EP1670781A1

EP1670781A1 - Quinoline derivatives and quinazoline derivatives, medicaments containing said compounds, use thereof, and method for the production thereof

Info

Publication number: EP1670781A1
Application number: EP04765571A
Authority: EP
Inventors: Frank Himmelsbach; Birgit Jung
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2003-09-30
Filing date: 2004-09-24
Publication date: 2006-06-21
Also published as: JP2007507445A; DE10345875A1; CA2540501A1; CA2540501C; WO2005033096A1

Abstract

The invention relates to bicyclic heterocycles of general formula (I), wherein R<a>, R<b>, R<c>, R<d>, and X are defined as indicated in claim 1, the tautomers, stereoisomers, mixtures, and salts thereof, especially the physiologically acceptable salts thereof with inorganic or organic acids that have valuable pharmacological properties, particularly an inhibitory effect on the signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, above all tumor diseases, benign prostate hyperplasia (BPH), and diseases of the lung and respiratory tract, and the production thereof.

Description

CHINOLINE AND CHINAZOLINE DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF

The present invention relates to bicyclic heterocycles of the general formula

their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids, which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, their use for the treatment of diseases, in particular tumor diseases, and benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract and their production.

In the above general formula I means

R ^{a is} a hydrogen atom or ad. alkyl group,

R ^{b is} a 1-phenylethyl group in which the phenyl nucleus is in each case substituted by the radicals R ¹ to R ³ , where

R ¹ and R ² , which may be the same or different, each have a hydrogen, fluorine, chlorine, bromine or iodine atom, a C 1 -C alkyl, hydroxy, C _{4 -4} alkoxy, C _2-3 Alkenyl or C ₂ -3-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or a cyano, nitro or amino group, and

R ^{3 represents} a hydrogen, fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group,

R ° is a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by a group R ⁴ -NR ⁵ , where

R ^{4 is} a hydrogen atom or a C _-3 alkyl group and

R ^{5 is} a hydrogen atom or a C _-3 alkyl group, an aminocarbony I C ₃ alkyl ₃ , C ₃ alkylaminocarbonyl C ₃ alkyl, di (Ci-s-alky aminocarbonyl-Ci- s-alkyl-, pyrrolidin-1 -ylcarbonyl-Cι _-3 -alkyl-, piperidin- 1 -ylcarbonyl-Cι- ₃ -alkyl-, homopiperidin-1 -ylcarbonyl-Cι _-3 -alkyl-, morpholin-4-yl- carbonyl-C- _3- alkyl-, homomorpholin-4-ylcarbonyl-C-3-alkyl-, piperazin-1 -ylcarbonyl-Cι- ₃ -alkyl-, 4-Cι _-3 -alkyl-piperazin-1 -ylcarbonyl-d- ₃ -alkyl-, homopiperazin-1-yl- carbonyl-Cι- ₃ -alkyl- or a 4-Cι-3-alkyl-homopiperazin-1-ylcarbonyl-Cι- ₃ -alkyl- group, a hydroxy -C ₂ - -alkyl-, -Cι _-3 -alkyloxy-C _2- -alkyl-, Cι- -alkyloxy-carbonylamino- C - ₄ -alkyl-, amino-C - ₄ -alkyl-, Cι _-3 -alkylamino- C _2-4 -alkyl-, di- (Cι _-3 -alkyl) amino- C ₂ - ₄ alkyl-, C _1-3 -alkylcarbonylamino-C _2- 4-alkyl-, aminocarbonylamino-C2- ₄ -alkyl- , Cι _-3 -Alkylaminocarbonylamino-C2-4-alkyl-, di- (Cι- ₃ -alkyl) amino-carbonylamino- C ₂ - ₄ -alkyl-, pyrrolidin-1 -ylcarbony lamino-C ₂ - ₄ -alkyl-, piperidin-1 -ylcarbonylamino- C _2-4 -alkyl-, morpholin-4-ylcarbonylamino-C ₂ - ₄ -alkyl-, Cι _-3 -AlkyIsulfonyI-C2- ₄ -alkyl- n ordlerr p eiinnee CC, ι- o ₃ --AΔlllk> r \ y / llsQiuιllffnonn \ y / llaammiinnno - πC2- _^ --aalllkf \ y / llπgrrιuιnpnp <e- » a (2-oxo-pyrrolidin-1-yl) -C _2-4 alkyl, (2-oxopiperidin-1-yl) -C _{_2-4} alkyl-, (3-oxo- morpholin-4-yl) -C _2-4 -alkyl-, (2-oxo-imidazolidin-1 -yl) -C ₂ -4-alkyl-, (2-oxo-3- Cι- ₃ -alkyl-imidazoIidin-1 -yl) -C ₂ - ₄ -alkyl-, (2-oxo-hexahydropyrimidin-1-yl) -C2-4-alkyl- or a (2-oxo-3-C _{-3 -3-} alkyl-hexahydropyrimidin-1-yl) -C _2-4 alkyl group,

a Cι _-4 -alkylsulfonyl-, chloro-Cι- alkylsulfonyl-, bromo-Cι _-4 -alkylsulfonyl-, amino- C-ι- ₄ -alkylsulfonyl-, Cι- ₃ -alkylamino-Cι- ₄ -alkylsulfonyl-, Di - (Cι _-3 -alkyl) amino- Cι _-4 -alkylsulfonyl-, (pyrrolidin-1-yl) -Cι _-4 -alkylsulfonyl-, (piperidin-1-yl) -Cι _-4 -alkyl- sulfonyl-, ( Homopiperidin-1-yl) -Cι _-4 -alkylsulfonyl-, (morpholin-4-yl) -Cι _-4 -alkyl- sulfonyl-, (homomorpholin-4-yl) -Cι _-4 -alkylsulfonyl-, (piperazin-1 -yl) -C-ι _-4 -alkyl- sulfonyl-, (4-Cι _-3 -alkyl-piperazin-1-yl) -Cι _-4 -alkylsulfonyl-, (homopiperazin-1-yl) - Cι- ₄ - alkylsulfonyl or a (4-Cι _-3- alkyl-homopiperazin-1-yl) -Cι- ₄ -alkylsulfonyl group,

a Cι-4-alkyloxycarbonyl group,; ■ = ^•

formyl, Cι _-4 alkyl-carbonyl, Cι-Cι _-3 alkyloxy _-4 alkyl-carbonyl, Tetrahydrofuranylcarbonyl-, Tetrahydropyranylcarbonyl-, carbonyl, C _{3 -3} alkylamino C _{4 -4} alkyl carbonyl, di (C _{3 -3} alkyl) amino C 4 alkyl carbonyl, pyrrolidine-1 -yl-C 1 alkyl carbonyl -, Piperidin-1 -yl -CC. ₄ -alkyl-carbonyl-, (homopiperidin-1-yl) -Cι- ₄ -alkyl-carbonyl-, morpholin-4-yl-Cι _-4 -alkyl-carbonyl-, (homomorpholin-4-yl) -Cι- ₄ -alkyl-carbonyl-, (piperazin-1-yl) -Cι _-4 -alkyl-carbonyl-, (4-Cι- ₃ -alkyl-piperazin-1-yl) -Cι _-4 -alkyl-carbonyl-, (homopiperazine -1-yl) -Cι- -alkyl- carbonyl-, (4-Cι _-3 -alkyl-homopiperazin-1-yl) -Cι- ₄ -alkyl-carbonyl- or a ds-alkylsulfonyl-Ci ^ -alkyl-carbonyl group .

a cyano-, aminocarbonyl-, C-ι- ₃ -alkyl-aminocarbonyl-, di- (Cι _-3 -alkyl) amino-carbonyl-, (Cι _-3 -alkyoxy-C _2- 4-alkyl) aminocarbonyl-, N - (Cι.3-alkyl) -N- (Cι _-3 - alkyloxy-C ₂ - ₄ alkyl) aminocarbonyl, arylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidine-1 -ylcarbonyl, homopiperidine-1 -ylcarbonyl -, morpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-ylcarbonyl-, 3-oxa-8-aza-bicyclo [3.2.1 ] oct-8-ylcarbonyl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-ylcarbonyl-, piperazin-1 -ylcarbonyl-, 4-Cι- ₃ -alkyl-piperazin-1 -ylcarbonyl- . Homopiperazin-1 -ylcarbonyl-, 4-Gι _-3- alkyl-homopiperazin-1 -ylcarbonyl-, aminosulfonyl-, Cι _-3 -alkyl-aminosulfonyl-, di- (Cι _-3 -alkyl) aminosulfonyl-, pyrrolidine 1-yl-sulfonyl-, piperidin-1 -ylsulfonyl-, homopiperidin-1 -ylsulfonyl-, morpholin-4-ylsulfonyl-, homomorpholin-4-ylsulfonyl-, piperazin-1 -ylsulfonyl-, 4- Cι _-3 -AlkyI- represent piperazin-1 -ylsulfonyl-, homopiperazin-1 -ylsulfonyl- or a 4- Cι _-3- alkyl-homopiperazin-1 -ylsulfonylgruppe,

a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by a group R ^s , where

R ^{6 is} 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 -Cι. ₃ -alkyl-imidazolidin-1 -yl-, 2-oxo-hexahydro-pyrimidin-1-yl or a 2-oxo-3-Cι _-3 -alkyl-hexahydropyrimidin-1-yl group,

an azetidin-3-yI group which is substituted in the 1 position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

a pyrrolidin-3-yl group which is substituted in the ^ position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

a piperidin-3-yl group which is substituted in the 1 position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

a piperidin-4-yl group which is substituted in the 1-position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

R ^{d is} a hydrogen atom or a fluorine, chlorine or bromine atom,

a hydroxy group, a C _1-4 alkyloxy group,

a methoxy group substituted by 1 to 3 fluorine atoms,

an ethyloxy group substituted by 1 to 5 fluorine atoms,

a C -4-alkyloxy group which is substituted by a radical R ⁶ or R ⁷ , wherein

R ⁶ is defined as mentioned above and

R ^{7 is} a hydroxy, C ₃ _-3 alkyloxy, C ₃ - ₆ cycloalkyloxy, amino, C _{3 -3} alkylamino, di (C _{3 -3} alkyl) amino, bis (2- methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yI, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl-, 8-oxa-3-aza-bicyclo [3.2.1] oct- 3-yl, piperazin-1-yl, 4-Cι _-3- alkyl-piperazin-1-yl, homopiperazin-1-yl or Cι-3-alkyl-homopiperazin-l-yl group, or a formylamino , Cι- ₄ -Alkylcarbonylamino-, ds-alkyloxy-Cι-3-alkyl- carbonylamino-, Cι. _4- alkyloxycarbonylamino-, aminocarbonylamino-, d-3-alkylaminocarbonylamino-, di- (d- ₃ -alkyl) aminocarbonyamino-, pyrrolidin-1-ylcarbonylamino-, piperidin-1 -ylcarbonylamino-, piperazin-1 -ylcarbonylamino-, 4- Cι _-3 -Alkyl-piperazin-1 -ylcarbonylamino-, morpholin-4-ylcarbonylamino- or a Cι- alkylsulfonylamino group,

a C ₃ - ₇ cycloalkyloxy or C ₃ - ₇ cycloalkyl-Cι- ₄ alkyloxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group,

a tetrahydrofuranyl-d _-4 -alkyloxy- or tetrahydropyranyl-Cι- alkyloxy group,

a C ₄ alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the radical R ⁸ , where R ^{ö represents} a hydrogen atom or a Cι _-3 alkyl group,

or a C _-4 alkoxy group which is substituted by a morpholinyl group substituted in the 4-position by the radical R ⁸ , where R ⁸ is defined as mentioned above, and

X represents a methine group or a nitrogen atom substituted by a cyano group, and

wherein the aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as a phenyl group which is mono- or disubstituted by R ⁹ , where the substituents can be identical or different and

R ^{9 represents} a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a d- ₃ alkyl, hydroxy, C _{3 -3} alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group .

the heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, the heteroaryl groups mentioned above in each case being mono- or disubstituted by the radical R ⁹ , the substituents being identical or different can and R ⁹ is defined as mentioned above, and

the above-mentioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups can each be substituted by one or two C _-3 alkyl groups, and

unless stated otherwise, the alkyl groups mentioned above can be straight-chain or branched.

Preferred compounds of the above general formula I are those in which

R ^{a is} a hydrogen atom, R ^{b is} a 1-phenylethyl group,

R ^{c is} a cyclopentyl group which is substituted in the 3-position by a group R ⁴ -NR ⁵ , where

R ^{4 represents} a hydrogen atom or ad _-3 alkyl group and

R ^{5 is} a hydrogen atom or a d- ₃ alkyl group, an aminocarbonyl-C _1-3 alkyl, Cι. ₃ -Alkylaminocarbonyl-Cι- ₃ -alkyl-, di- (d-3-al- kyl) aminocarbonyl-Cι _-3 -alkyl-, pyrrolidin-1 -ylcarbonyl-Cι _-3 -alkyl-, piperidin-1 -yl- carbonyl-Cι- ₃ -alkyl-, piperazin-1 -ylcarbonyl-Cι _-3 -alkyl-, 4-d _-3 -alkyl-piperazin-1 -yl- carbonyl-d- ₃ -alkyl- or morpholin-4-ylcarbonyl -Cι _-3 -alkyl group, a hydroxy-C _2-4 -alkyl-, Cι- ₃ -alkyloxy-C ₂ - ₄ -alkyl-, C _1- -alkyloxy-carbonylamino- C ₂ - ₄ -alkyl-, amino- C _2-4 alkyl, C _-3 alkylamino C ₂ - ₄ alkyl, di (C _{3 -3} alkyl) amino C ₂ - ₄ alkyl, C ₃ alkyl carbonylamino C _{2- 4-} alkyl-, aminocarbonylamino-C ₂ -4-alkyl-, Ci-s-alkylaminocarbonylamino ^^ - alkyl-, di- (Cι- ₃ -alkyl) amino-carbonylamino- C _2-4 -alkyl-, morpholine-4 -ylcarbonylamino-C _2-4 -alkyl-, -Cι _-3 -AlkyIsulfonyl-C _2-4 -alkyl- or Cι _-3 -alkylsulfonylamino-C _2-4 -alkyl group, a (2-oxo-pyrrolidin-1-yl) -C ₂ - ₄ -alkyl-, (2-oxopiperidin-1-yl) -C ₂ -4-alkyl-, (3-oxomorpholin-4-yl) -C _2-4 -alkyl-, (2- Oxo-imidazolidin-1 -yl) -C _2-4 -alkyl-, (2-oxo-3-methyl- im idazolidin-1-yl) -C ₂ - ₄ alkyl-, (2-oxo-hexahydropyrimidin-1-yl) -C ₂ - ₄ alkyl- or (2-oxo-3-methyl-hexahydropyrimidin-1-yl) -C ₂ . ₄ -alkyl group, a Cι _-3 alkylsulfonyl, chloro-C _2-4 alkylsulfonyl, bromo-C _2-4 alkylsulfonyl, amino C ₂ - ₄ alkylsulfonyl, C _{3 -3} alkylamino C ₂ - _4- Alkylsulfonyl-, di- (-Cι _-3 -alkyl) amino- C ₂ - ₄ -alkylsulfonyl-, (pyrrolidin-1 -yl) -C ₂ - ₄ -alkylsulfonyl-, (piperidin-1 -yl) -C _2-4 -alkyl-sulfonyl or (morpholin-4-yl) -C ₂ - ₄ -alkylsulfonyl group, a Cι _-4 -alkyloxy-carbonyl group, a formyl, C _-3 alkyl carbonyl, C 3 alkyloxy C 3 alkyl carbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranyl carbonyl, amino C 3 alkylcarbonyl, C 1. ₃ -Alkylamino-Cι _-3 -alkyl-carbonyl-, di- (Cι- ₃ -alkyl) amino-Cι- ₃ -alkyl-carbonyl-, pyrrolidin-1 -yl-Cι _-3 -alkyl-carbonyl-, piperidine- 1 -yl-Cι.3-alkyl-carbonyl-, piperazin-1-yl-Cι- ₃ -alkyl-carbonyl-, 4-Cι- ₃ -alkyl-piperazin-1-yl-Cι. ₃ -alkyl-carbonyl-, morpholin-4-yl-Cι _-3 -alkyl-carbonyl- or a C _1-3 -alkylsulfonyl-Cι- ₃ -alkyl- carbonyl group, a cyano, aminocarbonyl, Cι. _3- alkyl-aminocarbonyl-, di- (Cι _-3 -alkyl) amino- carbonyl-, (d _-3 -alkyloxy-C ₂ - ₄ -alkyl) aminocarbonyl-, N- (Cι _-3 -alkyl) -N- (Cι- ₃ alkyloxy-C ₂ -4-alkyl) aminocarbonyl-, phenylaminocarbonyl-, pyrrolidin-1 - ylcarbonyl-, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl-, Cι _-3- alkylmorpholin- 4- ylcarbonyl-, di- (Cι _-3 -alkyl) morpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-ylcarbonyl-, 3-oxa -8-aza-bicyclo [3.2.1] oct-8-ylcarbonyl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-ylcarbonyl-, piperazin-1 -ylcarbonyl-, 4- (Cι ₃ -alkyl) -piperazin-1 -ylcarbonyl-, aminosulfonyl-, Cι- ₃ -alkyl-aminosulfonyl-, di- (Cι. ₃ -alkyl) aminosulfonyl-, pyrrolidin-1 -yl-sulfonyl-, piperidine- 1 -ylsulfonyl- or a morpholin-4-ylsulfonyigruppe represent, or

a cyclopentyl group which is substituted in the 3-position by a group R ^δ , where

R ^{6 is} 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 represents methyl imidazolidin-1-yl, 2-oxo-hexahydro-pyrimidin-1-yl or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R ⁴ -NR ⁵ , where R ⁴ and R ⁵ are defined as mentioned above,

a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R ⁶ , where R ⁶ is defined as mentioned above,

a pyrrolidin-3-yl group which is substituted in the 1 position by the radical R ⁵ , where R ⁵ is defined as mentioned above, a piperidin-3-yl group which is substituted in the 1 position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

a piperidin-4-yl group which is substituted in the 1-position by the radical R ⁵ , where R ⁵ is defined as mentioned above, or

a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

R ^{d is} a hydrogen atom,

a Cι _-3 alkyloxy group,

a methoxy group which is substituted by one to three fluorine atoms,

an ethyloxy group which is substituted in the 2-position by a radical R ⁶ or R ⁷ , where R ⁶ is defined as mentioned above and

R ^{7 is} a hydroxy, C ₃ alkyloxy, amino, C ₃ alkylamino, di (C ₃ alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidine-1- yl-, piperidin-1-yl-, morpholin-4-yI-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8 -aza-bicyclo- [3.2.1] oct-8-yl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl-, piperazin-1-yl- or a 4-Cι _{- 3} -Alkyl-piperazin-1 -ylgruppe, or a formylamino, Cι _-4 -alkylcarbonylamino-, ds-alkyloxy-ds-alkyl carbonylamino-, C-ι. ₄ -alkyloxycarbonylamino-, aminocarbonylamino-, C _1-3 - alkylaminocarbonylamino-, di- (Cι _-3 -alkyl) aminocarbonylamino-, pyrrolidin-1 - ylcarbonylamino-, piperidin-1 -ylcarbonylamino-, piperazin-1 -ylcarbonylamino-, 4 -Cι _-3 -Alkyl-piperazin-1 -ylcarbonylamino- morpholin-4-ylcarbonylamino- or a Cι _-4 -alkylsulfonylamino group,

a propyloxy group which is substituted in the 3-position by a radical R ⁶ or R ⁷ , where R ⁶ and R ⁷ are defined as mentioned above, or a butyloxy group which is substituted in the 4-position by a radical R ^D or R, where R ⁶ and R ⁷ are defined as mentioned above, and

X represents a nitrogen atom,

unless stated otherwise, the alkyl groups mentioned above can be straight-chain or branched,

their tautomers, their stereoisomers, their mixtures and their salts.

Particularly preferred compounds of the general formula I above are those in which

R ^{a is} a hydrogen atom,

R ^{b is} a 1-phenylethyl group,

R ^{c is} a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R ⁴ -NR ⁵ , where

R ^{4 is} a hydrogen atom, a methyl or ethyl group and

R ^{5 is} a hydrogen atom, a methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, pyrrolidine-1 -ylcarbonylmethyl-, piperidine-1 -ylcarbonylmethyl-, piperazin-1 -ylcarbonylmethyl-, 4-methylpiperazin- 1 -ylcarbonylmethyl-, Morpholin-4-ylcarbonylmethyl, 2- (morpholin-4-ylcarbonyl) ethyl or 3- (morpholin-4-ylcarbonyl) propyl group, an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl , 2-methoxyethyl, 3-methoxypropyl, 2- (butyloxycarbonylamino) ethyl, 2-aminoethyl, 3-aminopropyl, 2- (acetylamino) ethyl, 3- (acetylamino) propyl, 2- (Ethylcarbonylamino) ethyl, 3- (ethylcarbonylamino) propyl, 2- (propylcarbonylamino) ethyl, 3- (propylcarbonylamino) propyl, 2- (ethylaminocarbonylamino) ethyl, 3- (ethylaminocarbonylamino) propyl, 2 - (Dimethylaminocarbonylamino) ethyl-, 3- (Dimethylaminocarbonylami- no) propyl-, 2- (morpholin-4-ylcarbonylamino) ethyl-, 3- (morpholin-4-ylcarbonylamino) propyl-, 2- (methylsulfonyl) ethyl-, 3- (methylsulfonyl) propyl-, 2- ( Methylsulfonylamino) ethyl or a 3- (methylsulfonylamino) propyl group,

a 2- (2-oxopyrrolidin-1-yl) ethyl, 2- (2-oxopiperidin-1-yl) ethyl, 2- (3-oxomorpholin-4-yl) ethyl, 2- ( 2-oxo-imidazolidin-1-yl) ethyl, 2- (2-oxo-3-methyl imidazolidin-1-yl) ethyl, 2- (2-oxo-hexahydropyrimidin-1-yl) ethyl or one 2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) ethyl group,

a 3- (2-oxopyrrolidin-1-yl) propyl-, 3- (2-oxopiperidin-1-yl) propyl-, 3- (3-oxomorpholin-4-yl) propyl-, 3- ( 2-oxo-imidazolidin-1-yl) propyl-, 3- (2-oxo-3-methylimidazolidin-1-yl) propyl-, 3- (2-oxo-hexahydropyrimidin-1-yl) propyl or one 3- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) propyl group,

a methylsulfonyl, ethylsulfonyl, 3-chloropropylsulfonyl, 2- (morpholin-4-yl) ethylsulfonyl or a 3- (morpholin-4-yl) propylsulfonyl group,

a propyloxycarbonyl or butyloxycarbonyl group,

a formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxyacetyl, (2-methoxyethyl) carbonyl, (3-methoxypropyl) carbonyl, tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, aminoacetyl, methylaminoacetyl -, dimethylaminoacetyl, morpholin-4-ylacetyl, [2- (morpholin-4-yl) ethyl] carbonyl, [3- (morpholin-4-yl) propyl] carbonyI or a methylsulfonylacetyl group,

a cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, (2-methoxyethyl) aminocarbonyl, N-methyl-N- (2-methoxyethyl) aminocarbonyl, (3-methoxypropyl) aminocarbonyl-, N-methyl-N- (3-methoxypropyl) - aminocarbonyl-, phenylaminocarbonyl-, pyrrolidin-1 -ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl- , 2,6-dimethylmorpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-y! Carbonyl-, 3-oxa-8-aza- bicyclo [3.2.1] oct-8-ylcarbonyl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-ylcarbonyl-, 4-methylpiperazin-1 -ylcarbonyl-, Represent aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or a morpholin-4-ylsulfonyl group,

a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R, where

R ^{6 is} 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 represents methyl imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

a pyrrolidin-3-yl group which is substituted in the 1 position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

R ^{d is} a hydrogen atom,

a methoxy, difluoromethoxy or ethyloxy group,

R ^{7 is} a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4- yl-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl -, 8-Oxa-3-aza-bicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl group, or an acetylamino, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino-, piperidin-1 -ylcarbonylamino- Represents ethylsulfonylamino or butylsulfonylamino group,

a propyloxy group which is substituted in the 3-position by a radical R ⁶ or R ⁷ , where R ⁶ and R ⁷ are defined as mentioned above, or

a butyloxy group which is substituted in the 4-position by a radical R ⁶ or R ⁷ , where R ⁶ and R ⁷ are defined as mentioned above, and

X represents a nitrogen atom,

their tautomers, their stereoisomers, their mixtures and their salts.

Very particularly preferred compounds of the general formula I are those in which

R ^{a is} a hydrogen atom,

R ^{b is} a 1-phenylethyl group,

R ^{c is} a cyclohexyl group which is in the 4-position by an amino, methylamino, dimethylamino, acetylamino, N- (acetyl) methylamino, methoxyacetylamino, N- (methoxyacetyl) methylamino, tetrahydropyran-4-ylcarbonylamino -, N-

(Tetrahydropyran-4-ylcarbonyl) methylamino, tert-butyloxycarbonylamino, N- (tert-butyloxycarbonyl) methylamino, N- (ethylaminocarbonyl) methylamino,

Dimethylaminocarbonylamino-, N- (dimethylaminocarbonyl) -methylamino-, N- (piperidin-1 -ylcarbonyl) -methylamino-, morpholin-4-ylcarbonylamino-, N- (morpholin-4-ylcarbonyl) - methylamino-, N- (4-methylpiperazin-1 -ylcarbonyl) -methylamino-, methylsulfonylamino-, N- (methylsulfonyl) -methylamino-, ethylsulfonylamino-, N- (ethylsulfonyl) -methylamino-, dimethylaminosulfonylamino-, N- (dimethylaminosulfonylamino-, N- (dimethylaminos-) methylamino, morpholin-4-ylsulfonylamino or N- (morpholin-4-yisulfonyl) methylamino group,

a pyrrolidin-3-yl group,

a pyrrolidin-3-yl group which is substituted in the 1-position by a tert-butyloxycarbonyl or methylsulfonyl group,

a piperidin-3-yl group,

a piperidin-3-yl group which is substituted in the 1-position by a tert-butyloxycarbonyl or methylsulfonyl group,

a piperidin-4-yl group,

a piperidin-4-yl group which is in the 1-position by a methyl, (aminocarbonyl) methyl, (dimethylaminocarbonyl) methyl, (morpholin-4-ylcarbonyl) methyl, 2- (tert.-

Butyloxycarbonylamino) ethyl, 2-aminoethyl, 2- (acetylamino) ethyl, 2-

(Methylsulfonylamino) ethyl, cyano, acetyl, methoxyacetyl, (dimethylamino) acetyl, (morpholin-4-yl) acetyl, tetrahydropyran-4-ylcarbonyl, ethylaminocarbonyl,

Isopropylaminocarbonyl, dimethyl aminocarbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl -, Homomorpholin-4-ylcarbonyl-, 4-methylpiperazin-1 -ylcarbonyl-, isopropyloxycarbonyl-, tert-butyloxycarbonyl-,

Methylsulfonyl, Dimethylaminosulfonyl- or Morpholin-4-ylsulfonylgruppe is substituted, or

a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

R ^{d is} a methoxy, ethyloxy or a 2- (methoxy) ethyloxy group,

and X represents a nitrogen atom,

their tautomers, their stereoisomers, their mixtures and their salts.

Particularly preferred compounds of the general formula I are those in which

R ^{a is} a hydrogen atom,

R ^{b is} a 1-phenylethyl group,

R ^{c is} a piperidin-4-yl group,

a piperidin-4-yl group which is substituted in the 1-position by a methyl, cyano, acetyl, morpholin-4-ylcarbonyl, tert-butyloxycarbonyl or methylsulfonyl group,

R ^{d is} a methoxy group

and

X represents a nitrogen atom,

their tautomers, their stereoisomers, their mixtures and their salts.

The compounds of the general formula I can be prepared, for example, by the following processes:

a) implementation of a compound of the general formula

in the

R ^a , R ^b , R ^d and X are defined as mentioned at the outset, with a compound of the general formula

Z ¹ - R °, (III)

in the

R ^c is defined as mentioned at the beginning and Z ^{1 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group or a hydroxyl group.

With a compound of the general formula III in which Z ^{1 represents} a hydroxyl group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as, for example, triphenylphosphine / diethyl azodicarboxylate, advantageously in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, Dioxane, toluene or ethylene glycol diethyl ether at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C.

b) For the preparation of compounds of the general formula I in which R ^{d represents} one of the optionally substituted alkyloxy groups mentioned at the outset:

Implementation of a compound of the general formula

in which R ^a , R ^b , R ° and X are defined as mentioned at the beginning, are with a compound of the general formula

Z ² - R ^{d '} , (V)

in the R ^{d '} ad ₄ -alkyl group, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a C _2-4 alkyl group substituted by a radical R ⁶ or R ⁷ , where R ⁶ and R ⁷ are defined as mentioned at the outset, a C _-4 alkyl group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the radical R ⁸ , or ad _-4 alkyl group which is substituted by a substituted in the 4-position by the radical R ⁸ morpholinyl group, where R ⁸ . is defined in each case as mentioned at the outset, and

Z ^{2 represents} a leaving group such as a halogen atom, an alkylsulfonyloxy, arylsulfonyloxy or a hydroxy group.

If the leaving group is a halogen atom such as a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group such as the methanesulfonyloxy or p-toluenesulfonyloxy group, the reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine performed. If the leaving group is a hydroxyl group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / diethyl azodicarboxylate. c) For the preparation of compounds of the general formula I in which R ^{d represents} one of the alkylcycloxy groups mentioned at the outset, which is substituted by an optionally substituted amino, alkylamino or dialkylamino group or by an optionally substituted heterocyclic group bonded via an imino nitrogen atom : Implementation of a compound of the general formula

in which R ^a , R ^b , R ^c and X are defined as mentioned at the outset and Z ^{3 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom or a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group

Ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or their suitable salts or derivatives, such as, for example, morpholine.

d) For the preparation of compounds of the general formula I in which R ^{d represents} a hydroxyl group:

Splitting off a protective residue from a compound of the general formula

in which R ^a , R ^b , R ^c and X are defined as mentioned at the outset and R ^{d "represents} a group which can be converted into a hydroxyl group, for example an optionally substituted benzyloxy group, a trimethylsilyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy , tert-butoxy or trityloxy group. The protective residue is split off, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or Potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

A benzyl or methoxybenzyl radical is cleaved off, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert-butyl or benzyl radical is split off, for example, by treatment with an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

e) For the preparation of compounds of the general formula I in which R ^{c contains} an -NH group:

Splitting off a protective residue from a compound of the general formula

in which R ^a , R ^b , R ^d and X are defined as mentioned at the beginning and R ° ^' with the proviso has the meanings mentioned at the beginning for R ^c that R ° contains a protected nitrogen atom.

Typical protective residues for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, for which Amino group, the phthalyl group also comes into consideration.

The protective residue is split off, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl residue is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether. A trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.

A phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

f) For the preparation of compounds of the general formula I in which R ^{c contains} an alkyl group substituted by an optionally substituted amino, alkylamino or dialkylamino group or by an optionally substituted heterocyclic group bonded via a nitrogen atom:

Implementation of a compound of the general formula

in which R ^a , R ^b , R ^d and X are defined as mentioned at the outset, Z ^{3 represents} a leaving group, for example a halogen atom such as a chlorine or bromine atom, or a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group, and R ^{c "} with the proviso that a hydrogen atom bound to an aliphatic carbon atom is replaced by the group Z ³ , which has the meanings mentioned for R ^c at the outset,

with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or their suitable salts or derivatives, such as, for example, morpholine. If, according to the invention, a compound of general formula I is obtained which contains an amino, alkylamino or imino group, this can be converted into a corresponding acyl, cyano or sulfonyl compound of general formula I by means of acylation, cyanation or sulfonylation, the acylating agent used for example isocyanates, carbamoyl chlorides,

Carboxylic acid halides, carboxylic acid anhydrides and carboxylic acids with activating agents such as N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or O- (benzotriazol-1 -yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate, as sulfonyl halide, as sulfonyl halide and chlorine or bromine cyanide are suitable as cyanating agents, and / or

a compound of the general formula I which contains an amino, alkylamino or imino group, this can be converted into a corresponding alkyl compound of the general formula I by means of alkylation or reductive alkylation and / or

a compound of general formula I, which contains a chloro-d _-4 -alkylsulfonyl- or bromo-d-4-alkylsulfonyl group, this can be converted into a corresponding amino -CC _-4 -alkylsulfonyl compound by reaction with an amine and / or

a compound of the general formula I which contains a tert-butyloxycarbonylamino, N-alkyl-N- (tert-butyloxycarbonyl) amino or an N-tert-butyloxycarbonylimino group, this can be treated by treatment with an acid such as hydrochloric acid or Trifluoroacetic acid can be converted into a corresponding amino, alkylamino or imino compound of the general formula I.

In the reactions described above, any reactive groups present, such as hydroxyl, amino, Al.kylamino or imino groups, can be protected during the reaction by conventional protective groups, which are split off again after the reaction. For example, the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group can be used as a protective radical for a hydroxyl group.

Protective residues for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

A trifluoroacetyl radical is preferably cleaved off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with Sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.

Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.

For example, the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-op-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of suitable optically active alcohol are (+) - or (-) - menthol and optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl. Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of general formulas II to IX used as starting materials are known from the literature or can be obtained by processes known per se from the literature or by the processes described above, optionally with the additional introduction of protective residues (e.g. compounds of the formula IV or VII and VIII).

As already mentioned at the beginning, the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), this being achieved, for example, by inhibiting the Ligand binding, receptor dimerization or the tyrosine kinase itself can be effected. It is also possible that the signal transmission on further downstream components may be blocked.

The biological properties of the new compounds were tested as follows:

The inhibition of human EGF receptor kinase was determined with the aid of the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418). For this purpose, the protein was expressed in Sf9 insect cells as a GST fusion protein using the baculovirus expression system.

The enzyme activity was measured in the presence or absence of the test compounds in serial dilutions. The polymer pEY (4: 1) from SIGMA was used as the substrate. Biotinylated pEY (bio-pEY) was added as a tracer substrate. Each 100 l reaction solution contained 10 μl of the inhibitor in 50% DMSO, 20 μl of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg / ml poly (EY), 5 // g / ml bio-pEY ) and 20 μ \ enzyme preparation. The enzyme reaction was started by adding 50 I of a 100 μM ATP solution in 10 mM magnesium chloride. The dilution of the enzyme preparation was adjusted so that the phosphate incorporation into the bio-pEY was linear with regard to time and the amount of enzyme. The enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerin.

The enzyme assays were carried out at room temperature over a period of 30 minutes and ended by adding 50 μl of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μ \ were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. The plate was then washed with 200 μl of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 μ \ of an HRPO-labeled anti-PY antibody (PY20H anti-PTyπHRP from Transduction Laboratories, 250 ng / ml), the mixture was incubated for 60 minutes. The microtiter plate was then washed three times with 200 μl wash solution. The samples were then mixed with 100 μl of a TMB peroxidase solution (A: B = 1: 1, Kirkegaard Perry Laboratories). After 10 minutes the reaction was stopped. The absorbance was measured at OD ₄₅₀ nm with an ELISA reader. All data points were determined as triplicates.

The data were adjusted using an iterative calculation using an analysis program for sigmoidal curves (Graph Pad Prism Version 3.0). All analyzes had a correlation coefficient of over 0.9. From the curves, the concentration of active substance has been derived, which inhibits the activity of EGF receptor kinase by 50% (IC ₅ o).

The compounds of the general formula I according to the invention inhibit signal transduction by tyrosine kinases, for example the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overactive tyrosine kinases. These are, for example, benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis). The compounds of the invention are also useful for the prevention and treatment of respiratory and lung diseases associated with an increased or altered mucus production caused by stimulation of tyrosine kinases, such as in inflammatory respiratory diseases such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), cough, emphysema, allergic or non-allergic rhinitis or sinusitis, chronic sinusitis or rhinitis, asthma, allergic bronchitis, alveolitis, Farmer ^'s disease, hyperreactive airways, bronchitis or pneumonitis caused by infections such as bacteria or Viruses, helminths, fungi or protozoa, pediatric asthma, bronchiectasis, acute respiratory distress syndrome (ARDS), pulmonary edema, bronchitis or pneumonitis or interstitial pneumonia or pulmonary fibrosis from various causes, such as through aspiration, inhalation of toxic gases or vapors, through the heart failure, radiation, chemotherapy, for lupus erythematosus, systemic scleroderma, asbestosis, silicosis, Boeck's disease or sarcoid, granulomatosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis or cystic fibrosis, or alphal-antitrypsin deficiency or nasal polyps.

The compounds are also suitable for the treatment of diseases of the gastrointestinal tract and of the bile ducts and bladder, which are associated with an impaired activity of the tyrosine kinases, such as are found, for example, in the case of chronic inflammatory changes, such as villous or adenomatous polyps of the stomach Colon tracts, polyps in familial polyposis coli, intestinal polyps in Gardner ^'s syndrome, polyps in Peutz-Jehers syndrome, inflammatory pseudopolyps, juvenile polyps, polyps in colitis cystica profunda and in pneumatosis cystoides intestinales, acute or chronic cholecystitis, M. Crohn's disease , Ulcerative colitis, ulcers or polyps of the gastrointestinal tract, diseases of the gastrointestinal tract associated with increased secretion, such as M. Menetrier, secreting adenomas or protein loss syndrome.

In addition, the compounds of general formula I and their physiologically tolerable salts can be used for the treatment of inflammatory diseases of the skin and joints which are caused by the aberrant function of tyrosine kinases such as epidermal hyperproliferation (psoriasis) and arthritis, and for the treatment of benign prostatic hyperplasia (BPH), diseases of the immune system and hyperproliferation of hematopoietic cells.

Because of their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example etoposide), mitotic inhibitors (e.g. vinblastine), compounds interacting with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies etc. For Treatment of respiratory diseases can use these compounds alone or in combination with other respiratory therapies, such as secretolytic (e.g. ambroxol, N-acetylcysteine), broncholytic (e.g. tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (e.g. theophylline or glucocorticoids) substances. For the treatment of diseases in the gastrointestinal tract, these compounds can also be given alone or in combination with substances affecting motility or secretion. These combinations can be administered either simultaneously or sequentially.

These compounds can be used either alone or in combination with other active substances, intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations in particular being suitable for inhalation.

In pharmaceutical use, the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg of body weight, preferably at 0.1-15 mg / kg. For administration, these are mixed with one or more customary inert carriers and / or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, Water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures are incorporated into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

The following examples are intended to illustrate the present invention without restricting it:

Making the end connections:

example 1

(R) -4- (1-phenylethylamino) -6- [1- (tert-butyloxycarbonyl) piperidin-4-yloxy] -7-methoxy-quinazoline

4.8 g (β) -4- (1-phenylethylamino) -6-hydroxy-7-methoxy-quinazoline (see WO 02/18351), 7.55 g 1- (tert-butyloxycarbonyl) -4- (p -toluenesulfonyloxy) piperidine, 5.7 g of potassium carbonate and 50 ml of dimethylformamide are stirred at 60 ° C for 48 hours. The reaction mixture is diluted with 300 ml of ethyl acetate and extracted three times with water. The organic phase is washed with brine, dried and concentrated. The residue is purified by chromatography on a silica gel column with ethyl acetate / methanol / conc. aqueous ammonia cleaned. Yield: 5.2 g (67% of theory)

R _f value: 0.53 (silica gel, ethyl acetate / methanol / conc. Aqueous ammonia = 95: 5: 1) mass spectrum (ESI ⁺ ): mz = 479 [M + H] ⁺

Example 2 ^(/?) - 4- (1-phenylethylamino) -6- (piperidin-4-yloxy) -7-methoxy-quinazoline dihydrochloride

Prepared by treating (R) -4- (1-phenylethylamino) -6- [1- (tert-butyloxycarbonyl) piperidin-4-yloxy] -7-methoxy-quinazoline with 5M isopropanol

Hydrochloric acid in methylene chloride at room temperature.

R _f value: 0.52 (reversed phase silica gel RP8, acetonitrile / water / trifluoroacetic acid

50: 50: 1)

Mass spectrum (ESI ⁺ ): m / z = 379 [M + H] ⁺

Example 3

(R) -4- (1-phenylethylamino) -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

Prepared by treating (fi) -4- (1-phenylethylamino) -6- (piperidin-4-yloxy) -7- methoxy-quinazoline dihydrochloride with formaldehyde, sodium triacetoxyborohydride and N-

Ethyl diisopropylamine in tetrahydrofuran.

Rr value: 0.48 (reversed phase silica gel RP8, acetonitrile / water / trifluoroacetic acid

50: 50: 1)

Mass spectrum (ESI ⁺ ): m / z = 393 [M + H] ⁺

Example 4 (/ Ϊ?) - 4- (1-phenylethylamino) -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline

Prepared by treating (fl) -4- (1-phenylethylamino) -6- (piperidin-4-yloxy) -7- methoxy-quinazoline-dihydrochloride with acetic anhydride and N-ethyl-diisopropylamine in

Tetrahydrofuran.

Rf value: 0.19 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 421 [M + H] ⁺

The following compounds are obtained analogously to Example 4:

(1) (R) -4- (1-phenylethylamino) -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

The reaction takes place with methanesulfonic acid chloride.

Rf value: 0.48 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1) mass spectrum (ESI ⁺ ): m / z = 457 [M + H] ⁺

(2) (f?) - 4- (1-phenylethylamino) -6- {1 - [(morpholin-4-yl) carbonyl] piperidin-4-yloxy} -7-methoxy-quinazoline

The reaction is carried out with (morpholin-4-yl) carbonyl chloride.

RrValue: 0.34 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 492 [M + Hf

(3) (?) - 4- (1-phenylethylamino) -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline

The reaction is carried out using cyanogen bromide in methylene chloride.

RrValue: 0.54 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 95: 5: 1)

Mass spectrum (ESI ⁺ ): m / z = 404 [M + H] ⁺

The following compounds can also be prepared analogously to the examples mentioned above and other processes known from the literature:

Example 5

Dragees with 75 mg of active substance

Composition:

1 coated tablet contains: active substance 75.0 mg calcium phosphate 93.0 mg maize starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Production: The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed through a sieve with a 1.5 mm mesh size on a suitable machine and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.

Core weight: 230 mg stamp: 9 mm, curved

The dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose. The finished film coated tablets are polished with beeswax.

Drage weight: 245 mg.

Example 6

Tablets with 100 mg of active substance

Composition: 1 tablet contains: Active ingredient 100.0 mg milk sugar 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Production process:

Active ingredient, milk sugar and starch are mixed and mixed with an aqueous solution of the

Polyvinylpyrrolidons evenly moistened. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C is sieved again (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets.

Tablet weight: 220 mg, diameter: 10 mm, biplane with double-sided facet and one-sided partial notch.

Example 7

Tablets with 150 mg of active substance

Composition: 1 tablet contains: Active ingredient 150.0 mg powdered milk sugar. 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg

production:

The active substance mixed with milk sugar, corn starch and silica is mixed with a

20% aqueous polyvinylpyrrolidone solution moistened and passed through a sieve with a 1.5 mm mesh size.

The granules dried at 45 ° C are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. The mixture becomes

Tablets pressed.

Tablet weight: 300 mg stamp: 10 mm, flat

Example 8 Hard gelatin capsules with 150 mg of active substance

Composition: 1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

production:

The active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device. The final mix is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg

Capsule shell: hard gelatin capsule size 1.

Example 9

Suppositories with 150 mg of active substance

Composition: 1 suppository contains: Active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg

production:

After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds. Example 10

Suspension with 50 mg of active substance

Composition:

100 ml suspension contain: Active ingredient 1.00 g carboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g cane sugar 10.00 g glycerin 5.00 g sorbitol solution 70% 20.00 g aroma 0.30 g water dist.ad 100.00 ml

production:

Distilled water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose are

Sodium salt dissolved. It is cooled to room temperature and with stirring

Active ingredient added and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the aroma, the suspension is evacuated with stirring for deaeration.

5 ml of suspension contain 50 mg of active ingredient.

Example 11

Ampoules with 10 mg of active substance

Composition: active ingredient 10.0 mg 0.01 n hydrochloric acid sq aqua bidest ad 2.0 ml production:

The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.

Example 12

Ampoules with 50 mg of active substance

Composition: active ingredient 50.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest to 10.0 ml

production:

The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

Example 13

Capsules for powder inhalation with 5 mg of active substance

1 capsule contains:

Active substance 5.0 mg lactose for inhalation purposes 15.0 mg 20.0 mg

production:

The active substance is mixed with lactose for inhalation purposes. The mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg).

Capsule weight: 70.0 mg Capsule size: 3 Example 14

Inhalation solution for hand nebulizers with 2.5 mg active substance

1 hub includes:

Active substance 2,500 mg benzalkonium chloride 0.001 mg 1 N hydrochloric acid q.s. EthanolΛ / Vasser (50/50) ad 15,000 mg

production:

The active substance and benzalkonium chloride are dissolved in ethanol / water (50/50). The pH of the solution is adjusted with 1 N hydrochloric acid. The adjusted solution is filtered and filled into containers (cartridges) suitable for the hand nebuliser.

Filling mass of the container: 4.5 g

Claims

claims

1. Bicyclic heterocycles of the general formula

in which

R ^{a is} a hydrogen atom or a C 1-4 alkyl group,

R ¹ and R ² , which may be the same or different, each have a hydrogen, fluorine, chlorine, bromine or iodine atom, a C _1-4 alkyl, hydroxy, Cι _-4 alkoxy, C ₂ - ₃ -AlkenyI or C2-3 alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or a cyano, nitro or amino group, and

R ^{3 represents} a hydrogen, fluorine, chlorine or bromine atom, a methyl or trifluoromethyl group, R ^{c is} a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by a group R -NR ⁵ , where

R ^{4 is} a hydrogen atom or ad ₃ alkyl group and

R ⁵ is a hydrogen atom or a Cι- ₃ alkyl group, a Cι-aminocarbonyl _-3 alkyl, Cι _-3 _{alkylaminocarbonyl-3} Cι- -alkyl, di- (C-ι- ₃ -AL- alkyl) aminocarbonyl -Cι- ₃ -aikyl-, pyrrolidin-1-ylcarbonyl-Cι- ₃ -alkyl-, piperidin-1 - ylcarbonyl-Cι _-3 -alkyl-, homopiperidin-1 -ylcarbonyl-Cι _-3 -alkyl-, morpholine-4 -yl- carbonyl-Cι- ₃ -alkyl-, homomorpholin-4-ylcarbonyl-Cι _-3 -alkyl- ,. Piperazin-1 -yl- carbonyl-Cι- ₃ -alkyl-, 4-Cι _-3 -alkyl-piperazin-1 -ylcarbonyl-Cι _-3 -alkyl-, Homo-piperazin-1-ylcarbonyl-Cι _-3 -alkyl- or a 4-Cι _-3- alkyl-homopiperazin-1-yl-carbonyl-Cι- ₃ alkyl group, a hydroxy-C ₂ - ₄ alkyl-, Cι _-3- alkyloxy-C ₂ - ₄ alkyl-, Cι - -Alkyloxy-carbonylamino- C ₂ - ₄ -alkyl-, amino-C ₂ - ₄ -alkyl-, Cι _-3 -alkylamino-C ₂ - ₄ -alkyl-, di- (C _1-3 -alkyl) amino- C ₂ - ₄ -alkyl-, Cι- ₃ -alkylcarbonylamino-C2- ₄ -alkyl-, aminocarbonylamino-C - ₄ -alkyl-, Cι _-3 -alkylaminocarbonylamino-C _2-4 -alkyl-, di- (Cι- ₃ -alkyl) amino-carbonylamino-C ₂ -4-alkyl-, pyrrolidin-1 -ylcarbonylamino-C _-4 -alkyl-, piperidin-1 -ylcarbonylamino- C ₂ - ₄ -alkyl-, morpholin-4-ylcarbonylamino-C _{2 -4} alkyl, Cι _-3 -Aikylsulfonyl-C _{_2-4} alkyl or Cι. ₃ alkylsulfonylamino-C ₂ - ₄ alkyl group, a (2-oxo-pyrrolidin-1-yl) C ₂ - ₄ alkyl, (2-oxopiperidin-1-yl) C ₂ - ₄ alkyl, (3-oxo- morpholin-4-yl) -C _{_2-4} alkyl- ~, (2-oxo-imidazolidin-1-yl) -4--C ₂ alkyl, (2-oxo-3- ₃ d- -alkyl-imidazolidin-l -yl) -C _2-4 -alkyl-, (2-oxo-hexahydropyrimidin-1 -yl) - C ₂ -4-alkyl- or a (2-oxo-3-Cι _-3 - alkyl-hexahydropyrimidin-1-yl) -C ₂ -4-alkyl group, a Cι- alkylsulfonyl, chloro-d- ₄ -alkylsulfonyl, bromo-Cι- ₄ alkylsulfonyl, amino-Cι- ₄ alkylsulfonyl -, Cι _-3 alkylamino-C _1-4 alkylsulfonyl-, di- (Cι- ₃ alkyl) amino- C _1-4 alkylsulfonyl-, (pyrrolidin-1-yl) -Cι- alkylsulfonyl-, ( Piperidin-1-yl) -Cι- ₄ -alkyl- sulfonyl-, (homopiperidin-1 -yl) -Cι _-4 -alkylsulfonyl-, (morpholin-4-yl) -Cι _-4 -alkyl- sulfonyl-, (homomorpholin-4-yl) -Cι _-4 -alkylsulfonyl-, (Piperazin-1 -yl) -C-ι _-4 -alkyl-sulfonyl-, (4-C _1, ₃ -alkyl-piperazin-1-yl) -Cι _-4 -alkylsulfonyl-,. (Homoρiperazin-1-yl) - Cι- ₄ alkylsulfonyl or a (4-Cι- ₃ alkyl-homopiperazin-1-yl) -Cι. ₄ alkylsulfonyl group, a Cι _-4 -AIkyloxycarbonylgruppe, formyl, Cι _-4 alkyl-carbonyl, Cι- ₃ alkyloxy-Cι. -alkyl-carbonyl-, tetrahydrofuranylcarbonyl-, tetrahydropyranylcarbonyl-, amino-Cι- ₄ -alkyl- carbonyl-, Cι _-3 -alkylamino-Cι- ₄ -alkyl-carbonyl-, di- (C _1. ₃ -alkyl) amino- Cι-4-alkyl-carbonyl-, pyrrolidine -yl-Cι _-4 -alkyl-carbonyl-, piperidin-1 -yl-Cι- ₄ -alkyl-carbonyl-, (homopiperidin-1-yl) -Cι. _4- alkyl-carbonyl-, morpholin-4-yl-C _1-4 -alkyl-carbonyl-, (homomorpholin-4-yl) -Cι. ₄ -alkyl-carbonyl-, (piperazin-1-yl) -Cι- -alkyl-carbonyl-, (4-Cι. ₃ -alkyl-piperazin-1-yl) -Cι _-4 -alkyl-carbonyI-, (homopiperazine -1-yl) -Cι- -alkyl- carbonyl-, (4-Cι- ₃ -alkyl-homopiperazin-1-yl) -Cι- ₄ -alkyl-carbonyl- or a Cι. ₃ -Alkylsulfonyl-Cι- ₄ alkyl carbonyl group, or a cyano, aminocarbonyl, ds-alkyl-raminocarbonyl, di- (Cι- ₃ alkyl) amino carbonyl, (Cι _-3 alkyloxy-C ₂ -4-alkyl) aminocarbonyl-, N- (Cι-3-alkyl) -N- (Cι-3-alkyloxy-C ₂ - ₄ -alkyl) aminocarbonyl-, arylaminocarbonyl-, pyrrolidin-1 -ylcarbonyl-, piperidine-1 -ylcarbonyl-, homopiperidin-1 -ylcarbonyl-, morpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-ylcarbonyl-, 3-oxa- 8-aza-bicyclo [3.2.1] oct-8-ylcarbonyl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-ylcarbonyl-, piperazin-1 -ylcarbonyl-, 4-Cι _-3 -Alkyl-piperazin-1 -ylcarbonyl-, homopiperazin-1 -ylcarbonyl-, 4-Cι _-3 -alkyl-homopiperazin-1 -ylcarbonyl-, aminosulfonyl-, Cι- ₃ -alkyl-aminosulfonyl-, di- (Cι _-3 -alkyl) amino-sulfonyl-, pyrrolidin-1 -yl-sulfonyl-, piperidin-1 -ylsulfonyl-, homopiperidin-1 -ylsulfonyl-, morpholin-4-ylsulfonyl-, homomorpholin-4-ylsulfonyl-, piperazin-1 -ylsulfonyl -, 4- Cι- _3- alkyl-piperazin-1 -ylsulfonyl-, homopiperazin-1 represent -ylsulfonyl- or a 4- Cι- ₃ alkyl-homopiperazin-1 -ylsulfonylgruppe,

a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by a group R ⁶ , where R ^{6 is} 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 -Cι _-3 -alkyl-imidazolidin-1-yl-, 2-oxo-hexahydro-pyrimidin-1-yl- or a 2-oxo-3-Cι- ₃ -alkyl-hexahydropyrimidin-1-yl group,

an azetidin-3-yl group which is substituted in the 1-position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

R ^{d is} a hydrogen atom or a fluorine, chlorine or bromine atom,

a hydroxy group,

a Cι- ₄ alkyloxy group,

a methoxy group substituted by 1 to 3 fluorine atoms,

an ethyloxy group substituted by 1 to 5 fluorine atoms,

a C _{_2-4} alkyloxy group which is substituted by a radical R ⁶ or R ^7, wherein

R ⁶ is defined as mentioned above and R ⁷ is a hydroxy, Cι _-3 alkyloxy-, C _3-6 cycloalkyloxy, amino, Cι _-3 alkylamino, di- ₍₃ Cι- alkyl) amino, bis- (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2 .1] hept-5-yl-, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3- yl-, pirerazin-1-yl-, 4-C _1-3 -alkyl-piperazin-1-yl-, homopiperazin-1-yl- or Cι _-3 -alkyl-homopiperazin-1-yl group, or a formylamino-, Cι _-4 -Alkylcarbonylamino-, -Cι-3-alkyloxy-C-ι. ₃ -alkyl- carbonylamino-, Cι- ₄ -alkyloxycarbonylamino-, aminocarbonylamino-, C1- ₃ - alkylaminocarbonylamino-, di- (Cι _-3 -alkyl) aminocarbonylamino-, pyrrolidin-1 - ylcarbonylamino-, piperidin-1 -ylcarbonylamino-, Represents piperazin-1 -ylcarbonylamino-, 4-Cι- ₃ -alkyl-piperazin-1 -ylcarbonylamino- morpholin-4-ylcarbonylamino- or a Cι- ₄ -alkylsulfonylamino group,

a C ₃ - ₇ cycloalkyloxy or C _3-7 cycloalkyl-Cι- ₄ alkyloxy group,

a tetrahydrofuranyl-d-4-alkyloxy or tetrahydropyranyl-Cι- ₄ alkyloxy group,

a C ₄ alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the radical R ⁸ , where

R ^{8 represents} a hydrogen atom or a C _-3 alkyl group,

X represents a methine group or a nitrogen atom substituted by a cyano group, wherein the aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as a phenyl group which is mono- or disubstituted by R ⁹ , where the substituents can be identical or different and

R ^{9 represents} a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a d-3-alkyl, hydroxy, Cι _-3 alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group , the heteroaryl groups mentioned in the definition of the abovementioned radicals should be understood to mean a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, where the heteroaryl groups mentioned above are each mono- or disubstituted by the radical R ⁹ , the substituents being identical or different and R ^{9 is} as defined above, and

the above-mentioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups can each be substituted by one or two d _-3 alkyl groups, and

their tautomers, their stereoisomers, their mixtures and their salts.

2. Bicyclic heterocycles of the general formula I according to claim 1, in which

R ^{a is} a hydrogen atom,

R ^{b is} a 1-phenylethyl group

R ^{4 is} a hydrogen atom or ad _-3 alkyl group and R ^{5 represents} a hydrogen atom or a C ₃ alkyl group,

an aminocarbonyl-Cι _-3 alkyl, ds-alkylaminocarbonyl-ds-alkyl, di- (d _-3 -alkyl) aminocarbonyl-Cι _-3 alkyl, pyrrolidine-1 -ylcarbonyl-d _-3 alkyl -, Piperidin-1 -yl-carbonyl-d- ₃ -alkyl-, piperazin-1 -ylcarbonyl-Cι _-3 -alkyl-, 4-Cι _-3 -alkyl-piperazin-1 -yl- carbonyl-Cι-3- alkyl or morpholin-4-ylcarbonyl-d-3-alkyl group,

a hydroxy-C ₂ - ₄ -alkyl-, Cι- ₃ alkyloxy-C ₂ - ₄ -alkyl-, Cι- ₄ -alkyloxy-carbonylamino- C _-4 -alkyl-, amino-C -4-alkyl-, Cι _-3- alkylamino-C _2-4 -alkyl-, di- (Cι- ₃ -alkyl) amino- C _2-4 -alkyl-, Cι _-3 -alkylcarbonylamino-C _2-4 -alkyl-, aminocarbonylamino-C ₂ - ₄ -alkyl-, Cι _-3 -alkylaminocarbonylamino-C ₂ - ₄ -alkyl-, di- (Cι _-3 -alkyl) amino-carbonylamino- C ₂ - ₄ -alkyl-, morpholin-4-ylcarbonylamino-C2-4 alkyl, Cι- ₃ alkylsulfonyl-C ₂ -4-alkyl or Cι- alkylsulfonylamino-C ₂ - ₄ alkyl group,

a (2-oxopyrrolidin-1 -yl) -C2-4-alkyl-, (2-oxopiperidin-1-yl) -C - ₄ -alkyl-, (3-oxomorpholin-4-yl) -C2 -4-alkyl-, (2-oxo-imidazolidin-1 -yl) -C ₂ -4-alkyl-, (2-oxo-3-methyl-imidazolidin-1-yl) -C ₂ - ₄ -alkyl-, (2-oxo-hexahydropyrimidin-1-yl) -C ₂ - ₄ -alkyl- or (2-oxo-3-methyl-hexahydropyrimidin-1-yl) -C2- ₄ -alkyl group,

a Cι _-3 alkylsulfonyl, chloro-C ₂ - ₄ alkylsulfonyl, bromo-C _2-4 alkylsulfonyl, amino C ₂ - ₄ alkylsulfonyl, Cι-3 alkylamino-C2 _-4 alkylsulfonyl , Di- (C _1-3 -alkyl) amino- C ₂ - ₄ -alkylsulfonyl-, (pyrrolidin-1-yl) -C _2-4 -alkylsulfonyl-, (piperidin-1-yl) -C _2-4 - alkylsulfonyl or (morpholin-4-yl) -C ₂ - ₄ alkylsulfonyl group,

a Cι- ₄ alkyloxycarbonyl group,

a formyl, Cι. _3- alkyl-carbonyl, -C-3-alkyloxy-Cι. ₃ -alkyl-carbonyl-, tetrahydrofuranylcarbonyl-, tetrahydropyranylcarbonyl-, amino-Cι_ ₃ -alkyl- carbonyl-, Cι _-3 -alkylamino-Cι. ₃ -alkyl-carbonyl-, di- (Cι- ₃ -alkyl) amino-Cι- ₃ -alkyl- carbonyl-, pyrrolidin-1 -yl-Cι- ₃ -alkyl-carbonyl-, piperidin-1 -yl-d- ₃ -alkyl-carbonyl-, piperazin-1 -yl-Cι- ₃ -alkyl-carbonyl-, 4-Cι _-3 -alkyl-piperazin-1 -yl-Cι _-3 -alkyl-carbonyl-, morpholin-4-yl -Cι _-3 -alkyl-carbonyl- or a Ci-s-alkylsulfonyl-ds-alkylcarbonyl group, or a cyano, aminocarbonyl, C _{3 -3} alkyl aminocarbonyl, di (C _1-3 alkyl) amino carbonyl, (C _1-3 alkyloxy C _2-4 alkyl) aminocarbonyl, N - (Cι _-3- alkyl) -N- (Cι _-3- alkyloxy-C _2-4 -alkyl) aminocarbonyl-, phenylaminocarbonyl-, pyrrolidin-1 - ylcarbonyl-, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl- , Cι _-3 -Alkyl-morpholin- 4-ylcarbonyl-, di- (Cι _-3 -alkyl) morpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo [2.2.1 ] hept-5-y! carbonyl-, 3-oxa-8-azabicyclo [3.2.1] oct-8-ylcarbonyl-, 8-oxa-3-azabicyclo [3.2.1] oct-3-ylcarbonyl -, Piperazin-1 -ylcarbonyl-, 4- (d _-3 -alkyl) -piperazin-1 -ylcarbonyl-, aminosulfonyl-, Cι _-3 -alkyl-aminosulfonyl-, di- (Cι- -alkyl) aminosulfonyl- Represent pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl or a morpholin-4-yl-sulfonyl group,

a cyclopentyl group which is substituted in the 3-position by a group R ⁶ , where

a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R -NR ⁵ , where R ⁴ and R ⁵ are defined as mentioned above,

a pyrrolidin-3-yl group which is substituted in the 1-position by the radical R ⁵ , where R ⁵ is defined as mentioned above,

a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, R ^{d is} a hydrogen atom,

a Cι-3-alkyloxy group,

a methoxy group which is substituted by one to three fluorine atoms,

R ^{7 is} a hydroxy, C 1 alkyloxy, amino, C ₃ alkylamino, di (C _1-3 alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidine-1 yl-, piperidin-1-yl-, morpholin-4-yl-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8 -aza-bicyclo- [3.2.1] oct-8-yl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl-, piperazin-1-yl- or a 4-Cι- ₃ -Alkyl-piperazin-1 -ylgruppe, or a formylamino, Cι _-4 -alkylcarbonylamino-, -Cι _-3 -alkyloxy-Cι- ₃ -alkyl- carbonylamino-, Cι- ₄ -alkyloxycarbonylamino-, aminocarbonylamino-, d _-3 - Alkylaminocarbonylamino-, di- (Cι- ₃ -alkyl) aminocarbonylamino-, pyrrolidin-1 - ylcarbonylamino-, piperidin-1 -ylcarbonylamino-, piperazin-1 -ylcarbonylamino-, 4-C-ι-3-alkyl-piperazin-1 represents -ylcarbonylamino- morpholin-4-ylcarbonylamino- or a Cι-4-alkylsulfonylamino group,

a propyloxy group which is substituted in the 3-position by a radical R ⁶ or R ⁷ , where R ^δ and R ⁷ are defined as mentioned above, or

X represents a nitrogen atom,

their tautomers, their stereoisomers, their mixtures and their salts.

3. Bicyclic heterocycles of the general formula 1 according to claim 1, in which

R ^{a is} a hydrogen atom,

R is a 1-phenylethyl group

R ^{4 is} a hydrogen atom, a methyl or ethyl group and

R ^{5 is} a hydrogen atom, a methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, pyrrolidine-1 -ylcarbonylmethyl, piperidine-1 -ylcarbonylmethyl-, piperazin-1 -ylcarbonylmethyl-, 4-methylpiperazin- 1 -ylcarbonylmethyl-, Morpholin-4 ylcarbonylmethyl, 2- (morpholin-4-yl-carbonyl) ethyl or 3- (morpholin-4-yl-carbonyl) propyl group, an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (butyloxycarbonylamino) ethyl, 2-aminoethyl, 3-aminopropyl, 2- (acetylamino) ethyl, 3- (acetylamino) propyl, 2- ( Ethylcarbonylamino) ethyl-, 3- (ethylcarbonylamino) propyl-, 2- (propylcarbonylamino) ethyl-, 3- (propy! Carbonylamino) propyl-, 2- (ethylaminocarbonylamino) ethyl-, 3- (ethylaminocarbonylamino) propyl-, 2- (dimethylaminocarbonylamino) ethyl-, 3- (dimethylaminocarbonylamino) propyl-, 2- (morpholin-4-ylcarbonylamino) ethyl-, 3- (morpholin-4-ylcarbonylamino) propyl-, 2- (methylsulfonyl) ethyl -, 3- (Methylsulfonyl) propyl-, 2- (methyls sulfonylamino) ethyl or a 3- (methylsulfonylamino) propyl group, a 2- (2-oxopyrrolidin-1-yl) ethyl, 2- (2-oxopiperidin-1-yl) ethyl, 2- (3rd -Oxomorpholin-4-yl) ethyl-, 2- (2-oxo-imidazolidin-1-yl) ethyl-, 2- (2-oxo-3-methyl-imidazolidin-1-yl) ethyl-, 2- (2-oxo-hexahydropyrimidin-1-yl) ethyl or a 2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) ethyl group, a 3- (2-oxopyrrolidin-1-yl) propyl-, 3- (2-oxopiperidin-1-yl) propyl-, 3- (3-oxomorpholin-4-yl) propyl-, 3- ( 2-oxo-imidazolidin-1-yl) propyl-, 3- (2-oxo-3-methyl-imidazolidin-1-yl) propyl-, 3- (2-oxo-hexahydropyrimidin-1-yl) propyl or a 3- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) propyl group, a methylsulfonyl, ethylsulfonyl, 3-chloropropylsulfonyl, 2- (morpholin-4-yl) ethylsulfonyl or a 3- (morpholine -4-yl) propylsulfonyl group, a propyloxycarbonyl or butyloxycarbonyl group, a formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxyacetyl, (2-methoxyethyl) carbonyl, (3-methoxypropyl) carbonyl, tetrahydrofuran-2- ylcarbonyl-, tetrahydropyran-4-ylcarbonyl-, aminoacetyl-, methylaminoacetyl-, dimethylaminoacetyl-, morpholin-4-ylacetyl-, [2- (morpholin-4-yl) ethyl] carbonyI-, [3- (morpholin-4-yl ) propyl] carbonyl or a methylsulfonylacetyl group, a cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, pro pylaminocarbonyl-, (2-methoxyethyl) aminocarbonyl-, N-methyl-N- (2-methoxyethyl) aminocarbonyl-, (3-methoxypropyl) aminocarbonyl-, N-methyl-N- (3-methoxypropyl) - aminocarbonyl-, phenylaminocarbonyi -, pyrrolidin-1 -ylcarbonyl-, piperidin-1 - ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl-, 2,6-dimethylmorpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyI-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-ylcarbonyl-, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-ylcarbonyl-, 8-oxa-3-aza- bicyclo [3.2.1] oct-3-ylcarbonyl, 4-methylpiperazin-1 -ylcarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or a morpholin-4-ylsulfonyl group,

a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R ⁶ , where

R ^{6 is} 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 represents methyl imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group, a pyrrolidin-3-yl group which is substituted in the 1 position by the radical R ⁵ , where R ⁵ is defined as mentioned above, a piperidin-3-yl group which is substituted in the 1 position by the radical R ⁵ , where R ^{5 is} as defined above, a piperidin-4-yl group which is substituted in the 1-position by the radical R ⁵ , where R ^{5 is} as defined above, or

a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

R ^{d is} a hydrogen atom,

a methoxy, difluoromethoxy or ethyloxy group,

an ethyloxy group which is in the 2-position by a radical R ⁶ . or R ^{7 is} substituted, wherein R ⁶ is defined as mentioned above and

R ^{7 is} a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4- yI-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl -, 8-Oxa-3-aza-bicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl group, or an acetylamino -, Ethylcarbonylamino-, Propylcarbonylamino-, Butylcarbonylamino-, Methoxyacetylamino-, Butyloxycarbonylamino-, Ethylaminocarbonylamino-, Dimethylaminocarbonylamino-, Pyrrolidin-1 - ylcarbonylamino-, Piperidin-1 -ylcarbonylamino-, Methylcarbonylamino-, Methylphonamino- Butylsulfonylamino group,

a propyloxy group which is substituted in the 3-position by a radical R ⁶ or R ⁷ , where R ⁶ and R ⁷ are defined as mentioned above, or a butyloxy group which is substituted in the 4-position by a radical R ⁶ or R ⁷ , where R ⁶ and R ⁷ are defined as mentioned above, and

X represents a nitrogen atom,

their tautomers, their stereoisomers, their mixtures and their salts.

4. Bicyclic heterocycles of the general formula I according to claim 1, in which

R ^{a is} a hydrogen atom,

R is a 1-phenylethyl group,

R ^{c is} a cyclohexyl group which is in the 4-position by an amino, methylamino, dimethylamino, acetylamino, N- (acetyl) methylamino, methoxyacetylamino, N- (methoxyacetyl) methylamino, tetrahydropyran-4- ylcarbonylamino-, N-

Dimethylaminocarbonylamino-, N- (Dimethylaminocarbonyl) -methylamino-, N- (Piperidin-1 -ylcarbonyl) -methylamino-, Morpholin-4-ylcarbonylamino-, N- (Morpholin-4-ylcarbonyl) - methylamino-, N- (4- Methylpiperazin-1 -ylcarbonyl) -methylamino-, methylsulfonylamino-, N- (methylsulfonyl) -methylamino-, ethylsulfonylamino-, N- (ethylsulfonyl) -methylamino-, dimethylaminosulfonylamino-, N- (dimethylaminosulfonyl) -methylolinino- ylsulfonylamino or N- (morpholin-4-ylsulfonyl) methylamino group is substituted,

a pyrrolidin-3-yl group,

a pyrrolidin-3-yl group which is substituted in the 1-position by a tert-butyloxycarbonyl or methylsulfonyl group, a piperidin-3-yl group, a piperidin-3-yl group which is substituted in the 1-position by a tert-butyloxycarbonyl or methylsulfonyl group,

a piperidin-4-yl group,

Butyloxycarbonylamino) ethyl, 2-aminoethyl, 2- (acetylamino) ethyl, 2-

(Methylsulfonylamino) ethyl, cyano, acetyl, methoxyacetyl, (dimethylam (no) acetyl, (morpholin-4-yl) acetyl, tetrahydropyran-4-ylcarbonyl, ethylaminocarbonyl,

Isopropylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1 -ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl-, 2,6-dimethylmorpholin-4-ylcarbonyl-, Homomorpholin-4-ylcarbonyl-, 4-methylpiperazin-1 -ylcarbonyl-, isopropyloxycarbonyl-, tert-butyloxycarbonyl-,

a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

R ^{d is} a methoxy, ethyloxy or a 2- (methoxy) ethyloxy group,

and

X represents a nitrogen atom,

their tautomers, their stereoisomers, their mixtures and their salts.

5. Bicyclic heterocycles of the general formula I according to claim 1, in which

R ^{a is} a hydrogen atom,

R ^{b is} a 1-phenylethyl group, R ^{c is} a piperidin-4-yl group,

R ^{d is} a methoxy group

and

X represents a nitrogen atom,

their tautomers, their stereoisomers, their mixtures and their salts.

6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases.

7. Medicament containing a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents.

8. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the treatment of benign or malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lungs and for the treatment of diseases of the gastrointestinal tract and the bile ducts and bladder is suitable.

9. A method for producing a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 6 is incorporated into one or more inert carriers and / or diluents in a non-chemical way.

10. A process for the preparation of the compounds of general formula I according to claims 1 to 5, characterized in that

a) a compound of the general formula

in the

R ^a , R ^b , R ^d and X are as defined in claims 1 to 6, with a compound of the general formula

in the

R ° is as defined in claims 1 to 6 and Z ^{1 represents} a leaving group, is implemented, or

b) for the preparation of compounds of the general formula I in which R ^{d represents} one of the optionally substituted alkyloxy groups mentioned in claims 1 to 6,

a compound of the general formula

in which R ^a , R, R ^c and X are defined as mentioned in claims 1 to 6, with a compound of the general formula

Z ² - R ^{d '} , (V)

in R ^{d '} a d-4-alkyl group, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a C ₂ - ₄ alkyl group substituted by a radical R ⁶ or R ⁷ , where R ⁶ and R ^{7 are} as defined in claims 1 to 6, a C 1 - alkyl group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the radical R ⁸ , or a d - ₄ alkyl group which is substituted by a morpholinyl group substituted in the 4-position by the radical R ⁸ , where R ^{8 is in} each case defined as mentioned in claims 1 to 6, and

Z ^{2 represents} a leaving group, is implemented or

c) for the preparation of compounds of the general formula I in which R ^{d represents} one of the alkyloxy groups mentioned in claims 1 to 6, which is substituted by an optionally substituted amino, alkylamino or dialkylamino group or by an optionally substituted heterocyclic bonded via an imino nitrogen atom Group is substituted,

with a compound of the general formula

in which R ^a , R, R ^c and X are defined as mentioned in claims 1 to 6 and Z ^{3 represents} a leaving group, with Ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or their suitable salts or derivatives is reacted or

d) for the preparation of compounds of the general formula I in which R ^{d represents} a hydroxyl group,

a protective residue of a compound of the general formula

in which R ^a , R ^b , R ° and X are defined as mentioned in claims 1 to 6 and R ^{d "represents} a group which can be converted into a hydroxyl group, is split off or

e) for the preparation of compounds of the general formula I in which R ^{c contains} an —NH group,

a protective residue of a compound of the general formula

^b in which R ^a, R, R ^d and X are defined as mentioned in claims 1 to 6 and R ^{c 'with} the proviso has the meanings mentioned ^c in claims 1 to 6 for R, that R ^c contains a protected nitrogen atom , is split off or

f) for the preparation of compounds of the general formula I in which R ^c is substituted by an optionally substituted amino, alkylamino or dialkyamino group or by contains an optionally substituted heterocyclic group substituted alkyl group bonded via a nitrogen atom,

a compound of the general formula

in which R ^a , R ^b , R ^d and X are defined as mentioned in claims 1 to 6, Z ^{3 represents} a leaving group and R ^{G "} with the proviso that a hydrogen atom bonded to an aliphatic carbon atom is replaced by the group Z ³ which has meanings for R ^{c mentioned} in claims 1 to 6,

is reacted with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or their suitable salts or derivatives and

if desired, a compound of the general formula I thus obtained, which contains an amino, alkylamino or imino group, is converted into a corresponding acyl, cyano or sulfonyl compound of the general formula I by means of acylation, cyanation or sulfonylation and / or

a compound of the general formula I thus obtained, which contains an amino, alkylamino or imino group, is converted into a corresponding alkyl compound of the general formula I by means of alkylation or reductive alkylation and / or

a compound of the general formula I thus obtained, which contains a chloro-d- _4- alkylsulfonyl or a bromo-d- _4- alkylsulfonyl group, is converted into a corresponding amino-Ci ^ -alkylsulfonyl compound by reaction with an amine and / or a compound of the general formula I thus obtained, which contains a tert-butyloxycarbonylamino, N-alkyl-N- (tert-butyloxycarbonyl) amino or an N-tert-butyloxycarbonylimino group, by treatment with an acid in a corresponding amino -, Alkylamino- or imino compound of the general formula I is converted, and / or

if necessary, a protective residue used in the reactions described above is split off again and / or

if desired, a compound of the general formula I thus obtained is separated into its stereoisomers and / or

a compound of the general formula I thus obtained is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.