DE10006453A1 - New piperidylcarboxylic acid derivatives, are integrin antagonists useful for treating inflammatory, autoimmune or immunological diseases, e.g. atherosclerosis, asthma, diabetes, rheumatoid arthritis or transplant rejection - Google Patents

Abstract

The present invention relates to compounds of the general formula (I), processes for their preparation, pharmaceutical compositions containing them as well as their use for the production of pharmaceutical compositions for the treatment of inflammatory diseases.

Description

The present invention relates to compounds of the formula (I)

their preparation and use as a pharmaceutical composition as integrin antagonists, especially as α ₄ β ₁ - and / or α ₄ β ₇ - and / or α ₉ β ₁ integrin antagonists, and in particular for the production of pharmaceutical compositions for inhibition or Prevention of cell adhesion and diseases mediated by cell adhesion are suitable. Examples include the treatment and prophylaxis of atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, graft rejection or other inflammatory, autoimmune or immune diseases.

Adhesive interactions between the leukocytes and the endothelial cells play a crucial role in the transport of leukocytes to inflammation location. These operations are essential in the normal defense of the Hosts against pathogens and in the recovery of damaged tissue, they however, can also lead to pathological findings in various inflammatory and contribute to autoimmune diseases. So is the intrusion of eosinophils Cells and T cells in the tissues are a well-known major characteristic of allergic Inflammation such as asthma.

The interaction of circulating leukocytes with adhesion molecules leukocyte transmigration appears to the luminal surface of blood vessels modulate. These vascular cell adhesion molecules keep circulating leuko zytes and thus serve as the first step in their recruitment to the location of the  infected or inflamed tissue. Then go the leukocytes that the Reach extravascular space with connective tissue cells like fibroblasts as well with extracellular matrix proteins such as fibronectin, laminin and collagen Interactions. Adhesion molecules on the leukocytes and on the Vascular endothelium are thus essential in leukocyte migration and bodies Attractive therapeutic starting points for intervention in a variety of inflammatory diseases.

The recruitment of the leukocytes to the site of the inflammation is gradual, starting with the connection of the leukocytes to the endothelial cells lining the blood vessels. This is followed by leukocyte rolling, activation, firm adhesion and transmigration. A number of cell adhesion molecules that are involved in these four recruitment steps have been identified and characterized. It was shown that the interaction between the vascular cell adhesion molecule 1 (VCAM-1) and the very late antigen 4 (VLA-4, α ₄ β ₁ integrin) and also the interaction between mucosal addressin cell adhesion molecule 1 (MAdCAM -1) and α ₄ β ₇ integrin mediated the attachment, rolling and adhesion of lymphocytes and eosinophilic cells, but not of neutrophils, to endothelial cells under physiological flow conditions. This suggests that the interactions mediated by VCAM-1 / VLA-4 and / or MAdCAM-1 / α ₄ β ₇ -integrin could in particular mediate selective recruitment of leukocyte subpopulations. The inhibition of this interaction is a starting point for therapeutic interventions (AJ Wardlaw, J. Allergy Clin. Immunol. 1999, 104, 917-26).

VCAM-1 is a member of the immunoglobulin (Ig) superfamily and one of the Main regulators in the transport of leukocytes to the inflammation sites. VCAM-1 is used together with the intracellular adhesion molecule 1 (ICAM-1) and E-selectin expressed on inflamed endothelium, activated by cytokines like Interleukin 1 (IL-1) and the tumor necrosis factor α (TNF-α), as well Lipopolysaccharide (LPS), via a nuclear factor kB- (NF-kB-) dependent pathway.  

However, these molecules are not expressed on resting endothelium. VCAM-1 mediated cell adhesion can be involved in numerous physiological and pathological processes including myogenesis, hematopoiesis, inflammatory reactions and the development of autoimmune diseases. The integrins VLA-4 and α ₄ β ₇ both function as leukocyte receptors for VCAM-1.

The integrin α ₄ β ₁ is a heterodimeric protein which is expressed to a considerable extent on all circulating leukocytes with the exception of mature neutrophils. It regulates the migration of cells into tissue during inflammatory reactions and normal lymphocyte transport. VLA-4 binds to various determinants of the primary sequence, such as. B. a QIDSP motif from VCAM-1 and an ILDVP sequence of the cell type-specific main adhesion site of the differentially spliced domain of the type III connecting segment (CS-1) of fibronectin.

In vivo studies with neutralizing monoclonal antibodies and inhibitor peptides have shown that the interaction with α ₄ integrins plays a crucial role in leukocyte-mediated inflammation. Blocking the VLA-4 / ligand interactions therefore appears to be promising for a therapeutic intervention in various inflammatory, autoimmune and immune diseases (Zimmerman, C .; Exp. Opin. Ther. Patents 1999, 9, 129-133).

Furthermore, compounds with a bisarylurea unit as a substituent as α ₄ β ₁ integrin receptor antagonists have been disclosed: WO 96/22966, WO 97/03094, WO 99/33789, WO 99/37605. However, no piperidylcarboxylic acids or ring-shaped analogs of the type presented here have been described.

In addition to their α ₄ β ₁ integrin antagonist activity, the compounds of the present invention can also be used as α ₄ β ₁ or α ₉ β ₁ integrin antagonists.

It is an object of the present invention to provide new, alternative piperidylcarboxylic acids or integrin antagonists derived from ring-shaped analogs for the treatment of inflammatory, autoimmune and immune diseases. The present invention therefore relates to compounds of the general formula (I):

in which
R ¹ and R ^{2 form} a 4- to 8-membered saturated or unsaturated ring-shaped radical which can contain 0 to 1 nitrogen atom and 0 to 2 heteroatoms, independently selected from the group S and O,
the ring-shaped radical formed by R ¹ and R ² having a 4- to 8-membered saturated, unsaturated or aromatic ring-shaped radical which may contain 0 to 2 heteroatoms, independently of one another, selected from the group consisting of N, S and O, can be condensed
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring condensed with the ring-shaped radical formed by R ¹ and R ² optionally independently of one another by 0 to 2 substituents -R ^1-1 -R ^1-2 -R ^1-3 -Z may be substituted, wherein
R ^1-1 for a bond, -O-, -S-, NR ^1-4 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl, a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-1 can} optionally be substituted by 1 to 2 substituents selected from the group R ^1-4 , where R ^{1-4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl , C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical having up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-4 may} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-2 stands} for a bond, -O-, -S-, NR ^1-5 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-2 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-5 , where
R ^{1-5 represents} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C _2-10 alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-5 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-3 represents} a bond, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-3 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-6 , where
R ^1-6 for hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-6 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
with the proviso that when R ^{1-3 represents} a bond, R ^{1-2 must} not be a heteroatom,
and with the proviso that R ^1-1 and R ^1-2 cannot both simultaneously represent a heteroatom,
Z for hydrogen, -C (O) OR ^Z-1 , -C (O) NR ^Z-2 R ^Z-3 , -SO ₂ NR ^Z-2 R ^Z-3 , -SO (OR ^Z-1 ), - SO ₂ (OR ^Z-1 ), -P (O) R ^Z-1 (OR ^Z-3 ), -PO (OR ^Z-1 ) (OR ^Z-3 ) or 5-tetrazolyl, where
R ^Z-2 for hydrogen, -C (O) R ^Z-4 or -SO ₂ R ^Z-4 , C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, wherein
R ^{Z-2 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, where
R ^{Z-4 represents} C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^{Z-4 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
R ^Z-1 and R ^{Z-3 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₆ or C. ₁₀ aryl, whereby
R ^Z-1 and R ^{Z-3 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ^{2 is} optionally substituted by 0 to 2 substituents R ^1-8 , halogen, nitro, amino, cyano and oxo can be where
R ^{1-8 can be selected} independently of one another from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, and wherein
R ^1-8 can be substituted by 0-5 halogen atoms,
R ^{3 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic Radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 R ^3-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^3-1 radicals, wherein
R ^3-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^3-2 , -SR ^3-2 , -NR ^3-3 R ^3-4 , -C (O) R ^3-2 , S ( O) R ^3-2 , -SO ₂ R ^3-2 , -CO ₂ R ^3-2 , -OC (O) R ^3-2 , -C (O) NR ^3-3 R ^3-4 , -NR ^{3 -2} C (O) R ^3-2 , -SO ₂ NR ^3-3 R ^3-4 , NR ^3-2 SO ₂ R ^3-2 , -NR ^3-2 C (O) NR ^3-3 R ^{3- 4} , -NR ^3-2 C (O) OR ^3-2 , - OC (O) NR ^3-3 R ^3-4 , halogen, cyano, nitro or oxo, where
R ^{3-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy by a substituent , Phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano may be substituted, and wherein
R ^3-3 and R ^{3-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^3-3 and R ^3-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^3-3 and R ^{3-4 are} bound and which contains up to 2 additional heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur and contains up to 2 double bonds,
R ^{4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic Radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^4-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^4-1 radicals, wherein
R ^4-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^4-2 , -SR ^4-2 , -NR ^4-3 R ^4-4 , -C (O) R ^4-2 , S ( O) R ^4-2 , -SO ₂ R ^4-2 , -CO ₂ R ^4-2 , OC (O) R ^4-2 , -C (O) NR ^4-3 R ^4-4 , -NR ^{4- 2} C (O) R ^4-2 , -SO ₂ NR ^4-3 R ^4-4 , NR ^4-2 SO ₂ R ^4-2 , -NR ^4-2 C (O) NR ^4-3 R ^4-4 , -NR ^4-2 C (O) OR ^4-2 , -OC (O) NR ^4-3 R ^4-4 , halogen, cyano, nitro or oxo, where
R ^{4-2 is} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy by a substituent , Phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano may be substituted, and wherein
R ^4-3 and R ^{4-4 are the} same or different and each represents hydrogen, C _1-4 alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^4-3 and R ^4-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^4-3 and R ^{4-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur and contains up to 2 double bonds,
R ^{5 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic Radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 R ^5-1 radicals and which is furthermore simply selected by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyl radical having up to 2 heteroatoms can be substituted from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R ^5-1 , where
R ^5-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^5-2 , -SR ^5-2 , -NR ^5-3 R ^5-4 , -C (O) R ^5-2 , S ( O) R ^5-2 , -SO ₂ R ^5-2 , -CO ₂ R ^5-2 , -OC (O) R ^5-2 , -C (O) NR ^5-3 R ^5-4 , -NR ^{5 -2} C (O) R ^5-2 , -SO ₂ NR ^5-3 R ^5-4 , NR ^5-2 SO ₂ R ^5-4 -NR ^5-2 C (O) NR ^5-3 R ^5-4 , -NR ^5-2 C (O) OR ^5-2 , -OC (O) NR ^5-3 R ^5-4 , halogen, cyano, nitro or oxo, where
R ^{5-2 is} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy by a substituent , Phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano may be substituted, and wherein
R ^5-3 and R ^{5-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^5-3 and R ^5-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^5-3 and R ^{5-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur and contains up to 2 double bonds,
R ^{6 represents} phenyl or a 5-6-membered aromatic heterocyclic radical with up to 3 heteroatoms, independently selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be condensed with a 5-8-membered saturated or unsaturated ring-shaped radical having up to 2 heteroatoms, independently selected from the group consisting of oxygen, nitrogen or sulfur,
and which can optionally be substituted by 0 to 2 substituents which independently of one another from the group bond, C _1-10 alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ - C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms, independently selected from the group consisting of oxygen, nitrogen or sulfur, are selected, these substituents optionally being substituted by 1 to 3 R ^6-1 radicals can be where
R ^6-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-2 , -SR ^6-2 , -NR ^6-2 R ^6-3 , -C (O) R ^6-2 , S ( O) R ^6-2 , -SO ₂ R ^6-2 , -CO ₂ R ^6-2 , -OC (O) R ^6-2 , -C (O) NR ^6-2 R ^6-3 , -NR ^{6 -3} C (O) R ^6-2 , -SO ₂ NR ^6-2 R ^6-3 , NR ^6-3 SO ₂ R ^6-2 , -NR ^6-3 C (O) NR ^6-2 R ^{6- 4} , -NR ^6-3 C (O) OR ^6-2 , -OC (O) NR ^6-2 R ^6-3 , halogen, cyano, nitro or oxo, where
R ^{6-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur,
which can optionally be substituted by 1 to 3 substituents R ^6-5 , where
R ^{6-5 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-6 , -SR ^6-6 , -NR ^6-7 R ^6-8 , where
R ^6-6 for hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C by 1 to 3 substituents ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, and where
R ^6-7 and R ^{6-8 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which is optionally substituted by 1 to 2 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy can be,
or
R ^6-7 and R ^6-8 together form a 4-7-membered ring with up to 2 additional heteroatoms, selected from the group consisting of oxygen, nitrogen or sulfur, and with up to 2 double bonds, which are optionally selected from 1 to 2 substituents the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxyl, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo may be substituted, and wherein
R ^6-3 and R ^{6-4 are the} same or different and each represents hydrogen, a bond, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-9 , -SR ^6-9 , -NR ^6-10 R ^6-11 , where
R ^{6-9 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
which is optionally substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy can be, and being
R ^6-10 and R ^{6-11 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which is optionally substituted by 1 to 2 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy can be,
or
R ^6-9 and R ^6-10 together form a 4-7-membered ring with up to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and with up to 2 double bonds, which are optionally selected from the group by 1 or 2 substituents C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo can be substituted
or
R ^6-2 and R ^6-3 and / or R ^6-3 and R ^6-4 together form a 4-7-membered ring which has the nitrogen atom to which R ^6-3 , R ^6-3 and R ^{6- 4 are} bound, and which contains up to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and up to 2 double bonds, which are optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C by 1 or 2 substituents ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo can be substituted,
and which can furthermore be independently substituted by 0 to 3 substituents R ^6-5
or
R ³ and R ⁴ or R ⁴ and R ⁵ together form a 4-7-membered saturated or unsaturated ring with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, which is optionally selected from the group C ₁ by 1 or 2 substituents -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo and which can be substituted with a 3-7-membered homocyclic or heterocyclic, saturated, unsaturated or aromatic ring can be condensed
A for -C (O) -, -C (O) -C (O) -, -SO-, -SO ₂ -, -P (O) R ^A-1 -, -PO ₂ -, 2-pyrimidyl, 4-pyrimidyl, 2-pyridyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl or a ring selected from the following group:

wherein the ring systems listed above may optionally be substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, nitro, amino, cyano, where
R ^{A-1 can be selected} from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy,
X stands for a bond, -CR ^X-1 R ^X-2 -, oxygen or -NR ^X-3 , where R ^X-1 , R ^X-2 , R ^X-3 independently of one another from the group bond, hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl can be selected,
or
together with R ^{6 form} a 4-7-membered ring which includes the nitrogen atom to which R ⁶ and R ^X-1 or R ^X-2 or R ^X-3 can be bound and which can contain up to two additional heteroatoms independently selected from one another from the group consisting of oxygen, nitrogen or sulfur, and can contain up to 2 double bonds, which are optionally selected from the group C ₁ -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ by 1 to 2 substituents -C ₄ alkyloxy, halogen, nitro, cyano, oxo can be substituted,
Y represents a bond, -C (O) -, -S (O) -, -SO ₂ -, -O-, -S-, -CR ^Y-1 R ^Y-2 -, or -NR ^Y-3 , where R ^Y-1 , R ^Y-2 , R ^{Y-3 can be selected} independently from the group bond, hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl,
and optionally substituted by 1 to 2 substituents independently selected from the group C ₁ -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo ,
D represents N, or CR ^D-1 , where
R _{D can be selected} independently from the group bond, hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl
and optionally substituted by 1 to 2 substituents independently selected from the group C ₁ -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo ,
and with the proviso that Y and D are not heteroatoms at the same time,
and their pharmaceutically acceptable salts.

In a preferred embodiment, the present invention relates to compounds of the general formula (I) in which
R ¹ and R ^{2 form} a 4- to 8-membered saturated or unsaturated ring-shaped radical,
which can contain 0 to 1 nitrogen atom and 0 to 1 heteroatom, independently selected from the group S and O,
wherein the ring-shaped radical formed by R ¹ and R ^{2 is} condensed with a 5- to 7-membered saturated, unsaturated or aromatic ring-shaped radical, which may contain 0 to 2 heteroatoms, independently selected from the group consisting of N, S and O. can,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring condensed with the ring-shaped radical formed by R ¹ and R ² optionally optionally independently of one another by 1 to 2 substituents -R ^1-1 -R ^1-2 -R ^{1 -3} -Z can be substituted, wherein
R ^1-1 for a bond, -O-, -S-, NR ^1-4 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl, a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-1 can} optionally be substituted by 1 to 2 substituents selected from the group R ^1-4 , where R ^{1-4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl , C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-4 may} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-2 stands} for a bond, -O-, -S-, NR ^1-5 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-2 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-5 , where
R ^1-5 for hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C _2-10 alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-5 may} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-3 represents} a bond, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-3 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-7 , where
R ^1-7 for hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-7 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
with the proviso that when R ^{1-3 represents} a bond, R ^{1-2 must} not be a heteroatom,
and with the proviso that R ^1-1 and R ^1-2 cannot both simultaneously represent a heteroatom,
Z for hydrogen, -C (O) OR ^Z-1 , -C (O) NR ^Z-2 R ^Z-3 , -SO ₂ NR ^Z-2 R ^Z-3 , -SO (OR ^Z-1 ), - SO ₂ (OR ^Z-1 ), or 5-tetrazolyl, where
R ^{Z-2 represents} hydrogen, -C (O) R ^Z-4 or -SO ₂ R ^Z-4 , C ₁ -C ₄ alkyl, C ₃ - C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^{Z-2 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, where
R ^{Z-4 represents} C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^{Z-4 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
R ^Z-1 and R ^{Z-3 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^Z-1 and R ^{Z-3 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ^{2 is} optionally substituted by 0 to 2 substituents R ^1-8 , halogen, nitro, amino, cyano and oxo can be where
R ^{1-8 can be selected} independently of one another from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, and wherein
R ^1-8 can be substituted by 0-5 halogen atoms,
R ^{3 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or Sulfur stands,
which may optionally be substituted by 1 to 2 R ^3-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^3-1 radicals, wherein
R ^{3-1 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^3-2 , -NR ^3-3 R ^3-4 , -CO ₂ R ^3-2 , halogen, cyano, nitro or oxo, where
R ^{3-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl and where
R ^3-3 and R ^{3-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^3-3 and R ^3-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^3-3 and R ^{3-4 are} bound and which contains up to 2 additional heteroatoms selected from the group consisting of oxygen , Contains nitrogen or sulfur,
R ^{4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or Sulfur stands,
which may optionally be substituted by 1 to 3 R ^4-1 radicals,
and which is furthermore simply selected from C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^4-1, may be substituted, wherein
R ^{4-1 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^4-2 , -NR ^4-3 R ^4-4 , -CO ₂ R ^4-2 , halogen, cyano, nitro or oxo, where
R ^{4-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl and where
R ^4-3 and R ^{4-4 are the} same or different and each represents hydrogen, C _1-4 alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^4-3 and R ^4-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^4-3 and R ^{4-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Contains nitrogen or sulfur,
R ^{5 represents} hydrogen, C ₁ -C ₁₀ alkyl,
which may optionally be substituted by 1 to 3 R ^5-1 radicals and which is furthermore simply selected by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical having up to 2 heteroatoms can be substituted from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R ^5-1 , where
R ^{5-1 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^5-2 , -NR ^5-3 R ^5-4 , -CO ₂ R ^5-2 , halogen, cyano, nitro or oxo, where
R ^{5-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl and where
R ^5-3 and R ^{5-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^5-3 and R ^5-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^5-3 and R ^{5-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Contains nitrogen or sulfur,
R ^{6 represents} phenyl or a 6-membered aromatic heterocyclic radical with up to 2 nitrogen atoms,
which may optionally be independently selected from the group bond independently by a substituent,
where these substituents can optionally be substituted by a radical R ^6-1 , wherein
R ^6-1 for -C (O) NR ^6-2 R ^6-3 , -NR ^6-3 (O) R ^6-2 , -SO ₂ NR ^6-2 R ^6-3 , NR ^6-3 SO ₂ R ^6-2 , -NR ^6-3 C (O) NR ^6-2 R ^6-4 , -NR ^6-3 C (O) OR ^6-2 , -OC (O) NR ^6-2 R ^6-3 stands, where
R ^{6-2 represents} C ₆ or a 5-6-membered unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 2 substituents R ^6-5 , where
R ^{6-5 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-6 , -SR ^6-6 , -NR ^6-7 R ^6-8 , where
R ^{6-6 represents} hydrogen, C ₁ -C ₄ alkyl, and wherein
R ^6-7 and R ^{6-8 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl,
or
R ^6-7 and R ^6-8 together form a 5-6-membered ring which contains up to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and wherein
R ^6-3 and R ^{6-4 are the} same or different and each represents hydrogen, a bond, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl,
and which can furthermore be independently substituted by 0 to 2 substituents R ^6-5 ,
or
R ³ and R ⁴ together form a 4-7-membered saturated ring with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, which is optionally substituted by 1 to 2 substituents selected from the group C ₁ -C ₄ alkyl, phenyl, Benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo, may be substituted
A stands for -C (O) -, -SO ₂ -,
X represents a bond, -CR ^X-1 R ^X-2 -, oxygen or -NR ^X-3 , where
R ^X-1 , R ^X-2 , R ^{X-3 can be selected} independently of one another from the group bond, hydrogen, C ₁ -C ₄ alkyl,
Y represents a bond, -C (O) -, -SO ₂ -, -O-, -CR ^Y-1 R ^Y-2 - or -NR ^Y-3 , where
R ^Y-1 , R ^Y-2 , R ^{Y-3 can be selected} independently of one another from the group bond, hydrogen, C ₁ -C ₄ alkyl,
D represents N or CR ^D-1 , where
R ^{D-1 can be selected} independently from the group bond, hydrogen, C ₁ -C ₄ alkyl,
with the proviso that Y and D are not both heteroatoms at the same time, and that
and their pharmaceutically acceptable salts.

In a more preferred embodiment, the present invention relates to compounds of the general formula (I) in which
R ¹ and R ^{2 form} a 5- or 6-membered saturated ring-shaped radical which may contain 1 nitrogen atom,
wherein the ring-shaped radical formed by R ¹ and R ² can be condensed with a 5-membered saturated ring-shaped radical which contains a nitrogen atom,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ^{2 is} optionally independent of a substituent -R ^1-1 -R ^1-2 - R ^1-3 - Z can be substituted, wherein
R ^{1-1 represents} a bond or C ₁ -C ₂ alkyl, where
R ^{1-1 can} optionally be substituted by 1 C ₆ aryl,
R ^{1-2 represents} a bond,
R ^{1-3 represents} a bond,
Z represents -C (O) OR ^Z-1 or 5-tetrazolyl,
R ^{Z-1 represents} hydrogen or C ₂ alkyl,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ² may optionally be substituted by 0 or 1 substituents R ^1-8 , where
R ^{1-8 represents} C ₁ alkyl, and wherein
R ^1-8 is substituted by 3 fluorine atoms,
R ^{3 represents} isobutyl,
R ⁴ and R ^{5 represent} hydrogen,
R ⁶ for

stands,
A stands for -C (O) -,
X stands for -CH ₂ -
Y stands for -C (O) -,
D stands for nitrogen,
and their pharmaceutically acceptable salts.

In a particularly preferred embodiment, the present invention relates to compounds of the general formula (I) in which R ¹ and R ^{2 form} a piperidine ring.

In a further particularly preferred embodiment, the present invention relates to compounds of the general formula (I) in which R ¹ and R ^{2 form} a pyrrolindine ring.

In yet another particularly preferred embodiment, the present invention relates to compounds of the general formula (I) in which R ^{6 is}

stands.

In the most preferred embodiment, the present invention relates to compounds of the general formula (I), the compound being selected from the following group:
N - ((1S) -3-Methyl-1 - {[3- (1H-tetraazol-5-yl) -1-pyrrolidinyl] carbonyl} butyl) - 2- {4 - [(2-toluidinocarbonyl) amino] phenyl } acetamide
1 - {({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -2- piperidinecarboxylic acid,
1 - {({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3- piperidinecarboxylic acid,
1 - {({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -4- piperidinecarboxylic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -2-piperidinyl) acetic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3- piperidinyl) acetic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -4- piperidinyl) acetic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3-piperidinyl) propionic acid,
(3S) -1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -4- (trifluoromethyl) -3-pyrrolidinecarboxylic acid,
5- (ethoxycarbonyl) -1- {2 - ({4 - [(2-toluidinocarbonyl) amino] phenyl} acetyl) -L-leucine} octahydropyrrolo [3,4-b] pyrrole-2-carboxylic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -2-piperidinyl) (phenyl) acetic acid and
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3-oxo-2-piperazinyl) acetic acid.

In other embodiments, the invention relates to the use of a Compound of general formula (I) for the manufacture of a medicament for Treating a condition mediated by integrins, and pharmaceutical compositions comprising a compound of the general formula (I) and contain a pharmaceutically acceptable carrier.

In the context of the present invention, alkyl represents a straight-chain or branched alkyl radical such as methyl, ethyl, n-propyl, isopropyl, n-pentyl. C ₁ -C ₁₀ alkyl is preferred.

Alkenyl and alkynyl represent straight-chain or branched radicals which contain one or more double or triple bonds, for. B. vinyl, allyl, isopropynyl, ethynyl. C ₁ -C ₁₀ alkenyl or alkynyl is preferred.

Cycloalkyl stands for a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. C ₃ -C ₇ cycloalkyl is preferred.

In the context of the present invention, halogen represents fluorine, chlorine, bromine or Iodine. Unless otherwise stated, chlorine or fluorine are preferred.

Heteroaryl stands for a monocyclic heteroaromatic system with 4 to 9 Ring atoms, which have a carbon atom or optionally a Nitrogen atom can be bound in the ring, for example furan-2-yl, furan-3-yl, Pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, thienyl, thiazolyl, oxazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidyl or pyridazinyl.

A saturated or unsaturated heterocyclic radical represents a heterocyclic radical System with 4 to 9 ring atoms, which has one or more double bonds can contain and which via a ring carbon atom or optionally via a nitrogen atom may be attached e.g. B. tetrahydrofur-2-yl, pyrrolidin-1-yl, Piperidin-1-yl, piperidin-1-yl, morpholin-1-yl, 1,4-diazepin-1-yl or 1,4-dihydropyrin-1-yl.

Unless otherwise stated, heteroatom is within the scope of the present Invention for O, S, N or P.

Condensed stands for 1,1- or 1,2-condensed ring systems, e.g. B. Spirosystems or systems with a [0] bridge.

Surprisingly, the compounds of the present invention show good integrin antagonistic activity. They are therefore particularly suitable as α ₄ β ₁ and / or α ₄ β ₇ and / or α ₉ β ₁ integrin antagonists and particularly for the production of pharmaceutical compositions for inhibiting or preventing cell adhesion and diseases mediated by cell adhesion. Examples include the treatment and prophylaxis of atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, graft rejection and other inflammatory, autoimmune and immune diseases.

The integrin antagonists according to the invention are not only suitable for treatment of the physiological conditions mentioned above, but also for example Clean integrins and test for activity.

In the treatment of the diseases mentioned above, he can use 46132 00070 552 001000280000000200012000285914602100040 0002010006453 00004 46013 according to the invention Compounds show non-systemic or systemic activity, the latter is preferred. To achieve systemic activity, the active ingredients can be found below other orally or parenterally administered, with an oral administration is preferred.

Forms of administration are particularly suitable for parenteral administration to the mucous membranes (i.e. buccal, lingual, sublingual, rectal, nasal, pulmonary, conjunctival or intravaginal) or inside the body. The administration can be avoided while avoiding absorption (i.e. intracardial, intraarterial, intravenous, intraspinal or intralumbar administration) or with absorption (i.e. intracutaneous, subcutaneous, percutaneous, intramuscular or intraperitoneal Administration).

For the above purposes, the active ingredients as such or in Administration forms are administered.

Suitable forms of administration for oral administration include normal and enteric coated tablets, capsules, coated tablets, pills, Granules, pellets, powders, solid and liquid aerosols, syrups, emulsions, Suspensions and solutions. Suitable for parenteral administration Forms of administration are solutions for infusion and injection.  

In the administration forms, the active ingredient can be used in concentrations of 0.001-100% by weight is present; preferably the concentration of the Active ingredient 0.5-90 wt .-%, d. H. Amounts sufficient to cover the to achieve the specified dosage range.

The active ingredients can be known in the manner mentioned above Dosage forms are transferred using inert, not toxic pharmaceutically suitable excipients, such as excipients, Solvents, vehicles, emulsifiers and / or dispersants.

The following auxiliaries can be listed as examples: water, solid Carriers such as ground natural or synthetic minerals (e.g. talc or Silicates), sugar (e.g. lactose), non-toxic organic solvents such as Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), emulsifiers, dispersants (e.g. Polyvinyl pyrrolidone) and lubricants (e.g. magnesium sulfate).

When administered orally, tablets can of course also contain additives such as Contain sodium citrate and additives such as starch, gelatin and the like. Aqueous preparations for oral administration can also be flavored and Dyes are added.

In order to achieve effective results with parenteral administration, it has generally proven to be beneficial, amounts of about 0.001 to 100 mg / kg Body weight, preferably about 0.01 to 1 mg / kg. With oral Administration is about 0.01 to 100 mg / kg body weight, preferably about 0.1 to 10 mg / kg.

Nevertheless, it may be necessary from the amounts mentioned deviate, depending on the body weight concerned, on the Method of administration, from individual behavior towards the active ingredient, the  Type of wording and the time or interval at which the Administration takes place.

Suitable pharmaceutically acceptable salts of the compounds of the present Invention containing an acidic component include addition salts which can be formed with organic or inorganic bases. That of such bases derived salt-forming ion can be a metal ion, e.g. B. aluminum Alkali metal ion such as sodium or potassium, an alkaline earth metal ion such as calcium or Magnesium, or an amine salt ion, a number of which are considered for this purpose suitably known. Examples include ammonium salts, arylalkylamines such as Dibenzylamine and N, N-dibenzylethylenediamine, lower alkylamines such as Methylamine, t-butylamine, procaine, lower alkylpiperidines such as N-ethylpiperidine, Cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantylamine, Benzathin, or derived from amino acids such as arginine, lysine or the like Salt. The physiologically acceptable salts such as the sodium or Potassium salts and the amino acid salts can be medicated as described below are used and are preferred.

Suitable pharmaceutically acceptable salts of the compounds of the present Invention containing a basic component include organic or salts formed from inorganic acids. The one derived from these acids salt-forming ion can be a halide ion or the ion of a natural one or non-natural carbon or sulfonic acid, a number of which act as is known to be suitable for this purpose. Examples include chlorides, acetates, Tartrates or salts derived from amino acids such as glycine or the like. The physiologically acceptable salts such as the chloride salts and the Amino acid salts can be used medicinally as described below and are preferred.  

These and other salts that are not necessarily physiologically safe are for insulation or cleaning purposes for the purposes described below acceptable product.

The salts are prepared by changing the acid form of the invention Compound with an equivalent of the base that the desired basic ion is used for Provides, or with the basic form of the compound of the invention an equivalent of the acid providing the desired acid ion in a medium in which the salt precipitates or can react in an aqueous medium and then lyophilized. The free acid or base form of the invention Compounds can be prepared by conventional neutralization methods, e.g. B. with Potassium bisulfate, hydrochloric acid, sodium hydroxide, sodium hydrogen carbonate, etc., from the salt can be obtained.

The compounds of the invention can be noncovalent Addition compounds such as adducts or inclusion compounds such as hydrates or Form clathrates. This is known to the person skilled in the art and these compounds fall also within the scope of the present invention.

The compounds according to the invention can be in various stereoisomers Forms exist that are mutually either like enantiomers (Figure and Mirror image) or like diastereomers (image and image, which is different from the mirror image differs) behave. The invention relates to the enantiomers and Diastereomers and their mixtures. They can be separated by common methods become.

The compounds of the invention can exist in tautomeric forms. This is known to those skilled in the art, and such compounds also fall within the Scope of the present invention.  

1. General synthesis of the compound

The synthesis of the compounds of general formula (I) can be illustrated by the following scheme 1:

The carboxylic acids (V) can be obtained by amide coupling of the carboxylic acids (II) with the amines (III) and subsequent saponification of the esters (IV). Coupling with the ring-shaped amines (VI) and subsequent elimination of the protective group PG ² gives carboxylic acids of the type (VIII). Further examples with different A, Y and D groups as defined in formula (I) are described below.

In the above scheme, PG ¹ and PG ^{2 represent} suitable protecting groups for the carboxy unit. Protective groups of this type are known to the person skilled in the art and are described in detail in TW Greene, PG Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley, New York, 1999. The carboxyl group is preferably esterified, where PG ^1,2 for C _1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, is a C _{3- 7-} Cycloalkyl such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or, cyclohexyl, aryl such as phenyl, benzyl or tolyl or a substituted derivative thereof.

1.1 Step A

The amides (IV) can be formed by using the corresponding carboxylic acid (II) - activated with a coupling reagent such as DCC and HOBt; EDCI and HOBt or HATU - with the desired amine (III) or a suitable salt thereof can react. Activated derivatives of acids (II) such as anhydrides, Halides, N-carboxylic anhydrides and esters, e.g. B. succinyl or Pentafluorophenyl ester.

Type (IV) amides can be prepared, for example, as follows:

A solution of carboxylic acid, HOBt and EDCI in an inert solvent is used at R. t. touched. After adding the amine and a non-nucleophilic base such as Ethylisopropylamine is sold to R. t. or stirred at an elevated temperature. You pour the mixture in water and works up according to standard procedures.

Compounds of the general formula (II) are commercially available or known or they can be prepared from known carboxylic acid derivatives by customary methods being represented.

For example, biphenyl-substituted acetic acid derivatives can be Aryl coupling of the corresponding phenylacetic acid derivatives and a suitable one Represent phenyl system.

Possible coupling reactions are, for example, the reaction of two unsubstituted phenyl groups in the presence of AlCl ₃ and an acid (Scholl reaction), the coupling of two phenyl iodides in the presence of copper (Ullmann reaction), the reaction of the unsubstituted carboxylic acid derivative with a phenyldiazonium compound under basic Conditions (Gomberg-Bachmann reaction) or coupling involving organometallic reagents, such as the coupling of a phenyl halide with an organometallic phenyl compound in the presence of a palladium compound, for example a Pd (0) -, a Pd (II) - or a Pd (IV ) Compound, and a phosphine such as triphenylphosphine (e.g. Suzuki reaction).

Bisarylureas can be obtained by coupling an aminophenylacetic acid derivative and of a phenyl isocyanate. Bisarylamides can be represented by an aminophenylacetic acid and an activated benzoic acid derivative as under Step A described couples. Bisarylcarbamate can be obtained by coupling one Isocyanatophenylacetic acid ester and a phenol derivative with subsequent Display saponification as described in step B.

Compounds of the general formula (III) are commercially available, or are known or can be prepared by conventional methods starting from known α-amino acids or precursors for conventional α-amino acid synthesis. In this case, the carboxyl group is blocked with a suitable protective group PG ¹ for the production process according to the invention.

In the α-position to the carboxyl group, these carboxylic acid derivatives can have substituents as described under R ³ and R ⁴ , for example hydrogen C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, aryl, an alkenyl radical or an alkynyl radical. The alkyl, alkenyl and cycloalkyl radicals and the benzyl radical can be introduced by reacting the ester of the starting compound with suitable alkyl, alkenyl, cycloalkyl or benzyl halides in a basic medium if the corresponding derivatives are not commercially available. The alkynyl radical can be introduced, for example, by reacting the bromo ester of the starting compound present with an appropriate acetylide anion. In the case of the phenyl radical, the starting materials used are preferably the corresponding α-phenyl-α-aminocarboxylic acid derivatives, and the other substituents on the α-carbon atom to form the carboxyl group are introduced, if necessary, via the corresponding alkyl halide.

The above reactions and their implementation are well known to those skilled in the art and detailed in standard works such as Houben-Weyl, methods of organic chemistry, Georg Thieme Verlag, Stuttgart.

Should the substituents themselves be substituted, e.g. B. with R ', the substituent should contain suitable reactive groups that allow further functionalization. These reactive groups should be inert to the reaction conditions of the previous step. For this purpose, the substituent can also be unsaturated, which enables further functionalizations such as palladium-catalyzed CC coupling reactions (e.g. Heck reaction or Sonogashira reaction), possibly with subsequent hydrogenation (Scheme 2):

In the above scheme, hal represents a leaving group such as a halogen, tosyl, mesyl or triflate, [Pd] represents a palladium (0) or palladium (II) unit. PG ³ stands for a protective group of the amino group. Such protective groups are known to the person skilled in the art and are described in detail in TW Greene, PG Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley, New York, 1999.

If the substituent R ³ or R ⁴ carries a corresponding substituted aryl or heteroaryl unit in the α position to the carboxyl group, the CC coupling reactions described in the synthesis of the precursors (II) are further methods suitable for introducing an additional substituent.

If A - as defined in formula (I) - differs from carbonyl, the represent the corresponding compounds (IV) as follows:

Forms A z. B. a sulfinamide or sulfonamide, you can the compounds as in Represent step C described. Oxalic acid amides can be made in the same way as represent the amides described above. Phosphinic acid amides and Phosphonic acid amides can be prepared by activating Coupled phosphinic / phosphonic acids with amine (III). If A is a heteroaromatic or aromatic system, one can use the corresponding Compounds (IV) by nucleophilic substitution of the corresponding represent fluorine-substituted systems with a suitable amine (III).

1.2 Step B

The protective group PG ¹ can be split off either with an acid such as trifluoroacetic acid or a base such as potassium hydroxide or lithium hydroxide, depending on the nature of PG ¹ . The reactions are carried out in aqueous, inert organic solvents such as alcohols, e.g. B. methanol or ethanol, ethers, e.g. B. tetrahydrofuran or dioxane, or in polar aprotic solvents, e.g. B. dimethylformamide. If necessary, mixtures of the abovementioned solvents can also be used.

1.3 Step C

The amides (VII) can be formed by using the corresponding carboxylic acid (V) - activated with a coupling reagent such as DCC and HOBt; EDCI and HOBt or HATU - with the desired amine (VI) or a suitable salt thereof can react. Activated derivatives of acids (V), such as anhydrides, Halides, N-carboxylic anhydrides and esters, e.g. B. succinyl or Pentafluorophenyl ester.

For example, amides of type (VII) can be prepared as follows:  

A solution of carboxylic acid, HOBt and EDCI in an inert solvent is used at R. t. touched. After adding the amine and a non-nucleophilic base such as Ethylisopropylamine is sold to R. t. or stirred at an elevated temperature. You pour the mixture in water and works up according to standard procedures.

Is Y different from carbonyl and / or does D differ from nitrogen? as defined in formula (I) -, one can the corresponding compounds (VII) as represent as follows:

If Y and D form a sulfinamide or sulfonamide, for example, they can Implementation of the corresponding sulfinic acid chlorides or sulfonic acid chlorides the desired amine (VI) or a suitable salt thereof.

When Y and D form an ether or thioether, the O-C and S-C bonds, respectively by alkylation of the corresponding alcohol or thiol with Alkylating agents such as alkyl halides, alkyl tosylates and the like educated. By oxidation with reagents such as mCPBA or hydrogen peroxide the thioethers can be converted into the corresponding sulfoxides or sulfones.

Do Y and D form a carbon-nitrogen bond or a nitrogen Carbon bond, the bond is through reductive amination through the corresponding aldehyde or ketone and the corresponding amine in the presence of a Reductant such as sodium cyanoborohydride formed.

If Y and D form a carbon-carbon bond, the bond can be formed by Wittig reaction of the corresponding ketone or aldehyde and the corresponding phosphonium ylid with subsequent reduction of Double bond, e.g. B. by catalytic hydrogenation.

If Y is carbonyl and D is a carbon unit, you can use the Binding by a Grignard reaction of the corresponding aldehyde of Y and  corresponding Grignard compound of D with subsequent oxidation of the so formed alcohol in the ketone, e.g. B. by Swern oxidation or Jones oxidation, form.

The above reactions and their implementation are well known to those skilled in the art and extensively in standard works such as Houben-Weyl, methods of organic chemistry, Georg Thieme Verlag, Stuttgart.

If more than one reaction method is available, the person skilled in the art is able to the appropriate path according to the selectivity and the possible use by protecting groups such as in T. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley, New York, 1999.

The compounds of the general formula (VI) are commercially available, known or they can be prepared from known ones by conventional methods Carboxylic acid derivatives are shown.

Piperidine-substituted esters, for example, can be obtained by catalytic hydrogenation of the corresponding commercially available pyridine-substituted esters.

The reactions can be carried out according to general instruction 1:

The pyridine-substituted ester, in an acidified organic solvent such as an alcohol, e.g. B. ethanol, is in the presence of a suitable catalyst, e.g. B. a suitable form of palladium or platinum, hydrogenated. The hydrogenation can at 20-200 ° C and 1-300 bar hydrogen pressure.

If R ^1-1 , R ^1-2 and / or R ^1-3 are methylene groups, the carbon chain can be extended by the Arndt-Eistert reaction and, if necessary, using conventional methods for the α-derivatization of carboxylic acids, such as nucleophilic substitution , derivatize.

Let hexahydropyrrolo [3,4-b] pyrrole-2,5 (1H) -dicarboxylic acid dialkyl ester derivatives condensation of ethyl allyl- (2-oxoethyl) carbamate with (Benzylamino) ethyl acetate and subsequent cleavage of the Obtained benzyl group by means of catalytic hydrogenation.

5- (3-pyrrolidinyl) -1H-tetrazole derivatives can be obtained by reacting suitable ones N-protected 3-pyrrolidine carbonitriles with azides such as tributyltin azide and represent subsequent splitting off of the protective group. Such N-protecting groups are known to the person skilled in the art and are described in detail in T. W. Greene, P.G. Groups in Organic Synthesis, 3rd ed., John Wiley, New York, 1999.

1.4 Step D

The protective group PG ¹ can be split off either with an acid such as trifluoroacetic acid or a base such as potassium hydroxide or lithium hydroxide, depending on the nature of PG ¹ . The reactions are carried out in aqueous, inert organic solvents such as alcohols, e.g. B. methanol or ethanol, ethers, e.g. B. tetrahydrofuran or dioxane, or in polar aprotic solvents, e.g. B. dimethylformamide. If necessary, mixtures of the abovementioned solvents can also be used.

Abbreviations

AcOH = acetic acid
DCC = dicyclohexylcarbodiimide
GC = gas chromatography
EDCI = 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide × HCl
Eq. = Equivalents
HATU = 2- (7-aza-3-oxido-1H-1,2,3-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
HOBt = N-hydroxybenzotriazole monohydrate
HPLC = high performance liquid chromatography
ICAM-1 = intracellular adhesion molecule 1
IL-1 = interleucin 1
LPS = lipopolysaccharide
MAdCAM-1 = mucosal addressin cell adhesion molecule 1
MeOH = methanol
Mp = melting point
NF-κB = nuclear factor κB
NMR = nuclear magnetic resonance
min. = Minutes
nb = not determined
R. t. = Room temperature
R _f

= DC: R _f

-Value = distance that the spot has migrated / distance that the solvent front has migrated
DC = thin layer chromatography
TNF-α = tumor necrosis factor α
t _R

= Retention time, determined by means of HPLC
VCAM-1 = vascular cell adhesion molecule 1
VLA-4 = very late antigen 4

3. Examples 3.1 General

In the examples below, all quantities relate, if not otherwise stated, by weight percent.

Flash chromatography was carried out using silica gel 60, 40-63 μm (E. Merck, Darmstadt) carried out.

Thin layer chromatography was carried out using silica gel 60 F ₂₅₄ -coated aluminum foils (E. Merck, Darmstadt), the solvent being indicated.

The melting points were determined in open capillaries and are not corrected.

The retention times are in minutes and were, if not different, unless otherwise indicated, by high performance liquid chromatography (HPLC) with UV detection determined at 210/250 nm. An acetonitrile / water mixture was used as the eluent with 0.1% trifluoroacetic acid (v / v) with a linear gradient of: 0 min. = 0% Acetonitrile, 25 min. = 100% acetonitrile, 31 min = 100% acetonitrile, 32 min 0% Acetonitrile, 38 min 0% acetonitrile used. With method A one came LiChrospher 100 RP-18 column, 5 µm, 250 × 4 mm (E. Merck, Darmstadt) and at the Method B a Purospher RP-18e column, 5 µm, 250 × 4 mm (E. Merck, Darmstadt) for use.

The mass determinations were carried out with the electron spray ionization (ESI) method carried out using loop injection (ESI-MS) or split Injection via an HPLC system (HPLC-MS) was applied.  

3.2 Synthesis of the preliminary stage 3.2.1 Example I

2- {4 - [(2-Toluidinocarbonyl) amino] phenyl} acetic acid

A solution of 2- (4-aminophenyl) acetic acid (108.8 g, 0.72 mol) in dichloromethane (1.0 l) and triethylamine (120 ml) was added to R. t. A solution of 2-methylphenyl isocyanate (90.5 ml, 0.72 mol) in dichloromethane (500 ml) was added dropwise. The mixture was stirred at R.t. stirred, and then water (2.5 L) and dichloromethane (2.0 L) were added and the phases were separated. The organic phase was extracted with water (3 x 400 ml). The combined aqueous phases were concentrated to 3.0 l and acidified to pH 2 by the addition of concentrated aqueous HCl. The precipitate was filtered off, washed with cold water and dried in a desiccator over concentrated H ₂ SO ₄ to give 166.5 g (82%) of a white solid.

Mp 205-206 ° C; TLC (MeOH / dichloromethane 1: 9): R _f 0.14. ¹ H-NMR (400 MHz, D ₆ -DMSO): 12.21 (br s, 1H), 9.11 (s, 1H), 8.00 (s, 1H), 7.83 (d, 7, 6 Hz, 1H), 7.40 (d, 8.5 Hz, 2H), 7.17-7.12 (m, 4H), 6.96-6.92 (m, 1H), 3.48 ( s, 2H), 2.24 (s, 3H).

3.2.2 Preparation of piperidinecarboxylic acids

General regulation 1 (AV1)

Concentrated aqueous HCl was added to a solution of the pyridine derivative in ethanol until the pH of the solution was 2-3. Palladium-Mohr catalyst (20% w / w) was added, and the suspension was then hydrogenated at 60 ° C. and 3 bar hydrogen pressure for 18 hours. If the TLC or GC reaction was incomplete, additional catalyst was added (20% w / w) and the hydrogenation was repeated under the above conditions. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was taken up in water / ethyl acetate and the pH was adjusted to 10 by adding aqueous NaOH. The phases were separated and the aqueous phase was then extracted with ethyl acetate (3x). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , evaporated and dried in a high vacuum.

3.2.3 Example II Ethyl 2- (2-piperidinyl) acetate

10 g (60.5 mmol) of ethyl 2- (2-pyridinyl) acetate were dissolved in ethanol (100 ml). Yield: 12.0 g (95%). M.p .: 130 ° C ¹ H NMR (400 MHz, D ₆ -DMSO) 1.23 (t, 3H); 1.40-1.85 (m, 6H); 2.70 (dd, 1H); 2.83-2.93 (m, 2H); 3.19-3.25 (M, 1H); 3.30-3.40 (m, 1H); 4.10 (q, 2H); 9.20 (br. S, 1H).

3.2.4 Example III 2- (3-Piperidinyl) ethyl acetate

20.0 g (121 mmol) of ethyl 2- (3-pyridinyl) acetate were dissolved in ethanol (120 ml). Yield: 5.6 g (27%) of a light brown oil. ¹ H NMR (400 MHz, D ₆ -DMSO) 4.05 (q, 7.2 Hz, 2H), 2.88-2.78 (m, 2H), 2.48 (br s, 1H), 2.41-2.36 (m, 1H), 2.20-2.09 (m, 3H), 1.82-1.69 (m, 2H), 1.55-1.49 (m, 1H) ), 1.39-1.30 (m, 1H), 1.18 (t, 7.2 Hz, 3H), 1.09-1.01 (m, 1H).

3.2.5 Example IV 2- (4-Piperidinyl) ethyl acetate

20.0 g (121 mmol) of ethyl 2- (4-pyridinyl) acetate were dissolved in ethanol (150 ml). Yield: 13.2 g (64%) of a yellow oil. ¹ H NMR (400 MHz, D ₆ -DMSO) 4.04 (q, 7.1 Hz), 2.91-2.86 (m, 2H), 2.45-2.38 (m, 2H) , 2.16 (2H, 7.1 Hz), 1.95 (br s, 1H), 1.78-1.65 (m, 1H), 1.57-1.55 (m, 2H), 1 , 17 (t; 7.1 Hz), 1.09-0.98 (m, 2H).

3.2.6 Example V Ethyl 3- (3-piperidinyl) propionate

9.0 g (54.5 mmol) of ethyl 3- (3-pyridinyl) propionate were dissolved in ethanol (45 ml). Yield: 1.6 g (16%) of a yellow oil. ¹ H NMR (400 MHz, D ₆ -DMSO) 4.05 (q, 7.0 Hz), 2.90-2.82 (m, 3H); 2.40-2.35 (m, 1H), 2.78 (t, 7.5 Hz, 2H), 2.11-2.06 (m, 1H), 1.76-1.71 (m, 1H), 1.54-1.51 (m, 1H), 1.45-1.26 (m, 4H), 1.19 (t, 7.0 Hz), 0.99-0.91 (m , 1H).

3.2.7 Example VI 2-Phenyl-2- (2-piperidinyl) methyl acetate

4.50 g (19.8 mmol) of methyl 2-phenyl-2- (2-pyridinyl) acetate were dissolved in ethanol (90 ml). Yield: 3.82 g (83%) of a light brown oil. ESI-MS: 234.2 [M + H] ⁺

3.3 Synthesis of the compounds

The following examples were presented according to Scheme 2:

3.3.1 Step A 3.3.1.1 Example VII

2- {4 - [(2-Toluidinocarbonyl) amino] phenyl} acetyl-L-leucine methyl ester

A solution of 2- {4 - [(2-toluidocarbonyl) amino] phenyl} acetic acid (1.96 g, 6.89 mmol), HOBt (1.16 g, 7.58 mmol) and EDCI in 70 ml of dimethylformamide was added For 90 min at R. t. touched. After adding L-leucine methyl ester hydrochloride (1.25 g, 6.89 mmol) in dimethylformamide (20 ml) and ethyldiisopropylamine (5.75 ml, 34.5 mmol), the mixture was stirred at R.t. touched. The reaction mixture was poured onto water (350 ml) and extracted with ethyl acetate (4 × 150 ml). The combined organic phases were washed with 0.1 N aqueous HCl, saturated aqueous Na ₂ CO ₃ and brine, dried (MgSO ₄ ) and evaporated. Yield: 2.49 g (88%) of a white solid.

M.p. 166-168 ° C; TLC (dichloromethane / MeOH 9: 1): R _f 0.56; ¹ H NMR (400 MHz, D ₆ -DMSO): 8.96 (s, 1H), 8.42 (d, 7.7 Hz, 1H), 7.89 (s, 1H), 7.84 ( d, 7.44 Hz, 1H), 7.38 (d, 8.5 Hz, 2H), 7.18-7.11 (m, 4H), 6.96 (m, 1H), 4.30- 4.23 (m, 1H), 3.61 (m, 3H), 3.43-3.36 (m, 2H), 2.24 (s, 3H), 1.67-1.45 (m, 3H), 0.89 (d, 6.4 Hz, 3H), 0.82 (d, 6.4 Hz, 3H).

3.3.2 Step B 3.3.2.1 Example VIII

2- {4 - [(2-Toluidinocarbonyl) amino] phenyl} acetyl-L-leucine

A solution of 2- {4 - [(2-toluidocarbonyl) amino] phenyl} acetyl-L-leucine methyl ester (2.42 g, 5.88 mmol) and KOH (3.30 g, 58.75 mmol) in methanol / water 1: 1 (180 ml) was stirred at 50 ° C for 5 h. After washing with methyl tert. Butyl ether (80 ml) the reaction mixture was concentrated until a slight turbidity was to be observed. The solution was dissolved by adding 1N aqueous HCl acidified to a pH of 2. The precipitate was filtered off with washed cold water and dried in vacuo. Yield: 1.75 g (72%) of one white solid.

M.p. 178-179 ° C, TLC (dichloromethane / MeOH / AcOH 9: 1: 0.1): R _f 0.16; ¹ H NMR (400 MHz, D ₆ -DMSO): 12.51 (br s, 1H), 9.00 (s, 1H), 8.25 (d, 8.0 Hz, 1H), 7.93 (s, 1H), 7.83 (d, 7.5 Hz, 1H), 7.36 (d, 8.5 Hz, 2H), 7.17-7.12 (m, 4H), 6.95 -6.91 (m, 1H), 4.23-4.17 (m, 1H), 3.43-3.32 (m, 2H), 2.24 (s, 3H), 1.68-1 , 46 (m, 3H), 0.89 (d, 6.5 Hz, 3H), 0.82 (d, 6.5 Hz, 3H).

3.3.3 Step C General regulation C1 (AV C1) Coupling of amines with carboxylic acids

A solution of 1.0 eq. Carboxylic acid, 1.1 eq. HOBt and 1.1 eq. EDCI in DMF was maintained at R. t. touched. After adding 1.0 eq. Amine and 3.0 eq. Ethylisopropylamine was added to R. t. touched. The reaction mixture was poured into 4 times the amount of water. The precipitate was filtered off, washed with cold water and dried in vacuo. If no precipitate had formed, the product was extracted with ethyl acetate (4 ×). The combined organic phases were sown with 1N HCl. Washed aqueous NaHCO ₃ and brine and dried over MgSO ₄ . Evaporation of the solvent gave the product.

3.3.3.1 Example 4

2- (1 - {- 2- (2- {4 - [(2-Toluidinocarbonyl) amino] phenyl} - acetyl) -L-leucine} -2-piperidinyl) ethyl acetate

A solution of 2- {4 - [(2-toluidocarbonyl) amino] phenyl} acetyl-L-leucine (2.00 g, 5.03 mmol) in dimethylformamide (20 ml) was treated with 2- (2-piperidinyl) acetic acid - Ethyl ester (1.24 g, 5.54 mmol) implemented. Flash chromatography (dichloromethane / MeOH 9: 0.1-0.2) gave 1.05 g (38%) of a white solid. Mp 96-98 ° C, TLC (dichloromethane / MeOH / AcOH 9: 1: 0.1): R _f 0.70; ¹ H-NMR (400 MHz, D ₆ -DMSO): 8.96 (s, 1H), 8.34 (d, 9.0 Hz, 0.5H), 8.16 (d, 8.5 Hz, 0.5 H), 7.90 (s, 1H), 7.83 (d, 8.0 Hz, 1H), 7.36 (d, 8.0 Hz, 2H), 7.18-7.10 (m, 4H), 6.95-6.90 (m, 1H), 4.97-4.89 (m, 1H), 4.74-4.70 (m, 0.5H); 4.63-4.58 (m, 0.5H), 4.28-4.23 (m, 0.5H), 4.06-3.98 (m, 2H); 3.68-3.62 (m, 0.5H); 3.41-3.34 (m, 2H); 3.03-2.98 (m, 0.5H), 2.82-2.78 (m, 0.5H); 2.67-2.35 (m, 2H); 2.23 (s, 3H), 1.67-1.28 (m, 9H); 1.18-1.10 (m, 3H), 0.88-0.82 (m, 6H). ESI-MS: 551.4 [M + H] ⁺ .

3.3.3.2 Example 7

3- (1- {2- (2- {4 - [(2-Toluidinocarbonyl) amino] phenyl} - acetyl) -L-leucine} -3-piperidinyl) propionic acid ethyl ester

A solution of 2- {4 - [(2-toluidocarbonyl) amino] phenyl} acetyl-L-leucine (400 mg, 1.00 mmol) in dimethylformamide (20 ml) was treated with 3- (3-piperidinyl) - ethyl propionate (190 mg, 1.00 mmol) reacted. Through flash Chromatography (dichloromethane / MeOH 9: 0.1-0.2) gave 264 mg (47%) of a light brown foam.

TLC (dichloromethane / MeOH 9: 0.5): R _f 0.48; ¹ H NMR (400 MHz, D ₆ -DMSO): 8.94 (s, 1H), 8.30-8.21 (m, 1H), 7.87 (s, 1H), 7.83 (d , 8.0 Hz, 1H), 7.36 (d, 8.5 Hz, 2H), 7.17-7.11 (m, 4H), 6.95-6.91 (m, 1H), 4 , 78-4.72 (m, 1H), 4.25-4.00 (m, 3H), 3.81-3.67 (m, 1H), 3.41-3.35 (m, 2H) , 3.08-2.98 (m, 1H), 2.72-2.27 (m, 3H), 2.24 (s, 3H), 1.78-1.70 (m, 1H), 1 , 65-1.10 (m, 12H), 0.87-8.82 (m, 6H); ESI-MS: 564.9 [M + H] ⁺ .

3.3.4 Step D General regulation D1 (AV D1) Ester saponification

A solution or suspension of the ester and 1.1 eq. KOH in water / ethanol, methanol and / or dioxane was stirred at 25-50 ° C for 2-24 hours. After washing with methyl tert-butyl ether (80 ml), the reaction mixture was concentrated until a slight turbidity became visible. The solution was acidified to a pH of 2 by adding 1N aqueous HCl. The precipitate was filtered off, washed with cold water and dried in vacuo. If no precipitate had formed, the aqueous phase was extracted with ethyl acetate (4 ×). The combined organic phases were washed with water, dried over Na ₂ SO ₄ and evaporated.

3.3.4.1 2- (1- {2- (2- {4 - [(2-Toluidinocarbonyl) amino] phenyl} acetyl) -L-leucine} - 2-piperidinyl) acetic acid

Ethyl 2- (1- {2 - [(2- {4- (2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -2-pi peridinyl) (350 mg, 636 µmol) was added to water (50 ml), ethanol (50 ml) and dioxane (50 ml). The mixture was stirred at 30 ° C for 6 hours to give 236 mg (71%) of a white solid. Mp 121-123 ° C, TLC (dichloromethane / MeOH / AcOH 9: 1: 0.1) R _f 0.64; ¹ H NMR (400 MHz, D ₆ -DMSO): 12.29 (br s, 1H), 8.98 (s, 1H), 8.32-8.16 (m, 1H), 7.91 ( s, 1H), 7.83 (d, 8.0 Hz, 1H), 7.36 (d, 7.0 Hz, 2H), 7.37-7.13 (m, 4H), 6.95- 6.91 (m, 1H), 5.03-4.87 (m, 1H), 4.75-4.60 (m, 1H), 4.30-4.25 (m, 0.5H) , 3.72-3.62 (m, 0.5H); 3.39-3.32 (m, 2H), 3.10 ^-Z , 15 (m, 3H), 2.24 (s, 3H), 1.63-1.10 (m, 9H); 0.89-0.81 (m, 6H). ESI-MS: 523.3 [M + H] ⁺ .

General regulation D2 (AV D2) Deprotection of benzyl esters

A solution or suspension of the ester and 10% Pd-C (10%) in tetrahydrofuran was at R. t. and hydrogenated with hydrogen under normal pressure. The The reaction mixture was filtered through Celite. By evaporating the filtrate you got the product.  

4. In vitro assay Adhesion of Jurkat cells to immobilized VCAM-1 (Domains 1-3) 4.1 Representation of fluorescence-labeled Jurkat cells

Jurkat cells (American Type Culture Collection, Clone E6-1, ATCC TIB-152) were placed in RPMI 1640 medium (Nikken Bio Medical Laboratory, CM1101) containing 10% fetal bovine serum (Hyclone, A-1119-L), 100 U / ml penicillin (Gibco BRL, 15140-122) and 100 µg / ml streptomycin (Gibco BRL, 15140-122) was enriched in a humidified incubator at 37 ° C with 5% CO ₂ .

The Jurkat cells were incubated with phosphate-balanced solution (PBS, Nissui, 05913) containing 25 µM 5 (and 6) carboxyfluorescein diacetate, succinimidyl ester (CFSE, Dojindo Laboratories, 345-06441) for 20 minutes at room temperature, gently every 5 minutes was turned. After centrifuging at 1000 rpm for 5 min, the cell pellet was resuspended with adhesion assay buffer at a cell density of 2 × 10 ⁶ cells / ml. The adhesion assay buffer contained 24 mM Tris-HCl (pH 7.4), 137 mM NaCl, 27 mM KCl, 4 mM glucose, 0.1% bovine serum albumin (BSA, Sigma, A9647) and 2 mM MnCl ₂ .

4.2 Representation of VCAM-1 (extracellular domains 1-3)

Complementary DNA (cDNA) encoding the 7-domain form of VCAM-1 (GenBank accession # M60335) was obtained using Rapid-ScreenTM cDNA library boards (OriGene Technologies, Inc) at the Takara Gene Analysis Center (Shiga, Japan) . The primers used were 5'-CCA AGG CAG AGT ACG CAA AC-3 '(sense) and 5'-TGG CAG GTA TTA TTA AGG AG-3' (antisense). PCR amplification of the 3-domain VCAM-1 cDNA was obtained using Pfu DNA polymerase (Strategene) with the following primer sets: (U-VCAMd1-3) 5'-CCA TAT GGT ACC TGA TCA ATT TAA AAT CGA GAC CAC CCC AGA A-3 '; (L-VCAMd1-3) 5'-CCA TAT AGC AAT CCT AGG TCC AGG GGA GAT CTC AAC AGT AAA-3 '. The PCR cycle was 45 sec at 94 ° C, 45 sec at 55 ° C, 2 min at 72 ° C, 15 cycles being carried out. After purification of the PCR product, the fragment was digested with KpnI-AvrII. The digested fragment was ligated into pBluescript IISK (-) (Strategene), which was linearized by digesting with KpnI-XhoI. The ligation was followed by transformation to a Dam / Dcm methylase-free E. coli strain SCS 110 (Strategene), whereby the donor plasmid pHH7 was obtained. In order to direct the VCAM-1 molecule into the secretory path of the insect cell, the VCAM-1 coding sequence was fused with a signal peptide sequence from Bienenmelittin. The fused melittin VCAM thus obtained was inserted into the baculovirus polyhedrin promoter in the correct orientation. The baculovirus transfer vector containing the first 3-domain form VCAM-1 (pH10) was constructed by ligating a 0.9 kb fragment of pH7 obtained by digestion with AvrII / Klenow / BclI with pMelBacB (Invitrogen) digested with SalI / Klenow / BamHI . Recombinant baculoviruses were obtained using the Bac-N-Blue ^™ Transfection kit (Invitrogen) following the manufacturer's instructions. The recombinant virus was multiplied by infection in High-Five ^™ insect cells for 5-6 days and the virus titer was determined by a plaque assay.

The High-Five ^™ insect cells were pelleted in a 225 ml conical tube by centrifugation at 1000 rpm for 5 minutes. The supernatant was discarded and the pellet was then resuspended in 1.5 × 10 ⁹ pfu (MOI = 5) of a high-titer virus solution and then incubated for 1.5 hours at room temperature. The cells were pelleted again and washed once in fresh Express Five ^™ serum-free medium. The cells were pelleted again and finally resuspended in 200 ml of fresh Express Five ™ medium, transferred to a 1000 ml shaker bottle and incubated in a shaker for 48 hours at 27 ° C, 130 rpm, after which the culture supernatant was removed . The 3-domain form of VCAM-1 was purified from the culture supernatant by single-stage anion exchange chromatography. Protein concentration was determined using the Coomassie protein assay reagent (Pierce) according to the manufacturer's instructions.

4.3 Preparation of the microtiter plates

Recombinant human VCAM-1 (extracellular domains 1-3) was dissolved in PBS at 0.5 µg / ml. Each well of the microtiter plates (Nalge Nung International, Fluoronunc Cert, 437958) was coated with 100 ul substrate or, for background control, only with buffer for 15 hours at 4 ° C. After discarding the substrate solution, the wells were blocked with 150 µl / well of blocking solution (Kirkegaard Perry Laboratories, 50-61-01) for 90 minutes. The plate was washed with wash buffer containing 24mM Tris-HCl (pH 7.4), 137mM NaCl, 27mM KCl and 2mM MnCl ₂ immediately before adding the assay solution containing Jurkat cells and VLA-4 inhibitor.

4.4 Assay method

At a concentration of 3 µM or at different concentrations in the range of 0.0001 µM to 10 µM using a standard 5-point serial dilution, labeled Jurkat cells were incubated with each of the test compounds for 30 minutes at 37 ° C. The assay solution was transferred to the VCAM-1 coated plates at a cell density of 2 x 10 ⁵ cells per well and incubated for 1 hour at 37 ° C. The non-adherent cells were removed by washing the plates 3 times with washing buffer. The adherent cells were broken up by adding 1% Triton X-100 (Nacalai Tesque, 355-01). The released CFSC was quantified by fluorescence measurement in a fluorometer (Wallac, ARVO 1420 multilabel counter).

The adhesion of Jurkat cells to VCAM-1 was analyzed by the percentage Binding, calculated using the formula:  [(FTB - FBG) - (FTS - FBG)] / (FTB - FBG) × 100 =% binding, where FTB for the total fluorescence intensity of wells coated with VCAM-1 without test connection; FGB for the fluorescence intensity of wells without VCAM-1 and FTS for the fluorescence intensity of the invention Wells containing test compound is available.

4.5 In vitro activity

The ranges for the IC ₅₀ values observed in the Jurkat VCAM-1 in vitro assay for Examples 13-23 are given in the table below, the ranges for the IC ₅₀ values being defined as follows: D <10 µM ≧ C <2 µM ≧ B <0.5 µM ≧ A.

5. Pharmacokinetic studies 5.1 Solubility test

0.5 mg 16 was placed in a test tube (12 × 75 mm) with 0.5 ml of the first liquid, pH 1.2 for the solubility test, 66 mM phosphate buffer with 50 µM NaCl (isotonic phosphate buffer) and 20 mM of the sodium salt of deoxycholic acid and the mixture was then added using a magnetic stir bar 5 Stirred at 37 ° C for hours. The solutions were each over a 0.2 µm Filtered membrane filters (Millipore, Japan). The aliquot solutions were then each subjected to HPLC.

5.2 Lipophilicity test

0.8 ml of a solution of the compound in acetonitrile (50 ug / ml) was 8 ml of the isotonic phosphate buffer and the mixture was passed through a 0.2 µm Filtered membrane filter. A filtered solution of 2 ml was washed with 2 ml of n-octanol or shaken iso-octane (300 cycles / min.), provisionally with the Buffer solution saturated and centrifuged at 3000 rpm for 15 minutes. To An aliquot of the aqueous phase was removed to remove the organic phase, diluted with an eluent and subjected to HPLC.

5.3 In vivo test

The compounds were in 10% Cremophor EL in saline at a Concentration of 2 mg / ml dissolved. A dose of 10 mg / kg of the compound was given administered intraperitoneally to female BALB / c mice (JAPAN SLC Inc., Japan), and 5, 15, 30, 60, 120 and 180 min after administration, respectively heparinized syringes blood samples taken from the heart. After 5 minutes Centrifuging at 3000 rpm and 4 ° C became 0.25 ml of the plasma to 0.05 ml Added 1 M HCl and extracted with 7 ml ether. The organic phase was under  evaporated in a stream of nitrogen at 40 ° C and the residue was dissolved in 0.25 ml of the solvent. 0.15 ml of the solution was subjected to HPLC.

5.4 HPLC analysis

HPLC analysis was performed using a reverse phase column, 3 µm Capcell pak ^TM C ₁₈ UG 120, 4.6 x 100 mm (Shiseido, Japan) for the solubility and lipophilicity tests and a 1.3 µm Symmetry Shield ^TM RP8 <column, 4.6 × 100 mm (Waters, USA) for the in vivo investigations on a Hewlett Packard Series 1100 device which was equipped with a UV detector and column oven. The compounds were separated using a mobile phase consisting of acetonitrile and 5 μM formic acid, pH 3.0 (42: 52, v / v), at a column temperature of 40 ° C. and a flow rate of 1.0 ml / min and by UV Absorption detected at 258 nm.

Table 3.1

Physicochemical properties of 16

Table 3.2

Pharmacokinetic parameters of 16 after intraperitoneal administration of 10 mg / kg to mice

Claims (11)

1. Compounds of the general formula (I)
in which
R ¹ and R ^{2 form} a 4- to 8-membered saturated or unsaturated ring-shaped radical which may contain 0 to 1 nitrogen atom and 0 to 2 heteroatoms, independently selected from the group S and O,
wherein the ring-shaped radical formed by R ¹ and R ^{2 is} condensed with a 4- to 8-membered saturated, unsaturated or aromatic ring-shaped radical, which can contain 0 to 2 heteroatoms, independently selected from the group consisting of N, S and O. can,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ² optionally optionally independently of one another by 0 to 2 substituents -R ^1-1 -R ^1-2 -R ^{1 -3} -Z can be substituted, wherein
R ^1-1 for a bond, -O-, -S-, NR ^1-4 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl, a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-1 can} optionally be substituted by 1 to 2 substituents selected from the group R ^1-4 , where R ^{1-4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl , C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-4 may} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-2 stands} for a bond, -O-, -S-, NR ^1-5 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-2 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-5 , where
R ^{1-5 represents} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C _2-10 alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-5 may} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-3 represents} a bond, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-3 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-6 , where
R ^1-6 for hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-6 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
with the proviso that when R ^{1-3 represents} a bond, R ^{1-2 must} not be a heteroatom,
and with the proviso that R ^1-1 and R ^1-2 cannot both simultaneously represent a heteroatom,
Z for hydrogen, -C (O) OR ^Z-1 , -C (O) NR ^Z-2 R ^Z-3 , -SO ₂ NR ^Z-2 R ^Z-3 , -SO (OR ^Z-1 ), - SO ₂ (OR ^Z-1 ), -P (O) R ^Z-1 (OR ^Z-3 ), -PO (OR ^Z-1 ) (OR ^Z-3 ) or 5-tetrazolyl, where
R ^Z-2 for hydrogen, -C (O) R ^Z-4 or -SO ₂ R ^Z-4 , C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, wherein
R ^{Z-2 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, where
R ^{Z-4 represents} C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^{Z-4 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
R ^Z-1 and R ^{Z-3 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₆ or C. ₁₀ aryl, whereby
R ^Z-1 and R ^{Z-3 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ^{2 is} optionally substituted by 0 to 2 substituents R ^1-8 , halogen, nitro, amino, cyano and oxo can be where
R ^{1-8 can be selected} independently of one another from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, and wherein
R ^1-8 can be substituted by 0-5 halogen atoms,
R ^{3 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic Radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 R ^3-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^3-1 radicals, wherein
R ^3-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^3-2 , -SR ^3-2 , -NR ^3-3 R ^3-4 , -C (O) R ^3-2 , S ( O) R ^3-2 , -SO ₂ R ^3-2 , -CO ₂ R ^3-2 , -OC (O) R ^3-2 , -C (O) NR ^3-3 R ^3-4 , -NR ^{3 -2} C (O) R ^3-2 , -SO ₂ NR ^3-3 R ^3-4 , NR ^3-2 SO ₂ R ^3-2 , -NR ^3-2 C (O) NR ^3-3 R ^{3- 4} , -NR ^3-2 C (O) OR ^3-2 , OC (O) NR ^3-3 R ^3-4 , halogen, cyano, nitro or oxo, where
R ^{3-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy by a substituent , Phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano may be substituted, and wherein
R ^3-3 and R ^{3-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, or
R ^3-3 and R ^3-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^3-3 and R ^{3-4 are} bound and which contains up to 2 additional heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur and contains up to 2 double bonds,
R ^{4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic Radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^4-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^4-1 radicals, wherein
R ^4-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^4-2 , -SR ^4-2 , -NR ^4-3 R ^4-4 , -C (O) R ^4-2 , S ( O) R ^4-2 , -SO ₂ R ^4-2 , -CO ₂ R ^4-2 , OC (O) R ^4-2 , -C (O) NR ^4-3 R ^4-4 , -NR ^{4- 2} C (O) R ^4-2 , -SO ₂ NR ^4-3 R ^4-4 , NR ^4-2 SO ₂ R ^4-2 , -NR ^4-2 C (O) NR ^4-3 R ^4-4 , -NR ^4-2 C (O) OR ^4-2 , -OC (O) NR ^4-3 R ^4-4 , halogen, cyano, nitro or oxo, where
R ^{4-2 is} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy by a substituent , Phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano may be substituted, and wherein
R ^4-3 and R ^{4-4 are the} same or different and each represents hydrogen, C _1-4 alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^4-3 and R ^4-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^4-3 and R ^{4-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur and contains up to 2 double bonds,
R ^{5 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic Radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^5-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R ^5-1 , where
R ^5-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^5-2 , -SR ^5-2 , -NR ^5-3 R ^5-2 , -C (O) R ^5-2 , S ( O) R ^5-2 , -SO ₂ R ^5-2 -CO ₂ R ^5-2 , -OC (O) R ^5-2 , -C (O) NR ^5-3 R ^5-4 , -NR ^{5- 2} C (O) R ^5-2 , -SO ₂ NR ^5-3 R ^5-4 , NR ^5-2 SO ₂ R ^5-2 , -NR ^5-2 C (O) NR ^5-3 R ^5-4 , -NR ^5-2 C (O) OR ^5-2 , -OC (O) NR ^5-3 R ^5-4 , halogen, cyano, nitro or oxo, where
R ^{5-2 is} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy by a substituent , Phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano may be substituted, and wherein
R ^5-3 and R ^{5-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^5-3 and R ^5-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^5-3 and R ^{5-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur and contains up to 2 double bonds,
R ^{6 represents} phenyl or a 5-6-membered aromatic heterocyclic radical with up to 3 heteroatoms, independently selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be condensed with a 5-8-membered saturated or unsaturated ring-shaped radical having up to 2 heteroatoms, independently selected from the group consisting of oxygen, nitrogen or sulfur,
and which can optionally be substituted by 0 to 2 substituents which independently of one another from the group bond, C _1-10 alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ - C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms, independently selected from the group consisting of oxygen, nitrogen or sulfur, are selected, these substituents optionally being substituted by 1 to 3 R ^6-1 radicals can be where
R ^6-1 for C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-2 , -SR ^6-2 , -NR ^6-2 R ^6-3 , -C (O) R ^6-2 , S ( O) R ^6-2 , -SO ₂ R ^6-2 , -CO ₂ R ^6-2 , -OC (O) R ^6-2 , -C (O) NR ^6-2 R ^6-3 , -NR ^{6 -3} C (O) R ^6-2 , -SO ₂ NR ^6-2 R ^6-3 , NR ^6-3 SO ₂ R ^6-2 , -NR ^6-3 C (O) NR ^6-2 R ^{6- 4} , -NR ^6-3 C (O) OR ^6-2 , -OC (O) NR ^6-2 R ^6-3 , halogen, cyano, nitro or oxo, where
R ^{6-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen , Nitrogen or sulfur,
which can optionally be substituted by 1 to 3 substituents R ^6-5 , where
R ^{6-5 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-6 , -SR ^6-6 , -NR ^6-7 R ^6-8 , where
R ^6-6 for hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, which is optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C by 1 to 3 substituents ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, and where
R ^6-7 and R ^{6-8 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which is optionally substituted by 1 to 2 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy can be,
or
R ^6-7 and R ^6-8 together form a 4-7-membered ring with up to 2 additional heteroatoms, selected from the group consisting of oxygen, nitrogen or sulfur, and with up to 2 double bonds, which are optionally selected from 1 to 2 substituents the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxyl, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo may be substituted, and wherein
R ^6-3 and R ^{6-4 are the} same or different and each represents hydrogen, a bond, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-9 , -SR ^6-9 , -NR ^6-10 R ^6-11 , where
R ^{6-9 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
which is optionally substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy can be, and being
R ^6-10 and R ^{6-11 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which is optionally substituted by 1 to 2 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy can be,
or
R ^6-9 and R ^6-10 together form a 4-7-membered ring with up to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and with up to 2 double bonds, which are optionally selected from the group by 1 or 2 substituents C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo can be substituted
or
R ^6-2 and R ^6-3 and / or R ^6-3 and R ^6-4 together form a 4-7-membered ring which has the nitrogen atom to which R ^6-3 , R ^6-3 and R ^{6- 4 are} bound, and which contains up to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and up to 2 double bonds, which are optionally selected from the group C ₁ -C ₄ alkyl, C ₁ -C by 1 or 2 substituents ₄ alkyloxy, phenyl, benzyl, C ₃ -C ₆ cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo can be substituted,
and which can furthermore be independently substituted by 0 to 3 substituents R ^6-5
or
R ³ and R ⁴ or R ⁴ and R ⁵ together form a 4-7-membered saturated or unsaturated ring with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, which is optionally selected from the group C ₁ by 1 or 2 substituents -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo and which can be substituted with a 3-7-membered homocyclic or heterocyclic, saturated, unsaturated or aromatic ring can be condensed
A for -C (O) -, -C (O) -C (O) -, -SO-, -SO ₂ -, -P (O) R ^A-1 -, -PO ₂ -, 2-pyrimidyl, 4-pyrimidyl, 2-pyridyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl or a ring selected from the following group:
wherein the ring systems listed above may optionally be substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, nitro, amino, cyano, where
R ^{A-1 can be selected} from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy,
X represents a bond, -CR ^X-1 R ^X-2 -, oxygen or -NR ^X-3 , where
R ^X-1 , R ^X-2 , R ^{X-3 can be selected} independently of one another from the group bond, hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl,
or
together with R ^{6 form} a 4-7-membered ring which includes the nitrogen atom to which R ⁶ and R ^X-1 or R ^X-2 or R ^X-3 can be bound and which can contain up to two additional heteroatoms independently selected from one another from the group consisting of oxygen, nitrogen or sulfur, and can contain up to 2 double bonds, which are optionally selected from the group C ₁ -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ by 1 to 2 substituents -C ₄ alkyloxy, halogen, nitro, cyano, oxo can be substituted,
Y represents a bond, -C (O) -, -S (O) -, -SO ₂ -, -O-, -S-, -CR ^Y-1 R ^Y-2 -, or -NR ^Y-3 , where R ^Y-1 , R ^Y-2 , R ^{Y-3 can be selected} independently from the group bond, hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl,
and optionally substituted by 1 to 2 substituents independently selected from the group C ₁ -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo ,
D represents N, or CR ^D-1 , where
R ^{D-1 can be selected} independently from the group bond, hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₂ -C ₄ alkynyl
and optionally substituted by 1 to 2 substituents independently selected from the group C ₁ -C ₄ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo ,
and with the proviso that Y and D are not heteroatoms at the same time,
and their pharmaceutically acceptable salts. 2. Compounds according to claim 1, characterized in that
R ¹ and R ^{2 form} a 4- to 8-membered saturated or unsaturated ring-shaped radical which can contain 0 to 1 nitrogen atom and 0 to 1 hetero atom, independently selected from the group S and O,
wherein the ring-shaped radical formed by R ¹ and R ^{2 is} condensed with a 5- to 7-membered saturated, unsaturated or aromatic ring-shaped radical, which may contain 0 to 2 heteroatoms, independently selected from the group consisting of N, S and O. can,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring condensed with the ring-shaped radical formed by R ¹ and R ² optionally optionally independently of one another by 1 to 2 substituents -R ^1-1 -R ^1-2 -R ^{1 -3} -Z can be substituted, wherein
R ^1-1 for a bond, -O-, -S-, NR ^1-4 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl, a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-1 can} optionally be substituted by 1 to 2 substituents selected from the group R ^1-4 , where R ^{1-4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl , C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-4 may} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-2 stands} for a bond, -O-, -S-, NR ^1-5 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-2 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-5 , where
R ^1-5 for hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-5 may} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
R ^{1-3 represents} a bond, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, where
R ^{1-3 can} optionally be substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl or R ^1-7 , where
R ^1-7 for hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, where
R ^{1-7 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, halogen, nitro, cyano, oxo,
with the proviso that when R ^{1-3 represents} a bond, R ^{1-2 must} not be a heteroatom,
and with the proviso that R ^1-1 and R ^1-2 cannot both simultaneously represent a heteroatom,
Z for hydrogen, -C (O) OR ^Z-1 , -C (O) NR ^Z-2 R ^Z-3 , -SO ₂ NR ^Z-2 R ^Z-3 , -SO (OR ^Z-1 ), - SO ₂ (OR ^Z-1 ) or 5-tetrazolyl, where
R ^{Z-2 represents} hydrogen, -C (O) R ^Z-4 or -SO ₂ R ^Z-4 , C ₁ -C ₄ alkyl, C ₃ - C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^{Z-2 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, where
R ^{Z-4 represents} C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^{Z-4 can} optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
R ^Z-1 and R ^{Z-3 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, where
R ^Z-1 and R ^{Z-3 can} optionally be substituted by 1 to 3 substituents selected from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ^{2 is} optionally substituted by 0 to 2 substituents R ^1-8 , halogen, nitro, amino, cyano and oxo can be where
R ^{1-8 can be selected} independently of one another from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, phenyl, C ₃ -C ₆ cycloalkyl, and wherein
R ^1-8 can be substituted by 0-5 halogen atoms,
R ^{3 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or Sulfur stands,
which may optionally be substituted by 1 to 2 R ^3-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which may optionally be substituted by 1 to 3 R ^3-1 radicals, wherein
R ^{3-1 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^3-2 , -NR ^3-3 R ^3-4 , -CO ₂ R ^3-2 , halogen, cyano, nitro or oxo, where
R ^{3-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl and where
R ^3-3 and R ^{3-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^3-3 and R ^3-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^3-3 and R ^{3-4 are} bound and which contains up to 2 additional heteroatoms selected from the group consisting of oxygen , Contains nitrogen or sulfur,
R ^{4 is} hydrogen, C ₁ -C ₁₀ alkyl, C ₆ or C ₁₀ aryl, C ₃ -C ₇ cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or Is sulfur, which can optionally be substituted by 1 to 3 radicals R ^4-1 ,
and which is furthermore simply selected from C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms from the group consisting of oxygen, nitrogen or sulfur, which may be replaced by 1 to 3 R ^4-1 may be substituted, may be substituted, wherein
R ^{4-1 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^4-2 , -NR ^4-3 R ^4-4 , -CO ₂ R ^4-2 , halogen, cyano, nitro or oxo, where
R ^{4-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl and where
R ^4-3 and R ^{4-4 are the} same or different and each represents hydrogen, C _1-4 alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^4-3 and R ^4-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^4-3 and R ^{4-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Contains nitrogen or sulfur,
R ^{5 represents} hydrogen, C ₁ -C ₁₀ alkyl,
which may optionally be substituted by 1 to 3 R ^5-1 radicals,
and which can furthermore be simply substituted by C ₃ -C ₇ cycloalkyl, C ₆ or C ₁₀ aryl, C ₄ -C ₉ heteroaryl or a heterocyclic radical with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R ^5-1 , where
R ^{5-1 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^5-2 , -NR ^5-3 R ^5-4 , -CO ₂ R ^5-2 , halogen, cyano, nitro or oxo, where
R ^{5-2 represents} hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl and where
R ^5-3 and R ^{5-4 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl,
or
R ^5-3 and R ^5-4 together form a 4-7-membered ring which includes the nitrogen atom to which R ^5-3 and R ^{5-4 are} bonded and which has up to 2 additional heteroatoms selected from the group consisting of oxygen , Contains nitrogen or sulfur,
R ^{6 represents} phenyl or a 6-membered aromatic heterocyclic radical with up to 2 nitrogen atoms,
which may optionally be independently selected from the group bond independently by a substituent,
where these substituents can optionally be substituted by a radical R ^6-1 , wherein
R ^6-1 for -C (O) NR ^6-2 R ^6-3 , -NR ^6-3 C (O) R ^6-2 , -SO ₂ NR ^6-2 R ^6-3 , NR ^6-3 SO ₂ R ^6-2 , -NR ^6-3 C (O) NR ^6-2 R ^6-4 , -NR ^6-3 C (O) OR ^6-2 , -OC (O) NR ^6-2 R ^{6- 3} stands, whereby
R ^{6-2 represents} C ₆ or a 5-6-membered unsaturated heterocyclic radical with up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents R ^6-5 , where
R ^{6-5 represents} C ₁ -C ₄ alkyl, trifluoromethyl, trifluoromethoxy, -OR ^6-6 , -SR ^6-6 , -NR ^6-7 R ^6-8 , where
R ^{6-6 represents} hydrogen, C ₁ -C ₄ alkyl, and wherein
R ^6-7 and R ^{6-8 are the} same or different and each represents hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl,
or
R ^6-7 and R ^6-8 together form a 5-6-membered ring which contains up to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and wherein
R ^6-3 and R ^{6-4 are the} same or different and each represents hydrogen, a bond, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl,
and which can furthermore be independently substituted by 0 to 2 substituents R ^6-5 ,
or
R ³ and R ⁴ together form a 4-7-membered saturated ring with up to 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, which is optionally substituted by 1 to 2 substituents selected from the group C ₁ -C ₄ alkyl, phenyl, Benzyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₄ alkyloxy, halogen, nitro, cyano, oxo, may be substituted
A stands for -C (O) -, -SO ₂ -,
X represents a bond, -CR ^X-1 R ^X-2 -, oxygen or -NR ^X-3 , where
R ^X-1 , R ^X-2 , R ^{X-3 can be selected} independently of one another from the group bond, hydrogen, C ₁ -C ₄ alkyl,
Y represents a bond, -C (O) -, -SO ₂ -, -O-, -CR ^Y-1 R ^Y-2 - or -NR ^Y-3 , where
R ^Y-1 , R ^Y-2 , R ^{Y-3 can be selected} independently of one another from the group bond, hydrogen, C ₁ -C ₄ alkyl,
D represents N or CR ^D-1 , where
R ^{D-1 can be selected} independently from the group bond, hydrogen, C ₁ -C ₄ alkyl,
with the proviso that Y and D are not both heteroatoms at the same time, and that
and their pharmaceutically acceptable salts. 3. Compounds according to claim 1 or 2, characterized in that
R ¹ and R ^{2 form} a 5- or 6-membered saturated ring-shaped radical which may contain 1 nitrogen atom,
wherein the ring-shaped radical formed by R ¹ and R ² can be condensed with a 5-membered saturated ring-shaped radical which contains a nitrogen atom,
and wherein the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ^{2 is} optionally independent of a substituent -R ^1-1 -R ^1-2 - R ^1-3 - Z can be substituted, wherein
R ^{1-1 represents} a bond or C ₁ -C ₂ alkyl, where
R ^{1-1 can} optionally be substituted by 1 C ₆ aryl,
R ^{1-2 represents} a bond,
R ^{1-3 represents} a bond,
Z represents -C (O) OR ^Z-1 or 5-tetrazolyl,
R ^{Z-1 represents} hydrogen or C ₂ alkyl, and wherein
the ring-shaped radical formed by R ¹ and R ² and / or a ring fused with the ring-shaped radical formed by R ¹ and R ² may optionally be substituted by 0 or 1 substituents R ^1-8 , where
R ^{1-8 represents} C ₁ alkyl, and wherein
R ^1-8 is substituted by 3 fluorine atoms,
R ^{3 represents} isobutyl,
R ⁴ and R ^{5 represent} hydrogen,
R ⁶ for
stands,
A stands for -C (O) -,
X stands for -CH ₂ -
Y stands for -C (O) -,
D stands for nitrogen,
and their pharmaceutically acceptable salts. 4. Compounds according to any one of claims 1 to 3, characterized in that R ¹ and R ^{2 form} a piperidine ring. 5. Compounds according to any one of claims 1 to 3, characterized in that R ¹ and R ^{2 form} a pyrrolidine ring. 6. Compounds according to one of claims 1 to 5, characterized in that
R ⁶ for
stands, 7. Compounds according to one of claims 1 to 6, characterized in that the compound is selected from the following group:
N - ((1S) -3-Methyl-1 - {[3- (1H-tetraazol-5-yl) -1-pyrrolidinyl] carbonyl} butyl) - 2- {4 - [(2-toluidinocarbonyl) amino] phenyl } acetamide
1 - {({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -2- piperidinecarboxylic acid,
1 - {({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3- piperidinecarboxylic acid,
1 - {({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -4- piperidinecarboxylic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -2-piperidinyl) acetic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3- piperidinyl) acetic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -4- piperidinyl) acetic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3-piperidinyl) propionic acid,
(3S) -1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -4- (trifluoromethyl) -3-pyrrolidinecarboxylic acid,
5- (ethoxycarbonyl) -1- {2 - ({4 - [(2-toluidinocarbonyl) amino] phenyl} acetyl) -L-leucine} octahydropyrrolo [3,4-b] pyrrole-2-carboxylic acid,
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -2-piperidinyl) (phenyl) acetic acid and
(1- {2 - ({4 - [(2-toluidocarbonyl) amino] phenyl} acetyl) -L-leucine} -3-oxo-2-piperazinyl) acetic acid. 8. Use of a compound according to one of claims 1 to 7 for Manufacture of a drug. 9. Use of a compound according to one of claims 1 to 7 for Manufacture of a medication to treat a condition caused by Integrine is conveyed. 10. Pharmaceutical composition containing compounds according to a of claims 1 to 7 and a pharmaceutically acceptable carrier. 11. Process for the preparation of compounds of the general formula (VII)
according to one of claims 1 to 6, characterized in that a carboxylic acid of the general formula (V)
or one of its activated derivatives with compounds of the general formula (VI)
is implemented.