Benzooxazol-2-one derivatives as lipase and phospholipase inhibitors

Abstract

The invention relates to benzooxazol-2-one derivatives of general formula (I) with the meanings indicated in the description, the pharmaceutically usable salts thereof, and the use thereof as medicinal substances.

1 . A compound of the formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R1 is (C 5 -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, (C 8 -C 14 )-bicycle, where aryl, heteroaryl, cycloalkyl or bicycle may be substituted one or more times by 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 )-alkylaminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl; 
 R2 is hydrogen or (C 1 -C 6 )-alkyl; or 
 R1 and R2 form together with the nitrogen atom bearing them 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 from the series —CHR8-, —CR8R8a-, —(C=R8)-, —NR9-, —C(═O)—, —O—, —S—, —SO— or —SO 2 —, with the proviso that two units from the series —O—, —S—, —SO—, —SO 2 — may not be adjacent to each other; 
 R3, R4, R5, R6 independently of one another are 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 )-alkylamino, di-(C 2 -C 12 )-alkylamino, (C 1 -C 6 )-alkylcarbonyl, COOR7, trifluoromethyl, (C 1 -C 6 )-alkylsulfonyl, (C 1 -C 6 )-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, (C 5 -C 12 )-heteroaryl, CO—NR9R10, O—CO—NR9R10, 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—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;
 with the proviso that not more than one of the substituents R3, R4, R5 or R6 is halogen; 
 and with the proviso that not more than one of the substituents R3, R4, R5 or R6 is (C 1 -C 6 )-alkyl; 
 
 R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl; 
 R8, R8a independently of one another are (C 1 -C 6 )-alkyl, halogen, trifluoromethyl, COOR7, cyclopropyl or cyclopropylene; and 
 R9, R10 independently of one another are 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 or (C 8 -C 14 )-bicycle; or 
 
     a tautomer or a physiologically tolerated salt thereof. 
   
   
       2 . The compound of the formula I as claimed in  claim 1 , wherein
 R1 is (C 6 -C 12 )-alkyl, (C 1 -C 3 )-alkylene-(C 6 -C 10 )-aryl, (C 1 -C 3 )-alkylene-(C 5 -C 12 )-heteroaryl, (C 1 -C 3 )-alkylene-(C 4 -C 12 )-cycloalkyl or (C 8 -C 14 )-bicycle, where aryl, heteroaryl, cycloalkyl or bicycle may be substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxy, amino, (C 1 -C 6 )-alkylamino or trifluoromethyl;   R2 is hydrogen or (C 1 -C 6 )-alkyl; or   R1 and R2 form together with the nitrogen atom bearing them a monocyclic, saturated 5- to 6-membered ring system or a bicyclic saturated or partially unsaturated 9- to 10 membered ring system, of which individual members of the ring systems is optionally replaced by one to three atoms or atomic groups from the series —CHR8-, —CR8R8a-, —(C=R8)-, —NR9-, —O— or —S—, with the proviso that two units from the series —O—, —S— may not be adjacent to each other;   R3, R4, R5, R6 are independently of one another is hydrogen, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, COOR7, (C 1 -C 6 )-alkylsulfonyl, (C 1 -C 6 )-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, (C 5 -C 12 )-heteroaryl, (C 1 -C 6 )-alkylcarbonyl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH or O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10;   R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl;   R8, R8a are independently of one another (C 1 -C 6 )-alkyl, halogen, trifluoromethyl, COOR7, cyclopropyl, cyclopropylene; and   R9, R10 are independently of one another hydrogen, (C 1 -C 6 )-alkyl, (C 6 -C 10 )-aryl, (C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl.   
   
   
       3 . The compound of the formula I as claimed in  claim 1 , wherein
 R1 is (C 6 -C 12 )-alkyl, benzyl, (C 1 -C 3 )-alkylene-(C 5 -C 12 )-heteroaryl, (C 1 -C 3 )-alkylene-(C 4 -C 12 )-cycloalkyl, (C 8 -C 14 )-bicycle, where aryl, heteroaryl, cycloalkyl or bicycle may be substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxy, amino, (C 1 -C 6 )-alkylamino, trifluoromethyl;   R2 is hydrogen; or   R1 and R2 form together with the nitrogen atom bearing them a monocyclic, saturated 5- to 6-membered ring system or a bicyclic saturated or partially unsaturated 9- to 10 membered ring system, of which individual members of the ring systems may be replaced by one to three atoms or atomic groups from the series —CHR8-, —CR8R8a-, —(C═R8)-, —NR9-, —O—, —S—, with the proviso that two units from the series —O— or —S— may not be adjacent to each other;   R3, R4, R5, R6 are independently of one another hydrogen, hydroxy, COOR7, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, pentafluorosulfanyl, phenyl, (C 1 -C 6 )-alkylcarbonyl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH or O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10;   R7 is hydrogen or (C 1 -C 6 )-alkyl;   R8, R8a are independently of one another (C 1 -C 6 )-alkyl, halogen, trifluoromethyl, COOR7 or cyclopropyl; and   R9, R10 are independently of one another hydrogen or (C 1 -C 6 )-alkyl.   
   
   
       4 . The compound of the formula I as claimed in  claim 1 , wherein
 R3, R6 are hydrogen; and R4 or R5 is not hydrogen.   
   
   
       5 . The compound of the formula I as claimed in  claim 1 , wherein
 R1 and R2 form together with the nitrogen atom bearing them a monocyclic, saturated 5- to 6-membered ring system, of which individual members of the ring systems may be replaced by one to two atoms or atomic groups from the series —CHR8-, —NR9-, in which R8 is as defined in  claim 1  and R9 is (C 1 -C 6 )-alkyl or cyclopropyl.   
   
   
       6 . The compound of the formula I as claimed in  claim 1 , wherein
 R1 is (C 6 -C 12 )-alkyl, benzyl, —CH 2 —(C 5 -C 12 )-heteroaryl, (C 8 -C 14 )-bicycle, where benzyl, heteroaryl or bicycle may be substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxy, amino, (C 1 -C 6 )-alkylamino, trifluoromethyl;   R2 is hydrogen;   R3 is hydrogen;   R4, R5 are independently of one another hydrogen, hydroxy, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 6 )-alkylaminocarbonyl, COOR7, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, phenyl, (C 1 -C 6 )-alkylcarbonyl, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH or O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10; and   R6 is hydrogen.   
   
   
       7 . The compound of the formula I as claimed in  claim 1 , wherein
 R1 (C 6 -C 12 )-alkyl or benzyl, where benzyl may be substituted one or more times by (C 1 -C 6 )-alkyl;   R2 is hydrogen;   R3 is hydrogen;   R4, R5 are independently of one another hydrogen, halogen or (C 1 -C 6 )-alkylcarbonyl; and   R6 is hydrogen.   
   
   
       8 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       9 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 2  or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       10 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 3  or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       11 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 4  or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       12 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 5  or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       13 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 6  or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       14 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 7  or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       15 . A method for the treatment or prevention of disorders of fatty acid metabolism and glucose utilization disorders in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       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 as claimed in  claim 1  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 1  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 1  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 1  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 1  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 1  or a pharmaceutically acceptable salt thereof. 
   
   
       22 . 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 as claimed in  claim 1  or a pharmaceutically acceptable salt thereof and in combination with at least one other active ingredient. 
   
   
       23 . A process for preparing compounds of the formula I as claimed in  claim 1 , which comprises:
 a) acylating benzooxazol-2-one of the formula II with carbamoyl chloride of the formula III;   or   b) in two stages reacting benzooxazol-2-one of the formula II first with phosgene or its equivalents chosen from trichloromethyl chlorocarbonate, ditrichloromethyl carbonate or 4-nitrophenyl chloroformate and in a second step reacting with amine of the formula IV;   in which the substituents are as defined in  claim 1 .   
     
       
         
         
             
             
         
       
     
   
   
       24 . A process for preparing compounds of the formula I wherein R2 is hydrogen as claimed in  claim 1 , which comprises reacting benzooxazol-2-one of the formula II with isocyanates of the formula V: O═C═N—R1.