Beta-amino acid compounds as integrin antagonists

Abstract

The present invention relates to compounds of the general formula (I), wherein the residues R represent organic radicals, X represents a bond, oxygen or —NR 12 and Y represents oxygen or sulfur, processes for their preparation, pharmaceutical compositions containing them as well as their use for the production of pharmaceutical compositions for the treatment of inflammatory, autoimmune and immune diseases.

1 . A compound of formula (I),  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , together with the carbon atom to which it is attached, and R 2 , together with the nitrogen atom to which it is attached, form a piperidinyl ring;  
 R 3  represents hydrogen;  
 R 4  represents hydrogen;  
 R 5  represents hydrogen;  
 R 6  represents C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 6  or C 10  aryl, or C 3 -C 7  cycloalkyl, which can optionally be substituted by 1 to 3 radicals R 31  and which can furthermore be single-foldedly substituted by C 3 -C 7  cycloalkyl, or C 6  or C 10  aryl, which can optionally be substituted by 1 to 3 radicals R 31 , 
 wherein  
 R 31  represents —OR 32 ,  
 wherein  
 R 32  represents C 1 -C 4  alkyl;  
 
 R 7  represents hydrogen;  
 R 8  represents hydrogen;  
 R 9  represents 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 residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can furthermore be single-foldedly substituted by C 3 -C 7  cycloalkyl, C 6  or C 10  aryl, C 4 -Cg heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 3 radicals R 43 , and which can furthermore be single-foldedly substituted by C 3 -C 7  cycloalkyl, C 6  or C 10  aryl, C 4 -Cg heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 3 radicals R 43 , 
 wherein  
 R 43  represents C 1 -C 4  alkyl, trifluormethyl, trifluormethoxy, —OR 44 , —SR 44 , NR 45 R 46 , C(O)R 44 , S(O)R 44 , —SO 2 R 44 , —CO 2 R 44 , —OC(O)R 44 , —C(O)NR 45 R 46 , —NR 44 C(O)R 44 , —SO 2 NR 45 R 46 , NR 44 SO 2 R 44 , —NR 44 C(O)NR 4 R 46 , —NR 44 C(O)OR 44 , —OC(O)NR 45 R 46 , halogen, cyano, tetrazolyl, nitro or oxo, wherein R 44  represents hydrogen, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 6  or C 10  aryl which can optionally be substituted by 1 substituent selected from the group C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, phenyl, C 3 -C 6  cycloalkyl, halogen, nitro, cyano, and  
 wherein  
 R 45  and R 46  are identical or different and represent 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 residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can furthermore be substituted by C 1 -C 10  alkyl, C 3 -C 7  cycloalkyl, C 6  or C 10  aryl, benzyl, diphenylmethyl, C 4 -Cg heteroaryl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,  
 or  
 R 45  and R 46  together form a 4-7-membered ring, which includes the nitrogen atom to which R 45  and R 46  are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, which can furthermore be substituted by C 1 -C 10  alkyl, C 3 -C 7  cycloalkyl, C 6  or C 10  aryl, benzyl, diphenylmethyl, C 4 -Cg heteroaryl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can be fused with a 3-7 membered homocyclic or heterocyclic, saturated or unsaturated ring,  
 
 A represents —SO—, or —SO 2— ;  
 X represents a bond, oxygen or —NR 12 , 
 wherein  
 R 12  represents hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or C 2 -C 4  alkynyl;  
 
 Y represents oxygen; and  
 Z represents —C(O)OR 47 , 
 wherein  
 R 47  represents hydrogen;  
 
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of  claim 1 , 
 wherein    R 6  represents C 1 -C 10  alkyl, or C 10  aryl or C 3 -C 7  cycloalkyl, which can optionally be-substituted by 1 to 3 radicals R 31 , 
 wherein  
 R 31  represents —OR 32  or halogen,  
 wherein  
 R 32  represents methyl;  
   R 9  represents C 1 -C 10  alkyl, which is single-foldedly substituted by C 6  aryl, which is single-foldedly substituted by C 6  aryl, which can optionally be substituted by 1 to 3 radicals R 43 , 
 wherein  
 R 43  represents C 1 -C 4  alkyl, —OR 44  or halogen, wherein R 44  represents C 1 -C 4  alkyl,  
   or a pharmaceutically acceptable salt thereof.    
     
     
         3 . The compound of  claim 1 , 
 wherein    A represents —SO 2 —,    or a pharmaceutically acceptable salt thereof.    
     
     
         4 . (canceled)  
     
     
         5 . (canceled)  
     
     
         6 . (canceled)  
     
     
         7 . (canceled)  
     
     
         8 . (canceled)  
     
     
         9 . (canceled)  
     
     
         10 . (canceled)  
     
     
         11 . (canceled).  
     
     
         12 . A method of treating a condition mediated by integrins comprising administering to a mammal an effective amount of a compound of  claim 1 .  
     
     
         13 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         14 . A method of treating arteriosclerosis, asthma, allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, transplant rejection and other inflammatory, autoimmune and immune disorders, comprising administering to a mammal an effective amount of a compound of  claim 1.