DE102005023207A1 - New heteroaryl derivatives are phosphodiesterase-4 enzyme inhibitors useful for the treatment of e.g. respiratory or gastrointestinal complaints or diseases, depression, Alzheimer's disease and Parkinson's disease - Google Patents

Abstract

Heteroaryl derivatives (1) and their racemates, enantiomers, diastereomers, acid addition salts, solvates, hydrates and deuterated forms are new. Heteroaryl derivatives of formula (1) and their racemates, enantiomers, diastereomers, acid addition salts, solvates, hydrates and deuterated forms are new. A : CO, C=NH, 1-6C alkylene or 3-8C cycloalkylene; B 1> : phenyl or an aromatic or non-aromatic ring optionally containing two or three heteroatoms of O, S or N and optionally substituted with OH, O-1-6C alkyl, O-1-6C-haloalkyl, halo, 1-6C alkyl or 1-6C haloalkyl; B 2> : phenyl or hetero aryl containing 2 or 3 heteroatoms of O, S or N; X : e.g. O or S; n : 0-3; either R 1> : e.g. H, 1-6C alkyl, 1-6C haloalkyl; and R 2> : H, 1-6C alkyl or 1-6C haloalkyl; or NR 1>R 2> : non-aromatic heterocycle containing 2 or 3 heteroatoms of O or N; or R 2>+N+A+B 1> : bicyclic group of formula (g); A : CO, C=NH or 1-3C alkyl; m : 1-3; B 1> : sulfonyl compound of formula (h); Z 1> : H, OH, halo, 1-6C alkyl, 1-6C alkanol, O(1-6C alkyl), 6-10C aryl, O-6-10C aryl, NH 2, NH(1-6C alkyl), N(1-6C) alkyl or 3-7C cycloalkyl; and R 4> : e.g. 1-6C alkyl, 3-8C cycloalkyl, 1-6C haloalkyl, CN or halo. Full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are included for: (1) a medicament combination comprising (1) and further active substance, such as beta-mimetic, anticholinergic, corticosteroid, further phosphodiesterase-4-inhibitors, leukotriene D4 antagonists, epidermal growth factor receptor inhibitor, dopamine agonists, H1-antihistaminic, platelet-activating factor antagonist and/or phosphatidylinositol-3 kinase inhibitor; and (2) intermediate compounds of formula (i-iii) or (I-V). PG : H or a suitable protection group; and G : NO 2 or NH 2. [Image] [Image] [Image] [Image] [Image] ACTIVITY : Gastrointestinal-Gen.; Antidepressant; Neuroleptic; Antimanic; Neuroprotective; Nootropic; Antiparkinsonian; Analgesic; Cerebroprotective; CNS-Gen.; Respiratory-Gen.; Antiasthmatic; Antiinflammatory; Antiulcer. MECHANISM OF ACTION : Phosphodiesterase-4 enzyme inhibitor.

Description

die geeignet sind zur Behandlung von Atemwegs- oder gastrointestinalen Beschwerden oder Erkrankungen, entzündlichen Erkrankungen der Gelenke, der Haut oder der Augen, Erkrankungen des periphären oder zentralen Nervensystems oder Krebserkrankungen, sowie pharmazeutische Zusammensetzungen die diese Verbindungen beinhalten.The invention relates to novel compounds of the formula I and heteroderivatives thereof, as well as pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof,

which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, the skin or the eyes, diseases of the peripheral or central nervous system or cancers, as well as pharmaceutical compositions containing these compounds.

DESCRIPTION OF THE INVENTION

worin
A CO, C=NH, C_1-6-Alkylen oder C_3-8-Cycloalkylen;
B¹ Phenyl oder ein heterocyclischer, aromatischer Ring der ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann;
B² Phenyl oder ein heterocyclischer, aromatischen Ring, der ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann;
X O, S, NR⁵ oder CR⁶R⁷;
n 0, 1, 2 oder 3;
R¹ H, C_1-6-Alkyl, C_1-6-Halolalkyl, COR^1.1, COOR^1.1 CH₂COOR^1.1; bevorzugt H, C_1-6-Alkyl, C_1-6-Halolalkyl;
R^1.1 C_1-6-Alkyl;
R² H, C_1-6-Alkyl oder C_1-6-Halolalkyl;
oder R¹ und R² bilden gemeinsam mit dem Stickstoff einen heterocyclischen, nichtaromatischen Ring der ein oder zwei Heteroatome, ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann;
oder R¹ ist C_1-3-Alkylen das gleichzeitig einen Substituenten von B¹ darstellt, woraus insgesamt ein bicyclischer Heteroring aus B¹ und A-NR¹R² entsteht, worin A die Bedeutung von CO, C=NH oder C_1-3-Alkylen haben kann;
R³ H, OH, C_3-8-Cycloalkyl, C_1-6-Alkyl, C_1-6-Haloalkyl, Aryl, ein heterocyclischer, aromatischer Ring der ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und gegebenenfalls substituiert ist mit einem oder mehreren Rest ausgewählt aus der Gruppe bestehend aus C_1-6-Alkyl, C_3-8-Cycloalkyl und C_1-6-Haloalkyl;
ein Rest ausgewählt aus einer Gruppe bestehend aus Aryl und einem heterocyclischen, aromatischen Ring, substituiert mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Aryl, C_2-6-Alkenyl, C_2-6-Alkinyl, C_1-6-Haloalkyl, CONH₂, CONH-C_1-6-Alkyl, CON(C_1-6-Alkyl)₂, COOH, COO-C_1-6-Alkyl, COH, CO-C_1-6-Alkyl, COAryl, OH, O-C_1-6-Alkyl, O-C_1-6-Haloalkyl, Halogen, SH, S-C_1-6-Alkyl, S-C_1-6-Haloalkyl, SO₂-C_1-6-Alkyl, SO₂-C_1-6-Haloalkyl, SO₂-NH₂, SO₂-NH-C_1-6-Alkyl, SO₂-N(C_1-6-Alkyl)₂, NO₂, NH₂, NH-C_1-6-Alkyl und N(C_1-6-Alkyl)₂;
ein Rest ausgewählt aus einer Gruppe bestehend aus Aryl und einem heterocyclischen, aromatischen Ring, substituiert mit C_1-6-Alkyl, gegebenenfalls substituiert mit einem Rest ausgewählt aus der Gruppe bestehend aus COOR^3.3, NR^3.3R^3.4, NHCOR^3.3, NHCOOR^3.3, Phenyl, gegebenenfalls substituiert mit einem Rest ausgewählt aus der Gruppe bestehend aus C_1-6-Alkyl, C_2-6-Alkenyl, C_2-6-Alkinyl, CN, C_1-6-Haloalkyl, CONH₂, CONH-C_1-6-Alkyl, CON(C_1-6-Alkyl)₂, COOH, COO-C_1-6-Alkyl, COH, CO-C_1-6-Alkyl, OH, O-C_1-6-Alkyl, O-C_1-6-Haloalkyl, Halogen, SH, S-C_1-6-Alkyl, S-C_1-6-Haloalkyl, SO₂-C_1-6-Alkyl, SO₂-C_1-6-Haloalkyl, SO₂-NH₂, SO₂-NH-C_1-6-Alkyl, SO₂-N(C_1-6-Alkyl)₂, NO₂, NH₂, NH-C_1-6-Alkyl und N(C_1-6-Alkyl)₂, und ein heterocyclischer Ring der ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel enthalten kann und gegebenenfalls substituiert ist mit einer Oxogruppe;
R^3.3 H oder C_1-6-Alkyl;
R^3.4 H, C_1-6-Alkyl oder C_7-11-Aralkyl;
ein Rest ausgewählt aus einer Gruppe bestehend aus Aryl und einem heterocyclischen, aromatischen Ring, substituiert mit NR^3.1R^3.2;
R^3.1 H, C_1-6-Alkyl, C_3-6-Cycloalkyl, C_1-6-Haloalkyl, COR^3.1.1, COOR^3.1.1, CONR^3.1.1R^3.1.2 oder SO₂-R^3.1.1;
R^3.1.1 H, C_1-6-Alkyl, C_1-6-Haloalkyl, C_3-6-Cycloalkyl oder Aryl;
R^3.1.2 H, C_1-6-Alkyl, C_1-6-Haloalkyl, C_3-6-Cycloalkyl oder Aryl;
R^3.2 H oder ein Rest ausgewählt aus der Gruppe bestehend aus C_1-6-Alkyl, C_3-6-Cycloalkyl und C_1-6-Haloalkyl, gegebenenfalls substituiert mit einem oder mehreren NH₂, NH(C_1-6-Alkyl), N(C_1-6-Alkyl)₂, Oxo oder einem heterocyclischen, nichtaromatischer Ring der ein oder zwei Heteroatome ausgewählt aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthalten kann und gegebenenfalls substituiert ist mit C_1-4-Alkyl;
ein Rest ausgewählt aus einer Gruppe bestehend aus Aryl und einem heterocyclischen, aromatischen Ring, substituiert mit einem heterocyclischen Ring, gegebenenfalls substituiert mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Aryl, C_1-6-Alkyl, C_3-6-Cycloalkyl, CN, C_1-6-Haloalkyl, CONH₂, CONH-C_1-6-Alkyl, CON(C_1-6-Alkyl)₂, COOH, COO-C_1-6-Alkyl, COH, CO-C_1-6-Alkyl, Oxo, OH, O-C_1-6-Alkyl, Halogen, SH, S-C_1-6-Alkyl, NH₂, NH-C_1-6-Alkyl und N(C_1-6-Alkyl)₂;
Benzimdazolyl, gegebenenfalls substituiert mit einem Rest ausgewählt aus der Gruppe bestehend aus C_1-6-Alkyl, C_1-6-Haloalkyl und C_3-6-Cycloalkyl;
R⁴ C_1-6-Alkyl, C_3-8-Cycloalkyl, C_1-6-Haloalkyl, OR^4.1, NR^4.1R^4.2, CN oder Halogen;
R^4.1 H, C_1-6-Alkyl, C_3-8-Cycloalkyl oder C_1-6-Haloalkyl;
R^4.2 H, C_1-6-Alkyl, C_3-8-Cycloalkyl oder C_1-6-Haloalkyl;
R⁵ C_1-6-Alkyl, C_3-8-Cycloalkyl, C_1-6-Haloalkyl, COR^5.1, CONHR^5.1, CON(R^5.1)₂, SO₂-C_1-6-Alkyl, SO₂-C_1-6-Haloalkyl, SO₂-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus R^5.2, SO₂-C_1-6-Alkyl-R^5.2 und C_1-6-Alkyl-R^5.2, gegebenenfalls substituiert mit C_1-6-Alkyl, C_2-6-Alkenyl, C_2-6-Alkinyl, CN, C_1-6-Haloalkyl, CONH₂, CONH-C_1-6-Alkyl, CON(C_1-6-Alkyl)₂, COOH, COO-C_1-6-Alkyl, COH, CO-C_1-6-Alkyl, O-C_3-6-Cycloalkyl, O-C_1-6-Haloalkyl, O-C_1-6-Alkyl, Halogen, SO₂-C_1-6-Alkyl, SO₂-NH₂, SO₂-NH-C_1-6-Alkyl, SO₂-N(C_1-6-Alkyl)₂, NO₂, NH₂, NH-C_1-6-Alkyl und N(C_1-6-Alkyl)₂;
R^5.1 C_1-6-Alkyl oder C_7-11-Aralkyl;
R^5.2 Aryl oder ein heterocyclischer, aromatischer Ring;
R⁶ H, C_1-6-Alkyl oder C_1-6-Haloalkyl;
R⁷ H, C_1-6-Alkyl oder C_1-6-Haloalkyl;
oder R⁶ und R⁷ bilden gemeinsam einen 3-6 gliedrigen Carbocyclus;
bedeutet, sowie pharmakologisch wirksame Salze, Racemate oder Isomere, in reiner und gemischter, Form davon.Surprisingly, it has now been found that the compounds of the formula 1 are suitable for the treatment of inflammatory diseases. The present invention therefore relates to compounds of the formula 1

wherein
A is CO, C = NH, C _1-6 -alkylene or C _3-8 -cycloalkylene;
B ^{1 is} phenyl or a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;
B ^{2 is} phenyl or a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;
X is O, S, NR ⁵ or CR ⁶ R ⁷ ;
n is 0, 1, 2 or 3;
R ^{1 is} H, C _1-6 alkyl, C _1-6 haloalkyl, COR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 ; preferably H, C _1-6 alkyl, C _1-6 haloalkyl;
R ^{1.1 is} C _1-6 alkyl;
R ^{2 is} H, C _1-6 alkyl or C _1-6 haloalkyl;
or R ¹ and R ² together with the nitrogen form a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen;
or R ¹ is C _1-3 -alkylene which is simultaneously a substituent of B ¹ , resulting in a total of a bicyclic hetero ring of B ¹ and A-NR ¹ R ² is formed, wherein A is the meaning of CO, C = NH or C _{1- 3-} alkylene may have;
R ^{3 is} H, OH, C _3-8 -cycloalkyl, C _1-6 -alkyl, C _1-6 -haloalkyl, aryl, a heterocyclic, aromatic ring of the one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and May contain nitrogen and is optionally substituted by one or more radicals selected from the group consisting of C _1-6 alkyl, C _3-8 cycloalkyl and C _1-6 haloalkyl;
a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with one or more radicals selected from the group consisting of aryl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl , CONH ₂ , CONH-C _1-6 -alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, COAryl, OH, OC _1-6 -alkyl, OC _1-6 -haloalkyl, halogen, SH, SC _1-6 -alkyl, SC _1-6 -haloalkyl, SO ₂ -C _1-6 -alkyl, SO ₂ -C _1-6 - Haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6 -alkyl, SO ₂ -N (C _1-6 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-6 -alkyl and N (C _1-6 alkyl) ₂ ;
a radical selected from a group consisting of aryl and a heterocyclic aromatic ring, substituted with C _1-6 -alkyl, optionally substituted by a radical selected from the group consisting of COOR ^3.3 , NR ^3.3 R ^3.4 , NHCOR ^3.3 , NHCOOR ^3.3 , phenyl, optionally substituted by a radical selected from the group consisting of C _{1 6-} alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, CN, C _1-6 -haloalkyl, CONH ₂ , CONH-C _1-6 -alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, OH, OC _1-6 -alkyl, OC _1-6 -haloalkyl, halogen, SH, SC _1-6 -alkyl, SC _1-6 haloalkyl, SO ₂ -C _1-6 alkyl, SO ₂ -C _1-6 haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6 alkyl, SO ₂ -N (C _1-6- alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-6 -alkyl and N (C _1-6 -alkyl) ₂ , and a heterocyclic ring of the one, two or three heteroatoms selected from the group May contain oxygen, nitrogen and sulfur and is optionally substituted with an oxo group;
R ^3.3 is H or C _1-6 alkyl;
R ^{3.4 is} H, C _1-6 alkyl or C _7-11 aralkyl;
a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with NR ^3.1 R ^3.2 ;
R ^{3.1 is} H, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -haloalkyl, COR ^3.1.1 , COOR ^3.1.1 , CONR ^3.1.1 R ^3.1.2 or SO ₂ -R ^{3.1. 1} ;
R ^{3.1.1 is} H, C _1-6 -alkyl, C _1-6 -haloalkyl, C _3-6 -cycloalkyl or aryl;
R ^{3.1.2 is} H, C _1-6 -alkyl, C _1-6 -haloalkyl, C _3-6 -cycloalkyl or aryl;
R ^{3.2 is} H or a radical selected from the group consisting of C _1-6 -alkyl, C _3-6 -cycloalkyl and C _1-6 -haloalkyl, optionally substituted by one or more NH ₂ , NH (C _1-6 -alkyl ), N (C _1-6 alkyl) ₂ , oxo or a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and is optionally substituted with C _1-4 alkyl;
a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with a heterocyclic ring optionally substituted with one or more radicals selected from the group consisting of aryl, C _1-6 alkyl, C _3-6 cycloalkyl , CN, C _1-6 -haloalkyl, CONH ₂ , CONH-C _1-6 -alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _{1 -6-} alkyl, oxo, OH, OC _1-6 -alkyl, halogen, SH, SC _1-6 -alkyl, NH ₂ , NH-C _1-6 -alkyl and N (C _1-6 -alkyl) ₂ ;
Benzimidazolyl optionally substituted with one selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;
R ^{4 is} C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, OR ^4.1 , NR ^4.1 R ^4.2 , CN or halo;
R ^{4.1 is} H, C _1-6 -alkyl, C _3-8 -cycloalkyl or C _1-6 -haloalkyl;
R ^{4.2 is} H, C _1-6 -alkyl, C _3-8 -cycloalkyl or C _1-6 -haloalkyl;
R ^{5 is} C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, COR ^5.1 , CONHR ^5.1 , CON (R ^5.1 ) ₂ , SO ₂ C _1-6 alkyl, SO ₂ -C _1-6 haloalkyl, SO ₂ aryl or a radical selected from the group consisting of R ^5.2 , SO ₂ -C _1-6 alkyl R ^5.2 and C _1-6 alkyl R ^5.2 , optionally substituted with C _{1 -6-} alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, CN, C _1-6 -haloalkyl, CONH ₂ , CONH-C _1-6 -alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, OC _3-6 -cycloalkyl, OC _1-6 -haloalkyl, OC _1-6 -alkyl, halogen, SO ₂ -C _1-6 -alkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6 -alkyl, SO ₂ -N (C _1-6 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-6 -Alkyl and N (C _1-6 -alkyl) ₂ ;
R ^{5.1 is} C _1-6 alkyl or C _7-11 aralkyl;
R ^5.2 aryl or a heterocyclic aromatic ring;
R ^{6 is} H, C _1-6 -alkyl or C _1-6 -haloalkyl;
R ^{7 is} H, C _1-6 alkyl or C _1-6 haloalkyl;
or R ⁶ and R ⁷ together form a 3-6 membered carbocycle;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Preferred are the above compounds of formula 1 wherein
A is CO, C = NH, C _1-4 -alkylene or C _3-6 -cycloalkylene;
B ^{1 is} phenyl or a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;
B ^{2 is} phenyl or pyridinyl;
X is O, S, NR ⁵ or CR ⁶ R ^7;
n is 0, 1, 2 or 3;
R ^{1 is} H, C _1-4 alkyl, C _1-4 haloalkyl;
R ^{2 is} H, C _1-4 alkyl or C _1-4 haloalkyl;
or R ¹ and R ² together with the nitrogen form a heterocyclic non-aromatic ring which may contain one or two nitrogen atoms;
R ^{3 is} H, OH, C _3-6 -cycloalkyl, C _1-4 -alkyl, C _1-4 -haloalkyl, aryl, a heterocyclic, aromatic ring of the one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and May contain nitrogen and is optionally substituted by one or more radicals selected from the group consisting of C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 haloalkyl;
a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with one or more radicals selected from the group consisting of aryl, C _2-4 alkenyl, C _2-4 -alkynyl, C _1-4 -haloalkyl, CONH ₂ , CONH-C _1-4 -alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 alkyl, COAryl, OH, OC _1-4 alkyl, OC _1-4 haloalkyl, halogen, SH, SC _1-4 alkyl, SC _1-4 haloalkyl, SO ₂ -C _{1 -4-} alkyl, SO ₂ -C _1-4 -haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-4 alkyl and N (C _1-4 alkyl) ₂ ;
a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with C _1-4 alkyl, optionally substituted with a radical selected from the group consisting of COOR ^3.3 NR ^3.3 R ^3.4 , NHCOR ^3.3 , NHCOOR ^3.3 , phenyl optionally substituted with one selected from the group consisting of C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, CN, C _1-4 haloalkyl, CONH ₂ , CONH-C _{1- 4} alkyl, CON (C _1-4 alkyl) ₂ , COOH, COO-C _1-4 alkyl, COH, CO-C _1-4 alkyl, OH, OC _1-4 alkyl, OC _1-4 Haloalkyl, halogen, SH, SC _1-4 -alkyl, SC _1-4 -haloalkyl, SO ₂ -C _1-4 -alkyl, SO ₂ -C _1-4 -haloalkyl, SO ₂ -NH ₂ , SO ₂ - NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-4 -alkyl and N (C _1-4 -alkyl) ₂ , and a heterocyclic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and is optionally substituted by an oxo group;
R ^3.3 is H or C _1-4 alkyl;
R ^{3.4 is} H, C _1-4 alkyl or C _7-11 aralkyl;
a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with NR ^3.1 R ^3.2 ;
R ^{3.1 is} H, C _1-4 -alkyl, C _3-6 -cycloalkyl, C _1-4 -haloalkyl, COR ^3.1.1 , COOR ^3.1.1 , CONR ^3.1.1 R ^3.1.2 or SO ₂ -R ^{3.1. 1} ;
R ^{3.1.1 is} H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl or aryl;
R ^{3.1.2 is} H, C _1-4 -alkyl, C _1-4 -haloalkyl, C _3-6 -cycloalkyl or aryl;
R ^{3.2 is} H or a radical selected from the group consisting of C _1-4 -alkyl, C _3-6 -cycloalkyl and C _1-4 -haloalkyl, optionally substituted by one or more NH ₂ , NH (C _1-4 -alkyl ), N (C _1-4 alkyl) ₂ , oxo or a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and is optionally substituted with C _1-4 alkyl;
Aryl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of aryl, C _1-4 alkyl , C _3-6 -cycloalkyl, CN, C _1-4 -haloalkyl, CONH ₂ , CONH-C _1-4 -alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl , COH, CO-C _1-4 -alkyl, OH, OC _1-4 -alkyl, halogen, SH, SC _1-4 -alkyl, NH ₂ , NH-C _1-4 -alkyl and N (C _1-4 -Alkyl) ₂ ;
Aryl substituted with a heterocyclic non-aromatic ring containing one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo;
Benzimidazolyl optionally substituted with one selected from the group consisting of C _1-4 alkyl, C _1-4 haloalkyl and C _3-6 cycloalkyl;
R ^{4 is} C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, OR ^4.1 , NR ^4.1 R ^4.2 , CN or halo;
R ^{4.1 is} H, C _1-4 -alkyl, C _3-6 -cycloalkyl or C _1-4 -haloalkyl;
R ^{4.2 is} H, C _1-4 -alkyl, C _3-6 -cycloalkyl or C _1-4 -haloalkyl;
R ^{5 is} C _1-4 -alkyl, C _3-8 -cycloalkyl, C _1-4 -haloalkyl, COR ^5.1 , CONHR ^5.1 , CON (R ^5.1 ) ₂ , SO ₂ C _1-4 -alkyl, SO ₂ -C _1-4 -haloalkyl, SO ₂ -aryl or a radical selected from the group consisting of R ^5.2 , SO ₂ -C _1-4 -alkyl-R ^5.2 and C _1-4 -alkyl-R ^5.2 , optionally substituted by C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, CN, C _1-4 haloalkyl, CONH ₂ , CONH C _1-4 alkyl, CON (C _1-4 alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 -alkyl, OC _1-4 -cycloalkyl, OC _1-4 -haloalkyl, OC _1-4 -alkyl, halogen, SO ₂ -C _1-4 -alkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-4 Alkyl and N (C _1-4 alkyl) ₂ ;
R ^{5.1 is} C _1-4 alkyl or C _7-11 aralkyl;
R ^5.2 aryl or a heterocyclic aromatic ring;
R ^{6 is} H, C _1-4 alkyl or C _1-4 haloalkyl;
R ^{7 is} H, C _1-4 alkyl or C _1-4 haloalkyl;
or R ⁶ and R ⁷ together form a 3-6 membered carbocycle;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Preferred are the above compounds of formula 1 wherein
A is CO, C = NH, C _1-4 -alkylene or C _3-6 -cycloalkylene;
B ^{1 is} phenyl or a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;
B ^{2 is} phenyl or pyridinyl;
X is O, S, NR ⁵ or CR ⁶ R ^7;
n is 0, 1, 2 or 3;
R ^{1 is} H, C _1-4 alkyl, C _1-4 haloalkyl;
R ^{2 is} H, C _1-4 alkyl or C _1-4 haloalkyl;
or R ¹ and R ² together with the nitrogen form a heterocyclic non-aromatic ring which may contain one or two nitrogen atoms;
R ^{3 is} H, OH, C _3-6 -cycloalkyl, C _1-6 -alkyl, C _1-6 -haloalkyl, aryl, a heterocyclic aromatic ring which may contain one, two or three nitrogen atoms and is optionally substituted by a methyl group ;
Phenyl substituted with one or more radicals selected from the group consisting of aryl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CONH ₂ , CONH C _1-6 alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, COAryl, OH, OC _1-6 -alkyl, OC _1-4 -haloalkyl, Halogen, SH, SC _1-6 -alkyl, SC _1-4 -haloalkyl, SO ₂ -C _1-6 -alkyl, So ₂ -C _1-4 -haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6- alkyl, So ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NO ₂ , NH ₂ , NH-C _1-6 -alkyl and N (C _1-6 -alkyl) ₂ ;
Phenyl substituted with C _1-4 alkyl optionally substituted with a radical selected from the group consisting of COOR ^3.3 , NR ^3.3 R ^3.4 , NHCOR ^3.3 , NHCOOR ^3.3 and phenyl optionally substituted with one or more radicals selected from the group consisting of methyl, t-butyl, F, Cl, Br, CN and OH, and a heterocyclic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen and is optionally substituted with an oxo group;
R ^3.3 is H or C _1-4 alkyl;
R ^{3.4 is} H, C _1-4 alkyl or C _7-11 aralkyl;
Phenyl substituted with NR ^3.1 R ^3.2 ;
R ^{3.1 is} H, C _1-4 alkyl, C _1-4 haloalkyl, COR ^3.1.1 , COOR ^3.1.1 , CONR ^3.1.1 R ^3.1.2 or SO ₂ -R ^3.1.1 ;
R ^{3.1.1 is} H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl or aryl;
R ^{3.1.2 is} H, C _1-4 -alkyl, C _1-4 -haloalkyl, C _3-6 -cycloalkyl or aryl;
R ^{3.2 is} H, C _1-4 alkyl optionally substituted with one or more NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , oxo or a heterocyclic non-aromatic ring or may contain two nitrogen atoms and is optionally substituted with a methyl group;
Aryl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of aryl, C _1-4 -alkyl, C _3-6 -cycloalkyl, CN, C _1-4 -haloalkyl, CONH ₂ , CONH-C _1-4 -alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 -alkyl, OH, OC _1-4 -alkyl, halogen, SH, SC _1-4 -alkyl, NH ₂ , NH-C _1-4 -alkyl and N (C _1-4 Alkyl) ₂ ;
Aryl substituted with a heterocyclic non-aromatic ring containing one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo;
Benzimidazolyl optionally substituted with one selected from the group consisting of C _1-4 alkyl, C _1-4 haloalkyl and C _3-6 cycloalkyl;
R ^{4 is} C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, OR ^4.1 , NR ^4.1 R ^4.2 , CN or halo;
R ^{4.1 is} H, C _1-4 -alkyl, C _3-6 -cycloalkyl or C _1-4 -haloalkyl;
R ^{4.2 is} H, C _1-4 -alkyl, C _3-6 -cycloalkyl or C _1-4 -haloalkyl;
R ^{5 is} C _1-4 -alkyl, C _3-8 -cycloalkyl, C _1-4 -haloalkyl, COR ^5.1 , CONHR ^5.1 , CON (R ^5.1 ) ₂ , SO ₂ C _1-4 -alkyl, SO ₂ -C _1-4 -haloalkyl, SO ₂ -aryl or a radical selected from the group consisting of R ^5.2 , SO ₂ -C _1-4 -alkyl-R ^5.2 and C _1-4 -alkyl-R ^5.2 , optionally substituted by C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, CN, C _1-4 haloalkyl, CONH ₂ , CONH C _1-4 alkyl, CON (C _1-4 alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 -alkyl, OC _1-4 -cycloalkyl, OC _1-4 -haloalkyl, OC _1-4 -alkyl, halogen, SO ₂ -C _1-4 -alkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, So ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-4 Alkyl and N (C _1-4 alkyl) ₂ ;
R ^{5.1 is} C _1-4 alkyl or C _7-11 aralkyl;
R ^5.2 aryl or a heterocyclic aromatic ring;
R ^{6 is} H, C _1-4 alkyl or C _1-4 haloalkyl;
R ^{7 is} H, C _1-4 alkyl or C _1-4 haloalkyl;
or R ⁶ and R ⁷ together form a 3-6 membered carbocycle;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Preferred are the above compounds of formula 1 wherein
A is CO, C = NH, C _1-4 -alkylene or C _3-6 -cycloalkylene;
B ^{1 is} phenyl or pyridinyl;
B ^{2 is} phenyl or pyridinyl;
X is O or NR ⁵ ;
n is 0, 1, 2 or 3;
R ^{1 is} H, methyl, ethyl, propyl, preferably H, methyl, particularly preferably H;
R ^{2 is} H, methyl, ethyl, propyl, preferably H, methyl, more preferably H;
R ^{3 is} H, OH, C _3-6 -cycloalkyl, C _1-6 -alkyl, C _1-6 -haloalkyl, aryl, a heterocyclic aromatic ring which may contain one, two or three nitrogen atoms and is optionally substituted by a methyl group ;
Phenyl substituted with one or more radicals selected from the group consisting of aryl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CONH ₂ , CONH C _1-4 alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 -alkyl, COAryl, OH, OC _1-4 -alkyl, OC _1-4 -haloalkyl, Halogen, SH, SC _1-4 alkyl, SC _1-4 haloalkyl, SO ₂ -C _1-4 alkyl, SO ₂ -C _1-4 haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NO ₂ , NH ₂ , NH-C _1-4 -alkyl and N (C _1-4 -alkyl) ₂ ;
Phenyl substituted with C _1-4 alkyl optionally substituted with a radical selected from the group consisting of COOR ^3.3 , NR ^3.3 R ^3.4 , NHCOR ^3.3 , NHCOOR ^3.3 , p-fluorophenyl and a heterocyclic ring of the one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with an oxo group;
R ^3.3 is H or C _1-4 alkyl;
R ^{3.4 is} H, C _1-4 alkyl or C _7-11 aralkyl;
Phenyl substituted with NR ^3.1 R ^3.2 ;
R ^{3.1 is} H, C _1-4 alkyl, COR ^3.1.1 , COOR ^3.1.1 , CONR ^3.1.1 R ^3.1.2 or SO ₂ -R ^3.1.1 ;
R ^{3.1.1 is} H, C _1-4 alkyl or aryl;
R ^3.1.2 H, C _1-4 alkyl or aryl;
R ^{3.2 is} H, C _1-4 alkyl optionally substituted with one or more NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , oxo or a heterocyclic non-aromatic ring or may contain two nitrogen atoms and is optionally substituted with a methyl group;
Phenyl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of aryl, C _1-4 alkyl , C _1-4 -haloalkyl, C _3-6 -cycloalkyl, CN, CONH ₂ , CONH-C _1-4 -alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl , COH, CO-C _1-4 alkyl, OH, OC _1-4 alkyl, halogen, NH ₂ and N (C _1-4 alkyl) ₂ ;
Phenyl substituted with a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo;
Benzimidazolyl optionally substituted with a radical selected from the group consisting of methyl, ethyl, propyl, CF ₃ , CH ₂ CF ₃ , cyclopropyl, cyclopentyl and cyclohexyl;
R ^{4 is} C _1-4 alkyl, C _1-4 haloalkyl or halo;
R ^{5 is} C _1-4 -alkyl, C _3-6 -cycloalkyl, COR ^5.1 , CONHR ^5.1 , aryl, SO ₂ -C _7-11 -aralkyl, SO ₂ -aryl or C _7-11 -aralkyl, optionally substituted with C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, CN, C _1-4 haloalkyl, CONH ₂ , CONH C _1-4 alkyl, CON (C _1-4 alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 -alkyl, OH, OC _1-4 -alkyl, halogen, SO ₂ C _1-4 -alkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-4 -alkyl and N (C _1-4 -alkyl) ₂ ;
R ^{5.1 is} C _1-4 alkyl or C _7-11 aralkyl;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

worin A, X, n, B¹, B², R¹, R², R³ und R⁴ die oben genannte Bedeutung haben.Particular preference is given to the compounds of the formula 1a,

wherein A, X, n, B ¹ , B ² , R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning.

Particularly preferred are the above compounds of formula 1 or 1a wherein
B ¹ phenyl; and
B ² phenyl;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Particularly preferred are the above compounds of formula 1 or 1a wherein
X O;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Particularly preferred are the above compounds of formula 1 or 1a wherein
X NR ⁵ ;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Particularly preferred are the above compounds of formula 1 or 1a wherein
X CR ⁶ R ⁷ ;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Particularly preferred are the above compounds of formula 1 or 1a wherein
n is 0, 1, or 2, preferably 0 or 1, more preferably 0;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Particularly preferred are the above compounds of formula 1 or 1a wherein
A CH ₂ , CHMe, CMe ₂ , C = NH, 1,1'-cyclopropylene, 1,1'-cyclobutylidene;
B ¹ phenyl;
B ² phenyl;
X is O or NR ⁵ ;
n is 0, 1 or 2;
R ^{1 is} H, methyl or ethyl, preferably H;
R ^{2 is} H, methyl or ethyl, preferably H;
R ^{3 is} H, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl, or
Phenyl substituted selected from the group having a group consisting of phenyl, methyl, ethyl, propyl, butyl, CF _3, CONH _2, CONHMe, CONMe _2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F , Cl, Br, SH, SO ₂ Me, SONH ₂ , SONMe ₂ , NO ₂ , NH ₂ , NHMe and NMe ₂ ;
Phenyl substituted by a radical selected from the group consisting of methyl and ethyl, optionally substituted by a radical selected from the group consisting of COOH, COOMe, NH ₂ , NMe ₂ , NHCOMe, NHCOO tert -butyl, NMe (benzyl), p-fluorophenyl, pyrolidinyl, piperidinyl, morpholinyl, pyrolidinyl-2-nyl, imidazolyl and triazolyl;
Phenyl substituted with NR ^3.1 R ^3.2 ;
R ^{3.1 is} H, methyl, COH, COMe, COOMe, CONH ₂ , CONMe ₂ , SO ₂ Me, SO ₂ CF ₃ , SO ₂ -phenyl;
R ^{3.2 is} H, methyl, ethyl, optionally substituted with a radical selected from the group consisting of one or more NH ₂ , NHMe, NMe ₂ , N-piperidinyl, N-morpholinyl and N-methyl-piperazinyl, and optionally substituted with another oxo ;
Phenyl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, Butyl, cyclopropyl, cyclobutyl, CF ₃ , CN, CONH ₂ , CONMe ₂ , CONEt ₂ , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, NH ₂ , NMe ₂ , NEt ₂ and NPr ₂ ;
Phenyl substituted with a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo;
Benzimidazolyl optionally substituted with a radical selected from the group consisting of methyl, propyl, CF ₃ , CH ₂ CF ₃ , cyclopropyl and cyclohexyl;
R ^{4 is} methyl, ethyl, propyl, butyl, CF ₃ , CH ₂ CF ₃ , F, Cl, or Br;
R ^{5 is} methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF ₃ , CH ₂ CF ₃ , COR ^5.1 , CONHR ^5.1 , phenyl, phenylsulfonyl, benzyl, optionally substituted with methyl, ethyl, propyl, butyl, CF ₃ , CN, CONH ₂ , CONME ₂ , CONEt ₂ , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO ₂ Me, SONH ₂ , SONMe ₂ , NO ₂ , NH ₂ , NMe ₂ , NEt ₂ and NPr ₂ ;
R ^5.1 methyl, ethyl, propyl, butyl, benzyl;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Particularly preferred are the above compounds of formula 1 or 1a wherein
A CH ₂ , CHMe, CMe ₂ , CO, C = NH, 1,1'-cyclopropylene, 1,1'-cyclobutylidene;
B ¹ phenyl;
B ² phenyl;
X is O or NR ⁵ ;
n is 0 or 1;
R ^{1 is} H, methyl or ethyl, preferably H;
R ^{2 is} H, methyl or ethyl, preferably H;
R ^{3 is} H, OH, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl, or
Phenyl substituted with a radical selected from the group consisting of phenyl, OH, F and CONH ₂ ;
Phenyl substituted by a radical selected from the group consisting of methyl and ethyl, optionally substituted by a radical selected from the group consisting of COOH, COOMe, NH ₂ , NMe ₂ , NHCOMe, NHCOO tert -butyl, NMe (benzyl), p-fluorophenyl, pyrolidinyl, piperidinyl, morpholinyl, pyrolidinyl-2-nyl, imidazolyl and triazolyl;
Phenyl substituted with NR ^3.1 R ^3.2 ;
R ^{3.1 is} H, methyl, SO ₂ Me, SO ₂ CF ₃ , SO ₂ -phenyl;
R ^{3.2 is} H, methyl, ethyl, optionally substituted with one or more NH ₂ , NHMe, NMe ₂ , oxo, N-piperidinyl, N-morpholinyl, N-methyl-piperazinyl;
Phenyl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, Butyl, cyclopropyl, cyclobutyl, CF ₃ , CN, CONH ₂ , CONMe ₂ , CONEt ₂ , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO ₂ Me, SONH ₂ , SONMe ₂ , NO ₂ , NH ₂ , NMe ₂ , NEt ₂ and NPr ₂ , and;
Phenyl substituted with a heterocyclic non-aromatic ring containing one or two heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo.

Benzimidazolyl optionally substituted with a radical selected from the group consisting of methyl;
R ^{4 is} F or Cl;
R ^{5 is} methyl, ethyl, cyclopropyl, COMe, CONHR ^5.1 , phenyl, phenylsulfonyl, benzyl, optionally substituted with F;
R ^5.1 butyl, benzyl,
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

Particularly preferred are the above compounds of formula 1 or 1a wherein
A CH ₂ , CHMe, CMe ₂ , 1,1'-cyclopropylene, 1,1'-cyclobutylidene;
B ¹ phenyl;
B ² phenyl;
X is O or NR ⁵ ;
n is 0 or 1, preferably 0;
R ¹ H;
R ² H;
R ³ H or
Phenyl substituted with NR ^3.1 R ^3.2 ;
R ^{3.1 is} H, methyl, SO ₂ Me, SO ₂ CF ₃ , SO ₂ -phenyl;
R ^{3.2 is} H, methyl, ethyl, optionally substituted with one or more NH ₂ , NHMe, NMe ₂ , oxo, N-piperidinyl, N-morpholinyl, N-methyl-piperazinyl;
Phenyl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, Butyl, cyclopropyl, cyclobutyl, CF ₃ , CN, CONH ₂ , CONMe ₂ , CONEt ₂ , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO ₂ Me, SONH ₂ , SONMe ₂ , NO ₂ , NH ₂ , NMe ₂ , NEt ₂ and NPr ₂ , and;
Phenyl substituted with a heterocyclic non-aromatic ring containing one or two heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo.
R ^{4 is} H, F or Cl;
R ^{5 is} methyl, ethyl, cyclopropyl, cyclobutyl CH ₂ CF ₃ or benzyl, optionally substituted with F;
means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

B¹ Phenyl;
B² Phenyl;
X O oder NR⁵;
n 0 oder 1;
R¹ H;
R² H;
R³ H, OH oder ein Rest ausgewählt aus der Gruppe bestehend aus

R⁴ H, F oder Cl;
R⁵ Methyl oder ein Rest ausgewählt aus der Gruppe bestehend aus

bedeutet, sowie pharmakologisch wirksame Salze, Racemate oder Isomere, in reiner und gemischter, Form davon.Also particularly preferred are the above compounds of formula 1 or 1a wherein
A CH ₂ , CHMe, CMe ₂ , CO, C = NH, or a radical selected from the group consisting of

B ¹ phenyl;
B ² phenyl;
X is O or NR ⁵ ;
n is 0 or 1;
R ¹ H;
R ² H;
R ^{3 is} H, OH or a radical selected from the group consisting of

R ^{4 is} H, F or Cl;
R ^{5 is} methyl or a radical selected from the group consisting of

means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof.

USED TERMS AND DEFINITIONS

Unless otherwise indicated, all substituents are independent of each other. Should a group z. For example, if there are several C _1-6 -alkyl groups as substituents, in the case of three substituents C _1-6 -alkyl could independently of one another be methyl, once n-propyl and once tert-butyl.

In the context of this application, in the definition of possible substituents, these can also be represented in the form of a structural formula. An asterisk (*) in the structural formula of the substituent is understood to be the point of attachment to the remainder of the molecule. Furthermore, the atom of the substituent following the point of attachment is understood as the atom with the position number 1. For example, the residues N-piperidinyl (I), 4-piperidinyl (II), 2-tolyl (III), 3-tolyl (IV) and 4-tolyl (V) are shown as follows:

If there is no star (*) in the structural formula of the substituent, then each hydrogen atom can be removed from the substituent and the valence thus liberated as a binding site to the remainder of a Serve a molecule. For example, VI may have the meaning of 2-tolyl, 3-tolyl, 4-tolyl and benzyl.

The term "C _1-6 -alkyl" (including those which are part of other groups) is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms and branched and unbranched alkyl groups having 1 to 10 by the term "C _1-4 -alkyl" 4 carbon atoms understood. Preferred are alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. Optionally, the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise specified, the definitions of propyl, butyl, pentyl and hexyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl, etc.

The term "C _1-6 -alkylene" (including those which are part of other radicals) are to be understood as meaning branched and unbranched alkylene groups having 1 to 6 carbon atoms and branched and unbranched alkylene groups having 1 to 10 by the term "C _1-3 -alkylene" 3 carbon atoms understood. Preferred are alkylene groups having 1 to 3 carbon atoms. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2, -dimethylpropylene, 1, 2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless otherwise stated, the definitions propylene, butylene, pentylene and hexylene include all conceivable isomeric forms of the respective radicals of the same carbon number. For example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

Should the carbon chain be substituted with a radical which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, the following examples of the rings are included:

The term "C _2-6 alkenyl" (including those which are part of other radicals) are branched and unbranched alkenyl groups having 2 to 6 carbon atoms and the term "C _2-4 alkenyl" branched and unbranched alkenyl groups having 2 to 4 Carbon atoms understood, as far as they have at least one double bond. Preferred are alkenyl groups having 2 to 4 carbon atoms. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise described, the definitions propenyl, butenyl, pentenyl and hexenyl include all conceivable isomeric forms of the respective radicals. For example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.

The term "C _2-6 -alkynyl" (including those which are part of other radicals) are branched and unbranched alkynyl groups having 2 to 6 carbon atoms and the term "C _2-4 -alkynyl" branched and unbranched alkynyl groups having 2 to 4 Carbon atoms understood as far as they have at least one triple bond. Preferred are alkynyl groups having 2 to 4 carbon atoms. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless otherwise stated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all conceivable isomeric forms of the respective radicals. For example, propynyl includes 1-propynyl and 2-propynyl, butinyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.

The term "C _2-6 -alkynylene" (even if they are part of other groups) are branched and unbranched alkynylene groups having 2 to 6 carbon atoms and the term "C _2-4 -alkynylene" branched and unbranched alkylene groups having 2 to 4 carbon atoms understood. Alkynylene groups having 2 to 4 carbon atoms are preferred. Examples include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1, 2 Dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene. Unless otherwise stated, the definitions propynylene, butynylene, pentynylene and hexynylene include all conceivable isomeric forms of the respective radicals of the same carbon number. So includes at For example, propynyl also 1-methylethynylene and butynylene include 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.

Under the term "aryl" (as far as they are Are part of other radicals) are aromatic ring systems with 6 or 10 carbon atoms understood. For example: Phenyl or naphthyl, more preferably aryl, is phenyl. If not describe differently the aromatics are substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, Hydroxy, fluorine, chlorine, bromine and iodine.

The term "C _7-11 -aralkyl" (including those which are part of other groups) means branched and unbranched alkyl groups having 1 to 5 carbon atoms which are substituted by an aromatic ring system having 6 carbon atoms. For example: benzyl, 1- or 2-phenylethyl. 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, fluorine, chlorine, bromine and iodine.

The term "C _1-6 -haloalkyl" (including those which are part of other groups) means branched and unbranched alkyl groups having 1 to 6 carbon atoms which are substituted by one or more halogen atoms. By the term "C _1-4 -alkyl" is meant branched and unbranched alkyl groups having from 1 to 4 carbon atoms which are substituted by one or more halogen atoms. Preferred are alkyl groups having 1 to 4 carbon atoms. For example: CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ .

The term "C _3-8 -cycloalkyl" (including those which are part of other groups) means cyclic alkyl groups having 3 to 8 carbon atoms. The term "C _3-6 -cycloalkyl" accordingly means cyclic alkyl groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. 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, fluorine, chlorine, bromine and iodine.

The term "heterocyclic rings" is understood as meaning five-, six- or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, in which case the ring may have a carbon atom or if present, be linked to the molecule via a nitrogen atom. Although included within the term "heterocyclic rings", the term "heterocyclic non-aromatic rings" defines five-, six- or seven-membered unsaturated rings. Examples are:

Although included within the term "heterocyclic rings", the term "heterocyclic aromatic rings" defines five- or six-membered heterocyclic aromatics or 5-10 membered bicyclic heteroaryl rings containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen that can contain and contain as many conjugated double bonds that an aromatic system is formed. As examples of five- or six-membered heterocyclic aromatic compounds, there are mentioned:

So far not mentioned otherwise, For example, a heterocyclic ring may be provided with a keto group. As an example are called.

By the term "bicyclic rings" is meant eight-, nine- or ten-membered bicyclic rings which may optionally contain one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. The ring may be linked to the molecule via a carbon atom of the ring or, if present, via a nitrogen atom of the ring. By way of example,

Although included within the term "bicyclic rings", the term "fused bicyclic rings" defines bicyclic rings in which the bridge separating the rings is a direct single bond. As an example of a fused, bicyclic ring are mentioned:

Although encompassed by the term "bicyclic rings", the term "fused bicyclic hetero rings" defines bicyclic 5-10 membered hetero rings containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and in which the rings separating bridge means a direct single bond. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

"Halogen" is in the frame of the present invention for Fluorine, chlorine, bromine or iodine. Unless stated otherwise, Fluorine, chlorine and bromine are the preferred halogens.

links the general formula 1 can acid groups own, mainly Carboxyl groups, and / or basic groups such as e.g. Amino functions. Compounds of the general formula 1 can therefore be used as internal salts, as salts with pharmaceutically usable inorganic acids such as Hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, Citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically usable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. Diethylamine, triethylamine, triethanolamine et al available.

As mentioned above, the compounds of the formula 1 can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula 1 with inorganic or organic acids. On the other hand, in the case of R equal to hydrogen by reaction with inorganic bases, the compound of formula 1 can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, for example, can be used to prepare the acid addition salts. Lactic acid, citric acid, tartaric acid or maleic acid into consideration. Furthermore, mixtures of the abovementioned acids can be used. For the preparation of the alkali metal and alkaline earth metal salts of the compound of formula 1 in which R is hydrogen, the alkali metal and alkaline earth metal hydroxides and hydrides are preferably suitable, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium being preferred, sodium and potassium hydroxide are particularly preferred.

Possibly can the compounds of general formula (1) in their salts, in particular for the pharmaceutical application, in their pharmacologically acceptable Acid addition salts with an inorganic or organic acid. When acids come therefor for example succinic acid, hydrobromic, Acetic acid, fumaric acid, maleic acid, methane, Lactic acid, Phosphoric acid, Hydrochloric acid, Sulfuric acid, tartaric acid or citric acid into consideration. Furthermore, can Mixtures of the abovementioned acids be used.

object the invention, the respective compounds are optionally in Form of the individual optical isomers, mixtures of the individual Enantiomers or racemates, in the form of tautomers and in the form the free bases or the corresponding acid addition salts with pharmacological harmless acids - such as Acid addition salts with hydrohalic acids - for example Chloric or hydrobromic acid - or organic Acids - such as Oxalic, fumaric, diglycol or methanesulfonic acid

The Compounds of the invention can optionally present as racemates, but they can also be used as pure enantiomers, i.e. in (R) or (S) form. Preference is given to compounds are present as racemates or as (S) -form.

object the invention, the respective compounds are optionally in Form of the individual optical isomers, mixtures of the individual Enantiomers or racemates, in the form of tautomers and in the form the free bases or the corresponding acid addition salts with pharmacological harmless acids - such as Acid addition salts with hydrohalic acids - for example Chloric or hydrobromic acid - or organic Acids - such as Oxalic, fumaric, diglycol or methanesulfonic acid

The The following tables of Examples A and B summarize the present invention Compounds of formula 1 together.

EXAMPLES A

EXAMPLES B

in the The following are exemplary syntheses for the preparation of compounds of the formula 1 shown.

EXAMPLE 40 4- (1-AMINO-CYCLOPROPYL) -BENZOIC ACID TERT-BUTYL ESTER

50 ml of a 2 M lithium isopylate solution in THF were placed under argon atmosphere and 13.4 g of anhydrous Lthium iodide given. After 15 minutes, 45 ml of a 1 were dropped M Methyltitanisopropoxide solution in THF. Thereafter, the mixture was mixed with 8.1 g of tert-butyl 4-cyanobenzoate and stirred 10 min. Thereafter, 47.3 ml of a 15% were added within 60 minutes Diethyl zinc solution in hexane and stirred at RT 12 h. After hydrolysis with 20 ml of water was a further 30 min touched, filtered off and 3x with washed 100 ml of ether. After extraction of the organic phase with water was concentrated with silica gel and the substance with dichloromethane / methanol 98: 2 at 20 ml / min Silica gel 70 chromatographed. Residue: 3 g of oil.

4- (1-ALLYLOXYCARBONYLAMINO-CYCLOPROPYL) -BENZOIC ACID TERT-BUTYL ESTER

3 g. 4- (1-Amino-cyclopropyl) -benzoic acid tert. butyl ester in 30 ml of dichloromethane and 1.8 ml of pyridine. The solution was at 0 ° C chilled and dropwise at 0-5 ° C with 1.2 ml allyl chloroformate (dissolved in 5 ml of dichloromethane) added. One left 30 min at 0 ° C and post-reacted at RT for 2 h. The solution was mixed with silica gel and to the residue concentrated. This was chromatographed over silica gel 70 with dichloromethane. Yield: 1.46 g of oil.

4- (1-allyloxycarbonylamino-cyclopropyl) -benzoic acid

A solution of 1.46 g of 4- (1-allyloxycarbonylamino-cyclopropyl) -benzoic acid tert-butyl ester in 10 ml of acetonitrile were mixed with 1 g of montmorillonite and 3 h heated to reflux. Thereafter, montmorillonite was again added and boiled for 4 h. The suspension was filtered hot, the inorganic material 3x with hot acetonitrile stirred and filtered, the acetonitrile solutions combined and concentrated. Residue: 0.8 g of crystals.

(1- {4- [HYDROXY- (2-OXO-BENZOFURAN-3-YLIDENE) -METHYL] -PHENYL} -CYCLOPROPYL) -CARBAMINIC ACID ALLYL ESTER

0.8 g 4- (1-Allyloxycarbonylamino-cyclopropyl) benzoic acid and 0.585 ml of triethylamine were dissolved in 10 ml of anhydrous DMF and washed with 1.16 g TBTU added, left to stir at RT for 15 min, then 0.4 g coumaranone and allowed to stir for a further 10 min. Under ice bath cooling were added in portions 0.42 g of NaH as (60% suspension in white oil), Stirred for 2 h at RT and after completion of the reaction with water to about 150 ml total volume diluted. They acidified with 2N acetic acid at. The crystals were filtered off with suction and washed with water. Yield: 1.1 g of solid of melting point 125-126 ° C.

(1- {4- [METHOXY- (2-OXO-BENZOFURAN-3-YLIDEN) -METHYL] -PHENYL} -CYCLOPROPYL) -CARBAMINIC ACID ALLYL ESTER

1 g (1- {4- [hydroxy- (2-oxo-benzofuran-3-ylidene) -methyl] -phenyl} -cyclopropyl) -carbamic acid allyl ester, 0.78 g of trimethyloxonium tetrafluoroborate (Meerwein salt) and 1 ml of diisopropyl-ethylamine (Hünig's base) were boiled under reflux in 20 ml of dichloromethane for 2 h, treated again with 1 ml of Hünig's base and 0.5 g of seaweed salt and heated under reflux for a further 2 hours. After cooling, it was extracted 3 × with water, the organic phase was dried over MgSO ₄ and concentrated to the residue. Yield: 1.05 g crude.

(1- {4 - [[4- (1-METHYL-1H-IMIDAZOLE-4-YL) -PHENYLAMINO] - (2-OXO-BENZOFURAN-3-YLIDENE) -METHYL] -PHENYL} -CYCLOPROPYL) -CARBAMINIC ACID ALLYL ESTER

1.05 g of (1- {4- [methoxy- (2-oxo-benzofuran-3-ylidene) -methyl] -phenyl} -cyclopropyl) -carbamic acid allyl ester and 0.47 g of 4- (4-amino-phenyl ) -1-methyl-imidazole in 3 ml of DMPU were reacted in the microwave reactor at 180 ° C. After cooling, the mixture was diluted to 150 ml with ethyl acetate, extracted 2 × with water, the organic phase was dried over MgSO ₄ and concentrated to the residue with silica gel. The material was chromatographed on silica gel 70 with dichloromethane / methanol 97: 3 at a flow rate of 30 ml / min. Residue: 0.6 g of yellow oil.

3 - {[4- (1-amino-cyclopropyl) -phenyl] - [4- (1-METHYL-1H-IMIDAZOL-4-YL) phenylamino] methylene} -3H-benzofuran-2-ON

0.58 g (1- {4 - [[4- (1-methyl-1H-imidazol-4-yl) -phenylamino] - (2-oxo-benzofuran-3-ylidene) -methyl] -phenyl} -cyclopropyl ) -carbamic acid allyl ester were dissolved in 20 ml of dichloromethane. With argon, the solution was freed of oxygen. Subsequently, 0.52 ml of diethylamine and 0.058 g of tetrakis-triphenylphosphine-palladium (0) were added at RT. The mixture was stirred at RT for 2 h, the suspension was concentrated with silica gel and chromatographed on silica gel 70 with dichloromethane / methanol 97: 3 at a flow rate of 30 ml / min. The clean fractions were combined, concentrated to dryness, dissolved in dichloromethane, filtered and treated with diisopropyl ether. The dichloromethane was distilled off, the resulting crystals were filtered off with suction and washed with diisopropyl ether. Yield: 0.26 g of yellow crystals of melting point 190-191 ° C as the base. R _f value: 0.51 (dichloromethane / methanol 9: 1).

Analog were produced:

EXAMPLE 36 3 - {(4-AMINOMETHYL-PHENYL) - [4- (1-METHYL-1H-IMIDAZOLE-4-YL) -PHENYLAMINO] -METHYLENE} -1-METHYL-1,3-DIHYDRO-INDOL-2 ON

Starting from 4-cyano-benzoic acid, the synthesis proceeded as in Example 40. Only the last stage differed as follows. 6.15 g of 3 - {(4-cyano-phenyl) - [4- (1-methyl-1H-imidazol-4-yl) -phenyl-amino] -methylene} -1-methyl-1,3-dihydro-indole 2-on were dissolved in 200 ml of methanolic ammonia and tetrahydrofuran and hydrogenated with 5 g of Raney nickel at RT and a pressure of 50 psi. After about 10 hours, the catalyst was filtered off with suction and the filtrate filtered again through a glass filter, concentrated and the crystalline residue was filtered off with diisopropyl ether. The crystals were suspended in 400 ml of methanol, adjusted to pH 1 with 10% strength ethanolic hydrochloric acid and heated to boiling temperature. It was filtered off, the filtrate was concentrated to about 100 ml residual volume and mixed with 300 ml of ethanol. After renewed concentration to about 100 ml residual volume, the substance crystallized out. After cooling, it was sloughed off and washed with ice-cold ethanol. Yield: 6.15 yellow crystals of melting point> 300 ° C. R _f = 0.32 (dichloromethane / methanol / ammonia 85: 15: 1).

Analog were produced:

EXAMPLE 14 4 - [[4- (1-METHYL-1H-IMIDAZOLE-4-YL) -PHENYLAMINO] - (2-OXO-1-PHENYL-1,2-DIHYDRO-INDOL-3-YLIDENE) -METHYL] - benzamidine

outgoing of 4-cyano-benzoic acid The synthesis proceeded analogously to Example 40. Only the last stage differed as follows. 0.6 g of 3 - {(4-cyano-phenyl) - [4- (1-methyl-1H-imidazol-4-yl) -phenyl-amino] -methylene} -1-phenyl-1,3-dihydro-indole 2-one were dissolved in 20 ml of dichloromethane and 30 ml of 40% ethanolic hydrochloric acid and in fridge Kept for 12 hours. The solution was until the residue concentrated, mixed with 50 ml of 6 N ethanolic ammonia solution and 3 h below backflow cooked. The solution was concentrated with silica gel and chromatographed with dichloromethane / methanol 8: 2 over Silica gel 70 (flow rate 20 ml / min) cleaned. The clean fractions were concentrated and the crystals were filtered with acetone and washed. Yield: 0.2 g of yellow crystals of melting point 241 ° C (dec.).

Analogous Example 25 was prepared (mp 230-232 ° C as hydrochloride), as well Example 38 (melting point> 275 ° C under Zers. as the hydrochloride).

EXAMPLE 56 1- [4- (4,4-DIMETHYL-4,5-DIHYDRO-OXAZOLE-2-YL) PHENYL] -1-METHYL-ETHYLAMINE

130 g of anhydrous cerium (III) chloride were suspended in 1 l of THF and stirred for 1 h, cooled to -60 ° C with good mechanical stirring and treated dropwise with 330 ml of a 1.5 M methyllithium solution in THF / cumene, the inside temperature did not exceed -50 ° C. The yellow suspension was stirred for 30 min and treated at -50 ° C with a solution of 34.4 g of 2- (4-cyanophenyl) -4,4-dimethyl-4,5-dihydro-oxazole in 50 ml of THF. After a further 12 h at -55 ° C was added dropwise 330 ml of conc. Ammonia solution added, whereby a violet precipitate precipitated. The mixture was allowed to warm to RT, filtered and the residue was washed with 1 l THF. The organic phase was concentrated. The yellow oily residue was purified by chromatography (dichloromethane / methanol 9: 1, silica gel 70, flow rate 50 ml / min). The clean fractions gave 33.3 g of yellow oil with the R _f value 0.20 (dichloromethane / methanol 7: 3).

{1- [4- (4,4-DIMETHYL-4,5-DIHYDRO-OXAZOLE-2-YL) -HENYL] -1-METHYL-ETHYL} -carbamic Acid TERT-BUTYL ESTER

To a solution of 0.8 g of 1- [4- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -phenyl] -1-methyl-ethylamine in 15 ml of dioxane was added a solution of 0.4 g of sodium carbonate in 4 ml of water. Subsequently, a solution of 0.83 g Boc anhydride in dioxane was added dropwise within 10 min. The yellow solution was stirred at RT for 12 h. The dioxane was distilled off and the aqueous residue extracted 2 × with ethyl acetate. The organic phases were combined, dried over MgSO ₄ , filtered and concentrated to dryness. After crystallization, 0.87 g of white-yellow product was obtained.

4- (1-tert-butoxycarbonylamino-1-methyl-ethyl) -benzoic acid

A solution of 0.83 g of {1- [4- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -phenyl] -1-methyl-ethyl} -carbamic acid tert-butyl ester and 3 , 1 ml of methyl iodide in 2 ml of DMF were stirred in a pressure tube for 12 h at 60 ° C and concentrated after cooling to the residue. The oil was stirred with 15 ml of 1 M NaOH for 3 h at RT. The suspension was shaken out with ether. The aqueous phase was acidified to pH 2 with 1 M HCl and the precipitate precipitated was taken up in ether. After again shaking the aqueous phase twice with ether, the organic phases were combined, dried over MgSO ₄ , filtered and the filtrate was concentrated to dryness. Yield: 0.4 g of crystals of R _f value 0.41 (dichloromethane / methanol 9: 1).

Analogous The synthesis of Example 40 described above was continued until the removal of the Boc protective group.

3 - {[4- (1-AMINO-1-METHYL-ETHYL) -PHENYL] - [4- (1-METHYL-1H-IMIDAZOL-4-YL) phenylamino] methylene} -3H-benzofuran-2- ON

2.5 g (1-Methyl-1- {4 - [[4- (1-methyl-1 H -imidazol-4-yl) -phenylamino] - (2-oxo-benzofuran-3-ylidene) -methyl] - tert-butyl phenyl} ethylcarbamates (N-Boc derivative of Example 56) were dissolved in 50 ml of dioxane and 50 ml of a 4N solution of hydrogen chloride in dioxane were added. The solution was stirred at RT for 1 h and concentrated. The residue was dissolved in 50 ml of methanol and concentrated with further 150 ml of isopropanol to almost the residue and crystallized. After dilution with acetone, the product was filtered off with suction and washed with acetone. Yield: 1.9 g of yellow crystals of melting point> 280 ° C as the hydrochloride. R _f value: 0.18 (dichloromethane / methanol 8: 2).

The The above-mentioned building blocks for synthesis are known in the literature, commercially available or were shown as follows:

MODULE 1

26.3 g of 2-bromo-phenylacetic acid were dissolved in 200 ml of dichloromethane and mixed with 15 ml of oxalyl chloride and one drop of DMF. After 1 h at RT, the solution was concentrated and the acid chloride used directly. The acid chloride was dissolved in 40 ml of dichloromethane and added dropwise to a solution of 9 g of cyclobutylamine and 27 ml of diisopropylethylamine in dichloromethane at 15-20 ° C. After 12 h at RT, the dichloromethane was distilled off, the residue was dissolved in 600 ml of ethyl acetate and extracted 2 × with 4 N HCl, 2 × with 4 N NaOH and 3 × with water. The organic phase was dried over MgSO ₄ , filtered and concentrated to the crystalline residue. After addition of diisopropyl ether was filtered off and gave 24.1 g of 2-bromo-phenylacetic acid cyclobutylamide of melting point 159-161 ° C. R _f value: 0.67 (dichloromethane / methanol 9: 1).

400 ml of toluene were degassed with argon and then 13.4 g of 2-bromo-phenylacetic acid cyclobutylamide, 9.7 g of powdered K ₂ CO ₃ , 0.9 g of tris (dibenzylideneacetone) dipalladium (0) and 1.2 g of tri-o- added tolylphosphine. After 72 hours of stirring at 100 ° C and cooling was diluted with diethyl ether to 2 liters, filtered from the insolubles and concentrated to the residue. After crystallization in diisopropyl ether was filtered off and the filtrate was concentrated with silica gel to residue. The purification was carried out by chromatography on silica gel 60 (mobile phase dichloromethane). Yield: 3.75 g of R _f oil: 0.18 (dichloromethane).

MODULE 2

100 g p-nitrophenacyl bromide and 400 ml of formamide were stirred for 2 h at 175 ° C. To cooling The mixture was made alkaline with 20 ml of ammonia, in 800 ml of water and the precipitate is sucked off. The crystals were in methanol recrystallized and filtered with suction. Yield: 46.5 g of the melting point 217-219 ° C.

45 g of 1H-4- (4-nitro-phenyl) -imidazole were placed in 300 ml of DMSO and under ice-cooling 30 g of potassium tert-butoxide added in portions. The mixture was heated to RT and stirred for 1 h. Subsequently 16.5 ml of methyl iodide were added dropwise between 20-25 ° C and a further 2 h stirred at RT. Subsequently was the mixture is poured onto 300 g of ice, stirred, the precipitate precipitated sucked off and thoroughly with Washed water. Yield: 39.8 g.

22 g of 1-methyl-4- (4-nitro-phenyl) -imidazole were dissolved in 1.6 L of methanol and used with 4 g of Pd / C (10%). The mixture was hydrogenated at 50 psi and RT for about 5 hours. Thereafter, another gram of catalyst was added and 18 hydrogenated, then with a further 2 g of catalyst addition for another 12 h. Finally, the catalyst was filtered off with suction and the filtrate was concentrated. The residue was taken up in toluene and a little methanol, a little concentrated until a dark gray precipitate formed. This was filtered off with suction, taken up in methanol, admixed with 4 g of activated charcoal and filtered off. The filtrate was mixed with 100 ml of toluene, evaporated and crystallized. Yield: 22 g of R _f value: 0.34 (dichloromethane / methanol 9: 1).

MODULE 3

100 g of 3-nitroaniline were dissolved in 400 ml of pyridine and 57 ml of methanesulfonyl chloride were added dropwise with gentle ice cooling. After 12 h at RT, the red reaction mixture was poured onto 1.2 l of ice, stirred, filtered with suction, the solid slurried with a lot of water, washed and dried. Yield: 148 g of solid of melting point 165-166 ° C. R _f value. 0.65 (dichloromethane / methanol 9: 1).

50 g of 3-methanesulfonylamino-nitrobenzene were initially charged in 200 ml of DMF, 31 g of potassium tert-butylate added and the reaction mixture stirred for 1 h at RT. After addition of 28.5 g of 2-chloro-N, N-dimethylacetamide, the mixture was stirred at 60 ° C for 12 h. After cooling to RT, water was added and extracted 5 × with ethyl acetate. The organic phases were washed with water, dried over MgSO ₄ , filtered and the filtrate was concentrated to dryness. The residue was crystallized from diisopropyl ether. Yield: 31.5 g.

31.5 g 2- (N-Methanesulfonyl-N- (3-nitrophenyl) -amino) -N, N-dimethylacetamide were mixed with 3 g of Pd / C at RT and 50 psi in ammoniacal methanol Hydrogenated for 24 h. Subsequently the catalyst was filtered off with warm suction and several times with ethyl acetate washed. The filtrate was concentrated to the residue. Yield: 20 g of solid of melting point 143144 ° C.

INDICATIONS

As was found, the compounds of formula 1 are characterized diverse applications in the therapeutic field. To emphasize are such applications, for which the Compounds of the invention of formula 1 due to its pharmaceutical activity as a PDE4 inhibitor can preferably be used. Mentioned by way of example his respiratory or gastrointestinal diseases or ailments, inflammatory Diseases of the joints, the skin or the eyes, cancers, as well as diseases of the peripheral or central nervous system.

in this connection Preference should be given to the prevention and treatment of respiratory tract or lung diseases, with increased mucus production, inflammation and / or obstructive respiratory diseases. exemplary therefor its called, acute, allergic or chronic bronchitis, chronic obstructive bronchitis (COPD), cough, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, farmers' disease, hyperreactive airways, infectious Bronchitis or pneumonitis, pediatric asthma, bronchiectasis, Pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial edema, pulmonary edema, bronchitis, Pneumonia or interstitial pneumonia triggered by various causes such as aspiration, inhalation of toxic gases or bronchitis, Pneumonia or interstitial pneumonia caused by heart failure, Radiation, chemotherapy cystic fibrosis or cystic fibrosis, alpha1-antitrypsin deficiency.

Also Preferably mentioned is the treatment of inflammatory diseases of the gastrointestinal tract. Exemplary for this its called, acute or chronic inflammatory changes in gallbladder inflammation, Morbus Crohn's, ulcerative colitis, inflammatory Pseudopolyps, juvenile polyps, colitis cystica profunda, pneumatosis cystoides intestinal, diseases of the bile ducts and gallbladder, e.g. gallstones and conglomerates, for the treatment of inflammatory diseases of the joints such as rheumatoid arthritis or inflammatory diseases of the skin and the eyes.

Also Preferably mentioned is the treatment of cancer. exemplary therefor its called all forms of acute and chronic leukemia like, Acute lymphocytic and acute myeloid leukemia, chronic lymphocytic and chronic myeloid leukemia, and bone tumors such as osteosarcoma and all kinds of Gliomas such as oligodendroglioma and glioblastoma.

Of Further preferred is the prevention and treatment of Diseases of the peripheral or central nervous system. Examples include depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as injuries of the Brain caused by stroke, hypoxia or craniocerebral trauma.

More particularly, the present invention relates to the use of compounds of formula 1 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory organs, including the lung, such as allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chro niche bronchitis and asthma.

At the most preferred is the use of the compounds of the formula 1 for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic Sinusitis, asthma, Crohn's disease, ulcerative colitis, in particular COPD, chronic bronchitis and asthma.

Also preferred is the use of the compounds of formula 1 for the treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic Depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as brain damage caused by stroke, hypoxia or traumatic brain injury.

One outstanding aspect of the present invention is the reduced Profile of side effects. This includes within the scope of the invention understood to administer a dose of a pharmaceutical composition to be able to without vomiting in the patient, preference is given to nausea, more preferably Cause discomfort. Maximum preferred is the administration of a therapeutically effective substance amounts, without Cause emesis or nausea, at every stage of the disease process.

COMBINATIONS

• • Betamimetika mit Corticosteroiden, PDE4-Inhibitoren, EGFR-Hemmern oder LTD4-Antagonisten,
• • Anticholinergika mit Betamimetika, Corticosteroiden, PDE4-Inhibitoren, EGFR-Hemmern oder LTD4-Antagonisten,
• • Corticosteroiden mit PDE4-Inhibitoren, EGFR-Hemmern oder LTD4-Antagonisten
• • PDE4-inhibitoren mit EGFR-Hemmern oder LTD4-Antagonisten
• • EGFR-Hemmern mit LTD4-Antagonisten.

The compounds of the formula 1 can be used alone or in combination with other active compounds of the formula 1 according to the invention. Optionally, the compounds of formula 1 can also be used in combination with other pharmacologically active ingredients. Preference is given here to those active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1-antihistamines, PAF antagonists and PI3- Kinase inhibitors or two or three combinations thereof, such as combinations of

• • betamimetics with corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
• Anticholinergics with betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
• • Corticosteroids with PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists
• • PDE4 inhibitors with EGFR inhibitors or LTD4 antagonists
• EGFR inhibitors with LTD4 antagonists.

Also the combinations of three drugs each one of the o.g. compound classes is part of the invention.

Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharines, isoprenalines, levosalbutamol, mabuterol, meluadrine , Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmeterol, Salmefamol, Soterenol, Sulphoneterol, Tiaramide, Terbutaline, Tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3- (4- {6- [ 2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) - 1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4 methoxybenzyl-amino} -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] eth anole, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino ] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4h-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl ] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one, 1- (4-amino 3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol, 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] - ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,1-dimethyl-ethylamino] - ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethyl-ethylamino] - ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} - 6-hydroxy-4H-benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl } -4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6- hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethoxy-phe nyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4- {2- [2-hydroxy- 2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] -2-methyl-propyl} -phenoxy) -butyric acid, 8- 2- [2- (3,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one and 1 - (4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

Prefers the betamimetics are selected from the group consisting of bambuterol, bitolterol, carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenaline, Ibuterol, Pirbuterol, Procaterol, Reproterol, Salmeterol, Sulphone terol, Terbutaline, Tolubuterol, 3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy} -butyl) -benzenesulfoneamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol . 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4-triazol-3- yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2- tert-butylamino) ethanol, 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4 ] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4 ] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on, 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) -ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3- on, 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on, 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethyl-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) ethylamino] -2 methyl-propyl} -phenoxy) -butyric acid, 8- {2- [2- (3,4-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H- benzo [1,4] oxazin-3-one and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, solvates or hydrates.

Especially preferred betamimetics are selected from the group consisting from fenoterol, formoterol, salmeterol, 3- (4- {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzenesulfoneamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, 1- [3- (4-methoxybenzyl-amino) 4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8- yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetate) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on, 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) -ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3- on, 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazine-3- on, 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on, 8- {2- [2- (4-ethyl-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) ethylamino] -2 methyl-propyl} -phenoxy) -butyric acid, 8- {2- [2- (3,4-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H- benzo [1,4] oxazin-3-one and 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- (3- (4-methoxyphenyl) -1,2,4-triazol-3- yl] -2-methyl-2-butylamino} ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates or hydrates.

Of these betamimetics, particularly preferred according to the invention are formoterol, salmeterol, 3- (4- {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy} -butyl) -benzenesulfoneamide, 6 hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxa zin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4] oxazin-3-one,
6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-on, 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethoxyphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) ethylamino] -2-methyl- propyl} phenoxy) butyric acid, 8- {2- [2- (3,4-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo 1,4] oxazin-3-one and 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, optionally in Form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

According to the invention preferred are the acid addition salts the betamimetics selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, Hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, Hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, Hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, Hydrofumarate and hydromethanesulfonate understood. From the above mentioned acid addition salts are the salts of hydrochloric acid, methanesulfonic acid, the benzoic acid and the acetic acid particularly according to the invention prefers.

When Anticholinergics are preferably compounds for Application that are selected from the group consisting of tiotropium salts, oxitropium salts, Flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts 2,2-diphenylpropionate-methobromide, 2-fluoro-2,2-diphenylacetic acid copopper ester methobromide, 2-fluoro-2,2-diphenylacetic acid tropol ester methobromide, 2,2-diphenylpropionic acid co-ester methobromide, 3,3 ', 4,4'-Tetrafluorbenzilsäuretropenolester methobromide, 3,3 ', 4,4'-Tetrafluorbenzilsäurescopinester methobromide, 4,4'-difluorobenzilate methobromide, 4,4'-Difluorobenzilic acid copoprene methobromide, 3,3'-difluorobenzilic acid-tropol ester methobromide, 3,3'-Difluorbenzilsäurescopinester methobromide, 9-hydroxy-fluorene-9-carbonsäuretropenolester methobromide, 9-fluoro-fluorene-9-carbonsäuretropenolester methobromide, 9-hydroxy-fluorene-9-carbonsäurescopinester methobromide, 9-fluoro-fluorene-9-carbonsäurescopinester Methobromide, 9-methyl-fluorene-9-carboxylic acid tropol ester, methobromide, 9-methyl-fluorene-9-carbonsäurescopinester Methobromide, benzylic acid cyclopropyltropine ester methobromide, 2,2-diphenylpropionic acid cyclopropyltropine ester methobromide, 9-hydroxy-xanthene-9-carbonsäurecyclopropyltropinesterMethobromid, 9-methyl-fluorene-9-carbonsäurecyclopropyltropinester methobromide, 9-methyl-xanthene-9-carbonsäurecyclopropyltropinester methobromide, 9-hydroxy-fluorene-9-carbonsäurecyclopropyltropinester methobromide, Methyl 4,4'-difluorobenzilate cyclopropyltropine ester methobromide, 9-hydroxy-xanthene-9-carboxylic acid tropol ester methobromide, 9-hydroxy-xanthene-9-carbonsäurescopinester Methobromide, 9-methyl-xanthene-9-carboxylic acid-tropol ester-methobromide, 9-methyl-xanthene-9-carboxylic acid-co-ester methobromide, 9-ethyl-xanthene-9-carbonsäuretropenolester Methobromide, 9-Difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide. 9-hydroxymethyl-xanthene-9-carbonsäurescopinester methobromide, optionally in the form of their solvates or hydrates.

In the cations mentioned above are tiotropium, Oxitropium, Flutropium, Ipratropium, Glycopyrronium and Trospium the pharmacologically active ingredients. As anions, the above mentioned salts preferably contain chloride, bromide, iodide, sulfate, Phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, Tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, wherein Chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate are preferred as counterions. Of all the salts are the chlorides, Bromides, iodide and methanesulfonate particularly preferred.

From Of particular importance is the tiotropium bromide. In the case of tiotropium bromide contain the drug combinations according to the invention this is preferably in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. Will the tiotropium bromide in the drug combinations according to the invention used in anhydrous form, so preferably the anhydrous crystalline tiotropium bromide for use, which is known from WO 03/000265 is known.

Preferred corticosteroids here are compounds selected from the group consisting of prednisolone, prednisone, butixocortepionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS -126,6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-and Rosta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester and 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) esters, optionally in the form of their racemates, enantiomers or diastereomers, and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Especially Preferably, the steroid is selected from the group consisting of flunisolide, beclomethasone, triamcinolone, Budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta-1,4 -diene-17-carbothionic acid (S) -fluoromethyl ester and 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothioic acid (S) - (2-oxo-tetrahydrofuran-3S-yl ) ester, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Especially Preferably, the steroid is selected from the group consisting of budesonide, fluticasone, mometasone, ciclesonide and 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or Hydrates.

each Reference to steroids concludes a reference to their possibly existing salts or Derivatives, hydrates or solvates. Examples of possible Salts and derivatives of steroids may be: alkali salts, such as For example, sodium or potassium salts, sulfobenzoates, phosphates, Isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, Pivalate or furoate.

When further PDE4 inhibitors preferably reach compounds here to the application selected are from the group consisting of enprofylline, theophylline, roflumilast, Ariflo (Cilomilast), Tofimilast, Pumafentrin, Lirimilast, Arofylline, Atizoram, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, N- (3,5-Dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, (-) p - [(4aR *, 10bS *) - 9-ethoxy- 1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methyl-benzo [s] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, (R) - (+) - 1- (4-Bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol], (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates.

Especially Preferably, the PDE4 inhibitor is selected from the group consisting from Enprofylline, Roflumilast, Ariflo (Cilomilast), Arofylline, Atizoram, AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, CI-1018, CDC-801, D-22888, YM-58997, Z-15370, N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, cis [4-cyano-4- (3 cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3 cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol], 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine, possibly in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

Especially Preferably, the PDE4 inhibitor is selected from the group consisting from roflumilast, ariflo (cilomilast), arofylline, AWD-12-281 (GW-842470), 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one, Cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol], Atizoram, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3 -a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

Under Acid addition salts with pharmacologically acceptable acids for their formation the o.g. PDE4 inhibitors optionally in the For example, salts are selected from the group consisting hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, Hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate Understood.

When LTD4 antagonists are preferably compounds for Application that are selected from the group consisting of Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321, 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2- hydroxy-2-propyl) phenyl) thio) methylcyclopropane-acetic acid, 1 - (((1 (R) -3 (3- (2- (2,3-dichloro-thieno [3,2-b] pyridine-5-) yl) - (E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid and [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Prefers the LTD4 antagonist is selected from the group consisting of Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable Acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Especially Preferably, the LTD4 antagonist is selected from the group consisting from Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001 and MEN-91507 (LM-1507) optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable Acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Under Acid addition salts with pharmacologically acceptable acids The LTD4 antagonists may be capable of forming them For example, salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, Hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate Understood. Among salts or derivatives for their formation the LTD4 antagonists where appropriate, are understood to mean, for example: Alkali salts, such as sodium or potassium salts, alkaline earth salts, Sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, Palmitate, pivalate or furoate.

Compounds which are preferably selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1] are preferably used as EGFR inhibitors. oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1- oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1- oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) - 1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6 -methyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholine] 4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-china zoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene 1-yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene] 1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N - (2-methoxyethyl) -N-ethyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl ) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclo propylmethoxy quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methylamino] -1-oxo-2 -but-1-yl} -amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2 -but-1-yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} -amino) -7-cyclopentyloxy-quinazoline, 4 - [( 3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methyl-amino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene] 1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxy) ethoxy ) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [( R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4 - [(3-chloro-4-fluorophenyl ) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4 - {[3-chloro-4 ( 3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline, 4 - [(R) - (1-phenyl ethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7- [ (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] 1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- [-2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl 6-oxo-morpholin-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) -methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxomorpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans 4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonyl-amino-cyclohexan-1-yloxy) 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4- fluorophenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [ (morpholin-4-yl) carbonyl] piperidin-4-yl-oxy} -7-methoxy-quinazoline, 4 - [(3-Ch Lor-4-fluoro-phenyl) amino] -6- {1 - [(methoxymethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidine 4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (tetrahydropyran-4-yloxy) -7- (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino ] -cyclohexan-1-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] - cyclohexan-1-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {trans-4 - [(morpholin-4-yl) sulfonylamino] -cyclohexane 1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- {1- [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [( tetrahydropyran-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis -4- {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- (cis-4- {N - [(morpholin-4-yl) sulfonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy ) -7- (2-methoxy-e thoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxyethoxy ) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl -phenyl) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4 yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N - [(piperidin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] - N -methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholine-4- yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidine-1] yl) ethyl] -piperidin-4-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7- (2-methoxyethoxy) quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6 - (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) - 7 (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] - 6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexane-1 yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl -phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- {1- [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1 - [(cis] 2,6-dimethyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 [(2-methyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(S, S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline, 4 - [(3 chloro-4-fluoro-phenyl) amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino ) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7- methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1 - [(2-methoxyethyl) carbonyl] piperidin-4-yloxy} -7-methoxy quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3 Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholine -4-yl) carbonyl] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholine] 4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl -piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline , Cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Preferred EGFR inhibitors are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene-1. yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-butene-1] yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1] yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene] 1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholine 4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- ((R) -6-methyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy ] -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo -2-buten-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-m ethyl 2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy -ethyl) -N-methylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- { [4- (N, N -dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-2-buten-1-yl} amino) - 7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo -2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-buten-1 -yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1 -yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) 1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- ( {4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} -amino) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro) 4-fluorophenyl) amino] -6 - {[4- (N -cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [( 3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydro-furan- 2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline , 4 - [(3-chloro 4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N , N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4 - {[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} - 6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- ((R) -6-methyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-methoxy-quinazoline, 4 - [(3-chloro-4 fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis- (2-methoxy-ethyl) -amino] -1-oxo-2-buten-1-yl } amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholine 4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-) dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-chinazo lin, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(R ) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorpholine-4 -yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4 - (2-oxomorpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1 - (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexane-1 -yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl ] -piperidin-4-yl-oxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- {1 - [(methoxymethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy ) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7- methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) -sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidine -1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy ) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl- amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl ) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) sulfonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy ) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxyethoxy) -quinazoline , 4 - [(3-Ch Lor-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N - [(piperidin-1-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) - 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] -N- methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidin-1-yl) ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidine 4-yloxy} -7- (2-methoxyethoxy) quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline , 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- ( 1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7 ( 2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (cis-4 -methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N -methyl-amino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-Ethynyl-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino ] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- {1 - [(2-methyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- {1 - [(S, S) - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) carbonyl] piperidin-4-yloxy} -7-methoxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-y loxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methylamino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- { N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- [2- (2,2-dimethyl-6-oxo-morpho lin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) -methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1 -methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy quinazoline, and cetuximab, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Particularly preferred for the purposes of the present invention are those EGFR inhibitors which are selected from the group consisting of 4 - ((3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl ) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (morpholine-4 -yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - (( R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] - quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene 1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl -amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- ( 2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} ami no) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline , 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4 - [(3 chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino } -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino } -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholine-4 -yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo 3-chloro-4-fluoro-phenyl) -amino] -6- cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4 fluorophenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- ( tetrahydropyran-3-ylo xy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7 -methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexane -1-yloxy} -7-methoxy-quinazoline,
4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidin-1-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7- methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxyethoxy) quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) -carbonyl ] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholine) 4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidine) 1-yl) ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [(3-ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-methyl -piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [ (3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline, 4 - [(3-ethynyl-phenyl) -amino ] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethylamino) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N -methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N- methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) 7-methoxy-quinazoline, 4 - [(3-chloro-4 fluorophenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methylamino) cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4- fluorophenyl) amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans -4- {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) -methoxy] -quinazoline, 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, and 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2- methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Particularly preferred according to the invention as EGFR inhibitor are those compounds which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1- oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl -2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) 7-cyclopropylmethoxy quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3 Ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-methansulfonyla mino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 Ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methyl-piperidine-4 -yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl -phenyl) -amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis -4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis- 4- (N-acetyl-N-methyl-amino) -cy clohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-me thoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro -4-fluoro-phenyl) amino] -6- (trans-4- {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline and 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of theirs pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Under Acid addition salts with pharmacologically acceptable acids to whose formation the EGFR inhibitors may be able to For example, salts selected from the group consisting hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, Hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate Understood.

When Dopamine agonists in this case prefer connections to Application that selected are from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, Lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and Viozan. A reference to the aforementioned dopamine agonists includes in the context of the present invention, a reference to their optionally existing pharmacologically acceptable acid addition salts and optionally their hydrates. Among the physiologically acceptable acid addition salts available from the aforementioned dopamine agonists can be formed For example, pharmaceutically acceptable salts understood, the selected from the salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic are.

When H1-antihistamines are preferably compounds for Application that are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, Levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, Clemastine, Bamipin, Cexchlorpheniramine, Pheniramine, Doxylamine, Chlorphenoxamine, Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and Meclozin. A reference to the aforementioned H1 antihistamines includes in the context of the present invention, a reference to their optionally existing pharmacologically acceptable acid addition salts.

When PAF antagonists preferably reach compounds here Application that are selected from the group consisting of 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl] -6H-thieno [3,2-f] - [1 , 2,4] triazolo [4,3-a] [1,4] diazepine, 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl] -4H , 7H-cyclo-penta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine.

PRESENTATIONS

suitable Examples of applications are tablets, capsules, solutions, Juices, Emulsions or inhalable powders or aerosols. Here is the Proportion of pharmaceutically active compound (s) in each case in the range from 0.1 to 90% by weight, preferably from 0 to 5 to 50% by weight of the total composition lie, i. in amounts sufficient to the below indicated Reach dosage range.

The Oral administration may take the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension. In the case of an inhalative administration, the active ingredient combination may be used as Powder, as aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.

Prefers Therefore, pharmaceutical formulations are characterized by the content of one or more compounds of the formula 1 according to the above preferred embodiments.

It is particularly preferred if the compounds of the formula 1 are administered orally, it is particularly preferred if the administration takes place once or twice daily. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or depot effecting agents such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Corresponding can Dragees by coating of cores produced analogously to the tablets with usually used in dragee coatings Agents, such as Kollidon or shellac, gum arabic, Talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities the core also consist of several layers. Likewise also the dragee cover To obtain a depot effect consist of several layers using the excipients mentioned above for the tablets can be.

Juices of active ingredients according to the invention or combinations of active substances may additionally contain a sweetener, like saccharin, cyclamate, glycerine or sugar as well as a taste improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. You can Furthermore Suspending adjuvants or thickening agents, such as sodium carboxymethylcellulose, Wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents such as p-hydroxybenzoates.

The one or more active substances or combinations of active substances containing capsules For example, be prepared by using the active ingredients inert carriers, like lactose or sorbitol, mixed and encapsulated in gelatine capsules. Suitable suppositories can be, for example, by mixing with designated Carriers, such as neutral fats or polyethylene glycol or its derivatives.

When Excipients are, for example, water, pharmaceutically acceptable organic solvents, such as Paraffins (e.g., petroleum fractions), vegetable oils Origin (e.g., peanut or Sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerine), excipients such as. natural Minerals (e.g., kaolins, clays, talc, chalk) synthetic Minerals (e.g., fumed silica and silicates), sugars (e.g. Pipe, milk and dextrose) Emulsifying agents (for example lignin, Methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, Talc, stearic acid and sodium lauryl sulfate).

in the Case of oral use can the tablets of course except the said carriers also additives, such as. Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants, such as magnesium stearate, Sodium lauryl sulfate and talc are used for tableting. In the case of aqueous Suspensions can the active ingredients except the above-mentioned excipients with different flavor enhancers or dyes are added.

Also it is preferred if the compounds of the formula 1 are administered by inhalation be particularly preferred when the administration of a or twice daily he follows. To do this the compounds of formula 1 in inhalable dosage forms to be provided. Come as inhalable dosage forms Inhalation powder, propellant-containing MDIs or propellant-free inhalation solutions into consideration, if appropriate in admixture with customary physiologically compatible Excipients are present.

in the The scope of the present invention is propellant-free from the term inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The administration forms which can be used in the context of the present invention are described in detail in the following part of the description.

Inhalation Powder: Are the compounds of formula 1 in a mixture with physiological Contain safe excipients, can be used to prepare the inhalable powders of the invention the following physiologically acceptable excipients are used Monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, sucrose, maltose), oligo- and polysaccharides (e.g. Dextrans), polyalcohols (e.g., sorbitol, mannitol, xylitol), salts (e.g. Sodium chloride, calcium carbonate) or mixtures of these excipients together. Preferably mono- or disaccharides are used, the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. As particularly preferred in According to the invention lactose, most preferably lactose monohydrate as an excipient for use. Process for the preparation of the inhalable powders according to the invention by grinding and micronizing and by final mixing the ingredients are known in the art.

Propellant-Containing Inhalation Aerosols: Those within the scope of the use according to the invention usable propellant - containing inhalation aerosols can be 1 im Propellant dissolved or in dispersed form. The for the production of inhalation aerosols usable propellant gases are known from the prior art. suitable Propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons as preferably fluorinated Derivatives of methane, ethane, propane, butane, cyclopropane or Cyclobutane. The above-mentioned propellant gases can thereby used alone or in mixtures thereof. Especially preferred propellants are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,2,2,3,3-heptafluoropropane) and Mixtures thereof. The within the scope of the inventive use usable propellant-containing inhalation aerosols may further other ingredients such as co-solvents, stabilizers, surface-active Agents (surfactants), antioxidants, lubricants and agents to adjust the pH. All these ingredients are known in the art.

Propellant-free Inhalation solutions: The use according to the invention of compounds of formula 1 is preferably carried out for the preparation of propellant-free inhalation solutions and inhalation suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions into consideration. The solvent can only Be it water or it is a mixture of water and ethanol. The solutions or suspensions are treated with appropriate acids to a pH of 2 to 7, preferably set from 2 to 5. To set this pH can acids selected find use of inorganic or organic acids. Examples for special suitable inorganic acids are hydrochloric acid, hydrobromic, Nitric acid, sulfuric acid and / or phosphoric acid. examples for particularly suitable organic acids are: ascorbic acid, Citric, malic, tartaric, maleic, succinic, fumaric, acetic, formic and / or propionic and other. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It can also the acids Already used with one of the active ingredients an acid addition salt form. Among the organic acids are ascorbic acid, fumaric acid and citric acid prefers. If necessary, you can also mixtures of the acids mentioned be used, in particular in cases of acids, in addition to their Säuerungseigenschaften also other properties, e.g. as flavorings, antioxidants or complexing agents, such as citric acid or Ascorbic acid. Particularly according to the invention hydrochloric acid is preferred used to adjust the pH.

The in the context of the use according to the invention usable propellant-free inhalable solutions can co-solvents and / or additional auxiliaries are added. Preferred co-solvents are those containing hydroxyl groups or other polar groups, for example, alcohols - in particular Isopropyl alcohol, glycols - in particular Propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, Glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.

Under Additives and additives in this context, everyone pharmacologically compatible substance understood that is not an active substance, but together with the (the) Active substance (s) in the pharmacologically suitable solvent can be formulated to increase the qualitative properties of the drug formulation improve. Preferably, these substances do not develop or in context with the desired therapy no significant or at least no unwanted pharmacological effect. The auxiliaries and additives include e.g. surfactants Fabrics, such as e.g. Soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, Antioxidants and / or preservatives, the duration of use ensure or extend the finished drug formulation, flavors, Vitamins and / or other additives known in the art. Additives include also pharmacologically acceptable salts such as sodium chloride as isotonic agents. Preferred excipients include antioxidants, such as ascorbic acid, if not already for the pH adjustment uses vitamin A, vitamin E, tocopherols and similar in the human organism occurring vitamins or provitamins. Preservatives can Be used to the formulation against contamination with germs to protect. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or Benzoates such as sodium benzoate in the well-known in the art Concentration.

For the above Treatments described become ready-to-use packs of a medicament for the treatment of respiratory diseases, including an enclosed description, which, for example, the words respiratory disease, Contain COPD or asthma, a pteridine and one or more combination partners selected from the group described above.

Claims (19)

Compounds of the formula 1,

wherein A is CO, C = NH, C _1-6 -alkylene or C _3-8 -cycloalkylene; B ^{1 is} phenyl or a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; B ^{2 is} phenyl or a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; X is O, S, NR ⁵ or CR ⁶ R ⁷ ; n is 0, 1, 2 or 3; R ^{1 is} H, C _1-6 alkyl, C _1-6 haloalkyl, COR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 ; R ^{1.1 is} C _1-6 alkyl; R ^{2 is} H, C _1-6 alkyl or C _1-6 haloalkyl; or R ¹ and R ² together with the nitrogen form a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen; or R ¹ is C _1-3 -alkylene which is simultaneously a substituent of B ¹ , resulting in a total of a bicyclic hetero ring of B ¹ and A-NR ¹ R ² is formed, wherein A is the meaning of CO, C = NH or C _{1- 3-} alkylene may have; R ^{3 is} H, OH, C _3-8 cycloalkyl, C _1-6 -alkyl, C _1-6 -haloalkyl, aryl, a heterocyclic aromatic ring of the one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-6 alkyl, C _3-8 cycloalkyl and C _1-6 haloalkyl; a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with one or more radicals selected from the group consisting of aryl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl , CONH ₂ , CONH-C _1-6 -alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, COAryl, OH, OC _1-6 -alkyl, OC _1-6 -haloalkyl, halogen, SH, SC _1-6 -alkyl, SC _1-6 -haloalkyl, SO ₂ -C _1-6 -alkyl, SO ₂ -C _1-6 - Haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6 -alkyl, SO ₂ -N (C _1-6 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-6 -alkyl and N (C _1-6 alkyl) ₂ ; a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with C _1-6 -alkyl, optionally substituted by a radical selected from the group consisting of COOR ^3.3 , NR ^3.3 R ^3.4 , NHCOR ^3.3 , NHCOOR ^3.3 , Phenyl, optionally substituted by a radical selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, C _1-6 haloalkyl, CONH ₂ , CONH-C _{1 -6-} alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, OH, OC _1-6 -alkyl, OC _{1- 6} -haloalkyl, halogen, SH, SC _1-6 -alkyl, SC _1-6 -haloalkyl, SO ₂ -C _1-6 -alkyl, SO ₂ -C _1-6 -haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6 -alkyl, SO ₂ -N (C _1-6 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-6 -alkyl and N (C _1-6 -alkyl) ₂ , and a heterocyclic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and is optionally substituted with an oxo group; R ^3.3 is H or C _1-6 alkyl; R ^{3.4 is} H, C _1-6 alkyl or C _7-11 aralkyl; a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with NR ^3.1 R ^3.2 ; R ^{3.1 is} H, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _1-6 -haloalkyl, COR ^3.1.1 , COOR ^3.1.1 , CONR ^3.1.1 R ^3.1.2 or SO ₂ -R ^{3.1. 1} ; R ^{3.1.1 is} H, C _1-6 -alkyl, C _1-6 -haloalkyl, C _3-6 -cycloalkyl or aryl; R ^{3.1.2 is} H, C _1-6 -alkyl, C _1-6 -haloalkyl, C _3-6 -cycloalkyl or aryl; R ^{3.2 is} H or a radical selected from the group consisting of C _1-6 -alkyl, C _3-6 -cycloalkyl and C _1-6 -haloalkyl, optionally substituted by one or more NH ₂ , NH (C _1-6 -alkyl ), N (C _1-6 alkyl) ₂ , oxo or a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and is optionally substituted with C _1-4 alkyl; a radical selected from a group consisting of aryl and a heterocyclic aromatic ring substituted with a heterocyclic ring optionally substituted with one or more radicals selected from the group consisting of aryl, C _1-6 alkyl, C _3-6 cycloalkyl , CN, C _1-6 haloalkyl, CONH ₂ , CONH-C _1-6 -alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, oxo, OH, OC _1-6 Alkyl, halogen, SH, SC _1-6 alkyl, NH ₂ , NH-C _1-6 alkyl and N (C _1-6 alkyl) ₂ ; Benzimidazolyl optionally substituted with one selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl; R ^{4 is} C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, OR ^4.1 , NR ^4.1 R ^4.2 , CN or halo; R ^{4.1 is} H, C _1-6 -alkyl, C _3-8 -cycloalkyl or C _1-6 -haloalkyl; R ^{4.2 is} H, C _1-6 -alkyl, C _3-8 -cycloalkyl or C _1-6 -haloalkyl; R ^{5 is} C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, COR ^5.1 , CONHR ^5.1 , CON (R ^5.1 ) ₂ , SO ₂ C _1-6 alkyl, SO ₂ -C _{1 -6-} haloalkyl, SO ₂ -aryl or a radical selected from the group consisting of R ^5.2 , SO ₂ -C _1-6 -alkyl-R ^5.2 and C _1-6 -alkyl-R ^5.2 , optionally substituted by C _{1 6-} alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, CN, C _1-6 -haloalkyl, CONH ₂ , CONH-C _1-6 -alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, OC _3-6 -cycloalkyl, OC _1-6 -haloalkyl, OC _1-6 -alkyl, halogen, SO ₂ -C _{1 -6-} alkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6 -alkyl, SO ₂ -N (C _1-6 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-6 - Alkyl and N (C _1-6 alkyl) ₂ ; R ^{5.1 is} C _1-6 alkyl or C _7-11 aralkyl; R ^5.2 aryl or a heterocyclic aromatic ring; R ^{6 is} H, C _1-6 -alkyl or C _1-6 -haloalkyl; R ^{7 is} H, C _1-6 alkyl or C _1-6 haloalkyl; or R ⁶ and R ⁷ together form a 3-6 membered carbocycle; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds of formula 1 according to claim 1, wherein A is CO, C = NH, C _1-4 -alkylene or C _3-6 -cycloalkylene; B ^{1 is} phenyl or a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; B ^{2 is} phenyl or pyridinyl; X is O, S, NR ⁵ or CR ⁶ R ^7; n is 0, 1, 2 or 3; R ^{1 is} H, C _1-4 alkyl, C _1-4 haloalkyl; R ^{2 is} H, C _1-4 alkyl or C _1-4 haloalkyl; or R ¹ and R ² together with the nitrogen form a heterocyclic non-aromatic ring which may contain one or two nitrogen atoms; R ^{3 is} H, OH, C _3-6 -cycloalkyl, C _1-6 -alkyl, C _1-6 -haloalkyl, aryl, a heterocyclic aromatic ring which may contain one, two or three nitrogen atoms and is optionally substituted by a methyl group ; Phenyl substituted with one or more radicals selected from the group consisting of aryl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CONH ₂ , CONH C _1-6 alkyl, CON (C _1-6 -alkyl) ₂ , COOH, COO-C _1-6 -alkyl, COH, CO-C _1-6 -alkyl, COAryl, OH, OC _1-6 -alkyl, OC _1-4 -haloalkyl, Halogen, SH, SC _1-6 -alkyl, SC _1-4 -haloalkyl, SO ₂ -C _1-6 -alkyl, SO ₂ -C _1-4 -haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-6 alkyl, SO ₂ -N (C _1-6 alkyl) ₂ , NO ₂ , NO ₂ , NH ₂ , NH-C _1-6 alkyl and N (C _1-6 alkyl) ₂ ; Phenyl substituted with C _1-4 alkyl optionally substituted with a radical selected from the group consisting of COOR ^3.3 , NR ^3.3 R ^3.4 , NHCOR ^3.4 , NHCOOR ^3.3 and phenyl optionally substituted with one or more radicals selected from the group consisting of methyl, t-butyl, F, Cl, Br, CN and OH, and a heterocyclic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen and is optionally substituted with an oxo group; R ^3.3 is H or C _1-4 alkyl; R ^{3.4 is} H, C _1-4 alkyl or C _7-11 aralkyl; Phenyl substituted with NR ^3.1 R ^3.2 ; R ^{3.1 is} H, C _1-4 alkyl, C _1-4 haloalkyl, COR ^3.1.1 , COOR ^3.1.1 , CONR ^3.1.1 R ^3.1.2 or SO ₂ -R ^3.1.1 ; R ^{3.1.1 is} H, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl or aryl; R ^{3.1.2 is} H, C _1-4 -alkyl, C _1-4 -haloalkyl, C _3-6 -cycloalkyl or aryl; R ^{3.2 is} H, C _1-4 alkyl optionally substituted with one or more NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , oxo or a heterocyclic non-aromatic ring or may contain two nitrogen atoms and is optionally substituted with a methyl group; Aryl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of aryl, C _1-4 alkyl , C _3-6 -cycloalkyl, CN, C _1-4 -haloalkyl, CONH ₂ , CONH-C _1-4 -alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 alkyl, OH, OC _1-4 alkyl, halogen, SH, SC _1-4 alkyl, NH ₂ , NH-C _1-4 alkyl and N (C _1-4 alkyl ₂ ; Aryl substituted with a heterocyclic, non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 -alkyl and oxo; Benzimidazolyl optionally substituted with one selected from the group consisting of C _1-4 alkyl, C _1-4 haloalkyl and C _3-6 cycloalkyl; R ^{4 is} C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, OR ^4.1 , NR ^4.1 R ^4.2 , CN or halo; R ^{4.1 is} H, C _1-4 -alkyl, C _3-6 -cycloalkyl or C _1-4 -haloalkyl; R ^{4.2 is} H, C _1-4 -alkyl, C _3-6 -cycloalkyl or C _1-4 -haloalkyl; R ^{5 is} C _1-4 -alkyl, C _3-8 -cycloalkyl, C _1-4 -haloalkyl, COR ^5.1 , CONHR ^5.1 , CON (R ^5.1 ) ₂ , SO ₂ C _1-4 -alkyl, SO ₂ -C _1-4 -haloalkyl, SO ₂ -aryl or a radical selected from the group consisting of R ^5.2 , SO ₂ -C _1-4 -alkyl-R ^5.2 and C _1-4 -alkyl-R ^5.2 , optionally substituted by C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, CN, C _1-4 haloalkyl, CONH ₂ , CONH C _1-4 alkyl, CON (C _1-4 alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 -alkyl, OC _1-4 -cycloalkyl, OC _1-4 -haloalkyl, OC _1-4 -alkyl, halogen, SO ₂ -C _1-4 -alkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-4 Alkyl and N (C _1-4 alkyl) ₂ ; R ^{5.1 is} C _1-4 alkyl or C _7-11 aralkyl; R ^5.2 aryl or a heterocyclic aromatic ring; R ^{6 is} H, C _1-4 alkyl or C _1-4 haloalkyl; R ^{7 is} H, C _1-4 alkyl or C _1-4 haloalkyl; or R ⁶ and R ⁷ together form a 3-6 membered carbocycle; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds of formula 1 according to any one of claims 1 or 2, wherein A is CO, C = NH, C _1-4 alkylene or C _3-6 cycloalkylene; B ^{1 is} phenyl or pyridinyl; B ^{2 is} phenyl or pyridinyl; X is O or NR ⁵ ; n is 0, 1, 2 or 3; R ^{1 is} H, methyl, ethyl, propyl; R ^{2 is} H, methyl, ethyl, propyl; R ^{3 is} H, OH, C _3-6 -cycloalkyl, C _1-6 -alkyl, C _1-6 -haloalkyl, aryl, a heterocyclic aromatic ring which may contain one, two or three nitrogen atoms and is optionally substituted by a methyl group ; Phenyl substituted with one or more radicals selected from the group consisting of aryl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CONH ₂ , CONH C _1-4 alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl, COH, CO-C _1-4 -alkyl, COAryl, OH, OC _1-4 -alkyl, OC _1-4 -haloalkyl, Halogen, SH, SC _1-4 alkyl, SC _1-4 haloalkyl, SO ₂ -C _1-4 alkyl, SO ₂ -C _1-4 haloalkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NO ₂ , NH ₂ , NH-C _1-4 -alkyl and N (C _1-4 -alkyl) ₂ ; Phenyl substituted with C _1-4 alkyl optionally substituted with a radical selected from the group consisting of COOR ^3.3 , NR ^3.3 R ^3.4 , NHCOR ^3.3 , NHCOOR ^3.3 , p-fluorophenyl and a heterocyclic ring of the one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with an oxo group; R ^3.3 is H or C _1-4 alkyl; R ^{3.4 is} H, C _1-4 alkyl or C _7-11 aralkyl; Phenyl substituted with NR ^3.1 R ^3.2 ; R ^{3.1 is} H, C _1-4 alkyl, COR ^3.1.1 , COOR ^3.1.1 , CONR ^3.1.1 R ^3.1.2 or SO ₂ -R ^3.1.1 ; R ^{3.1.1 is} H, C _1-4 alkyl or aryl; R ^3.1.2 H, C _1-4 alkyl or aryl; R ^{3.2 is} H, C _1-4 alkyl optionally substituted with one or more NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , oxo or a heterocyclic non-aromatic ring or may contain two nitrogen atoms and is optionally substituted with a methyl group; Phenyl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of aryl, C _1-4 alkyl , C _1-4 -haloalkyl, C _3-6 -cycloalkyl, CN, CONH ₂ , CONH-C _1-4 -alkyl, CON (C _1-4 -alkyl) ₂ , COOH, COO-C _1-4 -alkyl , COH, CO-C _1-4 alkyl, OH, OC _1-4 alkyl, halogen, NH ₂ and N (C _1-4 alkyl) ₂ ; Phenyl substituted with a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo; Benzimidazolyl optionally substituted with a radical selected from the group consisting of methyl, ethyl, propyl, CF ₃ , CH ₂ CF ₃ , cyclopropyl, cyclopentyl and cyclohexyl; R ^{4 is} C _1-4 alkyl, C _1-4 haloalkyl or halo; R ^{5 is} C _1-4 alkyl, C _3-6 cycloalkyl, COR ^5.1 , CONHR ^5.1 , aryl, SO ₂ C _7-11 aralkyl, SO ₂ aryl or C _7-11 aralkyl appropriate, substituted with C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, CN, C _1-4 haloalkyl, CONH _2, CONH-C _1-4 -alkyl, CON (C _{1- 4} alkyl) ₂ , COOH, COO-C _1-4 alkyl, COH, CO-C _1-4 alkyl, OH, OC _1-4 alkyl, halo, SO ₂ C _1-4 alkyl, SO ₂ -NH ₂ , SO ₂ -NH-C _1-4 -alkyl, SO ₂ -N (C _1-4 -alkyl) ₂ , NO ₂ , NH ₂ , NH-C _1-4 -alkyl and N (C _{1 -4-} alkyl) ₂ ; R ^{5.1 is} C _1-4 alkyl or C _7-11 aralkyl; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds of the formula 1a,

wherein A, X, n, R ¹ , R ² , R ³ and R ⁴ are as defined in claims 1 to 3 and B ^{1 is} phenyl; and B ^{2 is} phenyl; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds of formula 1 or 1a according to one of claims 1 to 4 wherein X O; means, as well as pharmacologically effective Salts, racemates or isomers, in pure and mixed form thereof. Compounds of formula 1 or 1a according to any one of claims 1 to 4 wherein X is NR ⁵ ; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds of formula 1 or 1a according to any one of claims 1 to 4 wherein X is CR ⁶ R ⁷ ; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds of formula 1 or 1a according to one of claims 1 to 4 wherein A is CH _2, CHMe, CMe _2, C = NH, 1,1'-cyclopropylene, 1,1-cyclobutylidene; B ¹ phenyl; B ² phenyl; X is O or NR ⁵ ; n is 0, 1 or 2; R ^{1 is} H, methyl or ethyl; R ^{2 is} H, methyl or ethyl; R ^{3 is} H, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl, or phenyl substituted with a radical selected from the group consisting of phenyl, methyl, ethyl, propyl, butyl, CF ₃ , CONH ₂ , CONHMe, CONMe _2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SH, SO ₂ Me, SONH _2, sonme _2, NO _2, NH _2, NHMe and NMe _2; Phenyl substituted by a radical selected from the group consisting of methyl and ethyl, optionally substituted by a radical selected from the group consisting of COOH, COOMe, NH ₂ , NMe ₂ , NHCOMe, NHCOO tert -butyl, NMe (benzyl), p-fluorophenyl, pyrolidinyl, piperidinyl, morpholinyl, pyrolidinyl-2-nyl, imidazolyl and triazolyl; Phenyl substituted with NR ^3.1 R ^3.2 ; R ^{3.1 is} H, methyl, COH, COMe, COOMe, CONH ₂ , CONMe ₂ , SO ₂ Me, SO ₂ CF ₃ , SO ₂ -phenyl; R ^{3.2 is} H, methyl, ethyl, optionally substituted with a radical selected from the group consisting of one or more NH ₂ , NHMe, NMe ₂ , N-piperidinyl, N-morpholinyl and N-methyl-piperazinyl, and optionally substituted with another oxo ; Phenyl substituted with a heterocyclic aromatic ring of one, two or three heteroatoms, from selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF ₃ , CN, CONH ₂ , CONMe ₂ , CONEt ₂ , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, NH ₂ , NMe ₂ , NEt ₂ and NPr ₂ ; Phenyl substituted with a heterocyclic non-aromatic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo; Benzimidazolyl optionally substituted with a radical selected from the group consisting of methyl, propyl, CF ₃ , CH ₂ CF ₃ , cyclopropyl and cyclohexyl; R ^{4 is} methyl, ethyl, propyl, butyl, CF ₃ , CH ₂ CF ₃ , F, Cl, or Br; R ^{5 is} methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF ₃ , CH ₂ CF ₃ , COR ^5.1 , CONHR ^5.1 , phenyl, phenylsulfonyl, benzyl, optionally substituted with methyl, ethyl, propyl, butyl, CF ₃ , CN, CONH ₂ , CONME ₂ , CONEt ₂ , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO ₂ Me, SONH ₂ , SONMe ₂ , NO ₂ , NH ₂ , NMe ₂ , NEt ₂ and NPr ₂ ; R ^5.1 methyl, ethyl, propyl, butyl, benzyl; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds of formula 1 or 1a according to any one of claims 1 to 4 or 8, wherein A is CH ₂ , CHMe, CMe ₂ , 1,1'-cyclopropylene, 1,1'-cyclobutylidene; B ¹ phenyl; B ² phenyl; X is O or NR ⁵ ; n is 0 or 1; R ¹ H; R ² H; R ^{3 is} H or phenyl substituted with NR ^3.1 R ^3.2 ; R ^{3.1 is} H, methyl, SO ₂ Me, SO ₂ CF ₃ , SO ₂ -phenyl; R ^{3.2 is} H, methyl, ethyl, optionally substituted with one or more NH ₂ , NHMe, NMe ₂ , oxo, N-piperidinyl, N-morpholinyl, N-methyl-piperazinyl; Phenyl substituted with a heterocyclic aromatic ring which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, Butyl, cyclopropyl, cyclobutyl, CF ₃ , CN, CONH ₂ , CONMe ₂ , CONEt ₂ , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO ₂ Me, SONH ₂ , SONMe ₂ , NO ₂ , NH ₂ , NMe ₂ , NEt ₂ and NPr ₂ , and; Phenyl substituted with a heterocyclic non-aromatic ring containing one or two heteroatoms selected from the group consisting of oxygen and nitrogen and optionally substituted with one or more radicals selected from the group consisting of C _1-4 alkyl and oxo. R ^{4 is} H, F or Cl; R ^{5 is} methyl, ethyl, cyclopropyl, cyclobutyl CH ₂ CF ₃ or benzyl, optionally substituted with F; means, and pharmacologically active salts, racemates or isomers, in pure and mixed, form thereof. Compounds according to one of claims 1 to 9 as a medicine. Use of compounds according to one of claims 1 to 10, for the manufacture of a medicament for the treatment of diseases, which can be treated by inhibition of the PDE4 enzyme. Use of compounds according to one of claims 1 to 9 for the manufacture of a medicament for the treatment of respiratory tract or gastrointestinal discomfort or disease, as well inflammatory Diseases of the joints, the skin or the eyes, cancers, as well as diseases of the peripheral or central nervous system. Use of compounds according to one of claims 1 to 9 for the preparation of a medicament for prevention and treatment respiratory or lung diseases associated with increased mucus production, inflammation and / or obstructive respiratory diseases. Use of compounds according to any one of claims 1 to 9 and 13 for the manufacture of a medicament for the treatment of inflammatory and obstructive diseases such as COPD, chronic sinusitis, Asthma, Crohn's disease, ulcerative colitis. Use of compounds according to one of claims 1 to 9 for the manufacture of a medicament for the treatment of inflammatory Diseases of the gastrointestinal tract. Use of compounds according to one of claims 1 to 9 for the preparation of a medicament for prevention and treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic Depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as injuries of the Brain caused by stroke, hypoxia or craniocerebral trauma. Pharmaceutical formulations characterized by the content of one or more compounds of formula 1 or 1a according to one of the claims 1 to 9. Inhalable pharmaceutical formulation, characterized by a content of a compound of formula 1 or 1a according to one claims 1 to 9. Drug combinations, in addition to one or a plurality of compounds of the formula 1 or 1a according to one of claims 1 to 9 contain as further active ingredient one or more compounds, the selected are from the classes of betamimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 kinase inhibitors or two or three combinations thereof.