Inhibitors of the 11-β-hydroxysteroid dehydrogenase type 1 enzyme

Abstract

The present invention relates to compounds that are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.

1. A compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof 
                 
 
       wherein
 one of A 1 , A 2 , A 3  and A 4  is selected from the group consisting of alkylcarbonyl, alkylsulfonyl, and,  —S(O) 2 —N(R 5 R 6 ), with the exception that the remaining members of the group consisting of A 1 , A 2 , A 3  and A 4  are each individually selected from the group consisting of hydrogen and alkyl;  
 D is a bond;  
 E is selected from the group consisting of a cycloalkyl and aryl, wherein R 4  and E together with the atoms to which they are attached form a cycloalkyl ring;  
 R 1  is selected from the group consisting of hydrogen and alkyl;  
 R 2  is selected from the group consisting of hydrogen and alkyl;  
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 3  and R 4  together with the atom to which they are attached form a cycloalkyl ring; and  
 R 5  and R 6  are each independently selected from the group consisting of hydrogen,  and alkyl.  
 
     
     
       2. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen; and  
 R 1  and R 2  are hydrogen.  
 
     
     
       3. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen; and    D is a bond.    
     
     
       4. The compound according to  claim 1 , wherein A 2 , A 3  and A 4  are hydrogen;
 R 1  and R 2  are hydrogen; D is a bond;  and  
 E is aryl.  
 
     
     
       5. The compound according to  claim 1 , wherein A 2 , A 3  and A 4  are hydrogen;
 R 1  and R 2  are hydrogen; D is a bond;   
 E is aryl;  
 R 3  and R 4  are hydrogen; and  
 A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).  
 
     
     
       6. The compound according to  claim 1 , wherein A 2 , A 3  and A 4  are hydrogen;
 R 1  and R 2  are hydrogen; D is a bond;  
 E is aryl;  
 R 3  is hydrogen;  
 R 4  is alkyl; and  
 A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).  
 
     
     
       7. The compound according to  claim 1 , wherein A 2 , A 3  and A 4  are hydrogen;
 R 1  and R 2  are hydrogen; D is a bond;  
 E is aryl;  
 R 3  and R 4  are alkyl; and  
 A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).  
 
     
     
       8. The compound according to  claim 1 , wherein A 2 , A 3  and A 4  are hydrogen;
 R 1  and R 2  are hydrogen; D is a bond;  
 E is aryl; and  
 R 3  and R 4  together with the atom to which they are attached form a cycloalkyl ring.  
 
     
     
       9. The compound according to  claim 1 , wherein A 2 , A 3  and A 4  are hydrogen;
 R 1  and R 2  are hydrogen; D is a bond;  
 E is aryl;  
 R 3  and R 4  together with the atom to which they are attached form a cycloalkyl ring; and  
 A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).  
 
     
     
       10. The compound according to  claim 1 , wherein A 2 , A 3  and A 4  are hydrogen;
 R 1  and R 2  are hydrogen; D is a bond;  
 R 4  and E together with the atoms to which they are attached form a cycloalkyl ring; and  
 A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).  
 
     
     
       11. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen; and    R 1  and R 2  are hydrogen.    
     
     
       12. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen; and    E is aryl.    
     
     
       13. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl.    
     
     
       14. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  and R 4  are hydrogen; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       15. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  is hydrogen;    R 4  is alkyl; and    A 1  is alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       16. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  and R 4  are alkyl; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       17. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl; and    R 3  and R 4  together with the atom to which they are attached form a cycloalkyl.    
     
     
       18. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  and R 4  together with the atom to which they are attached form a cycloalkyl ring; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       19. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl.    
     
     
       20. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  and R 4  are hydrogen; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       21. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  is hydrogen;    R 4  is alkyl; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       22. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  and R 4  are alkyl; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       23. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  and R 4  together with the atom to which they are attached form a cycloalkyl;    R 27 , R 28 , R 29 , R 30  are each independently selected from the group consisting of hydrogen and alkyl; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       24. The compound according to  claim 1 , wherein
 A 2 , A 3  and A 4  are hydrogen;    R 1  and R 2  are hydrogen;    E is aryl;    R 3  and R 4  together with the atom to which they are attached form a cycloalkyl ring; and    A 1  is selected from the group consisting of alkylsulfonyl and —S(O) 2 —N(R 5 R 6 ).    
     
     
       25. The compound according to  claim 1  selected from the group consisting of
 E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylic acid;    E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic acid;    E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid;    E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylic acid amide;    E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic acid amide;    E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid amide;    E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;    E-4-{[(1-phenylcyclopentyl)carbonyl]amino}-adamantane-1-carboxamide;    E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide;    E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;    E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;    E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide; and    E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;    E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxamide;    
       or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof. 
     
     
       26. The compound according to  claim 1  selected from the group consisting of
 methyl (E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane -1-carboxylate;  
 methyl (E)-4-{[(1-phenylcyclopropyl)carbonyl]amino}adamantane-1-carboxylate;  
 (E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;  
 (E)-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxylic acid;  
 N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-phenylcyclopropanecarboxamide;  
 (E)-4-[(2-methyl-3-phenylpropanoyl)amino]adamantane-1-carboxamide;  
 methyl (E)-4-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)adamantane-1-carboxylate;  
 N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanamide;  
 (E)-N-[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;  
 (E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-1-carboxylic acid;  
 (E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylic acid;  
 (E)-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxylic acid;  
 4-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoic acid;  
 3-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoic acid;  
 (E)-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylic acid;  
 (E)-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylic acid; and  
 (E)-4-({2-[4-cyclohexylmethoxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylic acid;  
 or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof.  The compound according to  claim 1  selected from the group consisting of N-[(E)- 5 -(aminosulfonyl)- 2 -adamantyl]- 1 -phenylcyclopropanecarboxyamide; and N-[(E)- 5 -(aminosulfonyl)- 2 -adamantyl]- 2 -( 4 -chlorophenyl)- 2 -methylpropanamide; or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof. 
 
     
     
       27. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) of  claim 1  in combination with a pharmaceutically suitable carrier.