WO2003089439A1

WO2003089439A1 - Bicyclic heterocycles, medicaments containing these compounds, their use, and method for the production thereof

Info

Publication number: WO2003089439A1
Application number: PCT/EP2003/003828
Authority: WO
Inventors: Frank Himmelsbach; Birgit Jung; Flavio Solca
Original assignee: Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2002-04-19
Filing date: 2003-04-14
Publication date: 2003-10-30
Also published as: CA2484395A1; UY27767A1; CA2484395C; TW200408643A; AU2003226806A1; EP1499619A1; AR039571A1; JP2005526837A; PE20040171A1; DE10217689A1; JP4527406B2

Abstract

The invention relates to bicyclic heterocycles of general formula (I), in which Ra, Rb, Rc, A, B, C, D, E and X are defined as in Claim 1, to tautomers, stereoisomers, mixtures and salts thereof, particularly their physiologically compatible salts with inorganic or organic acids, which have valuable pharmacological properties, particularly an inhibitory action on the signal transduction imparted by tyrosine kinases. The invention also relates to the use of these compounds for treating diseases, particularly tumor diseases and benign prostatic hyperplasia (BPH), diseases of the lungs and of the respiratory passages 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, which have valuable pharmacological properties, in particular an inhibitory effect on tyrosine kinase-mediated signal transduction, their use for the treatment of diseases, especially of tumor diseases and benign prostatic hyperplasia (BPH), lung and respiratory diseases and their production.

In the above general formula I means

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

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

R ¹ and R ² , which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,

C _1-4 alkyl, hydroxy, C _1-4 alkoxy, C _2-3 alkenyl or C _2-3 alkynyl,

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,

represent a methyl or trifluoromethyl group,

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

a hydroxy or C 1 -alkyloxy group,

a methoxy group substituted by 1 to 3 fluorine atoms,

an ethyloxy group substituted by 1 to 5 fluorine atoms,

a C _2-4 alkyloxy group substituted by a radical R ⁴ , wherein

R ⁴ is a hydroxy, Cι _-3 alkyloxy-, C ₃ _ ₆ cycloalkyloxy, C ₃ _ ₆ cycloalkyl, Cι-3-alkyloxy, amino, Cι _-3 alkylamino, di- (Cι _{- 3-} alkyl) amino, bis (2-C _1, ₃ -alkyloxyethyl) amino, bis (3-C ₃ -alkyloxy-propyl) amino, pyrrolidin-1-yl, Pipe - ridin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl, 4- (C _1-3 alkyl) -piperazine-1 -yI-, homopiperazin-1-yl or 4- (Cι _-3 -AlkyI) - represents homopiperazine-1-yl group,

a C _2- alkyloxy group substituted by the group E, wherein E is defined as mentioned below,

a C _3-7 alkyloxy group cycloalkyloxy or C _3- 7 cycloalkyl Cι_ _4, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group,

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

a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy group,

a 1- (Cι _-3 alkyl) -pyrrolidin-3-yloxy, 1- ₍₃ Cι- alkyl) -piperidin-3-yloxy or 1- ₍₃ Cι_ alkyl) - piperidin-4-yloxy Group,

a Cι _-4 alkoxy group which is substituted by a substituted in the 1 position by the group R ⁵ pyrrolidinyl, piperidinyl or homopiperidinyl group wherein

R ^{5 is} a hydrogen atom or a -C. Represents ₃ ~ alkyl group,

or Cι _-4 -AIkoxygruppe which is substituted by a 4-position by the radical R ⁵ substituted morpholinyl or homomorpholinyl group, wherein R ⁵ is defined as mentioned above,

A one imino or Cι _-4 -alkylimino,

B is a carbonyl or sulfonyl group,

C is a 1, 3-allenylene, 1, 1-vinylene or 1, 2-vinylene group, which may each be substituted by one or two methyl groups or by a trifluoromethyl group,

an ethynylene group or

a 1,3-butadiene-1,4-ylene group which may be substituted by one or two methyl groups or by a trifluoromethyl group,

D is a straight-chain or branched C _1-4 -alkylene group, E is a pyrrolidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 5 carbon atoms, if the two hydrogen atoms are on adjacent carbon atoms, or contains 2 to 4 carbon atoms, when there are two hydrogen atoms on carbon atoms which are separated by an atom, whilst the abovementioned pyrrolidin-1-yl groups each additionally by one or two C-ι- ₃ Alkyl groups may be substituted,

a piperidin-1-yl or homopiperidin-1-yl group in which in each case two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached are carbon atoms, which are separated by two atoms, wherein the above-mentioned piperidine-1 yl and homopiperidin-1-yl groups each additionally by one or two Cι _-3 alkyl groups may be substituted,

a piperazine-1-yl or homopiperazin-1-yl group in which in each case two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached are carbon atoms, which are separated by two atoms, whilst the abovementioned piperazin-1-yl and homopiperazin-1-yl groups each additionally by one or two Cι _-3 alkyl groups may be substituted, a morpholin-4-yl or homomorpholin-4-yl group in which each two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached carbon atoms are separated by two atoms, whilst the abovementioned morpholin-4-yl-4-yl groups and Homomorpholin each additionally by one or two Cι _-3 alkyl groups may be substituted,

and

X is a methine group substituted by a cyano group or a nitrogen atom,

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 ⁶ , where the substituents may be identical or different and

R ⁶ is a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a Cι methoxy- _-3 alkyl, hydroxy, C-ι- ₃ alkyloxy, difluoromethyl, trifluoromethyl, difluoro-, trifluoromethoxy or cyano group,

the heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, the abovementioned heteroaryl groups being in each case mono- or disubstituted by the radical R ⁶ , where the substituents are identical or may be different and R ^{6 is} as defined above, and

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

Preferred compounds of the above general formula I are those in which R ^{a is} a hydrogen atom,

R ^{b is} a substituted by the radicals R ¹ to R ³ phenyl group, wherein

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 pyridinyloxy or pyndinylmethoxy group, wherein the pyridinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group,

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

R ^{3 represents} a hydrogen atom,

R ° is a hydrogen atom,

a C _1-3 -alkyloxy group,

a C _4-6 cycloalkyloxy or C _3-6 cycloalkyl-Cι _-2 alkyloxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C ₂ -alkyloxy or tetrahydropyranyl-C ₁ -C ₂ -alkyl- ^o- y-gamma group,

) an ethyloxy group which is substituted in the 2-position by a radical R ⁴ , wherein

R ⁴ is a hydroxy, Cι _-3 -alkyloxy-, amino, Cι _-3 alkylamino, di- (C _1-3 alkyl) amino, bis- (2-Methoxyethyl) amino, pyrrolidin-1 -yl, piperidin-1-yl, homopiperidin-1-yl, Morpholin-4-yl, Homomorpholin-4-yl, piperazin-1-yl, 4- (C _-3 alkyl) -piperazin-1-yl, homopiperazin-1-yl, or 4- (Cι _3- alkyl) homopiperazin-1-yl group,

a propyloxy group which is substituted in the 3-position by a radical R ⁴ , wherein R ⁴ is defined as mentioned above, or

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

A is an imino group,

B is a carbonyl or sulfonyl group,

C is a 1, 1-vinylene, 1, 2-vinylene or ethynylene group,

D is a methylene, 1, 1-ethylene or 1, 2-ethylene group,

E is a piperidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms, or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms represented by two atoms are separated, whereby the above-mentioned piperidin-1-yl groups each additionally by one or two Cι _-3 alkyl groups may be substituted,

a piperazin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing from 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing from 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms, or contain 1 to 3 carbon atoms, when the two hydrogen atoms on carbon atoms are, which are separated by an atom, or contains 1 or 2 carbon atoms, when the two hydrogen atoms are on carbon atoms which are separated by two atoms, wherein the above-mentioned piperazin-1-yl groups each additionally by one or two C ₃ Alkyl groups may be substituted, or

a morpholin-4-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms separated by two atoms are, with the above-mentioned morpholin-4-yl groups may each additionally by one or two Cι _-3 alkyl groups,

and

X is a nitrogen atom,

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 is} a hydrogen atom,

R ^{b is} a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl group,

R ^{c is} a hydrogen atom, a methoxy, ethyloxy, 2- (methoxy) ethyloxy, 3- (morpholin-4-yl) propoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy , Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy or tetrahydropyran-4-ylmethoxy group,

A is an imino group,

B is a carbonyl group,

C is a 1, 2-vinylene group,

D is a methylene group,

E is a 2-azabicyclo [2.2.1] hept-2-yl, 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diaza-bicyclo 2.2.1] hept-2-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, 2-azabicyclo [2.2.2] oct-2-yl, 3 -Aza-bicyclo [3.2.1] oct-3-yl, 8-azabicyclo [3.2.1] oct-8-yl, 3,8-diazabicyclo [3.2.1] oct-3-yl -, 8-methyl-3,8-diaza-bicyclo [3.2.1] oct-3-yl, 3,8-diaza-bicyclo [3.2.1] oct-8-yl, 3-methyl-3, 8-diaza-bicyclo [3.2.1] oct-8-yl, 3-oxa-8-aza-bicyclo [3.2.1joct-8-yl or 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl group and

X is a nitrogen atom,

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

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

R ^{a is} a hydrogen atom,

R is a 3-chloro-4-fluoro-phenyl group, R ^{c is} a tetrahydrofuran-3-yloxy, cyclopentyloxy or cyclopropylmethoxy group,

A is an imino group,

B is a carbonyl group,

C is a 1, 2-vinylene group,

D is a methylene group,

E is a 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl group, a 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl group or an 8- Oxa-3-azabicyclo [3.2.1] oct-3-yl group and

X is a nitrogen atom,

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

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

(a) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline,

(b) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline,

(c) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,

(d) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, - 1.1 -

(e) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4f-2) -oxa-5-aza-bicyclo [2.2.1] 5-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline,

(f) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,

(9) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -1-oxo-2-buten-1-yl] amino} -7 - [( ^: ?) - (tetrahydrofuran-3-yl) oxy] quinazoline and

(h) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] 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 , R ^b , R ^c , A, B and X are as defined above and R ⁷ and R ⁸ , which may be the same or different, Cι. ₄ alkyl groups, with a compound of general formula

OHC - D - E, (III) in the

D and E are defined as mentioned above. The reaction is conveniently carried out in a solvent or solvent mixture such as tetrahydrofuran, tetrahydrofuran / water, acetonitrile, acetonitrile, water, dioxane, ethylene glycol dimethyl ether, isopropanol, methylene chloride, dimethylformamide or sulfolane optionally in the presence of an inorganic or organic base, for example sodium carbonate, potassium hydroxide or 1, 8 Diazabicyclo [5.4.0] undec-7-ene and. optionally in the presence of a lithium salt such as lithium chloride at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C carried out. The reaction may also be carried out with a reactive derivative of the compound of general formula III, for example the hydrate or a hemiacetal.

b) reaction of a compound of the general formula

in which R ^a , R ^b , R ^c , A, B, C, D and X are as defined above and Z ^{1 is} a leaving group such as a halogen atom or a substituted sulphonyloxy group such as a chlorine or bromine atom, a Methansulfonyloxy- or p- Toluolsulfonyloxygruppe, with a compound of general formula

H - E, (V)

is defined in the E as mentioned above.

The reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, sulfolane, toluene or methylene chloride or mixtures thereof optionally in the presence of an inorganic or organic base, for example sodium carbonate, potassium carbonate, potassium hydroxide, triethylamine or N-ethyl diisopropylamine and optionally in the presence of a reaction accelerator such as an alkali metal iodide at temperatures between -20 and 150 ° C, but preferably at temperatures between 0 and 100 ° C carried out leads. However, the reaction can also be carried out without a solvent or in an excess of the compound of general formula V used.

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

Suitable 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 groups ,

The optional subsequent cleavage of a protective moiety used 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 an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

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

The cleavage 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 using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

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 ° C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.

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

The separation of enantiomers 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 as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents. Especially - 1.5 -

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. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

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 is blocked at further downstream components.

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

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

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

The enzyme assays were performed at room temperature for a period of 30 minutes and terminated by addition of 50 μl of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μl was placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate was washed with 200 μl of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 μl of an HRPO-labeled anti-PY antibody (PY20H anti-ptyπHRP from Transduction Laboratories, 250 ng / ml) was incubated for 60 minutes. Thereafter, the microtiter plate was washed three times with 200 ul of washing solution. The samples were then spiked with 100 μl of a TMB peroxidase solution (A: B = 1: 1, Kirkegaard Perry Laboratories). After 10 minutes, the reaction was stopped. The absorbance was measured at OD4 _50nm with an ELISA reader. All data points were determined as triplicates.

The data was fit by means of an iterative calculation using a sigmoid curve analysis program (Graph Pad Prism Version 3.0) with variable hill slope. All released iteration data showed a correlation coefficient of over 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5. From the curves, the drug concentration was derived, which inhibits the activity of EGF receptor kinase by 50% (ICso) ,

The following results were 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 cough, 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 those found 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 tolerable salts can be used for the treatment of other diseases caused by aberrant function of tyrosine kinases, such as epidermal hyper proliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the Immune system, hyperproliferation of hematopoietic cells etc.

Because of their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (eg etoposide). , Mitosis inhibitors (eg vinblastine), compounds interacting with nucleic acids (eg cisplatin, cyclophosphamide, adriamycin), 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 may be used alone or in combination with other respiratory therapeutics, such as secretolytically (e.g., ambroxol, N-acetylcysteine), broncholytically (e.g., tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (e.g., theophylline or glucocorticoids) substances. For the treatment of diseases in the 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 at 0.1-15 mg / kg. For administration, these are administered with one or more conventional inert carrier - 10 -

substances and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures in common pharmaceutical 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-f (3-chloro-4-fluoro-phenyl) -aminol-6-f (diethoxy-phosphoryl) -acetylamino 1-7-r (S) - (tetrahydrofuran-3-yl) oxy-1-quinazoline

60.07 g Diethoxyphophorylessigsäure be presented in 750 ml of N, N-dimethylformamide and treated at room temperature with 48.67 g of N, N'-carbonyldiimidazole. After completion of gas evolution 90.00 g of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-amino - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline are added and the reaction mixture _. is stirred for about 4-5 hours at room temperature until the reaction is complete. Now, the reaction mixture is heated slightly in a water bath and it is added twice per 750 ml of water. The thick suspension is stirred overnight and the next morning, 350 ml of water are added again. The suspension is cooled in an ice bath, stirred for an hour and filtered with suction. The filter cake is washed with 240 ml of N, N-dimethylformamide / water (1: 2) and 240 ml of diisopropyl ether and dried in a circulating air dryer at 40 ° C. Yield: 117.30 g (88% of theory) R _f value: 0.37 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESI ⁺ ): m / z = 553, 555 [M + H] ⁺

Analogously to Example I, the following compound is obtained: (1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(diethoxy-phosphoryl) -acetylamino] -7 - [(R) -

(Tetrahydrofuran-3-yl) oxy] -quinazoline

Mass spectrum (ESI ⁺ ): m / z = 553, 555 [M + H] ⁺

Example II

(1S, 4S) - (2-Oxa-5-aza-bicyclof2.2.1lhept-5-yl) -acetaldehyde hydrochloride prepared by treating (1S, 4S) -5- (2,2-dimethoxy-ethyl) - 2-oxa-5-azabicyclo [2.2.1] heptane with conc. Hydrochloric acid in water at 80 ° C. The solution obtained is reacted further directly under Ex. 2 and Ex. 2 (5).

The following compounds are obtained analogously to Example II:

(1) (3-Oxa-8-azabicyclo [3.2.1] oct-8-yl) -acetaldehyde hydrochloride The resulting solution is further reacted directly under Ex. 2 (1).

(2) (1R, 4R) - (2-Oxa-5-azabicyclo [2.2.1] hept-5-yl) -acetaldehyde hydrochloride

The resulting solution is reacted further directly under Ex. 2 (2) and Ex. 2 (4).

(3) (8-Oxa-3-azabicyclo [3.2.1] oct-3-yl) -acetaldehyde hydrochloride The resulting solution is further reacted directly under Ex. 2 (3).

Example III

(1S, 4SV5- (2,2-Dimethoxy-ethyn-2-oxa-5-aza-bicyclo) -2.nheptane prepared by reacting (1S, 4S) -2-oxa-5-aza-bicyclo [2.2. 1] heptane hydrochloride with bromoacetaldehyde dimethyl acetal in the presence of potassium carbonate in N 2

Methylpyrrolidinone at 100 ° C.

R _f value: 0.35 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia logo CNRS logo INIST

90: 10: 1)

Mass spectrum (ESl ⁺ ): m / z = 188 [M + H] ⁺

The following compounds are obtained analogously to Example III:

(1) 8- (2,2-Dimethoxy-ethyl) -3-oxa-8-aza-bicyclo [3.2.1] octane - 2.1 -

R _f value: 0.81 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 90: 10: 1)

(2) (1R, 4R) -5- (2,2-dimethoxy-ethyl) -2-oxa-5-aza-bicyclo [2.2.1] heptane

R _f value: 0.23 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1)

Mass spectrum (ESl ⁺ ): m / z = 188 [M + H] ⁺

The used (1R, 4R) -2-oxa-5 ~ aza-bicyclo [2.2.1] heptane hydrochloride is by

Reaction of (2R, 4R) -1- (tert-butyloxycarbonyl) -2 - [(4-methylphenylsulfonyloxy) methyl] -4-hydroxy-pyrrolidine (see J. Org. Chem., 1992, 57, 3783-3789) with sodium hydride in tetrahydrofuran and subsequent treatment with hydrochloric acid in dioxane.

(3) 3- (2,2-Dimethoxy-ethyl) -8-oxa-3-azabicyclo [3.2.1] octane

R _f value: 0.84 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1)

Preparation of the end compounds:

example 1

4-r (3-chloro-4-fluoro-phenyl) -amino 1-6-fr4 - ((1 S.4S) -2-oxa-5-aza-bicvclor2.2-hept-5-yl) -1-oxo -2-buten-1-vπamino} -7-cvclopropylmethoxy-quinazoline

4.50 g of bromoteronic acid are dissolved in 40 ml of methylene chloride and treated with 4.70 ml of oxalyl chloride. After addition of 0.02 ml of N, N-dimethylformamide begins vigorous evolution of gas, which is complete after about two hours. The reaction mixture is concentrated in vacuo and the flask residue dissolved in 40 ml of methylene chloride. This solution is added dropwise with ice-bath cooling to a mixture of 7.00 g of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-amino-7-cyclopropylmethoxy-quinazoline and 9.60 ml of Hünig base in 80 ml of tetrahydrofuran. The reaction solution is stirred for one hour in an ice bath and for a further hour at room temperature. Now one-fifth of this solution is removed and 740 mg (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride and 1 ml Hünig base are added. The reaction mixture is stirred overnight at 60 ° C and then concentrated in vacuo. The flask residue is taken up with ethyl acetate and a little methanol and extracted with water. The organic phase is applied to silica gel and chromatographed on a silica gel column with ethyl acetate / methanol (95: 5 to 70:30) as the eluent. The product obtained is crystallized from diisopropyl ether and filtered off with suction. Yield: 850 mg (42% of theory) R _f value: 0.36 (silica gel, ethyl acetate / methanol = 9: 1) Mass spectrum (ESI ⁺ ): m / z = 524, 526 [M + H] ⁺

Analogously to Example 1, the following compound is obtained:

(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino] -7-cyclopentyloxy-quinazoline

R _f value: 0.40 (Reversed phase DC precast plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1) Mass spectrum (ESL): m / z = 536, 538 [MH] ^"

Example 2

4-r (3-chloro-4-fluoro-phenyl) -amino 1-6- (r 4 - ((1 S. 4 S) -2-oxa-5-aza-bicyclopror2.2-hept-5-yl) -1- oxo-2-buten-1-vnaminoV7-r (S) - (tetrahvdrofuran-3-yl) oxy1-quinazoline

A solution of 4.44 g of 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (diethoxy-phosphoryl) -acetylamino] at room temperature is added to a solution of 340 mg of lithium chloride in 22 ml of water at room temperature. Add 7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline in 22 ml of tetrahydrofuran. Then 2.73 g of potassium hydroxide pellets are added and the reaction mixture is cooled to -3 ° C in the ice / acetone cooling bath. Now the obtained under Example II solution of (1S, 4S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) acetaldehyde hydrochloride within 5 min at a temperature of 0 ° C added dropwise. After completion of the addition, the reaction mixture is stirred for 10 min at 0 ° C and a further 20 min at room temperature. For workup, 100 ml of ethyl acetate are added and the aqueous phase is separated off. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is chromatographed on a silica gel column with methylene chloride / methanol / conc. methanolic ammonia (980: 18: 2 to 750: 225: 25) as the eluent. The product obtained is crystallized with a little diisopropyl ether. Yield: 2.60 g (60% of theory)

R _f value: 0.33 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 90: 10: 1) Mass spectrum (ESI ⁺ ): m / z = 540, 542 [M + H] ⁺

Analogously to Example 2, the following compounds are obtained:

(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4- (3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl) -1 - oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline

Mass Spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] ⁺

(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline

R _f value: 0.08 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1) Mass spectrum (ESI ^" ): m / z = 538, 540 [MH] ^"

(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline

R _f value: 0.77 (alumina, ethyl acetate / methanol = 95: 5) Mass spectrum (ESI ⁺ ): m / z = 554, 556 [M + H] ⁺

(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline

Mass spectrum (ESI ⁺ ): m / z = 540, 542 [M + H] ⁺

(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) - 1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline

Mass spectrum (ESI ⁺ ): m / z = 540, 542 [M + H] ⁺

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

Example 3

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 4

Tablets with 100 mg active substance

Composition: 1 tablet contains:

Active substance 100.0 mg - 36 -

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 sieving the moist mass (2.0 mm mesh size) and drying in a tray drying oven at 50 ° 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 5

Tablets with 150 mg active substance

Composition: 1 tablet contains:

Active ingredient 150.0 mg lactose powdered 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 silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve with a mesh size of 1.5 mm.

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 6

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 7

Suppositories 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 8

Suspension with 50 mg active substance

Composition:

100 ml suspension contain:

Active ingredient 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

Glycerol 5.00 g

Sorbitol solution 70% 20.00 g

Aroma 0.30 g

Water dest.ad 100.00 ml

production:

Dest. Water is heated to 70 ° C. P-hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethylcellulose

Dissolved sodium salt. It is cooled to room temperature and with stirring

Active ingredient added 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 9

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 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.

Example 10

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 11

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

production:

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

Capsule weight: 70.0 mg Capsule size: 3

Example 12

Inhalation solution for handheld nebulizers with 2.5 mg active substance

1 hub contains:

Active substance 2,500 mg

Benzalkonium chloride 0.001 mg 1N 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 1N hydrochloric acid. The adjusted solution is filtered and filled into suitable containers for the hand-operated sprayer (cartridges).

Fill weight of the container: 4.5 g

Claims

claims

1. Bicyclic heterocycles of the general formula

in which

R ^a is a hydrogen atom or a Cι _-4 alkyl group,

a Cι_ alkyl, hydroxy, Cι _-4 alkoxy, C _2-3 -alkenyl or C _{_2-3} -alkynyl,

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,

represent a methyl or trifluoromethyl group,

R ^{c is} a hydrogen atom or a fluorine, chlorine or bromine atom, a hydroxy or Cι _-4 alkyloxy,

a methoxy group substituted by 1 to 3 fluorine atoms,

an ethyloxy group substituted by 1 to 5 fluorine atoms,

a C _2-4 alkyloxy group substituted by a radical R ⁴ , wherein

R ⁴ is hydroxy, C _1-3 alkyloxy, C _3-6 cycloalkyloxy, C _3-6 cycloalkyl C _1-3 alkyloxy, amino, Cι _-3 alkylamino, di- ( C _1-3 alkyl) amino, bis (2-C _1-3 alkyloxyethyl) amino, bis (3-C _1-3 alkyloxypropyl) amino, pyrrolidine-1 yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, Homomorpholin-4-yl, piperazin-1-yl, 4- (Cι _-3 alkyl) -piperazine Represents 1-yl, homopiperazin-1-yl or 4- (C ₃ -alkyl) homopiperazine-1-yl group,

a C ₃ _ ₇ alkyloxy cycloalkyloxy or C _3-7 cycloalkyl-Cι- _4,

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

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

a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy group,

a 1- (Cι _-3 alkyl) -pyrrolidin-3-yloxy, 1- (. _Cι-C3 alkyl) -piperidin-3-yloxy or 1 ~ (Cι _-3 alkyl) - piperidin-4-yloxy -Group,

a Cι _-4 alkoxy group which is substituted by a substituted in the 1 position by the group R ⁵ pyrrolidinyl, piperidinyl or homopiperidinyl group wherein R ⁵ represents a hydrogen atom or a C-ι _-3 alkyl group,

or Cι _-4 alkoxy group which is substituted by a 4-position by the radical R ⁵ substituted morpholinyl or homomorpholinyl group, wherein R ⁵ is defined as mentioned above,

A one imino or Cι _-4 -alkylimino,

B is a carbonyl or sulfonyl group,

an ethynylene group or

D represents a linear or branched Cι _-4 alkylene,

E is a pyrrolidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 5 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms, or contain 2 to 4 carbon atoms, when the two hydrogen atoms are on carbon atoms which are separated by an atom, wherein the abovementioned pyrrolidin-1-yl groups each additionally by one or two C _1-3 alkyl groups can be substituted

a piperidin-1-yl or homopiperidin-1-yl group in which in each case two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to 5 Contains carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms on carbon atoms which are separated by two atoms, wherein the above-mentioned piperidin-1-yl and homopiperidin-1-yl groups each additionally by one or two C-. _3- alkyl groups may be substituted,

a piperazin-1-yl or homopiperazin-1-yl group in which each two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached Carbon atoms which are separated by two atoms, wherein the abovementioned piperazin-1-yl and homopiperazin-1-yl groups may each be additionally substituted by one or two C _t-3- alkyl groups,

a morpholin-4-yl or homomorpholin-4-yl group in which each two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached carbon atoms are separated by two atoms, whilst the abovementioned morpholin-4-yl-4-yl groups and Homomorpholin each additionally by one or two Cι _-3 alkyl groups may be substituted,

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

R ^{6 is} a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a Cι- alkyl, hydroxy, C-ι _-3 alkyloxy, difluoromethyl trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group represents,

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

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

R ^{a is} a hydrogen atom,

R ^{b is} a substituted by the radicals R ¹ to R ³ phenyl group, wherein

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

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

R ^{3 represents} a hydrogen atom,

R ^{c is} a hydrogen atom,

a Cι _-3 alkyloxy,

a

or C _3-6 -cycloalkyl-C _1-2 -alkyloxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C 1, ₂ -alkyloxy or tetrahydropyranyl-C ₂ -alkyloxy group,

an ethyloxy group which is substituted in the 2-position by a radical R ⁴ , wherein

R ⁴ is a hydroxy, Cι _-3 alkyloxy, amino, C ^ s-alkylamino, di- (Cι _-3 alkyl) amino, bis- (2-methoxyethyl) -amino, pyrrolidin-1 yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, Homomorpholin-4-yl, piperazin-1-yl, 4- (Cι _-3 alkyl) -piperazine 1- yl, homopiperazin-1-yl or 4- (Cι _-3 alkyl) homopiperazine-1-yl-group,

a butoxy group substituted in the 4-position by a radical R ⁴ , wherein R ⁴ is defined as mentioned above, A is an imino group,

B is a carbonyl or sulfonyl group,

C is a 1, 1-vinylene, 1, 2-vinylene or ethynylene group,

D is a methylene, 1, 1-ethylene or 1, 2-ethylene group,

E is a piperidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms that are represented by two atoms each of which the above-mentioned piperidin-1-yl groups may additionally be substituted by one or two C _1-3 alkyl groups,

a piperazin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms, or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms separated by two atoms are, wherein the above-mentioned piperazin-1-yl groups may each be additionally substituted by one or two Cι_ ₃ alkyl groups, or

a morpholin-4-yl group in which two hydrogen atoms on the carbon backbone are replaced by a straight-chain alkylene bridge, this bridge containing from 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing from 1 to 4 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms, or contain from 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain one or two carbon atoms when the two hydrogen atoms are on carbon atoms through two atoms are separated, whereby the above-mentioned morpholin-4-yl groups each additionally by one or two Cι _-3 alkyl groups may be substituted,

and

X is a nitrogen atom,

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

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

R ^{a is} a hydrogen atom,

R ^{c is} a hydrogen atom,

a methoxy, ethyloxy, 2- (methoxy) ethyloxy, 3- (morpholin-4-yl) propyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy , Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy or tetrahydropyran-4-yl-methoxy group,

A is an imino group,

B is a carbonyl group, C is a 1,2-vinylene group,

D is a methylene group,

E is a 2-azabicyclo [2.2.1] hept-2-yl, 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diaza-bicyclo 2.2.1] hept-2-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, 2-azabicyclo [2.2.2] oct-2-yl, 3 -Aza-bicyclo [3.2.1] oct-3-yl, 8-azabicyclo [3.2.1] oct-8-yl, 3,8-diazabicyclo [3.2.1] oct-3-yl -, 8-methyl-3,8-diaza-bicyclo [3.2.1] oct-3-yl, 3,8-diaza-bicyclo [3.2.1] oct-8-yl, 3-methyl-3, 8-diaza-bicyclo [3.2.1] oct-8-yl, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl or 8-oxa-3-aza-bicyclo [3.2. 1] oct-3-yl group and

X is a nitrogen atom,

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

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

R ^{a is} a hydrogen atom,

R ^{b is} a 3-chloro-4-fluoro-phenyl group,

R ^{c is} a tetrahydrofuran-3-yloxy, cyclopentyloxy or cyclopropylmethoxy group,

A is an imino group,

B is a carbonyl group,

C is a 1, 2-vinylene group,

D is a methylene group,

E is a 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl group, a 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl group or an 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl group;

X is a nitrogen atom,

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

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

(a) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline,

(d) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,

(e) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline,

(g) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1,4-R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline and

and their salts.

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

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a physiologically acceptable salt according to claim 6, optionally together with one or more inert carriers and / or diluents.

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

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

10. 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 ^a , R ^b , R ^c , A, B and X are as defined in claim 1 and R ⁷ and R ⁸ , which may be the same or different, represent C _1-4 alkyl groups, with a compound of the general formula OHC - D - E, (III) in the

D and E are defined as mentioned above, or is implemented

b) a compound of the general formula

in the

R ^a , R ^b , R ^c , A, B, C, D and X are as defined in claim 1 and Z ^{1 is} a leaving group such as a halogen atom or a substituted sulphonyloxy group such as a chlorine or bromine atom, a Methansulfonyloxy- or p- Toluolsulfonyloxygruppe, with a compound of general formula

H - E, (V)

is defined in the E as mentioned above, is implemented and

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.