N-biarylamides

Abstract

The invention relates to N-biarylamides, methods for production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases and for improvement in cognition, concentration power, learning power and/or memory.

1 - 11 . (canceled) 
     
     
         12 : A method for treating cognitive impairment in a patient suffering from mild cognitive impairment comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         in a pharmaceutically effective amount, 
         wherein:
 R 1  is a group of the formula —NR 2 —CO—NR 3 R 4 , —NR 2 —CO—CO—OR 5 , —NH—SO 2 R 6 , —SO 2 NHR 7  or —NH—CO—R 8 ; 
 R 2  is hydrogen or C 1 -C 6 -alkyl; 
 R 3  and R 4  are independently of one another hydrogen, C 1 -C 6 -alkyl, C 3 —C-cycloalkyl or phenyl, which is optionally substituted by up to 3 radicals independently of one another selected from the group of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, trifluoromethyl and trifluoromethoxy; or 
 R 3  and R 4  together with the nitrogen atom to which they are bonded form a 5- to 6-membered heterocyclyl, 
 R 5  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl or aryl, where C 1 -C 6 -alkyl is optionally substituted by aryl, 
 R 6  is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to 6-membered heteroaryl, where C 1 -C 6 -alkyl is optionally substituted by aryl, 
 R 7  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to 6-membered heteroaryl, where C 1 -C 6 -alkyl is optionally substituted by aryl; 
 R 8  is C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkyl or phenyl, wherein C 1 -C 6 -alkyl is substituted by C 1 -C 6 -alkoxy and phenyl by 1 to 3 radicals independently of one another selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, trifluoromethyl and trifluoromethoxy, 
 
         or a salt thereof. 
       
     
     
         13 : The method of  claim 12 , further comprising co-administering a second active ingredient for the treatment of the mild cognitive impairment. 
     
     
         14 : The method of  claim 12 , wherein the administering is by an oral, transdermal, parenteral or inhalation route. 
     
     
         15 : The method of  claim 12 , wherein the compound of Formula (I) is selected from the group consisting of:
 [(4′-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}biphenyl-4-yl)amino]-(oxo)acetic acid hydrochloride;   (3R)—N-{4′-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{3′-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Ethylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Phenylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Benzylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide;   (3R)—N-[4′-(Aminosulfonyl)biphenyl-4-yl]quinuclidine-3-carboxamide hydrochloride;   (3R)—N-(4′-[(Isopropylamino)sulfonyl]biphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Benzylamino)sulfonyl]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-(4′-{[(Methylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide;   (3R)—N-(4′-{([(Cyclopentylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride;   (3R)—N-(4′-([(Ethylamino)carbonyl]amino) biphenyl-4-yl)quinuclidine-3-carboxamide;   (3R)—N-[4′-({[(3-Methoxyphenyl)amino]carbonyl}amino)biphenyl-4-yl]quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(3-Chlorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(3-Fluorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(2-Methoxyacetyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride; and   (3R)—N-{4′-[(Cyclopentylcarbonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   or a salt thereof.   
     
     
         16 : A method for treating cognitive impairment in a patient suffering from mild cognitive impairment comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:
 i) a compound of Formula (I):   
       
         
           
           
               
               
           
         
         
           wherein
 R 1  is a group of the formula —NR 2 —CO—NR 3 R 4 , —NR 2 —CO—CO—OR 5 , —NH—SO 2 R 6 , —SO 2 NHR 7  or —NH—CO—R 8 ; 
 R 2  is hydrogen or C 1 -C 6 -alkyl; 
 R 3  and R 4  are independently of one another hydrogen, C 1 -C 6 -alkyl, C 3 —C-cycloalkyl or phenyl, which is optionally substituted by up to 3 radicals independently of one another selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, trifluoromethyl and trifluoromethoxy; or 
 R 3  and R 4  together with the nitrogen atom to which they are bonded form a 5- to 6-membered heterocyclyl; 
 R 5  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl or aryl, wherein C 1 -C 6 -alkyl is optionally substituted by aryl; 
 R 6  is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to 6-membered heteroaryl, wherein C 1 -C 6 -alkyl is optionally substituted by aryl; 
 R 7  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to 6-membered heteroaryl, where C 1 -C 6 -alkyl is optionally substituted by aryl; and 
 R 8  is C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkyl or phenyl, where C 1 -C 6 -alkyl is substituted by C 1 -C 6 -alkoxy and phenyl by 1 to 3 radicals independently of one another selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, trifluoromethyl and trifluoromethoxy, 
 
           or a salt thereof; and 
         
         ii) a pharmaceutically acceptable carrier. 
       
     
     
         17 : The method of  claim 16 , further comprising co-administering a second active ingredient for the treatment of the mild cognitive impairment. 
     
     
         18 : The method of  claim 16 , wherein the administering is by an oral, transdermal, parenteral or inhalation route. 
     
     
         19 : The method of  claim 16 , wherein the compound of Formula (I) is selected from the group consisting of:
 [(4′-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}biphenyl-4-yl)amino]-(oxo)acetic acid hydrochloride;   (3R)—N-{4′-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{3-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Ethylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Phenylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Benzylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide;   (3R)—N-[4′-(Aminosulfonyl)biphenyl-4-yl]quinuclidine-3-carboxamide hydrochloride;   (3R)—N-(4′-[(Isopropylamino)sulfonyl]biphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(Benzylamino)sulfonyl]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-(4′-{[(Methylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide;   (3R)—N-(4′-{([(Cyclopentylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride;   (3R)—N-(4′-{([(Ethylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide;   (3R)—N-[4′-({[(3-Methoxyphenyl)amino]carbonyl}amino)biphenyl-4-yl]quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(3-Chlorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(3-Fluorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;   (3R)—N-{4′-[(2-Methoxyacetyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride; and   (3R)—N-{4′-[(Cyclopentylcarbonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride,   or a salt thereof.