EP2118075A1

EP2118075A1 - Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof

Info

Publication number: EP2118075A1
Application number: EP08708456A
Authority: EP
Inventors: Frank Himmelsbach; Birgit Jung; Ralf Lotz; Markus Ostermeier
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2007-02-06
Filing date: 2008-01-30
Publication date: 2009-11-18
Also published as: TW200846330A; CA2677336A1; EA200901041A1; US7998949B2; US20100022505A1; ECSP099562A; KR20090116782A; MX2009007610A; MA31171B1; CL2008000356A1; JP2010518045A; AU2008212999A1; BRPI0807234A2; JP5377332B2; AR065195A1; CO6210816A2; IL199923A0; TN2009000332A1; WO2008095847A1

Abstract

The invention relates to bicyclic heterocycles of general formula (I), wherein Ra, Rb and Rc are defined as in claim 1, to the tautomers thereof, the stereoisomers thereof, the mixtures thereof and the salts thereof, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable pharmacological properties, especially an inhibitory effect on tyrosinkinase-mediated signal transduction. The invention also relates to the use of said compounds in the treatment of diseases, especially of tumors and of benign prostatic hyperplasia (BPH), lung diseases and respiratory tract diseases, and to the production thereof.

Description

Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation

The present invention relates to bicyclic heterocycles of the general formula

their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically acceptable salts with inorganic or organic acids and bases, which have valuable pharmacological properties, in particular an inhibitory effect on tyrosine kinase-mediated signal transduction, their use for the treatment of diseases, in particular of Tumor diseases as well as benign prostatic hyperplasia (BPH), diseases of the lung and the respiratory tract and their production.

In the above general formula I means

R ^{a represents} a phenyl, 1-phenylethyl or indan-4-yl 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 represents a hydrogen, fluorine, chlorine, bromine or iodine atom,

a Ci _-4 alkyl, hydroxy, Ci _-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 substituted by 1 to 3 fluorine atoms methyl or methoxy group or

a cyano, nitro or amino group, and

R ^{3 is} a hydrogen, fluorine, chlorine or bromine atom or

represent a methyl or trifluoromethyl group,

R ^{b is} an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl , 4- (Ci _-4 -alkyl-carbonyl) -piperazin-1-yl, 4- (Ci _-4 -alkyl-sulfonyl) -piperazin-1 -yl, homopiperazin-1 -yl, 4- (Ci _-4 -Al kyl-carbonyl) - homopiperazin-1 -yl or 4- (Ci _-4- alkylsulfonyl) homopiperazin-1-yl group, each mono-, di- or by R ⁴ mono- may be trisubstituted, where the substituents may be the same or different and

R ^{4 is} a fluorine, chlorine, bromine or iodine atom,

a Ci _-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl group,

a methyl or methoxy group substituted by 1 to 3 fluorine atoms,

an amino, Ci _-4 alkylamino, di- (Ci _-4 alkyl) amino, Ci _-4 -alkyl-carbonylamino,

N- (Ci _-4 alkyl) -C _-4 alkyl-carbonylamino, Ci _-4 -alkyl-sulfonylamino, or N- (Ci _-4 alkyl -AI) -C _-4 alkyl-sulfonylamino group,

an amino-Ci _-4 alkyl, Ci _-4 alkylamino-Ci _-4 alkyl, di- (Ci _-4 alkyl) amino- Ci- ₄ alkyl, Ci _-4 alkyl-carbonylamino-Ci _-4 alkyl, N- (Ci _-4 alkyl) -C _-4 alkyl carbonylannino-Ci _-4 alkyl, Ci _-4 alkyl-sulfonylamino-Ci _-4 alkyl or N- (Ci- ₄ alkyl) -C _-4 alkyl-sulfonylamino-Ci _-4 alkyl group,

a hydroxy, Ci _-4 alkyloxy or Ci _-4 alkyl-carbonyloxy group

a hydroxy-Ci _-4 alkyl, Ci _-4 alkyl or alkyloxy-Ci _-4 Ci _-4 -alkyl-carbonyloxy Ci _-4 alkyl group,

a Ci _-4 alkyl-carbonyl, cyano, Ci _-4 -alkyl-oxycarbonyl, carboxy, aminocarbonyl, Ci _-4 -alkyl-aminocarbonyl, di- (Ci _-4 alkyl) amino carbonyl,

Pyrrolidin-1-yl-carbonyl, Pipehdin-1-yl-carbonyl, piperazin-1 -yl-carbonyl, 4-Ci _-4 -alkyl-piperazin-1-yl-carbonyl or morpholin-4-yl carbonyl group,

a Ci _-4 alkyl alkylcarbonyl-Ci _-4, cyano-Ci _-4 alkyl, Ci _-4 -Al kyloxycarbonyl- Ci- ₄ alkyl, aminocarbonyl-Ci ^ alkyl, Ci _-4 alkylaminocarbonyl -C _-4 alkyl,

Di- (Ci _-4 alkyl) aminocarbonyl-Ci _-4 alkyl, pyrrolidin-1-yl-carbonyl-Ci ^ alkyl, Pipehdin-1-yl-carbonyl-Ci ^ alkyl, piperazin-1 - yl-carbonyl-Ci ^ alkyl, 4-Ci _-4 -alkyl-piperazin-1-yl-carbonyl-Ci ^ alkyl-, or morpholine-4-yl-carbonyl-Ci _-4 alkyl group,

a Ci _-4 alkylsulphanyl, Ci _-4 alkylsulfinyl, Ci _-4 alkylsulfonyl, aminosulfonyl, Ci _-4 -alkyl-aminosulphonyl or di- (Ci _-4 alkyl) amino-sulfonyl group,

a Ci _-4 alkylsulfanyl-Ci _-4 alkyl, Ci _-4 alkylsulfinyl-Ci _-4 alkyl, Ci _-4 alkyl Al kylsulfonyl- Ci _-4 alkyl, aminosulfonyl-C _-4, Ci _-4 alkyl aminosulfonyl-Ci _-4 alkyl or di- (Ci _-4 alkyl) aminosulfonyl-Ci _-4 alkyl group

group, and wherein the above-mentioned under R ^b heterocycles may additionally be substituted by an oxo group, R ^{c is} a hydrogen atom,

a fluorine, chlorine, bromine or iodine atom,

a C kylgruppe _-4 Al,

a Ci _-4 -Al kylgruppe, which is substituted by a radical R ⁵ , wherein

R ⁵ is a hydroxy, Ci _-3 alkyloxy, Cs-e-cycloalkyloxy, amino, Ci _-3 alkylamino,

Di (Ci-3-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-azabicyclo [3.2.1] oct-8-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-Ci- _3- alkylpiperazin-1-yl, homopiperazin-1-yl or Ci-3-alkyl-homopiperazin-1-yl group or

a formylamino, Ci _-4 alkylcarbonylamino, Ci-3-alkyloxy-Ci-3-alkyl- carbonylamino, Ci _-4 -Alkyloxycarbonylamino-, aminocarbonylamino, Ci-3-Alkylanninocarbonylannino-, di- (Ci-3- alkyl) aminocarbonylannino, pyrrolidin-1 -ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-Ci-3-alkyl-piperazin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino- or a Ci Represents _-4- alkylsulfonylamino group,

a hydroxy group,

a C kyloxygruppe _-4 Al,

a methoxy or ethyloxy group substituted by 1 to 3 fluorine atoms, a C2 _-4 alkyloxy group which is substituted by the radical R, where R is as hereinbefore defined,

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

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

a tetrahydrofuranyl Ci _-4 alkyloxy or tetrahydropyranyl Ci _-4 alkyloxy group,

a Ci koxygruppe _-4 -alkyl which is substituted by a 1 in position by the radical R ⁶ is substituted pyrrolidinyl, piperidinyl or homopiperidinyl group wherein

R ^{6 represents} a hydrogen atom or a C _1-3 -alkyl group,

or a Ci _-4 koxygruppe -alkyl which is substituted by a substituted in the 4-position by the group R ⁶ morpholinyl, wherein R ⁶ is as hereinbefore defined, and wherein the above-mentioned in the definition of the radical R ^c pyrrolidinyl, Piperidinyl, piperazinyl and morpholinyl groups may each be substituted by one or two c _1-3 -alkyl groups, and

wherein the aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as meaning a phenyl group which is monosubstituted or disubstituted by R ⁷ , where the substituents may be identical or different and

R ⁷ denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a C _1-3 -alkyl, hydroxy, C _1-3 -alkyloxy, difluoromethyl-trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano Group represents, and

among the heteroaryl groups mentioned in the definition of the aforementioned radicals, a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group is understood, wherein the above-mentioned heteroaryl groups are each mono- or disubstituted by the radical R ⁷ , where the substituents may be identical or different and R ⁷ is defined as mentioned above, and

Unless otherwise stated, the alkyl groups mentioned above may be straight-chain or branched.

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

R ^{1 is} a hydrogen, fluorine, chlorine or bromine atom,

a methyl, trifluoromethyl or ethynyl group,

a phenyloxy or phenylmethoxy group, wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or

a pyridyloxy or pyridinylmethoxy group, wherein the pyridinyl moiety of the aforementioned groups is optionally substituted by a methyl or trifluoromethyl group,

R ^{2 is} a hydrogen, fluorine or chlorine atom or a methyl group and

R ^{3 represents} a hydrogen atom, R ^{b is} an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, homopiperidin-1-yl, morpholin-4-yl, homonnorpholin-4-yl, piperazin-1-yl , 4- _(Ci-C3 alkyl-carbonyl) -piperazin-1-yl, 4- (Ci _-3 alkyl-sulfonyl) -piperazin-1 -yl, homopiperazin-1 -yl, 4- (Ci ₃ -alkyl-carbonyl) - homopiperazine-1-yl or 4- (Ci- _3- alkylsulfonyl) -homopiperazin-1-yl-group, each of which may be mono- or disubstituted by R ⁴ , wherein the substituents may be the same or different and

R ^{4 is} a fluorine atom,

a Ci _-3 alkyl group,

an amino, Ci _-3 alkylamino, di- (Ci _-3 alkyl) amino, Ci _-3 -alkyl-carbonylamino, N- (Ci _-3 alkyl) -C _-3 alkyl-carbonylamino -, Ci _-3 -alkyl-sulfonylamino, or N- (Ci _-3 -AI alkyl) -C _-3 alkyl-sulfonylamino group,

an amino-Ci _-3- alkyl, Ci-s-alkylannino-Ci-s-alkyl, di- (Ci _-3 -alkyl) amino-C 3 -alkyl, Ci-s-alkyl-carbonylannino-Ci -S-alkyl, N- (Ci _-3 alkyl) -C _-3 alkyl- carbonylamino-Ci _-3 alkyl, Ci-s-alkyl-Ci-s-sulfonylannino-alkyl or N- (C - ₃ alkyl) -C _-3 alkyl-sulfonylamino-Ci _-3 alkyl group,

a hydroxy, Ci- _3- alkyloxy or Ci-s-alkyl-carbonyloxy group,

a hydroxy-C _1-3 -alkyl, C _1-3 -alkyloxy-C 1-6 -alkyl or C _1-3 -alkyl-carbonyloxy-C _1-3 -alkyl group,

a Ci- ₃ alkyl-carbonyl, cyano, Ci ^ alkyl-oxycarbonyl, carboxy, aminocarbonyl, _Ci-3 alkyl, aminocarbonyl or di- (Ci ₃ alkyl) amino-carbonyl group . a Ci-s-alkylcarbonyl-Ci-s-alkyl, cyano-Ci _-3 -alkyl, Ci _-4 -Al kyloxycarbonyl- C ₃ -alkyl group, Anninocarbonyl-C ₃ -alkyl-, Ci _-3 Alkylanninocarbonyl-C 1-3 -alkyl- or di-is-alkynylaminocarbonyl-C 1-6 -alkyl group,

a Ci _-4 alkylsulphanyl, Ci _-4 kylsulfinyl- Al, Ci _-4 alkylsulphonyl, aminosulphonyl,

Ci-3-alkyl-anninosulfonyl or di (Ci-3-alkyl) anninosulfonyl group,

a Ci _-4 alkylsulfanyl-Ci ₃ alkyl, Ci _-4 alkyl alkylsulfinyl-Ci _3,

C 1-4 -alkylsulfonyl-C _1-3 -alkyl, aminosulfonyl-C _1-3 -alkyl, C _1-3 -alkyl -nanninosulphonyl-C _1-3 -alkyl or -di- (C _1-3 -alkyl) -amino-sulfonyl-Ci _3- alkyl

group

group, and wherein the above-mentioned under R ^b heterocycles may additionally be substituted by an oxo group,

R ^{c is} a hydrogen atom,

a hydroxy group,

a C kyloxygruppe _-3 Al,

a methoxy group substituted by one to three fluorine atoms,

an ethyloxy group which is substituted in the 2-position by a radical R ⁵ , wherein

R ^{5 is} a hydroxy, Ci-3-alkyloxy, amino, Ci-3-alkylamino, di (Ci-3-alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidine-1 - yl, piperidine-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazine-1-yl or a 4-Ci- _3- alkyl-piperazin-1-yl-group, a propyloxy group which is substituted at the 3-position by the radical R ⁵ , wherein R ⁵ is defined as mentioned above, or

a butoxy group substituted in the 4-position by a radical R ⁵ , wherein R ⁵ is defined as mentioned above, and

Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,

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

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

R ^a phenyl, a 1-phenylethyl, 3-Ethinylphenyl-, 3-bromo-2-fluoro-phenyl, 3-bromo-4-fluoro, 3-chloro-2-fluoro-phenyl, 3-chloro- 4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-5-methylphenyl, 3-fluoro-5-methylphenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl-phenyl, 2,5-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan -4-yl group,

a 3-chloro-4-benzyloxy-phenyl, 3-chloro-4 - [(3-fluoro-benzyl) oxy] -phenyl, 4- (pyridin- 3-yloxy) -phenyl, 4 - [(6 -Methylpyridin-3-yl) oxy] -phenyl, 3-methyl-4- (pyridin-3-yloxy) -phenyl, 3-methyl-4 - [(6-methyl-pyhdin-3-yl) oxy] -phenyl, 3-chloro-4- (pyridin-3-yloxy) -phenyl or 3-chloro-4 - [(6-methyl-pyridin-3-yl) oxy] -phenyl group,

R ^{b is} an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, morpholin-4-yl, piperazin-1-yl,

4- (Ci _-3 alkyl-carbonyl) -piperazin-1-yl or 4- (Ci _-3 -alkyl-sulfonyl) -piperazin-1 -yl GGrruuppppee ,, tthhee RR jjeewweeiillss dduurrcchh ⁴⁴ mmoonnoo-- ooddeerr The substituents may be the same or different and R ^{4 is} a fluorine atom,

a Ci-3-alkyl group,

an amino, C _1-3 -alkylamino, di- (C _1-3 -alkyl) -annino, C 1-3 -alkyl-carbonylannino,

N- (C _1-3 -alkyl) -ci- ₃ -alkylcarbonylannino, C _1-3 -alkylsulphonylamino or N- (C 1-6 -alkyl) -J-C 1-6 -alkylsulphonylannino group,

an amino-C _1-3 -alkyl, C 1-6 -alkyl-cinnamic-C 1-6 -alkyl, -di (C _1-3 -alkyl) amino-C _1-3 -alkyl, C 1-6 -alkyl-carbonylannino-C ₁ -s-alkyl-, N- (C _1-3 -alkyl) -ci- ₃ -alkyl-carbonylamino-C _1-3 -alkyl, C 1-6 -alkyl-sulfonylannino-C 1-6 -alkyl- or N- (Ci s-alkylo-C 1 -5-alkylsulfonylannino-C 1 -5 -alkyl group,

a hydroxy, C _1-3 -alkyloxy or C _1-3 -alkyl-carbonyloxy group,

a hydroxy-C _1-3 -alkyl, C 1-3 -alkyloxy-Ci-s-alkyl or C 1-3 -alkyl-carbonyloxy-C 1-3 -alkyl group,

a Ci _-3 alkyl-carbonyl, cyano, Ci _-4 alkyl-oxycarbonyl, carboxy, aminocarbonyl, _Ci-3 alkyl, aminocarbonyl or di- (Ci _-3 alkyl) amino-carbonyl

Group,

a Ci-s-alkylcarbonyl-Ci-s-alkyl, cyano-Ci ₃ -alkyl, Ci _-4 -Al kyloxycarbonyl- C ₃ -alkyl group, aminocarbonyl-Ci-3-alkyl, Ci-3 -Alkylaminocarbonyl-C _1-3 -alkyl or di-C 1-4 -alkylaminocarbonyl-C 1-6 -alkyl group,

a Ci _-4 alkylsulphanyl, Ci kylsulfinyl- _-4 -alkyl, Ci _-4 alkylsulfonyl, aminosulfonyl, Ci _-3 -alkyl-aminosulphonyl or di- (Ci _-3 alkyl) amino-sulfonyl group . a Ci _-4 alkylsulfanyl-Ci ₃ alkyl, Ci ^ alkylsulfinyl-Ci ₃ alkyl,

C 1-4 -alkylsulfonyl-C _1-3 -alkyl, aminosulfonyl-C _1-3 -alkyl, C _1-3 -alkyl-aminosulfonyl-C 1-3 -alkyl or C 1-5 -sym-alkylamino-sulfonyl-C s-alkyl group,

R ^{c is} a hydrogen atom,

a methoxy or ethyloxy group,

an ethyloxy group which is substituted in the 2-position by the radical R ⁵ , wherein

R ^{5 is} a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidine-1-yl, morpholine-4 yl,

Represents homomorpholin-4-yl, piperazine-1-yl, 4-methyl-piperazine-1-yl or 4-ethyl-piperazin-1-yl-group,

a propyloxy group which is substituted at the 3-position by the radical R ⁵ , wherein R ⁵ is defined as mentioned above, or

a butoxy group substituted in the 4-position by the radical R ⁵ , wherein R ⁵ is defined as mentioned above, and

their tautomers, their stereoisomers, their mixtures and their salts. Very particularly preferred compounds of general formula I are those in which

R ^a phenyl, a 1-phenylethyl, 3-Ethinylphenyl-, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro, 5-chloro-2-fluoro-phenyl, 2-fluoro- 3-methylphenyl, 2-fluoro-5-methyl-phenyl, 3-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl phenyl, 2,5-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan-4-yl group,

R ^{b is} an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, morpholin-4-yl, piperazine-1-yl, 4- (Ci- _3- alkyl-carbonyl) - piperazin-1-yl or 4- (Ci _-3 -alkyl-sulfonyl) -piperazin-1 -yl group mono- by each of R ^4, or may be disubstituted, wherein the substituents may be identical or different and

R ^{4 is} a fluorine atom,

a Ci-3-alkyl group,

an amino, Ci-2-alkylamino, di (Ci-2-alkyl) amino, Ci-2-alkyl-carbonylamino, N- (Ci-2-alkyl) -Ci-2-alkyl-carbonylamino , Ci-2-alkyl-sulfonylamino or N- (Ci-2-alkyl) -Ci-2-alkyl-sulfonylamino group,

an amino-Ci- ₂ alkyl, Ci- alkyl ₂ alkylamino-Ci _2, di- (Ci- ₂ alkyl) amino Ci- ₂ alkyl, Ci ^ alkyl-carbonylamino-Ci ^ alkyl, N- (Ci- ₂ alkyl) ₂ -ci- alkyl- carbonylamino-Ci ₂ alkyl, Ci- ₂ alkyl-sulfonylamino-Ci- ₂ alkyl or N- (Ci ₂ Alkyl) -Ci-2-alkylsulfonylamino-C 1-2-alkyl group,

a hydroxy, Ci _-2 alkyloxy- or Ci ^ alkyl-carbonyloxy group,

a hydroxy-Ci ₂ alkyl, _Ci-2 alkyloxy C _2-4 alkyl or C ₂ alkyl-carbonyloxy Ci-2-alkyl group, a Ci _-2 alkyl-carbonyl, cyano, _Ci-2 alkyl oxycarbonyl, carboxy, aminocarbonyl, _Ci-2 alkyl anninocarbonyl- or di- (Ci- ₂ alkyl) Annino-carbonyl Group,

a Ci alkyl _2-alkyl-Ci _2, cyano-Ci- ₂ alkyl, Ci- ₂ alkyloxycarbonyl-

Ci ₂ alkyl group, aminocarbonyl-Ci- ₂ alkyl, Ci- ₂ -alkylaminocarbonyl- Ci-2-alkyl- or di- ^ i ^ -alkylJaminocarbonyl-Ci ^ alkyl group,

a C _2-2 -alkylsulfanyl, C _2-2 -alkylsulfinyl or C _2-2 -alkylsulfonyl group,

a Ci- ₂ alkylsulfanyl-Ci- ₂ alkyl, _Ci-2 alkylsulfinyl Ci- ₂ alkyl or Ci _-2 -Al kylsulfonyl-Ci-2-alkyl group,

R ^{c is} a hydrogen atom,

a methoxy, ethyloxy or 2- (methoxy) -ethyloxy group,

a 2- (morpholin-4-yl) ethyloxy, 3- (morpholin-4-yl) propyloxy or 4- (morpholin-4-yl) butyloxy group,

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

Especially preferred compounds of general formula I are those in which

R ^a is a 1-phenylethyl, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl- , 2-fluoro-5-methyl-phenyl, 3-fluoro-5-methyl phenyl, 4-fluoro-3-methylphenyl, 2,4-difluoro-3-methylphenyl, 3-chloro-2-methylphenyl or an indan-4-yl group,

R ^b is an azetidin-1-yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl or 3-oxo-piperazin-1-yl group, each represented by R ⁴ mono- or may be disubstituted, wherein the substituents may be the same or different and

R ^{4 represents} a methyl, hydroxy, cyano, aminocarbonyl, methylamino-carbonyl or dimethylamino-carbonyl group, and

R ^{c is} a methoxy group,

mean,

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

Among the bicyclic heterocycles of the general formula I described above and the subgroups which are each identified as being preferred, particularly preferred, very particularly preferred and especially preferred, those compounds in which

R ^{a is} a 3-chloro-2-fluoro-phenyl group,

a 2-fluoro-3-methyl-phenyl group,

a 2-fluoro-5-methyl-phenyl group or

represents a 3-chloro-2-methyl-phenyl group,

R ^{b is} a 3-oxo-piperazine-1-yl group or represents a 4-methyl-3-oxo-piperazin-1-yl group, and

R ^{c represents} a methoxy group,

where R ^{a is} in particular the 3-chloro-2-fluorophenyl group, R ^{b is} the 3-oxopiperazine-1-yl or 4-methyl-3-oxopiperazine-1-yl group and R ^{c is} the methoxy group, and

wherein the trans arrangement of the substituents in the 1, 4-position of the cyclohexane ring is in each case preferred.

For example, the following particularly preferred compounds of general formula I may be mentioned:

(a) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (morpholin-4-yl) -cyclohexyloxy] -7-methoxy-quinazoline,

(b) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (morpholin-4-yl) -cyclohexyloxy] -7-methoxy-quinazoline,

(c) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(R) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline,

(d) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(R) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline,

(e) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(S) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline, (f) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(S) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline,

(g) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline,

(h) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline,

(i) 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -cis-4- [2- (N, N-dinethylanninocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy ] -7-nnethoxy-quinazoline,

(j) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - {(S) -trans-4- [2- (N, N-dimethylanninocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy ] -7-nnethoxy-quinazoline,

(k) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - {(S) -cis-4- [2- (anninocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7- methoxy-quinazoline,

(I) 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -trans-4- [2- (anninocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7- methoxy-quinazoline,

(m) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-methyl-3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline,

(n) 4 - [(2-fluoro-3-methyl-phenyl) -annino] -6- [trans-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline,

(o) 4 - [(2-fluoro-5-methylphenyl) -annino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline, (p) 4 - [(2,4-difluoro-3-methylphenyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline and

(q) 4 - [(3-Chloro-2-methyl-phenyl) -amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

and their salts.

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

a) reaction of a compound of the general formula

in the

R ^a and R ^c are defined as mentioned above, with a compound of the general formula

in the R ^b is defined as mentioned above 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 or a hydroxy group.

With a compound of the general formula (III) in which Z ^{1 represents} a halogen atom or a sulphonyloxy group, the reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, preferably in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride or N-ethyl-diisopropylamine, at temperatures in the range of 20 ⁰ C to 160 ⁰ C, for example at temperatures in the range of 80 ° C to 140 ⁰ C. 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 triphenylphosphine / Azodicarbonsäurediethylester, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, Toluene or Ethylenglycoldiethylether at tempera temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C performed.

b) reaction of a compound of the general formula

in the

R ^a and R ^c are defined as mentioned above, and Z ^{2 is} a leaving group such as a halogen atom, for example a chlorine or bromine atom or a sulphonyloxy group such as a Methanesulfonyloxy- or p-toluenesulfonyloxy group, with a compound of the general formula

HR ^b , (V)

in the

R ^b is defined as mentioned above.

The reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate or N-ethyl-diisopropylamine, for example in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide or N-methylpyrrolidinone at temperatures in the range of 0 ⁰ C and 150 ⁰ C performed.

c) reaction of a compound of the general formula

in the

HR ^b, (VII)

in the R ^b is defined as mentioned above, in the presence of a reducing agent.

The reductive amination is, for example, in a solvent such as dichloromethane, 1, 2-dichloroethane, methanol, ethanol, tetrahydrofuran or dioxane in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanborhydrid, optionally in the presence of acetic acid at temperatures between 0 ⁰ C. and 80 ⁰ C performed. The reductive amination can also be carried out with hydrogen in the presence of a catalyst such as palladium on activated carbon or platinum oxide. Another possibility is to form the enamine from the ketone of general formula VI and the amine of general formula VII with elimination of water, for example with titanium (IV) isopropoxide, and then to reduce this, for example with sodium borohydride or hydrogen / palladium activated carbon.

d) reaction of a compound of general formula (VIII)

in which R ^b and R ^c are defined as mentioned above, with a

Halogenating agent, for example an acid halide such as thionyl chloride,

Thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride to an intermediate compound of general formula (IX),

in which R ^b and R ^c are defined as mentioned above and Z ^{3 represents} a halogen atom, such as a chlorine or bromine atom,

and subsequent reaction with a compound of general formula (X),

R ^a -NH ₂ (X), in which R ^a is defined as mentioned at the beginning, or its salts.

The reaction with the halogenating agent is optionally carried out in a solvent such as methylene chloride, chloroform, acetonitrile or toluene and optionally in the presence of a base such as N, N-diethylaniline, triethylamine or N-

Ethyl diisopropylamine at temperatures ranging from 20 ⁰ C to 160 ⁰ C, preferably carried out from 40 ° C to 120 ⁰ C. Preferably, however, the reaction with thionyl chloride and catalytic amounts of dimethylformamide at the boiling temperature of the reaction mixture or with phosphorus oxychloride in

Acetonitrile in the presence of triethylamine at the boiling point of

Reaction mixture performed.

The reaction of the compound of the general formula (IX) with the compound of the general formula (X) or salts thereof is expediently carried out in a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide, if appropriate in the presence of a base such as potassium carbonate, triethylamine or nitrogen. Ethyl diisopropylamine, at temperatures in the range of 20 ° C and 160 ° C, preferably from 60 ⁰ C to 120 ° C. Preferably, however, the reaction is carried out in isopropanol at the boiling temperature of the reaction mixture.

The reaction of a compound of the general formula (VIII) to give a compound of the general formula (I) can also be carried out as a one-pot reaction, for example in acetonitrile in the presence of triethylamine. e) For the preparation of compounds of the general formula I, in which R ^{c represents} one of the abovementioned, optionally substituted alkyloxy groups:

Reaction of a compound of the general formula

in the R ^a and R ^b are defined as mentioned above, are one with a compound of the general formula

Z ⁴ - R ^{c '} , (XII)

in which R ^c is a Ci _-4 alkyl group, substituted by 1 to 3 fluorine atoms, methyl or ethyl group, a C _3- 7 cycloalkyl or C ₃ -7-cycloalkyl-Ci _-4 alkyl group, a tetrahydrofuran-3-yl alkyl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, a tetrahydrofuranyl-Ci _-4 or tetrahydropyranyl-Ci _-4 alkyl group, a substituted by R ⁷ C2 _-4 alkyl group, wherein R ⁷ is as hereinbefore defined is a Ci _-4 -Al kylgruppe, which is substituted by a 1-position by the radical R ⁸ substituted pyrrolidinyl, piperidinyl or Homopiperidinylgruppe, or a Ci _-4 -Al kylgruppe, by a in 4-position the radical R ^{8 is} substituted substituted Morpholinylgruppe, wherein R ^{8 is in} each case defined as mentioned above, and

Z ^{4 represents} a leaving group such as a halogen atom, an alkylsulfonyloxy, arylsulfonyloxy or a hydroxy group. When 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 hydroxy 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 / Azodicarbonsäurediethylester performed.

f) For the preparation of compounds of the general formula I in which R ^{c represents} one of the abovementioned alkyloxy groups 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: Reaction a compound of the general formula

in which R ^a and R ^b are defined as mentioned above and Z ^{5 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom or a sulphonyloxy group such as a Methansulfonyloxy- or p-toluenesulfonyloxy group, with

Ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or their suitable salts or derivatives, such as morpholine. g) For the preparation of compounds of the general formula I, in which R ^{b contains} one or more hydroxyl groups:

Cleavage of protective residues from a compound of the general formula

in which R ^a and R ^c are defined as mentioned above and R ^{b contains} one or more groups convertible into hydroxyl groups, for example an optionally substituted benzyloxy group, a silyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxy or trityloxy group.

The cleavage of the protecting groups takes place, 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 metal base such as sodium hydroxide or Potassium hydroxide or aprotic, for example in the presence of iodothmethylsilane, at temperatures between 0 and 120 ⁰ C, preferably at temperatures between 10 and 100 ⁰ C.

The cleavage of a benzyl or Methoxybenzylrestes example, hydrogenolytically, for example 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 ⁰ C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. The splitting off of a However, 2,4-dimethoxybenzyl radical preferably occurs in trifluoroacetic acid in the presence of anisole.

The elimination of a tert-butyl or benzyl radical is carried out, for example, by treatment with an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The cleavage of a silyloxy group, for example a tert-butyl-dimethylsilyl group, is carried out, for example, by treatment with fluorides such as tetrabutylammonium fluoride, if appropriate using a solvent such as tetrahydrofuran or dioxane.

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

Cleavage of a protecting group from a compound of the general formula

in which R ^a and R ^c are defined as mentioned above and R ^b with the proviso has the meanings mentioned above for R ^b that R ^{b contains} a protected nitrogen atom.

Typical protecting groups 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, wherein the phthalyl group is additionally suitable for the amino group.

The cleavage of the protecting group is carried out, 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 a

Alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in

Presence of iodothymethylsilane, at temperatures between 0 and 120 ⁰ C, preferably at temperatures between 10 and 100 ⁰ C.

The cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrest.es, however, for example hydrogenolytically, for example 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 ⁰ C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.

The elimination of a tert-butyl or tert-Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The cleavage of a Trifluoracetylrestes preferably takes place by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with Sodium hydroxide, if appropriate in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ⁰ C.

The cleavage of a Phthalylrestes preferably takes place in the presence of hydrazine or a primary amine such as methylamine, ethylamine, n-butylamine or ethanolamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ⁰ C.

If, according to the invention, a compound of the general formula I which contains an amino, alkylamino or imino group can be obtained by acylation or

Sulfonylation into a corresponding acyl or sulfonyl compound of the general

Formula I are converted, wherein as the acylating agent, for example

Carboxylic acid halides, carboxylic 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 and as

Sulfonylating sulfonyl halides come into question, and / or

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

a compound of the general formula I which contains an alkoxycarbonyl group, this can be converted by ester cleavage into a carboxylic acid and / or

a compound of general formula I which contains an alkoxycarbonyl group, this can be converted by reaction with an amine in a carboxylic acid Dehvat and / or a compound of general formula I which contains a carboxy group, this can be converted by reaction with an amine in a carboxylic acid amide derivative.

In the reactions described above, optionally present reactive groups such as hydroxyl, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction.

For example, come as a protective group for a hydroxy group, the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group into consideration.

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

The optional subsequent cleavage of a protective moiety used is carried out, 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 metal base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ⁰ C, preferably at temperatures between 10 and 100 ⁰ C.

The cleavage of a Trifluoracetylrestes is preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ⁰ C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C. ,

Further suitable protecting groups and possibilities for their introduction and removal are described, for example, in "Protective Groups in Organic Synthesis" by Theodora W. Greene and Peter G. M. Wuts, Wiley-VCH.

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

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

The enantiomer separation is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound, salts or derivatives such. Ester or amide-forming optically active substance, especially acids and their activated derivatives or alcohols, and separating the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, wherein from the pure diastereomeric salts or derivatives the free antipodes can be released by the action of suitable agents. Particularly common optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.

Furthermore, the resulting compounds of the formula I can be converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids or bases. Examples of suitable acids are hydrochloric, hydrobromic, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, phosphoric, fumaric, succinic, benzoic, salicylic, mandelic, lactic, malonic, citric, L-malic, L-tartaric or maleic acids , Suitable bases for this example, sodium hydroxide, potassium hydroxide, calcium hydroxide, diethanolamine or N-methyl-D-glucamine into consideration. The term "Ci _-4 alkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, / so-butyl, sec-butyl or te / t-butyl. Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, f-Bu, etc. are also used for the abovementioned groups. Unless otherwise stated, the definitions propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / t-butyl, etc.

The term "C ₂ - ₃ alkenyl" (including those which are part of other radicals) are branched and unbranched alkenyl groups having 2 to 3 carbon atoms, provided they have at least one double bond. For example: ethenyl or allyl.

The term "C ₂ - ₃ -alkynyl" (including those which are part of other radicals) mean alkynyl groups having 2 to 3 carbon atoms, provided they have at least one triple bond. For example: ethinyl or propargyl.

The term "C _3-7 -cycloalkyl" (including those which are part of other groups) means cyclic alkyl groups having 3 to 7 carbon atoms. Examples include: cyclopropyl, cyclopentyl or cyclohexyl. Unless otherwise stated, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The term "aryl" (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6, 10 or 14 carbon atoms. For example: phenyl or naphthyl, more preferably aryl is phenyl. Unless otherwise stated, the aromatics may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.

Some of the compounds of the general formulas II to XV used as starting materials are known from the literature or can be obtained by processes known per se from the literature (see Examples I to XVIII) or the processes described above, if appropriate with additional introduction of protective radicals.

Standard methods for preparing the starting materials are described, for example, in "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, Wiley-VCH or in "Science of Synthesis / Houben-Weyl", Thieme.

For example, the compounds of general formula (IX) can be obtained as follows:

Scheme 1 Starting from a compound of general formula (XVI) in which PG is a protective group such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, the reaction is carried out with a compound of general formula (III) analogously to the process described above a) to a compound of general formula (XVII). The compounds of the general formula (XVI) are known from the literature (see, for example, WO 2004/108664 or WO 2007/003486) or can be obtained by methods known per se from the literature. The deprotection of a compound of the general formula (XVII) to give a compound of the general formula (VIII) is carried out if PG is benzyl, for example with hydrogen in the presence of a catalyst such as palladium / carbon (for example analogously to Example IV). The cleavage of the protecting group, if PG is 4-methoxybenzyl or 2,4-dimethoxybenzyl, may also be oxidative (eg with cerium (IV) ammonium nitrate or with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone) or with acids (eg with trifluoroacetic acid in the presence of anisole).

A compound of the general formula (VIII) can then be converted into a compound of the general formula (IX) as described in the above process d). The meanings for R ^b , R ^c , Z ¹ and Z ³ in the compounds of Scheme 1 are defined as mentioned above.

As already mentioned, the compounds according to the invention of the general formula I and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), which is inhibited, for example, by inhibition of the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. In addition, it is possible that the signal transmission to further downstream components is blocked. The biological properties of the new compounds are tested, for example, as follows:

Inhibition of EGF-R mediated signal transduction may be e.g. with cells expressing human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha, respectively. A murine hematopoietic cell line is genetically engineered to express functional human EGF-R. The proliferation of this cell line can therefore be stimulated by EGF.

The test is carried out as follows:

The cells are cultured in RPMI / 1640 medium. Proliferation is stimulated with 20 ng / ml human EGF (Promega). To investigate the inhibitory activity of the compounds according to the invention, these compounds are dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures at various dilutions, the maximum DMSO concentration being 1%. The cultures are incubated for 48 hours at 37 ° C.

To determine the inhibitory activity of the compounds according to the invention, the relative cell count is measured with the Cell Titer 96TM AQueous Non-Radioactive Cell Proliferation Assay (Promega) in OD units. The relative cell count is calculated as a percentage of the control and the drug concentration, which inhibits the proliferation of the cells to 50% (IC50) derived. The compounds of the general formula I according to the invention exhibit, for example, IC50 values of <10 micromolar, preferably of <1 micromolar. For example, the following results are obtained:

The compounds of the general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as shown by the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by hyperfunction of tyrosine kinases. These are e.g. 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 pulmonary diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases, e.g. in inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1 -anti-trypsin deficiency, or in cough, pulmonary emphysema, pulmonary fibrosis and hyper-reactive airways.

The compounds are also suitable for the treatment of diseases of the gastrointestinal tract and the bile ducts and bladder, which are associated with a disrupted activity of tyrosine kinases, such as in chronic inflammatory Changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion, such as M. Menetrier, secreting Adenomas and protein loss syndromes.

In addition, the compounds of general formula I and their physiologically acceptable salts can be used to treat other diseases caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc ..

Due to their biological properties, the compounds of 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 therapeutics, for example in combination with topoisomerase inhibitors (eg etoposide), mitotic inhibitors (eg, vinblastine), nucleic acid-interacting compounds (eg, cisplatin, cyclophosphamide, adhamycin), hormone antagonists (eg, tamoxifen), inhibitors of metabolic processes (eg, 5-FU, etc.), cytokines (eg, interferons), antibodies, etc. For the treatment of respiratory diseases, 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) are used. For the treatment of diseases in the region of the gastrointestinal tract, these compounds can also be given alone or in combination with motility or secretion-influencing substances. These combinations can be administered either simultaneously or sequentially. The use of these compounds, either alone or in combination with other active substances, may be intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, by inhalation or transdermally or orally, in particular aerosol formulations being suitable for inhalation.

In the pharmaceutical application, the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in dosages of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg. For administration, these are administered with one or more conventional inert carriers and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycehn, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories incorporated.

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

Preparation of the starting compounds:

Example I

4 - [(3-chloro-2-fluoro-phenyl) amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

To 9.0 g of 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline in 110 ml Tetrahydrofuran is added 25 ml of 4M sulfuric acid and the mixture stirred for 18 hours at room temperature. The mixture is made alkaline with 4M sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried, concentrated and stirred with diethyl ether. The solid is filtered off with suction and dried. Yield: 7.4 g (90% of theory) Mass spectrum (ESI ⁺ ): m / z = 416, 418 [M + H] ⁺

Analogously to Example I, the following compounds are obtained:

(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

Mass Spectrum (ESI ⁺ ): m / z = 416, 418 [M + H] ⁺ (2] _3-benzyl-3,4-dihydro-4-oxo-6- (4-oxo-cyclohexyloxy) -7-nnethoxy-quinazoline

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

Example Il

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline

To 18.1 g of 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6-hydroxy-7-methoxy-quinazoline (see, for example, Bioorganic & Medicinal Chemistry Letters (2006), 16 (18), 4908-4912) in 125 ml of dimethylformamide at 50 ⁰ C 12.5 g of potassium carbonate and 16 g of 8- methanesulfonyloxy-1, 4-dioxa-spiro [4.5] decane (for example, see Journal of Medicinal Chemistry (1992), 35 (12), 2243-7) and the mixture stirred at 80 ⁰ C for 18 hours. Another 4.7 g of potassium carbonate and 4.0 g of 8-methanesulfonyloxy-1,4-dioxa-spiro [4.5] decane are added and the reaction is continued for a further 7 hours 80 ⁰ C stirred. The reaction mixture is cooled, diluted with water and ethyl acetate and the precipitate formed is filtered off with suction and dried. Yield: 12.2 g (47% of theory) Mass spectrum (ESI ⁺ ): m / z = 460, 462 [M + H] ⁺

Analogously to Example II is obtained:

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline

Mass Spectrum (ESI ⁺ ): m / z = 460, 462 [M + H] ⁺

example

4 - [(2-fluoro-5-methyl-phenyl) amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

To 12.1 g of 3,4-dihydro-4-oxo-6- (1, 4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline in 120 ml of acetonitrile are added dropwise 6 ml of phosphorus oxychloride and the mixture is heated to 40 ⁰ C internal temperature. Subsequently, 9.3 ml of methylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to room temperature and after standing overnight the Half of the solution of the intermediate (4-chloro-6- (1, 4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline, see Example IX) dropwise with 2.7 ml of 2-fluoro 5-methylaniline in 5 ml of acetonitrile. The reaction mixture is heated for 3 hours at 40 ⁰ C, then cooled and concentrated. The residue is mixed with water and stirred. The precipitate formed is filtered off with suction and partitioned between 1 M sodium hydroxide solution and dichloromethane. The organic phase is separated, dried, concentrated and stirred with diisopropyl ether. The solid is filtered off with suction and dried. Mass spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺

The following compounds are obtained analogously to Example III:

(1) 4 - [(2,4-Difluoro-3-methyl-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

Synthesis of 2,4-difluoro-3-methylaniline see for example EP 28698

For complete cleavage of the ketal, the crude product is still with aqueous

Hydrochloric acid stirred.

Mass spectrum (ESI ⁺ ): m / z = 414 [M + H] ⁺

(2) 4 - [(2-Fluoro-3-methyl-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is still with aqueous

Hydrochloric acid stirred.

Mass spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺

(3) 4 - [(3-Chloro-2-methyl-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is still with aqueous

Hydrochloric acid stirred.

Mass spectrum (ESI ⁺ ): m / z = 412, 414 [M + H] ⁺

(4) 4 - [(5-Chloro-2-fluoro-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is stirred with aqueous hydrochloric acid. Mass Spectrum (ESI ⁺ ): m / z = 416, 418 [M + H] ⁺

(5) 4 - [(4-Fluoro-3-methyl-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is still with aqueous

Hydrochloric acid stirred.

Mass spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺

(6) 4 - [(3-Fluoro-5-methyl-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is stirred with aqueous hydrochloric acid.

Mass spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺

(7) (R) -4 - [(1-Phenylethyl) amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is stirred with aqueous hydrochloric acid. Mass spectrum (ESI ⁺ ): m / z = 392 [M + H] ⁺

(8) 4 - [(4-Indanyl) amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is still with aqueous

Hydrochloric acid stirred.

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

(9) 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline

For complete cleavage of the ketal, the crude product is still with aqueous

Hydrochloric acid stirred.

Mass Spectrum (ESI ⁺ ): m / z = 416, 418 [M + H] ⁺

Example IV

3,4-Dihydro-4-oxo-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline

16.0 g of 3-benzyl-3,4-dihydro-4-oxo-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline in 150 ml of glacial acetic acid are dissolved in the presence of 1.6 g of palladium on activated carbon (10% Pd) at 60 ⁰ C and a hydrogen pressure of 50 psi hydrogenated. The catalyst is filtered off and the filtrate is concentrated, treated with toluene and concentrated again. The residue is mixed with water and made slightly alkaline with saturated sodium bicarbonate solution. The precipitate is filtered off with suction and dried. Mass spectrum (ESI ⁺ ): m / z = 333 [M + H] ⁺

Analogously to Example IV, the following compounds can be obtained:

(1) 3,4-Dihydro-4-oxo-6- [cis / trans-4- (morpholin-4-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Carrying out at room temperature

Mass spectrum (ESI ⁺ ): m / z = 360 [M + H] ⁺

(2) 3,4-Dihydro-4-oxo-6- [trans-4- (4-methyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Example V

3-Benzyl-3,4-dihydro-4-oxo-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-nethoxy-quinazoline

To 20.0 g of 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150 ml N ₁ N- Dimethylfornnannid be (at 50 ⁰ C 16.0 g of potassium carbonate and 20.0 g of 8- methanesulfonyloxy 1, 4-dioxa-spiro [4.5] decane was added and stirred for 18 hours at 80 ⁰ C vigorously. to complete the reaction times each of potassium carbonate and 8-methanesulfonyloxy (1, 4-dioxa-spiro [4.5] decan will be added, and The reaction mixture is cooled and 500 ml of water are added slowly, the precipitate is filtered off with suction, washed with water and dried Mass spectrum (ESI ⁺ ): m / z = 423 [M + H] ⁺

Example VI

3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline 169 g of 3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline, 118.8 ml of benzyl bromide and 138 , 2 g of potassium carbonate are heated in 1600 ml of acetone for 8 hours at 35-40 ⁰ C. The mixture is stirred for 15 hours at room temperature and then treated with 2000 ml of water. The suspension is cooled to 0 ° C, the precipitate is filtered off with suction, with 400 ml of water and 400 ml of tert. Butyl methyl ether and dried at 50 ⁰ C dried. The solid is dissolved in 4000 ml

Methylene chloride dissolved, filtered and concentrated. The residue is in tert.

Butyl methyl ether suspended, filtered off with suction and dried at 50 ⁰ C. Yield: 203 g

(86% of theory)

Rf value: 0.80 (silica gel, methylene chloride / ethanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 325 [M + H] ⁺

Example VII

3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline

Method A:

168.5 g of 6-hydroxy-7-methoxy-benzo [d] [1,3] oxazin-4-one are dissolved in 1200 ml of toluene and 74.7 ml of benzylamine are added. The mixture is refluxed for 15 hours and then cooled to room temperature. The precipitate is filtered off and washed with tert. -Butylmethylether washed. Yield 124 g (72% of theory)

Method B: 200 g of 3-benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline are suspended in 200 ml of water and 1000 ml of ethanol. 300 ml of 10N sodium hydroxide solution are added at room temperature and the mixture is heated to 30 ° C. for 1 hour. After addition of 172 ml of acetic acid and 2000 ml of water, the mixture is stirred for 20 hours at room temperature. The precipitate is filtered off with suction, washed with water and acetone and dried at 60 ⁰ C. Yield: 172.2 g (98% of theory) Rf value: 0.25 (silica gel, methylene chloride / ethanol = 19: 1) Mass spectrum (ESI ⁺ ): m / z = 283 [M + H] ⁺ Example VIII

6-hydroxy-7-methoxybenzo [d] [1,3] oxazin-4-one

1 g of 2-amino-5-hydroxy-4-methoxy-benzoic acid (prepared by reacting 2-nitro-4,5-dimethoxy-benzoic acid methyl ester with potassium hydroxide solution to give 2-nitro-5-hydroxy-4-methoxybenzoic acid Potassium salt and subsequent catalytic hydrogenation in

Presence of palladium on activated carbon) and 20 ml of orthoformic acid-thethylester are heated for 2.5 hours at 100 ⁰ C. After cooling to room temperature, the precipitate is filtered off with suction and washed with diethyl ether. Yield: 0.97 g (93% of theory)

Rf value: 0.86 (silica gel, methylene chloride / methanol / acetic acid = 90: 10: 1)

Mass spectrum (ESI ⁺ ): m / z = 194 [M + H] ⁺

Example IX

4-Chloro-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline

To 12.1 g of 3,4-dihydro-4-oxo-6- (1, 4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline in 120 ml of acetonitrile are added dropwise 6 ml of phosphorus oxychloride and the mixture is heated to 40 ⁰ C internal temperature. Subsequently, 9.3 ml of triethylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to room temperature and allowed to stand overnight. The solution of the product is further reacted without purification (see Example III).

Analogously to Example IV, the following compounds can be obtained: (1) 4-Chloro-6- [cis / trans-4- (morpholin-4-yl) cyclohexyloxy] -7-nethoxyquinazoline

(2) 4-Chloro-6- [trans-4- (4-methyl-3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxy-quinazoline

Example X

(cis-1-Methanesulfonyloxy) - methyl-S-oxo -piperazine-i-yl-cyclohexane

To 500 mg of (cis) -1-hydroxy-4- (4-methyl-3-oxopiperazin-1-yl) cyclohexane and 0.52 ml of N, N-diisoproyl-ethylamine in 10 ml of dichloromethane are added 0.24 ml Methanesulfonyl chloride added dropwise at 0 ⁰ C and stirred for 1.5 hours at room temperature. The product is purified by column chromatography. Mass spectrum (ESI ⁺ ): m / z = 291 [M + H] ⁺

Example Xl

(cis) -1-hydroxy-4- (4-methyl-3-oxopiperazine-1-yl) -cyclohexane

To 3.3 g of 4- (4-methyl-3-oxo-piperazin-1-yl) -cyclohexan-1-one in 100 ml abs. Tetrahydrofuran are added dropwise 17 ml of a 1 M L-Selctride solution (in tetrahydrofuran) at -78 ° C. After 5.5 hours, 20 ml of methanol are added and the solution is concentrated. The residue is purified by column chromatography. The mixture of cis and trans compounds is separated by preparative HPLC. Mass spectrum (ESI ⁺ ): m / z = 213 [M + H] ⁺

Example XII

4- (4-Methyl-3-oxopiperazine-1-yl) -cyclohexan-1-one

To 0.46 ml of oxalyl chloride in 10 ml of dichloromethane are added dropwise at -60 ⁰ C 0.55 ml of dimethyl sulfoxide in 2 ml of dichloromethane within two minutes. After 5 minutes, 1.0 g of (trans) -1-hydroxy-4- (4-methyl-3-oxopiperazin-1-yl) cyclohexane in 8 ml of dichloromethane is added over 5 minutes. After 20 minutes, 3.3 ml of triethylamine are added and the mixture is stirred at room temperature for 70 minutes. 15 ml of water are added and extracted with dichloromethane. After evaporation of the solvent, the residue contains the product. Mass spectrum (ESI ⁺ ): m / z = 211 [M + H] ⁺

Example XIII

4- (4-Methyl-3-oxopiperazine-1-yl) -cyclohexan-1-one

2.3 g of 8- (4-methyl-3-oxopiperazin-1-yl) -1,4-dioxa-spiro [4.5] decane are dissolved in 20 ml of 4M HCl at room temperature for 48 hours, at 50 ^° C. for 7 hours and stirred at 70 ° C for two hours. The mixture is made alkaline with 4M sodium hydroxide solution and extracted five times with 40 ml dichloromethane. The organic phase is evaporated and the product purified by column chromatography. Mass spectrum (ESI ⁺ ): m / z = 211 [M + H] ⁺

Example XIV

(trans) -1-hydroxy-4- (4-methyl-3-oxopiperazin-1-yl) cyclohexane

10.0 g of (trans) -1-hydroxy-4 - {[N- (2,2-dimethoxy-ethyl) -N-methylamino] -carbonylmethylamino} -cyclohexane are dissolved in a solution of 60 ml of water, 140 ml of methanol and Hydrogenated 10.5 g of methanesulfonic acid with 3.25 g of platinum on carbon (5% Pt) at 50 ^° C. for 24 hours. The solution is made alkaline with 50% sodium hydroxide solution and concentrated. The residue is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated. Mass spectrum (ESI ⁺ ): m / z = 213 [M + H] ⁺

Analogously to Example XIV can be obtained:

(cis) -1-hydroxy-4- (4-methyl-3-oxopiperazine-1-yl) -cyclohexane

Example XV

(trans) -1-hydroxy-4 - {[N- (2,2-dimethoxy-ethyl) -N-methyl-amino] -carbonylmethylamino} -cyclohexane

A suspension of 10.6 g of (trans) -4-aminocyclohexanol, 16.25 g of sodium carbonate and 0.64 g of potassium iodide in 220 ml of acetonitrile at 85 ° C., gives 15.0 g of 2-chloro-N- (2,2-dimethoxy-ethyl) -N- Methyl acetamide in 80 ml of acetonitrile was added dropwise within one hour. It is stirred for one hour at 85 ° C and 16.5 hours at room temperature. It is filtered off and the filtrate is evaporated. The residue is purified by chromatography and then recrystallized in methyl tert-butyl ether and cyclohexane. Mass spectrum (ESI ⁺ ): m / z = 275 [M + H] ⁺

Analogously to Example XV can be obtained:

(cis) -1-Hydroxy-4 - {[N- (2,2-dimethoxy-ethyl) -N-methyl-amino] -carbonylmethylamino} -cyclohexane

Example XVI

8- (4-Methyl-3-oxopiperazin-1-yl) -1,4-dioxa-spiro [4.5] decane

To a solution of 10.0 g of 4-methyl-3-oxo-piperazine, 13.51 g of 1, 4-dioxaspiro [4.5] decan-8-one, 5.65 ml of acetic acid and 200 ml of dichloromethane are added at 5 ° C 26.18 g of sodium triacetoxyborohydride , After stirring for 23 hours at room temperature, 100 ml of dichloromethane and 100 ml of 4N sodium hydroxide solution are added. The phases are separated and the organic phase is evaporated. The residue is purified by chromatography. Mass spectrum (ESI ⁺ ): m / z = 255 [M + H] ⁺

Example XVII

3-Benzyl-3,4-dihydro-4-oxo-6- [trans-4- (4-methyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

To 632 mg of 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline and 1.09g of cesium carbonate in 4 ml of N-methyl-2-pyrrolidinone at 120 ⁰ C 650 mg (cis) -1 - Methanesulfonyloxy-4- (4-methyl-3-oxo-piperazin-1-yl) -cyclohexane in 3 ml of N-methyl-2-pyrrolidinone added dropwise over two hours. The product is isolated by preparative HPLC. Mass spectrum (ESI ⁺ ): m / z = 477 [M + H] ⁺

Example XVIII

3-Benzyl-3,4-dihydro-4-oxo-6- [cis / trans-4- (4-morpholin-4-yl) -cyclohexyloxy] -7-methoxy-quinazoline

prepared by reacting 3-benzyl-3,4-dihydro-4-oxo-6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline with morpholine analogously to Example 1. Mass spectrum (ESI ⁺ ): m / z = 450 [M + H] ⁺

Preparation of the end compounds:

example 1

4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (morpholin-4-yl) -cyclohexyloxy] -7-methoxy-quinazoline and 4 - [(3-chloro-2 fluorophenyl) amino] -6- [trans-4- (morpholin-4-yl) cyclohexyloxy] -7-methoxyquinazoline

To 800 mg of 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline in 25 ml of 1,2-dichloroethane are added 175 μl of morpholine, 600 mg of sodium triacetoxyborohydride and 115 μl of glacial acetic acid, and the mixture was stirred for 18 hours at room temperature under an argon atmosphere. It is added a little more sodium triacetoxyborohydride and stirred for a further 3 hours. The reaction mixture is mixed with 1 M sodium hydroxide solution and stirred briefly, then extracted several times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. Purification through a silica gel column with dichloromethane / methanol (99: 1 to 80:20) gives the two title compounds as a mixture. The cis / trans mixture is separated by preparative HPLC (xBridge ™ C18 from Waters, acetone itril, water, aqueous ammonia). The assignment of the isomers by means of 1 H NMR spectroscopy.

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (morpholin-4-yl) -cyclohexyloxy] -7-methoxy-quinazoline:

Yield: 250 mg (25% of theory)

Mass spectrum (ESI ⁺ ): m / z = 487, 489 [M + H] ⁺

4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (morpholin-4-yl) -cyclohexyloxy] -7-methoxy-quinazoline:

Yield: 320 mg (33% of theory)

Mass spectrum (ESI ⁺ ): m / z = 487, 489 [M + H] ⁺

Analogously to Example 1, the following compounds are obtained:

(1) 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - [(R) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline and 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(R) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - [(R) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 487, 489 [M + H] ⁺

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - [(R) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum ( ESI ⁺ ): m / z = 487, 489 [M + H] ⁺

(2) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(S) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline and 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(S) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - [(S) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass spectrum (ESI ⁺ ): m / z = 487, 489 [M + H] ⁺

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - [(S) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum ( ESI ⁺ ): m / z = 487, 489 [M + H] ⁺

(3) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline and [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (3-oxopiperazine-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

The reaction is carried out in 1, 2-dichloroethane.

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 500, 502 [M + H] ⁺

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 500, 502 [M + H] ⁺

(4) 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -cis-4- [2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy ] -7-methoxy-quinazoline and

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -trans-4- [2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7 methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -cis-4- [2- (N, N-dimethylanninocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7 -methoxy-quinazoline mass spectrum (ESI ⁺ ): m / z = 542, 544 [M + H] ⁺

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -trans-4- [2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7 -methoxy-quinazoline mass spectrum (ESI ⁺ ): m / z = 542, 544 [M + H] ⁺

(5) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - {(S) -cis-4- [2- (aminocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7- methoxy-quinazoline and

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -trans-4- [2- (aminocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7-methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -cis-4- [2- (aminocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7-methoxy-quinazoline

Mass Spectrum (ESI ⁺ ): m / z = 514, 516 [M + H] ⁺ 4 - [(3-chloro-2-fluoro-phenyl) -annino] -6 - {(S) -trans-4- [2- (anninocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy] -7-methoxy-quinazoline

Mass Spectrum (ESI ⁺ ): m / z = 514, 516 [M + H] ⁺

(6) 4 - [(2-Fluoro-5-methyl-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline; [(2-Fluoro-5-methyl-phenyl) -amino] -6- [trans-4- (3-oxopiperazine-i-yl-cyclohexyloxy) -methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(2-Fluoro-5-methyl-phenyl) -amino] -6- [cis-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 480 [M + H] ⁺

4 - [(2-Fluoro-5-methyl-phenyl) -amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 480 [M + H] ⁺

(7) 4 - [(2,4-difluoro-3-methylphenyl) amino] -6- [cis-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline and 4 - [(2,4-Difluoro-3-methyl-phenyl) -amino] -6- [trans-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(2,4-Difluoro-3-methyl-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 498 [M + H] ⁺

4 - [(2,4-Difluoro-3-methylphenyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxy-quinazoline mass spectrum (ESI ⁺ ): m / z = 498 [M + H] ⁺

(8) 4 - [(2-fluoro-3-methyl-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline and [(2-Fluoro-3-methyl-phenyl) -amino] -6- [trans-4- (3-oxopiperazine-1-yl-cyclohexyloxy-Z-methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(2-Fluoro-3-methyl-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 480 [M + H] ⁺ 4 - [(2-Fluoro-3-methyl-phenyl) -annino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 480 [M + H] ⁺

(9) 4 - [(3-chloro-2-methyl-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline and [(3-chloro-2-methylphenyl) amino] -6- [trans-4- (3-oxopiperazine-1-yl) cyclohexyloxy] -7-methoxyquinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(3-Chloro-2-methyl-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 496, 498 [M + H] ⁺

4 - [(3-Chloro-2-methyl-phenyl) -amino] -6- [trans-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 496, 498 [M + H] ⁺

(10) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline and [(3-chloro-4-fluorophenyl) amino] -6- [trans-4- (3-oxopiperazine-1-yl) cyclohexyloxy] -7-methoxyquinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 500, 502 [M + H] ⁺

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 500, 502 [M + H] ⁺

(11) 4 - [(5-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline and [(5-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (3-oxopiperazine-i-yl-cyclohexyloxy-Z-methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(5-Chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass spectrum (ESI ⁺ ): m / z = 500, 502 [M + H] ⁺

4 - [(5-Chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 500, 502 [M + H] ⁺

(12) 4 - [(4-fluoro-3-methylphenyl) amino] -6- [cis-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxy-quinazoline and [(4-fluoro-3-methylphenyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(4-Fluoro-3-methyl-phenyl) -amino] -6- [cis-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 480 [M + H] ⁺

4 - [(4-Fluoro-3-methyl-phenyl) -amino] -6- [trans-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 480 [M + H] ⁺

(13) 4 - [(3-Fluoro-5-methylphenyl) amino] -6- [cis-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxy-quinazoline and [(3-Fluoro-5-methylphenyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline

The reaction is carried out in tetrahydrofuran.

4 - [(3-Fluoro-5-methyl-phenyl) -amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 480 [M + H] ⁺

4 - [(3-Fluoro-5-methyl-phenyl) -amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

(14) (R) -4 - [(1-Phenylethyl) amino] -6- [cis-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline and (R) - 4 - [(1-phenylethyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

The reaction is carried out in tetrahydrofuran.

(R ^ - ^ i-Phenylethyl-aminol-θ-tcis ^^ S -oxo-piperazin-i-ylJ-cyclohexyloxy] ^ - methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 476 [M + H] ⁺

(R) -4 - [(1-phenylethyl) amino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline Mass Spectrum (ESI ⁺ ): m / z = 476 [M + H] ⁺

Example 2

4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-methyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

prepared by reacting 4 - [(3-chloro-2-fluorophenyl) amino] -6-hydroxy-7-methoxy-quinazoline with (cis) -1-methanesulfonyloxy-4- (4-methyl-3-oxo) piperazine-1-yl) cyclohexane in N-methyl-2-pyrrolidinone at 125 ° C in the presence of potassium carbonate.

Analogously to the abovementioned examples and other processes known from the literature, the following compounds can also be prepared:

Example 2

Dragees with 75 mg active substance

Composition:

1 drag core contains:

Active substance 75.0 mg

Calcium phosphate 93.0 mg

Cornstarch 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, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On a tableting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.

Core weight: 230 mg. Stamp: 9 mm, curved

The coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film dragees are shined with beeswax.

Dragee weight: 245 mg. Example 3

Tablets with 100 mg active substance

Composition: 1 tablet contains:

Active substance 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, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a rack oven at 50 ⁰ C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.

Tablet weight: 220 mg

Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.

Example 4

Tablets with 150 mg active substance

Composition: 1 tablet contains: Active substance 150.0 mg

Milk sugar powder 89.0 mg

Cornstarch 40.0 mg

Colloidal silicic acid 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 silicic acid is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and filtered through a sieve

1.5 mm mesh hit.

The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.

Tablet weight: 300 mg. Stamp: 10 mm, flat

Example 5

Hard gelatine capsules with 150 mg active substance

Composition: 1 capsule contains:

Active ingredient 150.0 mg

Corn starch drink. about 180.0 mg

Milk sugar powder 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 of 0.75 mm mesh size and mixed homogeneously in a suitable device. The final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg

Capsule shell: hard gelatin capsule size 1

Example 6

Suppositohen with 150 mg 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 distributed homogeneously therein and the melt is poured into pre-cooled molds.

Example 7

Suspension with 50 mg active substance

Composition: 100 ml Suspension contain: active substance 1.00 g

Carboxymethylcellulose 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

Glycerine 5.00 g sorbitol solution 70% 20.00 g

Aroma 0.30 g of distilled water. ad 100.00 ml

Preparation: Distilled water is heated to 70 ⁰ C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and glycerol and carboxymethyl cellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.

5 ml of suspension contain 50 mg of active ingredient.

Example 8

Ampoules with 10 mg active substance

Composition:

Active ingredient 10.0 mg 0.01 n hydrochloric acid s.q.

Aqua bidest ad 2.0 ml

production:

The active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules. Example 9

Ampoules with 50 mg active substance

Composition:

Active ingredient 50.0 mg

0.01 n hydrochloric acid s.q.

Aqua bidest ad 10.0 ml

production:

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

Example 10

Capsules for powder inhalation with 5 mg active substance

1 capsule contains:

Active substance 5.0 mg

Lactose for inhalation 15.0 mg

20.0 mg

Preparation: 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 11

Inhalation solution for handheld nebulizers with 2.5 mg active substance

1 hub contains:

Active substance 2,500 mg

Benzalkonium chloride 0.001 mg

1 N hydrochloric acid q.s. Ethanol / water (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 suitable for the hand nebulizer (cartridges).

Fill weight of the container: 4.5 g

Claims

claims

1. Bicyclic heterocycles of the general formula

in which

a Ci _-4 alkyl, hydroxy, Ci _-4 alkoxy, C ₂ alkenyl or C ₂ -3--3-alkynyl group,

an aryl, aryloxy, arylmethyl or arylmethoxy group,

a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group,

a substituted by 1 to 3 fluorine atoms methyl or methoxy group or

a cyano, nitro or amino group, and

R ^{3 is} a hydrogen, fluorine, chlorine or bromine atom or

represent a methyl or trifluoromethyl group, R ^{b is} an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, homopiperidin-1-yl, morpholin-4-yl, homonnorpholin-4-yl, piperazin-1-yl , 4- (Ci _-4 -alkyl-carbonyl) -piperazin-1-yl, 4- (Ci _-4 -alkyl-sulfonyl) -piperazin-1 -yl, homopiperazin-1 -yl, 4- (Ci _-4 -Al kyl-carbonyl) - homopiperazin-1 -yl or 4- (Ci _-4- alkylsulfonyl) homopiperazin-1-yl group, each mono-, di- or by R ⁴ mono- may be trisubstituted, where the substituents may be the same or different and

R ^{4 is} a fluorine, chlorine, bromine or iodine atom,

a Ci _-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl group,

a methyl or methoxy group substituted by 1 to 3 fluorine atoms,

N- (Ci _-4 alkyl) -C _-4 alkyl-carbonylamino, Ci _-4 alkyl-sulfonylamino or N- (Ci _-4 alkyl -AI) -C _-4 alkyl-sulfonylamino group,

an amino-Ci _-4 alkyl, Ci _-4 alkylamino-Ci _-4 alkyl, di- (Ci _-4 alkyl) amino- Ci- ₄ alkyl, Ci _-4 alkyl-carbonylamino-Ci _-4 alkyl, N- (Ci _-4 alkyl) -C _-4 alkyl- carbonylamino-Ci _-4 alkyl, Ci _-4 alkyl-sulfonylamino-Ci _-4 alkyl or N- (C _-4 -Al alkyl) -C _-4 alkyl-sulfonylamino-Ci _-4 alkyl group,

a hydroxy, Ci _-4 alkyloxy or Ci ^ alkyl-carbonyloxy group,

Pyrrolidine-1-yl-carbonyl, pipehdin-1-yl-carbonyl, piperazine-1-yl-carbonyl, 4-Ci _-4 -alkyl-piperazin-1-yl-carbonyl or morpholin-4-yl-carbonyl group,

a Ci _-4 alkyl alkylcarbonyl-Ci _-4, cyano-Ci _-4 alkyl, Ci _-4 -Al kyloxycarbonyl- Ci- ₄ alkyl, aminocarbonyl-Ci ^ alkyl, Ci _-4 alkylaminocarbonyl -C _-4 alkyl, di- (Ci _-4 alkyl) aminocarbonyl-Ci _-4 alkyl, pyrrolidin-1-yl-carbonyl-Ci ^ alkyl,

Piperidin-1-yl-carbonyl-Ci ^ alkyl, piperazin-1-yl-carbonyl-Ci ^ alkyl, 4-Ci _-4 -alkyl-piperazin-1-yl-carbonyl-Ci ^ alkyl- or morpholin-4-yl-carbonyl-Ci _-4 alkyl group,

a Ci _-4 alkylsulphanyl, Ci _-4 alkylsulfinyl, Ci _-4 alkylsulphonyl, aminosulphonyl,

Ci _-4 -alkyl-aminosulphonyl or di- (Ci _-4 alkyl) amino-sulfonyl group,

a Ci _-4 alkylsulfanyl-Ci _-4 alkyl, Ci _-4 alkylsulfinyl-alkyl Ci _-4,

Ci- ₄ alkylsulfonyl-Ci- ₄ alkyl, aminosulfonyl-Ci -alkyl _-4, Ci _-4 alkyl aminosulfonyl-Ci _-4 alkyl or di- (Ci _-4 alkyl) amino-sulfonyl Ci _-4 alkyl group

R ^{c is} a hydrogen atom,

a fluorine, chlorine, bromine or iodine atom,

a C kylgruppe _-4 Al,

a Ci _-4 -Al kylgruppe, which is substituted by a radical R ⁵ , wherein

Di (Ci-3-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-azabicyclo [3.2.1] oct-8-yl, 8-oxa-3-aza- bicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-Ci _-3 alkyl-piperazin-1-yl,

Homopiperazin-1-yl or Ci _-3 alkyl honnopiperazin-1-yl group or

a formylamino, C 1-4 -alkylcarbonylamino, C 1-3 -alkyloxy-C 1-3 -alkylcarbonylamino, C 1-4 -alkyloxycarbonylamino, aminocarbonylamino,

Ci-3-Alkylanninocarbonylannino, di- (Ci-3-alkyl) aminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-Ci-3-alkyl-piperazine- Represents 1-ylcarbonylamino, morpholin-4-ylcarbonylamino or a Ci _-4 alkylsulfonylamino group,

a hydroxy group,

a Ci _-4 alkyloxy,

a methoxy or ethyloxy group substituted by 1 to 3 fluorine atoms,

a C2 _-4 alkyloxy group which is substituted by the radical R ^5, wherein R ⁵ is as hereinbefore defined,

a Cs-z-cycloalkyloxy or Cs-z-cycloalkyl-d ^ -alkyloxy group,

a tetrahydrofuranyl Ci _-4 alkyloxy or tetrahydropyranyl Ci _-4 alkyloxy group,

R ^{6 represents} a hydrogen atom or a C _1-3 -alkyl group, or a Ci _-4 koxygruppe -alkyl which is substituted by a substituted in the 4-position by the group R ⁶ morpholinyl, wherein R ⁶ is as hereinbefore defined, and wherein the above-mentioned in the definition of the radical R ^c pyrrolidinyl, Piperidinyl, piperazinyl and morpholinyl groups may each be substituted by one or two c _1-3 -alkyl groups, and

the heteroaryl groups mentioned in the definition of the abovementioned radicals is to be understood as meaning a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, where the heteroaryl groups mentioned above are in each case mono- or disubstituted by the radical R ⁷ , where the substituents are identical or may be different and R ⁷ is defined as mentioned above, 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 ^{1 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl or ethynyl group,

a phenyloxy or phenylmethoxy group, wherein the phenyl part of the above-mentioned groups is optionally substituted by a fluoro or phenyl

Chlorine atom is substituted, or

R ^{2 is} a hydrogen, fluorine or chlorine atom or a methyl group and

R ^{3 represents} a hydrogen atom,

R ^{b is} an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl , 4- _(Ci-C3 alkyl-carbonyl) -piperazin-1-yl, 4- (Ci _-3 alkyl-sulfonyl) -piperazin-1 -yl, homopiperazin-1 -yl, 4- (Ci ₃ -alkyl-carbonyl) - homopiperazine-1-yl or 4- (Ci- _3- alkylsulfonyl) -homopiperazin-1-yl-group, each of which may be mono- or disubstituted by R ⁴ , wherein the substituents may be the same or different and

R ^{4 is} a fluorine atom,

a Ci _-3 alkyl group,

an amino, Ci _-3 alkylamino, di- (Ci _-3 alkyl) amino, Ci _-3 -alkyl-carbonylamino, N- (Ci _-3 alkyl) -C _-3 alkyl-carbonylamino -, Ci _-3 -alkyl-sulfonylamino, or N- (Ci _-3 alkyl) -C _-3 alkyl-sulfonylamino group, an amino-Ci-3-alkyl, Ci-s-alkylamino-Ci-s-alkyl, di- (Ci-3-alkyl) amino-Ci-3-alkyl, Ci-s-alkyl-carbonylamino-Ci -s-alkyl-, N- (C _1-3 -alkyl) -ci- ₃ -alkyl-carbonylamino-C _1-3 -alkyl, C 1-6 -alkyl-sulfonylamino-C 1-6 -alkyl- or N- (Ci ₃ -alkyl-kyO-Ci-s-alkyl-sulfonylannino-Ci-s-alkyl group,

a hydroxy, Ci-3-alkyloxy or Ci-3-alkyl-carbonyloxy group,

a hydroxy-C _1-3 -alkyl, C 1-6 -alkyloxy-C 1-6 -alkyl or C 3-3 -alkyl-carbonyloxy-C _1-3 -alkyl group,

a Ci- ₃ alkyl-carbonyl, cyano, Ci _-4 alkyl-oxycarbonyl, carboxy, aminocarbonyl, _Ci-3 alkyl, aminocarbonyl or di- (Ci ₃ alkyl) amino-carbonyl Group,

a Ci-s-alkylcarbonyl-Ci-s-alkyl, cyano-Ci- ₃ -alkyl, Ci _-4 -alkyloxycarbonyl-

C _1-3 -alkyl group, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl-C 1-3 -alkyl or di- C 1-4 -alkylaminocarbonyl-C 1-6 -alkyl group,

a Ci _-4 alkylsulphanyl, Ci kylsulfinyl- _-4 -alkyl, Ci _-4 alkylsulfonyl, aminosulfonyl, Ci _-3 -alkyl-aminosulphonyl or di- (Ci _-3 alkyl) amino-sulfonyl group .

a Ci _-4 alkylsulfanyl-Ci _-3 alkyl, Ci _-4 alkylsulfinyl-alkyl Ci _-3,

C 1-6 -alkylsulfonyl-C 1-6 -alkyl-, aminosulfonyl-C _1-3 -alkyl-, C _1-3 -alkylaminosulfonyl-C 1-3 -alkyl- or C 1-8 -alkylamino-sulfonyl-C 1-5 -alkyl- alkyl group

R ^{c is} a hydrogen atom,

a hydroxy group, a C kyloxygruppe _-3 Al,

a methoxy group substituted by one to three fluorine atoms,

R ^{5 is} a hydroxy, Ci-3-alkyloxy, amino, Ci-3-alkylamino, di (Ci-3-alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidine-1 - yl, piperidine-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazine-1-yl or a 4-Ci- _3- alkyl-piperazin-1-yl-group,

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 phenyl, a 1-phenylethyl, 3-Ethinylphenyl-, 3-bromo-2-fluoro-phenyl, 3-bromo-4-fluoro, 3-chloro-2-fluoro-phenyl, 3-chloro- 4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-5-methylphenyl, 3-fluoro-5-methylphenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl-phenyl, 2,5-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan -4-yl group, a 3-chloro-4-benzyloxy-phenyl, 3-chloro-4 - [(3-fluoro-benzyl) oxy] -phenyl, 4- (pyridin- 3-yloxy) -phenyl, 4 - [(6 -Methyl-pyridin-3-yl) oxy] -phenyl, 3-methyl-4- (pyridin-3-yloxy) -phenyl, 3-methyl-4 - [(6-methylpyridin-3-yl) oxy] -phenyl, 3-chloro-4- (pyridin-3-yloxy) -phenyl or 3-chloro-4 - [(6-methyl-pyridin-3-yl) oxy] -phenyl group,

R ^{b is} an azetidine-1 -yl, pyrrolidin-1-yl, piperidine-1-yl, morpholin-4-yl, piperazine-1-yl, 4- (cyclo- _3- alkyl-carbonyl) - piperazin-1-yl or 4- (ci- _3- alkylsulfonyl) -piperazin-1-yl group, each of which may be mono- or disubstituted by R ⁴ , wherein the substituents may be the same or different, and

R ^{4 is} a fluorine atom,

a Ci _-3 alkyl group,

an amino, Ci-3-alkylamino, di (Ci-3-alkyl) amino, Ci-3-alkyl-carbonylamino,

N- (C 1-3 -alkyl) -Ci-3-alkylcarbonylannino, C 1-3 -alkylsulphonylamino or N- (C 1-3 -alkyl) -Ci-3-alkylsulphonylannino group,

an amino-Ci-3-alkyl, Ci-s-alkylannino-Ci-s-alkyl, di (Ci-3-alkyl) amino-Ci-3-alkyl, Ci-s-alkyl-carbonylamino-Ci -s-alkyl-, N- (C _1-3 -alkyl) -ci- ₃ -alkyl-carbonylamino-C _1-3 -alkyl, C 1-6 -alkyl-sulfonylamino-C 1-6 -alkyl- or N- (Ci ₃ -alkyl) -Ci-3-alkylsulfonylamino-C 1-3 -alkyl group,

a hydroxy, Ci-3-alkyloxy or Ci-s-alkyl-carbonyloxy group

a hydroxy-Ci _-3 alkyl, Ci-s-alkoxy-Ci-s-alkyl or Ci _-3 alkyl-carbonyloxy Ci-3-alkyl group,

a Ci- ₃ alkyl-carbonyl, cyano, Ci ^ alkyl-oxycarbonyl, carboxy, aminocarbonyl, _Ci-3 alkyl, aminocarbonyl or di- (Ci ₃ alkyl) amino-carbonyl

Group, a Ci-s-alkylcarbonyl-Ci-s-alkyl, cyano-Ci _-3 -alkyl, Ci _-4 -Al kyloxycarbonyl- C ₃ -alkyl group, Anninocarbonyl-C ₃ -alkyl-, Ci _-3 Alkylanninocarbonyl-C 1-3 -alkyl- or di-is-alkynylaminocarbonyl-C 1-6 -alkyl group,

a Ci _-4 alkylsulphanyl, Ci kylsulfinyl- _-4 -alkyl, Ci _-4 alkylsulphonyl, aminosulphonyl, Ci-3-alkyl-anninosulfonyl- or di- (Ci-3-alkyl) Annino-sulfonyl group,

a Ci alkyl _-4 alkylsulfanyl-Ci ₃ Ci alkyl _-4 alkylsulfinyl-Ci ₃ Ci _-4 alkyl Al kylsulfonyl- Ci _{3-aminosulfonyl} Ci ₃ alkyl, C _1-3 -alkyl-aminosulfonyl-C 1-3 -alkyl or C 1-4 -alkylamino-sulfonyl-C 1-6 -alkyl group,

R ^{c is} a hydrogen atom,

a methoxy or ethyloxy group,

R ^{5 is} a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidine-1-yl, morpholine-4 represents yl, homomorpholin-4-yl, piperazine-1-yl, 4-methyl-piperazine-1-yl or 4-ethyl-piperazin-1-yl-group,

a butoxy group substituted in the 4-position by the radical R ⁵ , wherein R ⁵ is defined as mentioned above, and Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,

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

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

R ^{4 is} a fluorine atom,

a Ci _-3 alkyl group,

an amino-Ci- ₂ alkyl, Ci- alkyl ₂ alkylamino-Ci _2, di- (Ci- ₂ alkyl) amino Ci- ₂ alkyl, Ci ^ alkyl-carbonylamino-Ci ^ alkyl, N- (Ci- ₂ alkyl) ₂ -ci- alkyl- carbonylamino-Ci ₂ alkyl, Ci- ₂ alkyl-sulfonylamino-Ci- ₂ alkyl or N- (Ci ₂ Alkyl) -Ci-2-alkylsulfonylamino-C 1-2-alkyl group, a hydroxy, Ci _-2 alkyloxy- or Ci-2-alkyl-carbonyloxy group,

a hydroxy-Ci _-2 alkyl, Ci-2-alkyloxy-C _{_2-4} alkyl or Ci _-2 -alkyl-carbonyloxy Ci-2-alkyl group,

a Ci- ₂ alkyl-carbonyl, cyano, Ci-2-alkyl-oxycarbonyl, carboxy, aminocarbonyl, Ci- ₂ alkyl-aminocarbonyl or di- (Ci _-2 alkyl) amino-carbonyl Group,

a _Ci-2 alkylcarbonyl Ci- ₂ alkyl, cyano-Ci _-2 alkyl, Ci _-2 -Al kyloxycarbonyl-

Ci ₂ alkyl group, aminocarbonyl-Ci-2-alkyl, Ci _-2 -alkylaminocarbonyl- Ci ₂ alkyl or di ^ i ^ -alky ^ aminocarbonyl-Ci ^ alkyl group,

a C _2-2 -alkylsulfanyl, C 1- ₂ -alkylsulfinyl or C 1-2 -alkylsulfonyl group,

a Ci alkyl ₂ alkylsulphanyl-Ci _2, Ci-Ci ₂ alkyl sulfinyl ₂ alkyl or C ₂ alkylsulfonyl-Ci ₂ alkyl group

R ^{c is} a hydrogen atom,

a methoxy, ethyloxy or 2- (methoxy) -ethyloxy group,

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 1-phenylethyl, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl- , 2-Fluoro-5-methyl-phenyl, 3-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl-phenyl, 3-chloro 2-methyl-phenyl or an indan-4-yl group,

R ^{c is} a methoxy group,

mean,

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

6. The following compounds of general formula I according to claim 1:

(c) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(R) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline, (d) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(R) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline,

(e) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(S) -cis-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline,

(f) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - [(S) -trans-4- (3-hydroxy-pyrrolidin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline,

(i) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6 - {(S) -cis-4- [2- (N, N-din-ethylanninocarbonyl) -pyrrolidine-i-yl-cyclohexyloxy] methoxy-quinazoline,

(j) 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6 - {(S) -trans-4- [2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl] -cyclohexyloxy ] -7-methoxy-quinazoline,

(m) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-methyl-3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy quinazoline, (n) 4 - [(2-fluoro-3-methylphenyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline,

(o) 4 - [(2-fluoro-5-methylphenyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline,

(p) 4 - [(2,4-difluoro-3-methylphenyl) amino] -6- [trans-4- (3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxyquinazoline and

(q) 4 - [(3-Chloro-2-methyl-phenyl) -annino] -6- [trans-4- (3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline

and their salts.

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

8. A pharmaceutical composition comprising a compound according to at least one of claims 1 to 6 or a physiologically acceptable salt according to claim 7 besides optionally one or more inert carriers and / or diluents.

9. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of benign or malignant tumors, for the prevention and treatment of respiratory and pulmonary diseases and for the treatment of diseases of the gastrointestinal tract and the bile duct and bladder is suitable.

10. A process for the preparation of a medicament according to claim 8, characterized in that a non-chemical way to a compound at least one of claims 1 to 7 is incorporated into one or more inert carriers and / or diluents.

11. A process for the preparation of the compounds of general formula I according to claims 1 to 6, characterized in that

a) a compound of the general formula

in the

R ^b is defined as mentioned above and Z ^{1 represents} a leaving group, is reacted, or

b) a compound of the general formula

in the

R ^a and R ^c are defined as mentioned above, and Z ^{2 represents} a leaving group, with a compound of the general formula

HR ^b , (V)

in the

R ^{b is} as defined above, is implemented, or

c) a compound of the general formula

in the

HR ^b, (VII) in the

R ^{b is} as defined above, is implemented, or

d) a compound of the general formula (VIII)

in which R ^b and R ^c are defined as mentioned above, with a halogenating agent to give an intermediate of the general formula (IX),

in which R ^b and R ^c are defined as mentioned above and Z ^{3 represents} a halogen atom, is reacted, and this then with a compound of general formula (X),

R ^a -NH ₂ (X) in which R ^a is defined as mentioned above, is reacted.

e) For the preparation of compounds of the general formula I, in which R ^{c represents} one of the abovementioned, optionally substituted alkyloxy groups,

a compound of the general formula

in which R ^a and R ^b are defined as mentioned above, with one with a compound of the general formula

Z ⁴ - R ^{c '} , (XII)

in which R ^c is defined as mentioned above and Z ^{4 represents} a leaving group, is reacted, or

f) For the preparation of compounds of the general formula I in which R ^{c represents} one of the abovementioned alkyloxy groups 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 Compound of the general formula

in which R ^a and R ^b are defined as mentioned above and Z ^{5 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 g) For the preparation of compounds of the general formula I in which R ^{b contains} one or more hydroxyl groups,

Protective residues of a compound of the general formula

in which R ^a and R ^c are defined as mentioned above and R ^{b contains} one or more groups which can be converted into hydroxyl groups, are split off, or

a protecting group of a compound of the general formula

in which R ^a and R ^c are defined as mentioned above and R ^b, with the proviso has the meaning mentioned above for R ^b , that R ^{b contains} a protected nitrogen atom, is cleaved, and

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

a compound of general formula I which contains an alkoxycarbonyl group is converted by ester cleavage into a carboxylic acid, and / or

a compound of general formula I containing an alkoxycarbonyl group is converted by reaction with an amine into a carboxylic acid amide derivative, and / or

a compound of the general formula I containing a carboxy group is converted by reaction with an amine into a carboxylic acid amide derivative, and / or

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

if desired, a compound of 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 the pharmaceutical application into its physiologically tolerated salts.