Azolopyridin-2-one derivatives as lipase and phospholipase inhibitors

Abstract

The present invention provides compounds which have an inhibitory effect on hormone-sensitive lipase or endothelial lipase. The compounds of the invention are azolopyridin-2-one derivatives of the general formula I wherein the substituents are as defined herein. The compounds of formula I wherein R2 is hydrogen are distinguished by favorable effects on disorders of lipid metabolism. They beneficially influence the HDL to LDL ratio and increase in particular the HDL level and are suitable for the prevention and treatment of dyslipidemias and metabolic syndrome and their diverse sequelae such as atherosclerosis, coronary heart disease, heart failure, obesity and diabetes. The compounds of formula I wherein R1 and R2 together form a ring system are distinguished by favorable effects on metabolic disorders. They beneficially influence lipid and sugar metabolism; in particular they lower the triglyceride level and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis and the diverse sequelae thereof.

1 - 15 . (canceled) 
     
     
         16 . A method for the treatment or prevention of insulin resistance in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein: 
         is independently selected from ═C(—R)— and ═N—, with the proviso that at least one and at most two of X is ═N—; 
         Y is —O— or —S—; 
         R is independently selected from hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 E alkylamino, di-(C 7 -C 12 )-alkylamino, (C 1 -C 6 )-alkylcarbonyl, COOR3, trifluoromethyl, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, (C 5 -C 12 )-heteroaryl, CO—NR6R7, O—CO—NR6R7, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR6R7 and unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy; 
         R1 is selected from (C 4 -C 16 )-alkyl, (C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 1 -C 4 ) alkylene-(C 5 -C 12 )-heteroaryl, (C 1 -C 4 )-alkylene-(C 3 -C 12 )-cycloalkyl, and (C 8 -C 14 )-bicycle, wherein each of said aryl, heteroaryl, cycloalkyl and bicycle may be substituted one or more times by a substituent selected from halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alklaminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl, and aminosulfonyl; 
         R2 is selected from hydrogen and (C 1 -C 6 )-alkyl; or, in the alternative, 
         R1 and R2 form, together with the nitrogen atom to which they are attached, a monocyclic, saturated or partially unsaturated 4- to 7-membered ring system or a bicyclic saturated or partially unsaturated 8- to 14-membered ring system, of which individual members of the ring systems may be replaced by one to three atoms or atomic groups selected from —CHR4-, —CR4R5-, —(C═R4)-, —C(═O)—, —O—, —S—, —SO—, —SO 2 —, with the proviso that no two of the units —O—, —S—, —SO—, and —SO 2 — may be adjacent to each other; 
         R3 is hydrogen, (C 1 -C 6 )-alkyl, or benzyl; 
         R4 and R5 are independently selected from (C 1 -C 6 )-alkyl, halogen, trifluoromethyl, COOR3, cyclopropyl, and cyclopropylene; and 
         R6 and R7 are independently selected from hydrogen, (C 1 -C 6 )-alkyl, —(C 6 -C 10 )-aryl, (C 5 -C 12 )-heteroaryl, (C 3 -C 12 )-cycloalkyl, (C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 1 -C 4 )-alkylene-(C 5 -C 12 )-heteroaryl, (C 1 -C 4 )-alkylene-(C 4 -C 12 )-cycloalkyl, and (C 8 -C 14 )-bicycle; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . A method for the treatment or prevention of diabetes mellitus and the sequelae associated therewith in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I as claimed in  claim 16  or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A method for the treatment or prevention of dyslipidemias and the sequelae thereof in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I as claimed in  claim 16  or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A method for the treatment or prevention of conditions associated with metabolic syndrome in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I as claimed in  claim 16  or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method for the treatment or prevention of conditions associated with reduced HDL level in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I as claimed in  claim 16  or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A method for the treatment or prevention of atherosclerotic disorders in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I as claimed in  claim 16  or a pharmaceutically acceptable salt thereof 
     
     
         22 . A process for preparing a compound of formula I as claimed in  claim 16 , which comprises:
 acylating an azolopyridin-2-one derivative of formula II with a carbamoyl chloride of formula III;   or   in two stages, reacting said azolopyridin-2-one derivative of formula II first with phosgene or a phosgene equivalent chosen from trichloromethyl chlorocarbonate, ditrichloromethyl carbonate or 4-nitrophenyl chloroformate, and, in a second step, reacting the resulting intermediate with an amine of formula IV,   
       in which the substituents are as defined in  claim 16 . 
       
         
           
           
               
               
           
         
       
     
     
         23 . A process for preparing a compound of formula I as claimed in  claim 16 , wherein R2 is hydrogen, which comprises reacting an azolopyridin-2-one derivative of formula II with an isocyanate of formula V: O═C═N—R1.