a group of the formula - (CO) _a -NR ⁶ R ⁷ ,

wherein

a number means 0 or 1,

R> 6, u, "and JE R> 7 are the same or different and Is hydrogen, phenyl, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms,

or R ² , R ³ , R ⁴ and / or R ^{5 represent} straight-chain or branched alkyl or alkenyl each having up to 10 carbon atoms, which may optionally be up to 4 times the same or different by cyano, halogen, hydroxy, trifluomethyl, phenyl, straight-chain or branched alkoxy, alkylthio or alkynyl each having up to 6 carbon atoms or substituted by a group of the formula -NR ⁸ R ⁹ ,

wherein

R ⁸ and R ^{9 have} the meaning of R ⁶ and R ⁷ given above and are identical or different with this,

and / or the straight-chain or branched alkyl or alkenyl optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by a 5- to 6-membered, saturated or unsaturated heterocycle having up to 4 heteroatoms from the series S, N or O, where the Ring systems optionally substituted up to 4 times, identically or differently, by straight-chain or branched alkyl having up to 5 carbon atoms or by a group of the formula - (CO) _b -NR ¹⁰ R ^π ,

wherein

b has the meaning of a given above and is the same or different with it,

R ¹⁰ and R ^{11 are the} same or different and are those given above

Have the meaning of R ⁶ R ⁷ ,

and / or the straight-chain or branched alkyl or alkenyl optionally by a radical of the formula

are substituted,

or

R ² and R ° and / or R ⁴ and R ⁵ together, including the nitrogen atom, form a 5- to 7-membered saturated, optionally still benzo-condensed heterocycle with up to 3 heteroatoms from the series S, N and / or O, which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in turn can be substituted by hydroxy,

and their salts

The compounds of the general formula (I) according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here

Within the scope of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the new 2,4-di-substituted

Aminothiazoles can be salts of the inventive substances acidic with mineral, carboxylic acids or sulfonic acids are particularly preferably for example salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Ethansulfonsaure, toluenesulfonic acid, benzenesulfonic acid, naphtha thahndisulfonsaure, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid , Fumaric acid, maleic acid or benzoic acid Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol , Arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. The

Racem forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner

Heterocycle generally represents a 5- to 6-membered, saturated or unsaturated ring which can contain up to 4 heteroatoms from the series oxygen, sulfur and / or nitrogen. The following are preferably mentioned: thienyl, furyl,

Pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 4,5-dihydro-l, 2,3-triazolyl, piperidyl, morpholinyl, piperazine or pyrrolidinyl. Piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, thienyl, furyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 4,5-dihydro-l, 2,3-triazolyl are particularly preferred.

The compounds of the general formula (I) in which at least one of the radicals R ² , R ³ , R ⁴ , R ^{5 represents} hydrogen are in equilibrium with the tautomeric compounds of the general formula (Ia) which are likewise according to the invention

in which R, A, D and E have the meaning given above,

and

R ³ , R ⁴ and R ⁵ can have the meanings given above for R ² , R ³ , R ⁴ and R ⁵ .

Compounds of the general formula (I) are preferred

in which

A, D and E are the same or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, fluorine, chlorine, bromine or the rest SCF ₃ ,

R ^{1 represents} phenyl, which is optionally up to 3 times the same or different by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfide, cyclopentyl, cyclohexyl, straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms or by trifluoromethyl is substituted,

R ² , R ³ , R ⁴ and R ^{5 are the} same or different and are hydrogen or a radical of the formula

stand for, or for thienyl, furyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 4,5-dihydro-l, 2,3-triazolyl, tetrazolyl, piperidinyl, Pyrimidyl, pyridyl, piperazinyl or for cyclopropyl, cyclopentyl,

Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclodecyl or phenyl, the ring systems optionally being up to 5 times the same or different by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched alkoxycarbonyl or alkoxy each having up to 5 carbon atoms straight-chain or branched alkyl or hydroxy-substituted alkyl each having up to 4 carbon atoms, trifluoromethyl, carboxy, hydroxy, fluorine, chlorine, bromine or substituted by a group of the formula - (CO) _a -NR ⁶ R ⁷ ,

wherein

a represents a number 0 or 1,

R ⁶ and R ^{7 are the} same or different and

Is hydrogen, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl having up to 5 carbon atoms,

or

R ² , R ³ , R ⁴ and / or R ^{5 represent} straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may be up to 2 times the same or different by fluorine, chlorine, bromine, hydroxy, cyano, trifluomethyl, Phenyl, straight-chain or branched alkoxy, alkylthio or alkynyl each having up to 4 carbon atoms or substituted by a group of the formula -NR ⁸ R ⁹ ,

wherein R ⁸ and R ^{9 have} the meaning of R ⁶ and R ⁷ given above and are identical or different with this,

and / or the straight-chain or branched alkyl or alkenyl optionally by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, furyl, pyrrolidinyl, N-methyl-substituted pyrrolidinyl, morpholine, 1,2,3-triazolyl, 1,2 , 4-triazolyl, 4,5-dihydro-l, 2,3-triazolyl, tetrazolyl, piperidinyl, pyrimidyl, pyridyl or piperazinyl or are substituted by a group of the formula - (CO) _b -NR ¹⁰ R ^π ,

wherein

has the meaning of a given above and is the same or different with it,

R ¹⁰ and R ^{1 1 are} identical or different and have the meaning of R ⁶ R ⁷ given above,

are substituted,

or

R> 2. u.nd R and / or R »4 and R together including the nitrogen atom form a piperidinyl, piperazinyl or tetrahydroquinoline ring which are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, which in turn can be substituted by hydroxy,

and their salts.

Compounds of the general formula (I) are particularly preferred

in which

A, D and E are the same or different and stand for hydrogen, methyl, fluorine, chlorine, bromine or for the rest SCF,

R ^{1 represents} phenyl, which is optionally substituted up to 2 times by the same or different means by fluorine, methyl, methoxy, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclohexyl or by trifluoromethyl sulfide,

stand for, or for thienyl, furyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 4,5-dihydro-l, 2,3-triazolyl, tetrazolyl, piperidinyl, Pyrimidyl, pyridyl, piperazinyl or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or phenyl, the ring systems optionally being up to 5 times the same or different by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched chain Alkoxy each having up to 4 carbon atoms, straight-chain or branched alkyl or hydroxy-substituted alkyl each having up to 4 carbon atoms, trifluoromethyl, carboxy, hydroxy, fluorine, chlorine, bromine or by a group of the formula - (CO) _a -NR ⁶ R ^{7 are} substituted,

wherein

a number means 0 or 1,

R ⁶ and R ^{7 are the} same or different and

Is hydrogen, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl having up to 4 carbon atoms, or represent straight-chain or branched alkyl or alkenyl each having up to 7 carbon atoms, which may optionally be up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, cyano, trifluomethyl, phenyl, straight-chain or branched alkoxy, alkylthio or alkynyl each with up to 3 carbon atoms or are substituted by a group of the formula -NR R,

wherein

R and R have the meaning of R and R given above and are the same or different with this,

and / or alkyl or alkenyl optionally by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, thienyl, furyl, pyrrolidinyl, N-methyl-substituted pyrrolidinyl, morpholine, 1,2,3-triazolyl, 1,2,4-triazolyl , 4,5-dihydro-l, 2,3-triazolyl, tetrazylyl, piperidinyl, pyrimidyl, pyridyl or piperazinyl or are substituted by a group of the formula - (CO) _b -NR ¹⁰ R ¹¹ ,

wherein

b has the meaning of a given above and is the same or different with it.

R, ιo. and . R 11 are the same or different and have the meaning of R ⁶ R ⁷ given above,

and / or alkyl or alkenyl optionally by a radical of the formula

are substituted,

or

R and R and / or R and R together with the nitrogen atom form a piperidinyl, piperazinyl or tetrahydroquinoline ring which are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, which in turn can be substituted by hydroxy,

and their salts.

Those compounds of the general formula (I) in which A, D and E are hydrogen, the radical -OR ¹ is linked in the 2- or 3-position of the phenyl ring and R is phenyl in the 4-position are very particularly preferred bears one of the above-mentioned substituents and optionally carries in the 2-position another of the above-mentioned substituents, where both substituents can be the same or different.

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention was found, characterized in that

Thiourea derivatives of the general formula (II)

in which

R ² R ³ , R ⁴ and R ^{5 have} the meaning given above,

with acetophenone derivatives of the general formula (III)

in which

A, D, E and R ^{1 have} the meaning given above

and

L represents hydroxy or halogen, preferably bromine or chlorine,

optionally in the presence of an inert solvent and optionally under

Implement the addition of an auxiliary,

and in the case of the salts add an acid,

and in the case of R ² , R ³ , R ⁴ and / or R ⁵ ≠ H optionally carrying out an alkylation by customary methods

and the substituents R ² , R ³ , R ⁴ , R ⁵ , A, D and E are introduced and / or derivatized by known methods. The process according to the invention can be illustrated by the following formula scheme:

Inert organic or inorganic solvents are suitable as diluents for carrying out the process according to the invention. These include in particular aliphatic, alicyclic or aromatic, optionally halogenated, hydrocarbons, such as, for example, gasoline, benzene, toluene, xylene, chlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ethers, such as diethyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl - or -diethyl ether, ketones, such as acetone or butanone, nitriles, such as

Acetonitrile or propionitrile, amides, such as dimethylformamide, dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric acid triamide, esters, such as ethyl acetate or sulfoxides, such as dimethyl sulfoxide, alcohols such as methanol, ethanol or propanol, bases such as pyridine and optionally also mixtures thereof pure water. Ketones, in particular acetone, are preferred.

Inorganic or organic bases are generally suitable as auxiliaries. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate, or alkali metal alcoholates such as sodium methane late, sodium methoxide, potassium methanolate, potassium methoxide or potassium tert-butanolate. Also suitable are ammonia and primary, secondary or tertiary amines such as tetramethylamine, N, N-dimethylamine, pyridine, N, N-dimethylaminopyridine, diazabicyclooct ), Diazabicyclonones (DBN) or diazabicycloundecene (DBU). Lithium hydroxide, sodium hydroxide or potassium hydroxide are particularly preferably used

The auxiliary is generally used in an amount of 0.05 mol to 5 mol, based on 1 mol of the compounds of the general formula (II), preferably in an amount of 0.8 to 1.5 mol

The process according to the invention is generally carried out in a temperature range from 0 ° C. to 180 ° C., preferably from 20 ° C. to 150 ° C.

The method according to the invention is generally carried out under normal pressure. However, it is also possible to carry out the method under positive pressure or under negative pressure (for example in a range from 0.5 to 5 bar).

In general, the compounds of general formula (II) in one

Amount of 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, based on 1 mol of the compounds of the general formula (III) used

The reaction is carried out, worked up and isolated by generally customary methods. Any by-products which may occur can be separated off using customary chromatographic methods

The acid addition salts of the compounds of the formulas (I) and (Ia) can be obtained in a simple manner by customary salt formation methods, for example by dissolving a compound of the formula (I) in a suitable inert solvent and adding the acid, such as, for example, hydrochloric acid and isolated in a known manner, for example by filtration, and optionally cleaned by washing with an inert organic solvent

Some of the compounds of the general formulas (II) and (III) are known or new, but can then be prepared analogously to published methods, in particular by the processes described in DE 38 36 167 The compounds of the general formulas (I) and (Ia) according to the invention show an unforeseeable, new spectrum of action. They have an antibiotic effect on Helicobacter spp.

These valuable properties enable their use as chemotherapeutic agents for the therapy of Helicobacter pylori infections and the associated gastroduodenal diseases, which can be prevented, improved and / or cured by the compounds according to the invention.

In addition, the compounds according to the invention can also be used in combination with other therapeutic agents. Examples of possible combination partners are: nitroimidazole derivatives, for example metronidazole; Proton pump inhibitors, for example omeprazole, pantoprazole or lansoprazole; H ₇ receptor antagonists, such as, for example, cimetidine, ranitidine, famotidine or nizatidine; Bismuth compounds such as bismuth salicylate or CBS (colloidal bismuth subcitrate); other antibiotics, such as amoxicillin, azlocillin or clarithromycin; Antacids such as sodium hydrogen carbonate, aluminum hydroxide, hydrotalcite, magaldrate.

The minimum inhibitory concentrations (MIC) were determined in the agar dilution test on Columbia agar (Oxoid) with 10% lysed horse blood either at neutral pH or pH 5.0 with 1 g / 1 urea.

The test substances were tested in replica dishes which contained decreasing concentrations of the active ingredient at twice the dilution. For inoculation, fresh Helicobacter cultures were used in liquid culture or suspension of the germs of agar plates which have previously been diluted such that each inoculation point ca 10 ⁶ - containing 10 ⁷ colony-forming particles. The inoculated agar plates were incubated at 37 ° C in an atmosphere with 1% CO _{2 for} 48-72 h. The read MIC value (mg / 1) indicates the lowest active substance concentration at which no growth was visible to the naked eye.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for producing them

Preparations. The active ingredient (s) can optionally also be present in microencapsulated form in one or more of the carrier substances specified above

The therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about OJ to 99.5, preferably of about 0.5 to 95% by weight of the total mixture

In addition to the compounds according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients

In general, it has proven advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in

Total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form of a number of individual doses, to be administered to achieve the desired results. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 up to about 80, especially 3 to 30 mg / kg body weight

Output connections

Example I

l-cyano-2-methylisothiourea

H ₂ N _{^ ^} S.

M

^

N

A mixture of 175 g (1.2 mol) of dimethyl N-cyanothioiminocarbonate, 400 ml

Isopropanol and 125 ml of ammonium hydroxide solution are stirred for one day at room temperature. After about 15 minutes, a solution is formed, from which a precipitate then forms with the formation of methyl mercaptan. The crystals are filtered off, washed with petroleum ether and then dried. Yield: 100 g (72% of theory)

Example II

N - {[Amino- (N-methylpiperazin-4-yl)] methylene} cyanamide

50 g (0.43 mol) of l-cyano-2-methylisothiourea and 43 g (0.43 mol) of N-methylpiperazine are refluxed in 400 ml of butanol for one day. The solution is then concentrated in vacuo and the residue is stirred with acetone. The crystals are filtered off and dried. Yield: 51 g (70% of theory). Mp .: 188-190 ° C Example III

N - {[Amino- (N-methylpiperazin-4-yl)] methylene} thiourea

A solution of 10 g (0.060 mol) of N - {[amino- (N-methylpiperazin-4-yl)] - methylene} cyanamide in 1.5 l of pyridine makes lighter at 70-80 ° C for 5-6 h Stream of hydrogen sulfide passed. It is then concentrated in vacuo and the crude product is used for the next reaction without further purification. Crude yield: 12.9 g

The compounds listed in Table I are prepared analogously to the regulations of Examples I - III:

Table I:

The compounds listed in Table I are first converted into the corresponding thioureas in analogy to the procedure of Example III and then used as a crude product for the preparation of the compounds of the general formula (I) according to the invention. Manufacturing examples

example 1

2- [amino- (4-diethylamino-cyclohexyl) aminomethylene] amino-4- [2- (2,4-dimethylphenoxy) phenyl] thiazole

A mixture of 8.2 g (0.03 mol) of N- [amino- (4-diethylamino-cyclohexyl) aminomethylene] thiourea and 11.1 g (0.035 mol) of 2-bromo-l- [2- (2nd , 4-dimethylphenoxy) phenyl] -ethanone (cf. DOS 38 35 616) in 30 ml acetone 2 is heated under reflux. The mixture is then concentrated in vacuo and the residue is chromatographed by column chromatography on silica gel (eluent: toluene / ethanol, 5: 1).

Yield: 1.3 g (7.5% of theory). Mp .: 138 ° C

In the compounds of Table 1, in which no mp can be specified, the chemical shift characteristic of the thiazole is characteristic of the thiazoles.

Protons of position 5 indicated.

The 1H NMR spectra were recorded in DMSO-d ₆ (dimethyl sulfoxide-d ₆ ) with tetramethylsilane (TMS) as the internal standard. The chemical is given

Shift as a δ value in ppm.

The entire NMR spectrum and the mass spectrum are in all cases

Consistent with the specified structure.

The examples listed in Tables 1 and 2 are prepared in analogy to the instructions in Example 1:

Table 1:

Table 2:

Table 3

Claims

claims

Substituted aminothiazoles of the general formula (I)

in which

R ^{1 represents} phenyl, which is optionally up to 5 times the same or different by halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, trifluoromethyl sulfide, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms, hydroxy or is substituted by trifluoromethyl,

R ² , R ³ R ⁴ and R ^{5 are the} same or different and are hydrogen or a radical of the formula

stand, or for a 5- to 6-membered, saturated or unsaturated heterocycle with up to 4 heteroatoms from the series S, N or O, or for cycloalkyl with 3 to 11 carbon atoms or for aryl with 6 to 10 carbon atoms, where all ring systems optionally up to 5 times the same or different by cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkoxycarbonyl or alkoxy each having up to 6 carbon atoms, straight-chain or branched alkyl or hydroxy-substituted alkyl each having up to 6 carbon atoms, trifiuormethyl, Carboxy, hydroxy, halogen or substituted by a group of the formula - (CO) -NR ⁶ R ⁷ ,

wherein

a number means 0 or 1,

R ⁶ and R ^{7 are the} same or different and

Are hydrogen, phenyl, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms. or

R ² , R ³ , R ⁴ and / or R ^{5 represent} straight-chain or branched alkyl or alkenyl each having up to 10 carbon atoms, which may be up to 4-fold identical or different by cyano, halogen, hydroxy, trifluoromethyl, phenyl straight-chain or branched alkoxy, alkylthio or alkynyl each having up to 6 carbon atoms or substituted by a group of the formula -NR R,

wherein

and / or the straight-chain or branched alkyl or alkenyl optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by a 5- to 6-membered, saturated or unsaturated heterocycle having up to 4 heteroatoms from the series S, N or O, where the Ring systems are optionally substituted up to 4 times, identically or differently, by straight-chain or branched alkyl having up to 5 carbon atoms or by a group of the formula - (CO) _b -NR ¹⁰ R ^π ,

wherein

b has the meaning of a given above and is the same or different with it,

R ¹⁰ and R ^{11 are} identical or different and have the meaning of R ⁶ R ⁷ given above,

are substituted,

or

and R and / or R and R together, including the nitrogen atom, form a 5- to 7-membered saturated, optionally still benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, which may be by straight-chain or branched alkyl is substituted with up to 6 carbon atoms, which in turn can be substituted by hydroxy,

and their salts and tautomers.

Compounds of the general formula (I) according to Claim 1, characterized in that

R represents phenyl, which is optionally substituted up to 3 times identically or differently by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfide, cyclopentyl, cyclohexyl, straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms or by trifluoromethyl is R ² , R ³ , R ⁴ and R ^{5 are the} same or different and are hydrogen or a radical of the formula

stand for, or for thienyl, furyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 4,5-dihydro-l, 2,3-triazolyl, tetrazolyl, piperidinyl, pyrimidyl, Pyridyl, piperazinyl or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or phenyl, the ring systems optionally being up to 5 times the same or different by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched Alkoxycarbonyl or alkoxy each having up to 5 carbon atoms, straight-chain or branched alkyl or hydroxy-substituted alkyl each having up to 4 carbon atoms, trifluoromethyl, carboxy, hydroxy, fluorine, chlorine, bromine or by a group of the formula - (CO) _a -NR R are substituted,

wherein

a number means 0 or 1, R ⁶ and R ^{7 are the} same or different and

or

wherein

and / or the straight-chain or branched alkyl or alkenyl optionally by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, furyl, pyrrolidinyl, N-methyl-substituted pyrrolidinyl, morpholinyl, 1,2,3-triazolyl, 1,2,4 -Triazolyl, 4,5-dihydro-l, 2,3-triazolyl, tetrazolyl, piperidinyl, pyrimidyl, pyridyl or

Piperazinyl or are substituted by a group of the formula - (CO) _b -NR ¹⁰ R ^π ,

wonn

b has the meaning of a given above and is the same or different with it,

R ¹⁰ and R ^{π are} identical or different and have the meaning of RR given above,

are substituted,

or

R ² and R ³ and / or R ⁴ and R ⁵ together with the nitrogen atom form a piperidinyl, piperazinyl or tetrahydroquinoline ring, which are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, which in turn is substituted by hydroxy can be,

and their salts and tautomers.

A, D and E are the same or different and represent hydrogen, methyl, fluorine, chlorine, bromine or the rest SCF ₃ ,

R represents phenyl, which is optionally substituted up to two times, identically or differently, by fluorine, methyl, methoxy, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclohexyl or by trifluoromethylsulfide,

stand for, or for thienyl, furyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 4,5-dihydro-l, 2,3-triazolyl, tetrazolyl, piperidinyl, pyrimidyl, Pyridyl, piperazinyl or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or phenyl, the ring systems optionally being up to 5 times the same or different by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched alkoxycarbonyl or alkoxy each up to 4 carbon atoms, straight-chain or branched alkyl or hydroxy-substituted alkyl each with up to 4 carbon atoms, trifluoromethyl, carboxy, hydroxy, fluorine, chlorine, bromine or substituted by a group of the formula - (CO) _a -NR ⁶ R ⁷ are,

woπn

a number means 0 or 1,

R ⁶ and R ^{7 are the} same or different and Is hydrogen, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl having up to 4 carbon atoms,

or represent straight-chain or branched alkyl or alkenyl each having up to 7 carbon atoms, which may optionally be up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, cyano, trifluomethyl, phenyl, straight-chain or branched alkoxy, alkylthio or alkynyl each with up to 3 carbon atoms or are substituted by a group of the formula -NR ⁸ R,

wherein

and / or alkyl or alkenyl optionally by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, thienyl, furyl, pyrrolidinyl, N-methyl-substituted pyrrolidinyl, morpholinyl, 1,

2,

3-triazolyl, 1,2,4-triazolyl,

4,5-dihydro-1,2,3-triazolyl, tetrazolyl, piperidinyl, pyrimidyl, pyridyl or piperazinyl or are substituted by a group of the formula - (CO) _b -NR ¹⁰ R ^π ,

wherein

b has the meaning of a given above and is the same or different with it,

R ¹⁰ and R are identical or different and have the meaning of R ⁶ R ⁷ given above,

and / or alkyl or alkenyl optionally by a radical of the formula

are substituted,

or

and their salts and tautomers.

Process for the preparation of compounds of the general formula (I) according to Claim 1, characterized in that thiourea derivatives of the general formula (II)

in which

R ² R ³ , R ⁴ and R ^{5 have} the meaning given above,

with acetophenone derivatives of the general formula (III)

in which

A, D, E and R ^{1 have} the meaning given above

and

L represents hydroxy or halogen, preferably bromine or chlorine,

if appropriate in the presence of an inert solvent and if appropriate with the addition of an auxiliary,

adding an acid in the case of salts,

and the substituents R ² , R ³ , R ⁴ , R ⁵ , A, D and E are introduced and / or derivatized by known methods.

5. Compounds of general formula (I) according to claim 1 for use in combating diseases.

6. Use of compounds of general formula (I) according to claim 1 for the manufacture of medicaments.

7. Medicament containing one or more of the general formula (I) according to claim 1.