Benzothiazol-2-one derivatives as lipase and phospholipase inhibitors

A method for the treatment of insulin resistance in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I

• wherein:
• R1 is (C5-C16)-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C4-C12)-cycloalkyl, (C8-C14)-bicycle, where aryl, cycloalkyl or bicycle may be substituted one or more times by halogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylaminocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C1-C6)-alkylsulfonyl or aminosulfonyl;
• R2 is hydrogen or (C1-C6)-alkyl;
• R3 is hydrogen;
• R4, R5 are either identical or different and chosen from hydrogen, halogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, (C1-C6)-alkylcarbonyl, CO—OR7, trifluoromethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—-NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• R6 is hydrogen, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C1-C6)-alkyl;
• R7 is hydrogen, (C1-C6)-alkyl or benzyl;
• and
• R9, R10 are either identical or different and selected from hydrogen, (C1-C6)-alkyl, —(C6-C10)-aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl or (C8-C14)-bicycle;
• or a pharmaceutically acceptable salt thereof.

A method for the treatment of dyslipidemias in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I

• wherein:
• R1 is (C5-C16)-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C4-C12)-cycloalkyl, (C8-C14)-bicycle, where aryl, cycloalkyl or bicycle may be substituted one or more times by halogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylaminocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C1-C6)-alkylsulfonyl or aminosulfonyl;
• R2 is hydrogen or (C1-C6)-alkyl;
• R3 is hydrogen;
• R4, R5 are either identical or different and chosen from hydrogen, halogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, (C1-C6)-alkylcarbonyl, CO—OR7, trifluoromethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• R6 is hydrogen, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C1-C6)-alkyl;
• R7 is hydrogen, (C1-C6)-alkyl or benzyl;
• and
• R9, R10 are either identical or different and selected from hydrogen, (C1-C6)-alkyl, —(C6-C10)-aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl or (C8-C14)-bicycle;
• or a pharmaceutically acceptable salt thereof.

A process for preparing a compound of the general formula I,

• wherein:
• R1 is (C5-C16)-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C4-C12)-cycloalkyl, (C8-C14)-bicycle, where aryl, cycloalkyl or bicycle may be substituted one or more times by halogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylaminocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C1-C6)-alkylsulfonyl or aminosulfonyl;
• R2 is hydrogen or (C1-C6)-alkyl;
• R3 is hydrogen;
• R4, R5 are either identical or different and chosen from hydrogen, halogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, (C1-C6)-alkylcarbonyl, CO—OR7, trifluoromethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• R6 is hydrogen, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C1-C6)-alkyl;
• R7 is hydrogen, (C1-C6)-alkyl or benzyl;
• and
• R9, R10 are either identical or different and selected from hydrogen, (C1-C6)-alkyl, —(C6-C10)-aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl or (C8-C14)-bicycle;
• which comprises:
• a) acylating benzothiazol-2-one of the formula II with carbamoyl chloride of the formula III;
• or
• b) in two stages reacting first benzothiazol-2-one of the formula II with phosgene or its equivalents chosen from trichloromethyl chlorocarbonate, ditrichloromethyl carbonate or 4-nitrophenyl chloroformate and in a second step with an amine of the formula IV,

A process for preparing a compound of the general formula I

• wherein:
• R1 is (C5-C16)-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C4-C12)-cycloalkyl, (C8-C14)-bicycle, where aryl, cycloalkyl or bicycle may be substituted one or more times by halogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylaminocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C1-C6)-alkylsulfonyl or aminosulfonyl;
• R2 is hydrogen;
• R3 is hydrogen;
• R4, R5 are either identical or different and chosen from hydrogen, (C1-C6)-alkyl, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, (C1-C6)-alkylcarbonyl, CO—OR7, trifluoromethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• R6 is hydrogen, (C1-C3)-alkyloxy-(C1-C3)-alkylene, hydroxy, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, pentafluorosulfanyl, (C6-C10)-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C1-C6)-alkylene-CO—O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkylene-CO—OH, O—CO—(C1-C6)-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C1-C6)-alkyloxy;
• with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C1-C6)-alkyl;
• R7 is hydrogen, (C1-C6)-alkyl or benzyl;
• and
• R9, R10 are either identical or different and selected from hydrogen, (C1-C6)-alkyl, —(C6-C10)-aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl or (C8-C14)-bicycle;
• which comprises reacting benzothiazol-2-one of the formula II with isocyanate of the formula V:
• O═C═N—R1