4-Phenylpiperidine derivatives as renin inhibitors

Abstract

Compounds of the present invention having the formula exhibit inhibitory activity on the natural enzyme renin. Thus, compounds of formula (I) may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is —CH 2 —X, —O—X or —S(O) 0-2 —X; or  
 R 1  is —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which 
 R 8  is hydrogen or lower alkyl; and  
 
 X is —(CH 2 ) m —(CR 9 R 10 ) p —(CH 2 ) n -Z-(CH 2 ) q —W in which 
 m, n and q are independently zero or an integer from 1 to 5;  
 p is zero or 1;  
 R 9  and R 10  are independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or cycloalkyl; or  
 R 9  and R 10  combined are alkylene which together with the carbon atom to which they are attached form a 3- to 6-membered ring;  
 Z is a bond; or  
 Z is O, S(O) 0-2 , or —NR 11 — in which 
 R 11  is hydrogen or lower alkyl, provided that R 1  is —CH 2 —X when m, n and p are all zero;  
 
 W is aryl or heterocyclyl;  
 
 R 2  is hydrogen, halogen, cyano, hydroxy or lower alkoxy;  
 L is a bond; or  
 L is —(CH 2 ) s —O—(CH 2 ) v — in which 
 s and v are independently zero or an integer from 1 to 3; or  
 
 L is —C(O)—, —C(O)O—, —OC(O)—, —OC(O)NR 12 —, —NR 12 —, —NR 13 C(O)—, —NR 13 C(O)O— or —NR 13 C(O)NR 12 — in which 
 R 12  and R 13  are independently hydrogen or lower alkyl;  
 
 R 3  is hydrogen, hydroxy, halogen or cyano provided that L is a bond; or  
 R 3  is optionally substituted lower alkyl, aralkyl, heteroaralkyl, aryl or heterocyclyl; or  
 R 3  and R 12  combined are alkylene which together with the nitrogen atom to which they are attached form a 5- to 6-membered ring;  
 R 4  is hydrogen, optionally substituted lower alkyl or aryl;  
 R 5  and R 6  are independently hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl; or  
 R 5  and R 6  combined together with the carbon atoms to which they are attached form a fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 5  and R 6  are attached to carbon atoms adjacent to each other; or  
 R 5  and R 6  combined are alkylene which together with the carbon atoms to which they are attached form a fused 5- to 7-membered ring provided that R 5  and R 6  are attached to carbon atoms adjacent to each other; or  
 C—R 5  and C—R 6  may be replaced with nitrogen;  
 R 7  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy, cycloalkyl, alkanoyl, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and tetrazolyl; or  
 R 7  and R 6  combined are O, S(O) 0-2 , —NR 14 —, —(CH 2 ) 1-2 —, —O—CH 2 —, —CH 2 —O—, —S(O) 0-2 —CH 2 —, —CH 2 —S(O) 0-2 —, —NR 14 —CH 2 —, —CH 2 —NR 14 —, —S(O) 0-2 —NR 14 — or —NR 14 —S(O) 0-2 — in which 
 R 14  is hydrogen or lower alkyl, provided R 6  is located at the 2′ position; or  
 
 C—R 7  may be replaced with nitrogen;  
 Y is —(CH 2 ) r —, —O—(CH 2 ) r —, —(CH 2 ) r —O—, —S 0-2 —(CH 2 ) r — or —(CH 2 ) r —S 0-2 — in which 
 r is zero or an integer from 1 to 3;  
 
 Q combined with the atoms to which it is attached form a 5- to 6-membered monocyclic aromatic or heteroaromatic ring; or  
 Q combined with the atoms to which it is attached form a 7- to 12-membered bicyclic aromatic or heterocyclic ring;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein 
 R 1  is —CH 2 —X, —O—X or —S(O) 0-2 —X; or    R 1  is —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which 
 R 8  is hydrogen or lower alkyl; and  
   X is —(CH 2 ) m —(CR 9 R 10 ) p —(CH 2 ) n -Z-(CH 2 ) q —W in which 
 m and n are independently zero or an integer from 1 to 5;  
 p is zero or 1;  
 q is zero;  
 R 9  and R 10  are independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or cycloalkyl; or  
 R 9  and R 10  combined are alkylene which together with the carbon atom to which they are attached form a 3- to 6-membered ring;  
 Z is a bond; or  
 Z is O, S(O) 0-2 , or —NR 11 — in which 
 R 11  is hydrogen or lower alkyl, provided that R 1  is —CH 2 —X when m, n and p are all zero;  
 
 W is aryl or heterocyclyl;  
   R 2  is hydrogen, halogen, cyano, hydroxy or lower alkoxy;    L is a bond; or    L is —(CH 2 ) s —O—(CH 2 ) v — in which 
 s and v are zero; or  
   L is —C(O)—, —C(O)O—, —OC(O)—, —OC(O)NR 12 —, —NR 12 —, —NR 13 C(O)—, —NR 13 C(O)O— or —NR 13 C(O)NR 12 — in which 
 R 12  and R 13  are independently hydrogen or lower alkyl;  
   R 3  is hydrogen, halogen or cyano provided that L is a bond; or    R 3  is optionally substituted lower alkyl, aralkyl, heteroaralkyl, aryl or heterocyclyl; or    R 3  and R 12  combined are alkylene which together with the nitrogen atom to which they are attached form a 5- to 6-membered ring;    R 4  is hydrogen, optionally substituted lower alkyl or aryl;    R 5  and R 6  are independently hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl; or    R 5  and R 6  combined together with the carbon atoms to which they are attached form a fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 5  and R 6  are attached to carbon atoms adjacent to each other; or    R 5  and R 6  combined are alkylene which together with the carbon atoms to which they are attached form a fused 5- to 7-membered ring provided that R 5  and R 6  are attached to carbon atoms adjacent to each other; or    R 7  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted, lower alkyl, lower alkoxy or cycloalkyl; or    R 7  and R 6  combined are O, S(O) 0-2 , —NR 14 —, —(CH 2 ) 1-2 —, —O—CH 2 —, —CH 2 —O—, —S(O) 0-2 —CH 2 —, —CH 2 —S(O) 0-2 —, —NR 14 —CH 2 —, —CH 2 —NR 14 —, —S(O) 0-2 —NR 14 — or —NR 14 —S(O) 0-2 — in which 
 R 14  is hydrogen or lower alkyl, provided R 6  is located at the 2′ position;  
   Y is —(CH 2 ) r — in which 
 r is zero;  
   Q combined with the carbon atoms to which it is attached form a 5- to 6-membered monocyclic aromatic or heteroaromatic ring; or    Q combined with the carbon atoms to which it is attached form a 9- to 10-membered bicyclic aromatic or heterocyclic ring;    or a pharmaceutically acceptable salt thereof.    
     
     
         3 . A compound according to  claim 2  of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , L, R 3 , R 4 , R 5 , R 6 , R 7  and Q have meanings as defined in  claim 2;   
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         4 . A compound according to  claim 2  of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , L, R 3 , R 4 , R 5 , R 6 , R 7  and Q have meanings as defined in  claim 2;   
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         5 . A compound according to  claim 4  wherein 
 R 1  is —CH 2 —X, —O—X or —S—X; or    R 1  is —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which 
 R 8  is hydrogen or lower alkyl; and  
   X is —(CH 2 ) m —(CR 9 R 10 ) p —(CH 2 ) n -Z-W in which 
 m and n are independently zero or an integer of 1 or 2;  
 p is zero or 1;  
 R 9  and R 10  are independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or cycloalkyl; or  
 R 9  and R 10  combined are alkylene which together with the carbon atom to which they are attached form a 3- to 6-membered ring;  
 Z is a bond; or  
 Z is O, S(O) 0-2 , or —NR 11 — in which 
 R 11  is hydrogen or lower alkyl, provided that R 1  is —CH 2 —X when m, n and p are all zero;  
 
 W is aryl or heterocyclyl;  
   R 2  is hydrogen, halogen or hydroxy;    L is a bond;    R 3  is hydrogen or halogen;    R 4  is hydrogen, optionally substituted lower alkyl or aryl;    R 5  and R 6  are independently hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;    R 7  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl; or    R 7  and R 6  combined are O, S(O) 0-2 , —NR 14 —, —(CH 2 ) 1-2 —, —O—CH 2 —, —CH 2 —O—, —S(O) 0-2 —CH 2 —, —CH 2 —S(O) 0-2 —, —NR 14 —CH 2 —, —CH 2 —NR 14 —, —S(O) 0-2 —NR 14 — or —NR 14 —S(O) 0-2 — in which 
 R 14  is hydrogen or lower alkyl, provided R 6  is located at the 2′-position;  
   Q combined with the atoms to which it is attached form a 5- to 6-membered monocyclic aromatic or heteroaromatic ring; or    Q combined with the atoms to which it is attached form a 9- to 10-membered bicyclic aromatic or heterocyclic ring;    or a pharmaceutically acceptable salt thereof.    
     
     
         6 . A compound according to  claim 5  wherein 
 R 1  is —CH 2 —X, —O—X or —S—X; or    R 1  is —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which 
 R 8  is hydrogen or lower alkyl; and  
   X is —(CH 2 ) m —(CR 9 R 10 ) p —(CH 2 ) n -Z-W in which 
 m and n are independently zero or an integer of 1 or 2;  
 p is zero or 1;  
 R 9  and R 10  are independently hydrogen or lower alkyl; or  
 Z is a bond; or  
 Z is O, S(O) 0-2 , or —NR 11 — in which 
 R 11  is hydrogen or lower alkyl, provided that R 1  is —CH 2 —X when m, n and p are all zero;  
 
 W is aryl or heterocyclyl;  
   R 2  is hydrogen, halogen or hydroxy;    L is a bond;    R 3  is hydrogen or halogen;    R 4  is hydrogen;    R 5  and R 6  are independently hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;    R 7  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl; or    R 7  and R 6  combined are O, S(O) 0-2 , —NR 14 —, —(CH 2 ) 1-2 —, —O—CH 2 —, —CH 2 —O—, —S(O) 0-2 —CH 2 —, —CH 2 —S(O) 0-2 —, —NR 14 —CH 2 —, —CH 2 —NR 14 —, —S(O) 0-2 —NR 14 — or —NR 14 —S(O) 0-2 — in which 
 R 14  is hydrogen or lower alkyl, provided R 6  is located at the 2′-position;  
   Q combined with the atoms to which it is attached form a 5- to 6-membered monocyclic aromatic or heteroaromatic ring; or    Q combined with the atoms to which it is attached form a 9- to 10-membered bicyclic aromatic or heterocyclic ring;    or a pharmaceutically acceptable salt thereof.    
     
     
         7 . A compound according to  claim 6  wherein 
 R 1  is —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which 
 R 8  is hydrogen or lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
   
     
     
         8 . A compound according to  claim 6  wherein 
 Q combined with the carbon atoms to which it is attached form a pyridyl or pyrimidinyl ring;    or a pharmaceutically acceptable salt thereof.    
     
     
         9 . A compound according to  claim 6  wherein 
 Q combined with the carbon atoms to which it is attached form a thienyl, furyl, pyrrolyl or indolyl ring;    or a pharmaceutically acceptable salt thereof.    
     
     
         10 . A compound according to  claim 5  of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is —CH 2 —X, —O—X or —S—X; or  
 R 1  is —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which 
 R 8  is hydrogen or lower alkyl; and  
 
 X is —(CH 2 ) m —(CR 9 R 10 ) p —(CH 2 ) n -Z-W in which 
 m, n and p are independently zero or 1;  
 R 9  is hydrogen;  
 R 10  is hydrogen or lower alkyl;  
 Z is a bond; or  
 Z is O, S(O) 0-2 , or —NR 11 — in which 
 R 11  is hydrogen or lower alkyl, provided that R 1  is —CH 2 —X when m, n and p are all zero;  
 
 W is aryl or heterocyclyl;  
 
 R 2  is hydrogen;  
 R 3  is hydrogen or halogen;  
 R 5  and R 6  are independently hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;  
 R 7  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl; or  
 R 7  and R 6  combined are O, S(O) 0-2 , —NR 14 —, —(CH 2 ) 1-2 —, —O—CH 2 —, —CH 2 —O—, —S(O) 0-2 —CH 2 —, —CH 2 —S(O) 0-2 —, —NR 14 —CH 2 —, —CH 2 —NR 14 —, —S(O) 0-2 —NR 14 — or —NR 14 —S(O) 0-2 — in which 
 R 14  is hydrogen or lower alkyl, provided R 6  is located at the 2′-position;  
 
 R 15  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         11 . A compound according to  claim 10  wherein 
 R 1  is —O—X or —S—X; and    X is —(CH 2 ) m —(CR 9 R 10 ) p —(CH 2 ) n -Z-W in which 
 m is 1;  
 n and p are zero;  
 Z is a bond;  
 W is aryl or heterocyclyl;  
   R 3  is hydrogen or halogen;    R 5  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;    R 6  is hydrogen;    R 7  is hydrogen;    R 15  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;    or a pharmaceutically acceptable salt thereof.    
     
     
         12 . A compound according to  claim 11  wherein 
 R 3  is hydrogen;    or a pharmaceutically acceptable salt thereof.    
     
     
         13 . A compound according to  claim 12  wherein 
 W is monocyclic aryl;    or a pharmaceutically acceptable salt thereof.    
     
     
         14 . A compound according to  claim 5  wherein 
 p is 1;    R 9  and R 10  combined are alkylene which together with the carbon atom to which they are attached form a 3- to 6-membered ring;    or a pharmaceutically acceptable salt thereof.    
     
     
         15 . A compound according to  claim 14  of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is —CH 2 —X, —O—X or —S—X; or  
 R 1  is —NR 8 —X, —NR 8 C(O)—X or —NR 8 S(O) 2 —X in which 
 R 8  is hydrogen or lower alkyl; and  
 
 X is —(CH 2 ) m —CR 9 R 10 —(CH 2 ) n -Z-W in which 
 m and n are 1;  
 Z is a bond; or  
 Z is O, S(O) 0-2 , or —NR 11 — in which 
 R 11  is hydrogen or lower alkyl, provided that R 1  is —CH 2 —X when m, n and p are all zero;  
 
 W is aryl or heterocyclyl;  
 
 R 2  is hydrogen;  
 R 3  is hydrogen or halogen;  
 R 5  and R 6  are independently hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;  
 R 7  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl; or  
 R 7  and R 6  combined are O, S(O) 0-2 , —NR 14 —, —(CH 2 ) 1-2 —, —O—CH 2 —, —CH 2 —O—, —S(O) 0-2 —CH 2 —, —CH 2 —S(O) 0-2 —, —NR 14 —CH 2 —, —CH 2 —NR 14 —, —S(O) 0-2 —NR 14 — or —NR 14 —S(O) 0-2 — in which 
 R 14  is hydrogen or lower alkyl, provided R 6  is located at the 2′-position;  
 
 R 15  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         16 . A compound of  claim 15  wherein 
 R 1  is —O—X or —S—X; and    X is —CH 2 —CR 9 R 10 —CH 2 -Z-W in which 
 Z is a bond;  
 W is aryl;  
   R 3  is hydrogen;    R 5  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;    R 6  is hydrogen;    R 7  is hydrogen;    R 15  is hydrogen, halogen, hydroxy, trifluoromethyl, optionally substituted lower alkyl, lower alkoxy or cycloalkyl;    or a pharmaceutically acceptable salt thereof.    
     
     
         17 . A method for the inhibition of renin activity in mammals which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         18 . A method for the prevention and/or treatment of conditions associated with renin activity in mammals which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         19 . A method according to  claim 18 , which method comprises administering said compound in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent.  
     
     
         20 . A method for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         21 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with one or more pharmaceutically acceptable carriers.  
     
     
         22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a therapeutically effective amount of an anti-diabetic agents, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent.  
     
     
         23 . (canceled)  
     
     
         24 . (canceled)  
     
     
         25 . (canceled)  
     
     
         26 . (canceled)  
     
     
         27 . (canceled)  
     
     
         28 . (canceled)