Urea derivatives of tropane, their preparation and their therapeutic application

Abstract

The present invention is related to a compound of formula (I) wherein R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 4 , p, r and are as defined herein, its preparation, pharmaceutical composition and use as a modulator of the activity of the 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1).

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         X is an oxygen, sulfur or nitrogen atom or —SO 2  group; 
            is a single bond or a double bond; 
         R 1a , R 1b , R 1c , R 1d , R 2a  and R 2b  are independently hydrogen, halogen, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, (C 1 -C 5 ) haloalkyl, hydroxyl, hydroxy(C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy(C 1 -C 5 ) alkyl, cyano, —COOR 5 , —NR 6 R 7 , R 5 OOC—(C 1 -C 5 ) alkyl, NR 6 R 7 —(C 1 -C 5 ) alkyl, —CONR 6 R 7 , NR 6 R 7 —CO—(C 1 -C 5 ) alkyl, or —SO 2 NR 6 R 7 ; or 
         (R 2a ) p  or (R 2b ) r  may also form, with the carbon atom to which they are attached, a C═O group; 
         R 3  is hydrogen, fluorine, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, alkoxy(C 1 -C 5 ) alkyl, hydroxyl, hydroxy(C 1 -C 5 ) alkyl, (C 1 -C 5 )haloalkyl, cyano, —COOR 5 , —NR 6 R 7 , R 5 OOC—(C 1 -C 5 ) alkyl, NR 6 R 7 —(C 1 -C 5 ) alkyl, —CONR 6 R 7 , or NR 6 R 7 —CO—(C 1 -C 5 ) alkyl; 
         R 4  is:
 hydrogen or (C 1 -C 5 ) alkyl, 
 (C 3 -C 6 )cycloalkyl, 
 heterocyclyl, 
 (C 5 -C 10 ) monocyclic or bicyclic aryl, or 
 (C 2 -C 9 ) monocyclic or bicyclic heteroary, 
 wherein the aryl or heteroary) group is optionally substituted with 1 to 4 substituents chosen from the group consisting of halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, hydroxyl, hydroxy(C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy(C 1 -C 5 )alkyl, cyano, optionally substituted phenyl, optionally substituted benzyl, —COOR 5 , —NR 6 R 7 , R 5 OOC—(C 1 -C 5 ) alkyl, NR 6 R 7 —(C 1 -C 5 ) alkyl, 
 —CONR 6 R 7 , NR 6 R 7 —CO—(C 1 -C 5 ) alkyl, —SO 2 NR 6 R 7 , and —NR 6 —COR 5 ; 
 
         p and r, are independently 1 or 2; 
         R 5  is hydrogen, (C 1 -C 5 ) alkyl or (C 3 -C 6 )cycloalkyl; and 
         R 6  and R 7 , are independently hydrogen, (C 1 -C 5 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 5 ) alkylcarbonyl, hydroxymethyl(C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxymethyl (C 1 -C 5 ) alkyl, aryl or —SO 2 —R 5 , or 
         R 6  and R 7 , taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl; 
         or a salt, solvate or hydrate thereof, or an enantiomer or diasteroisomer thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein X is oxygen, or a salt, solvate or hydrate thereof, or an enantiomer or diasteroisomer thereof. 
     
     
         3 . The compound according to  claim 2 , wherein:
 p and r are 1;   R 1a , R 1b , R 1c , and R 1d  are hydrogen, or   one of the R 1a , R 1b , R 1c , and R 1d  is halogen and the other R 1a , R 1b , R 1c , and R 1d  are hydrogen;   R 2a  and R 2b  are hydrogen, or   one of the R 2a  and R 2b  is (C 1 -C 5 ) alkyl, and the other is hydrogen;   R 3  is hydrogen; and   R 4  is pyridyl, phenyl, or pyrazolyl;   or a salt, solvate or hydrate thereof, or an enantiomer or diasteroisomer thereof.   
     
     
         4 . The compound according to  claim 2 , wherein:
 X is oxygen atom;      is a single bond; and   R 4  is phenyl or pyridyl;   or a salt, solvate or hydrate thereof, or an enantiomer or diasteroisomer thereof.   
     
     
         5 . A process for preparing the compound according to  claim 1 , comprising reacting a compound of formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         X, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , p and r are as defined in  claim 1 , and 
         Lg is a leaving group; 
         with a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 3  and R 4  are as defined in  claim 1 . 
       
     
     
         6 . A pharmaceutical composition, comprising the compound according to  claim 1 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with at least one pharmaceutically acceptable excipient. 
     
     
         7 . A pharmaceutical composition, comprising the compound according to  claim 2 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with at least one pharmaceutically acceptable excipient. 
     
     
         8 . A pharmaceutical composition, comprising the compound according to  claim 3 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with at least one pharmaceutically acceptable excipient. 
     
     
         9 . A pharmaceutical composition, comprising the compound according to  claim 4 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with at least one pharmaceutically acceptable excipient. 
     
     
         10 . A method for treating obesity, diabetes, insulin resistance, metabolic syndrome, Cushing's syndrome, hypertension, atherosclerosis, cognitive disorder, dementia, glaucoma, osteoporosis or a certain pathological condition requiring activation of the immune system, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 1 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         11 . A method for treating obesity, diabetes, insulin resistance, metabolic syndrome, Cushing's syndrome, hypertension, atherosclerosis, cognitive disorder, dementia, glaucoma, osteoporosis or a certain pathological condition requiring activation of the immune system, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 2 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         12 . A method for treating obesity, diabetes, insulin resistance, metabolic syndrome, Cushing's syndrome, hypertension, atherosclerosis, cognitive disorder, dementia, glaucoma, osteoporosis or a certain pathological condition requiring activation of the immune system, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 3 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         13 . A method for treating obesity, diabetes, insulin resistance, metabolic syndrome, Cushing's syndrome, hypertension, atherosclerosis, cognitive disorder, dementia, glaucoma, osteoporosis or a certain pathological condition requiring activation of the immune system, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 4 , or an enantiomer or diasteroisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.