New beta-agonists, processes for preparing them and their use as pharmaceutical compositions

Abstract

The present invention relates to new beta-agonists of general formula 1: wherein the groups R 1 to R 12 have the meanings given in the claims and specification, the isomers thereof, processes for preparing these compounds and their use as pharmaceutical compositions.

1 . Compounds of general formula (I),  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 10 , R 11  independently of one another denote a group selected from among hydrogen, halogen, CN, NO 2 , and —NHCXNH 2  or  
 a group selected from among optionally substituted —COR 7 , —COOR 7 , —CONR 7 R 13 , —OR 14 , NR 13 R 15 , C 1 -C 10 -alkyl, C 3 -C 8 -cycloalkyl, —NR 16 CX—R 17 , —NR 18 CX—OR 19 , —NR 20 SO m R 21 , —SO p NR 22 R 23 and —SO q R 24 .  
 m, p, q denotes 0, 1 or 2  
 n denotes 0, 1, 2 or 3  
 R 3  denotes hydrogen or a group selected from among optionally substituted C 1 -C 10 -alkyl, C 6 -C 10 -aryl, heterocyclyl and C 3 -C 8 -Cycloalkyl, —CX—C 1 -C 10 -alkyl, —CX—C 6 -C 14 -aryl,  
 R 4 , R 5  independently of one another denote hydrogen, halogen or optionally substituted C 1 -C 10 -alkyl, or  
 R 4  and R 5  together denote a C 3 -C 8 -alkyl bridge,  
 R 6  denotes a group selected from among the general formulae  
                     
 l,k independently of one another denote 1, 2 or 3,  
 R 25 , R 26 , R 27 , R 28  independently of one another denote a group selected from among hydrogen, OH, halogen, CN and NO 2 , or  
 a group selected from among optionally substituted C 1 -C 10 -alkyl, C 6 -C 18 -aryl, heteroaryl, heterocyclyl, —CX—R 17 , —OR 14 , NR 13 R 15 , C 2 -C 8 -cycloalkyl —NR 20 SO m R 21 , —SO p NR 22 R 23 , —SO q R 24 , —NR 18 CX—R 19 , —NR 18 CXOR 17 ,while R 25  and R 26  cannot simultaneously denote hydrogen,  
 R 8  denotes hydrogen or a group selected from among optionally substituted C 1 -C 10 -alkyl, C 6 -C 18 -aryl, —SO q —C 1 -C 10 -alkyl, —SO q —C 6 -C 14 -aryl, —CX—C 1 -C 10 -alkyl, —CX—C 6 -C 14 -aryl, C 6 -C 10 -aryl, heterocyclyl and C 3 -C 8 -cycloalkyl  
 R 9  denotes hydrogen or a group selected from among optionally substituted C 1 -C 10 -alkyl, C 6 -C 14 -aryl, heteroaryl, C 3 -C 8 -cycloalkyl and heterocycloalkyl,  
 R 12  denotes hydrogen or a group selected from among optionally substituted benzyl, C 1 -C 12 -alkyl and C 6 -C 14 -aryl,  
 R 7 , R 13 , R 15 , R 16 , R 18 , R 20 , R 22 , R 23  independently of one another denote hydrogen, or  
 a group selected from among optionally substituted C 1 -C 10 -alkyl, C 6 -C 14 -aryl, heterocyclyl and C 3 -C 8 -cycloalkyl  
 R 14 , R 19 , R 29  independently of one another denote hydrogen or a group selected from among optionally substituted C 1 -C 10 -alkyl, C 6 -C 14 -aryl, C 3 -C 8 -cycloalkyl, heteroaryl, heterocyclyl, —CXNR 13 R 15  and —CXR 7    
 R 17  denotes a group selected from among C 1 -C 10 -alkyl, C 6 -C 14 -aryl, heterocyclyl, heteroaryl and C 3 -C 8 -cycloalkyl  
 R 21 , R 24  independently denote hydrogen or OH, or  
 a group selected from among optionally substituted N(C 1 -C 10 -alkyl) 2 , N(C 3 -C 8 -cycloalkyl), C 1 -C 10 -alkyl, C 6 -C 14 -aryl, heterocyclyl, heteroaryl and C 3 -C 8 -cycloalkyl and  
 X denotes O, S or NR 29 ,  
 optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, as well as optionally the pharmacologically acceptable acid addition salts thereof.  
 
     
     
         2 . Compounds according to  claim 1 ,  
       wherein 
 R 10 , R 11  independently of one another denote hydrogen or halogen,  
 m, p, q independently of one another denote 0, 1 or 2  
 n denotes 0, 1, 2 or 3  
 R 3  denotes hydrogen or C 1 -C 5 -alkyl  
 R 4 , R 5  independently of one another denote hydrogen or C 1 -C 5 -alkyl,  
 R 8  denotes a group selected from among hydrogen, C 1 -C 5 -alkyl, —SO q —C 1 -C 5 -alkyl, —SO q —C 6 -C 14 -aryl, phenyl and C 3 -C 6 -cycloalkyl  
 R 9  denotes hydrogen or C 1 -C 10 -alkyl  
 R 12  denotes hydrogen or benzyl  
 R 13 , R 15 , R 16 , R 18  independently of one another denote a group selected from among hydrogen, C 1 -C 5 -alkyl, C 3 -C 6 -cycloalkyl and phenyl  
 R 14 , R 19  independently of one another denote hydrogen or C 1 -C 5 -alkyl, and  
 R 17  denotes optionally substituted C 1 -C 5 -alkyl or C 6 -C 10 -aryl.  
 
     
     
         3 . Compounds according to  claim 1  or  2 , wherein 
 R 10,  R 11  denote hydrogen  
 m, p, q denote 0, 1 or 2  
 n denotes 0, 1, 2 or 3  
 R 3  denotes hydrogen  
 R 4 , R 5  independently of one another denote hydrogen or methyl,  
 R 8  denotes hydrogen, —SO q —C 6 -C 14 -aryl or —SO 2 —C 1 -C 5 -alkyl  
 R 9  denotes hydrogen  
 R 12  denotes hydrogen or benzyl,  
 R 13 , R 15 , R 16 , R 18  independently of one another denote a group selected from among hydrogen, C 1 -C 15 -alkyl and phenyl,  
 R 14 , R 19  independently of one another denote hydrogen or C 1 -C 5 -alkyl, and  
 R 17  denotes C 1 -C 5 -alkyl or C 6 -C 14 -aryl.  
 
     
     
         4 . Compounds according to one of  claims 1  to  3 , wherein 
 R 1  denotes a group selected from among hydrogen, NO 2 , NH 2 , —NHCX—R 17  and —NHSO 2 R 21    
 R 2  denotes hydrogen or halogen  
 n denotes 2,  
 R 3  denotes hydrogen  
 R 4 , R 5  denote hydrogen or methyl  
 R 6  denotes a group selected from among the general formulae  
                     
 l,k denote 1  
 R 26 , R 27  denote hydrogen,  
 R 8  denotes hydrogen or —SO 2 CH 3 ,  
 R 9  denotes hydrogen,  
 R 10,  R 11  denote hydrogen, and  
 R 12  denotes hydrogen or benzyl.  
 
     
     
         5 . Compounds according to one of  claims 1  to  4 , wherein 
 R 6  denotes a group selected from among the general formulae  
                     
 
     
     
         6 . Compounds according to one of  claims 1  to  5 , wherein 
 R 6  denotes an optionally substituted group of formula (j)  
                     
 
     
     
         7 . Compounds of formula (I) according to one of  claims 1  to  6  for use as pharmaceutical compositions.  
     
     
         8 . Compounds of formula (I) according to one of  claims 1  to  6  for use as pharmaceutical compositions with a selective beta-3-agonistic activity.  
     
     
         9 . Use of a compound of formula (I) according to one of  claims 1  to  6  for preparing a pharmaceutical composition for the treatment and/or prevention of diseases connected with the stimulation of beta-3-receptors.  
     
     
         10 . Method for the treatment and/or prevention of diseases connected with the stimulation of beta-3-receptors, characterised in that an effective amount of a compound of formula I according to  claim 1  to  6  is administered to a patient.  
     
     
         11 . Pharmaceutical composition, containing as active substance one or more compounds of general formula (I) according to one of  claims 1  to  6  or the physiologically acceptable salts thereof optionally combined with conventional excipients and/or carriers.  
     
     
         12 . Pharmaceutical composition containing as active substance one or more compounds of general formula (I) according to one of  claims 1  to  6  or the physiologically acceptable salts thereof and one or more active substances selected from among antidiabetics, inhibitors of protein tyrosinephosphatase 1, substances which influence deregulated glucose production in the liver, lipid lowering agents, cholesterol absorption inhibitors, HDL-raising compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors.  
     
     
         13 . Process for preparing a compound of general formula (I),  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 -R 28  and X may have the meanings given in  claims 1  to  6 ,  
 characterised in that a compound of general formula (II)  
                     
 wherein  
 R 4  and R 5  have the meanings given in  claims 1  to  6 ,  
 is converted by means of a chlorinating agent into a compound of formula (III)  
                     
 the compound of formula (III), optionally provided with an amino protective group, is reacted with an optionally substituted compound selected from among the general formulae (IVa) to (IVi)  
                     
 wherein  
 k, l, R 27  and R 28  have the meanings given in  claims 1  to  6 ,  
 and the product of formula (V)  
                     
 wherein n, R 4 , R 5 , R 6  and R 8  have the meanings given in  claims 1  to  6 ,  
 is reacted with a compound of formula (VI)  
                     
 wherein R 1 , R 2 , R 9  and R 10  to R  12  have the meanings given in  claims 1  to  6 .