Triazolopyridine derivatives as inhibitors of lipases and phospholipases

Abstract

The invention relates to triazolopyridine derivatives of general formula (I), which are defined as cited in the description, to their pharmaceutically applicable salts and to their use as medicaments.

1 . A compound of the formula I: 
     
       
         
         
             
             
         
       
       wherein: 
       X is identically or differently ═C(—R)— or ═N—, where at least one and at most two X is ═N—; 
       W is —(C═O)—, —(S═O)— or —(SO 2 )—; 
       R is identically or differently hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, phenoxy, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, cyano, nitro, COOR3, mono-(C 1 -C 6 )-alkylaminocarbonyl, di(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkylmercapto, (C 1 -C 6 )-alkylsulfinyl, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, pentafluorosulfanyl, aryl, heteroaryl, (C 3 -C 12 )-cycloalkyl, (C 1 -C 6 )-alkylcarbonyl, O—CO—NR3R3a, 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—NR3R3a or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy; 
       R1 is (C 5 -C 16 )-alkyl, (C 5 -C 12 )-cycloalkyl, Y-aryl, Y-heteroaryl, Y—(C 5 -C 12 )-cycloalkyl, or bicycle, where aryl, heteroaryl, cycloalkyl or bicycle are optionally substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-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, d i-(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkyloxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl; 
       Y is (C 1 -C 3 )-alkylene which is optionally substituted one or more times by halogen, (C 1 -C 2 )-alkyl or hydroxy; 
       R2 is hydrogen or (C 4 -C 12 )-alkyl; or 
       R1 and R2 together with the nitrogen atom carrying them form a monocyclic, saturated or partly unsaturated 4- to 7-membered ring system or a bicyclic saturated or partly unsaturated 8- to 14 membered ring system whose individual members of the ring systems may be replaced by one to three atoms or atomic groups from the series —CHR4-, —CR4R5-, ═(C—R4)-, —NR5-, —C(═O)—, —O—, —S—, —SO— or —SO 2 —, with the proviso that two units from the series —O—, —S—, —SO— or —SO 2 — are not adjacent to each other; 
       R3, R3a are identically or differently hydrogen, (C 1 -C 6 )-alkyl or benzyl; and 
       R4, R5 are identically or differently (C 1 -C 12 )-alkyl, (C 1 -C 6 )-alkyloxy, halogen, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-haloalkyloxy, COOR3, nitro, cyano, aryl, heterocycle, (C 3 -C 12 )-cycloalkyl, (C 1 -C 3 )-alkylene-aryl, (C 1 -C 3 )-alkylene-heterocycle or (C 1 -C 3 )-alkylene-cycloalkyl, where aryl, heterocycle or cycloalkyl are optionally substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyloxy, O—(C 1 -C 3 )-alkylene-aryl, trifluoromethyl, trifluoromethoxy, hydroxy, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, CO—(C 1 -C 6 )-alkyl, CO—O—(C 1 -C 6 )-alkyl or NR3R3a; or 
       a tautomer thereof or a physiologically tolerated salt thereof, 
       with the proviso that the compound with the meanings of X in position 4, 5 and 6=C(—R)— and in position 7=N—, W is —(C═O—)—, R is H and R1 and R2 form a morpholine, is excluded; and 
       with the proviso that the compounds with the meanings of X in position 4 and 6=C(—R)—, and in position 5 and 7=N—, W is —(C═O)—, and R is aryl, heteroaryl or phenoxy, are excluded. 
     
   
   
       2 . The compound of the formula I as claimed in  claim 1 , wherein:
 X is identically or differently ═C(—R)— or ═N—, where one X is ═N—; and   W is —(C═O)—.   
   
   
       3 . The compound of the formula I as claimed in  claim 1 , wherein:
 X is identically or differently ═C(—R)— or ═N—, where one X is ═N—;   W is —(C═O)—;   R is identically or differently hydrogen, halogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, phenoxy, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, cyano, nitro, COOR3, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkyl-aminocarbonyl, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, pentafluorosulfanyl, phenyl, (C 1 -C 6 )-alkylcarbonyl, O—CO—NR3R3a, 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—NR3R3a or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;   R1 is (C 6 -C 12 )-alkyl, (C 5 -C 12 )-cycloalkyl, Y-phenyl, Y-heteroaryl or bicycle, where phenyl, heteroaryl, cycloalkyl or bicycle are optionally substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-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 )-alkyloxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;   Y is —CH 2 —, which is optionally substituted once by fluorine, methyl or hydroxy;   R2 is hydrogen or (C 5 -C 10 )-alkyl; or   R1 and R2 together with the nitrogen atom carrying them form a monocyclic, saturated or partly unsaturated 5- to 6-membered ring system or a bicyclic saturated or partly unsaturated 9- to 10-membered ring system whose individual members of the ring systems may be replaced by one to three atoms or atomic groups from the series —CHR4-, —CR4R5-, ═(C—R4)-, —NR5-, —C(═O)—, —O—, —S— or —SO 2 —, with the proviso that two units from the series —O—, —S— or —SO 2 — are not adjacent to each other;   R3, R3a are identically or differently hydrogen, (C 1 -C 6 )-alkyl or benzyl; and   R4, R5 are identically or differently (C 1 -C 10 )-alkyl, (C 1 -C 6 )-alkyloxy, halogen, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-haloalkyloxy, COOR3, nitro, cyano, aryl, heterocycle, (C 3 -C 7 )-cycloalkyl, (C 1 -C 3 )-alkylene-aryl, or (C 1 -C 3 )-alkylene-heteroaryl, where aryl, heterocycle or cycloalkyl are optionally substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyloxy, O—(C 1 -C 3 )-alkylene-aryl, trifluoromethyl, trifluoromethoxy, hydroxy, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, CO—(C 1 -C 6 )-alkyl, CO—O—(C 1 -C 6 )-alkyl or NR3R3a; or   a tautomer thereof or a physiologically tolerated salt thereof.   
   
   
       4 . The compound of the formula I as claimed in  claim 1 , wherein:
 X is identically or differently =C(—R)— or ═N—, where one X is ═N—;   W is —(C═O)—;   R is identically or differently hydrogen, halogen, (C 1 -C 6 )-alkyl, trifluoro-methyl, hydroxy, amino, cyano, COOR3, mono-(C 1 -C 6 )-alkylamino-carbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, pentafluorosulfanyl, (C 1 -C 6 )-alkylcarbonyl, O—CO—NR3R3a, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;   R1 is (C 6 -C 12 )-alkyl, Y-phenyl, Y-heteroaryl or bicycle, where aryl, heteroaryl or bicycle are optionally substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyloxy, hydroxy, 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 )-alkyloxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;   Y is —CH 2 —;   R2 is hydrogen or (C 5 -C 10 )-alkyl; or   R1 and R2 together with the nitrogen atom carrying them form a monocyclic, saturated or partly unsaturated 5- to 6-membered ring system or a bicyclic saturated or partly unsaturated 9- to 10-membered ring system whose individual members of the ring systems may be replaced by one to three atoms or atomic groups from the series —CHR4-, —CR4R5-, ═(C—R4)-, —NR5-, —C(═O)—, —O— or —S—, with the proviso that two units from the series —O— or —S—, are not adjacent to each other;   R3, R3a are identically or differently hydrogen, (C 1 -C 6 )-alkyl or benzyl; and   R4, R5 are identically or differently (C 1 -C 10 -alkyl, (C 1 -C 6 )-alkyloxy, halogen, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-haloalkyloxy, COOR3, nitro, cyano, aryl, heteroaryl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 3 )-alkylene-aryl or (C 1 -C 3 )-alkylene-heteroaryl, where aryl, heteroaryl or cycloalkyl are optionally substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyloxy, O—(C 1 -C 3 )-alkylene-aryl, trifluoromethyl, trifluoromethoxy, hydroxy, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, CO—(C 1 -C 6 )-alkyl, CO—O—(C 1 -C 6 )-alkyl or amino; or   a tautomer thereof or a physiologically tolerated salt thereof.   
   
   
       5 . The compound of the formula I as claimed in  claim 1 , wherein:
 X is identically or differently ═C(—R)— or ═N—, where one X is ═N—;   W is —(C═O)—;   R is identically or differently hydrogen, halogen, (C 1 -C 6 )-alkyl, trifluoro-methyl, hydroxy, amino, cyano, COOR3, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, (C 1 -C 6 )-alkylcarbonyl or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;   R1 is (C 6 -C 12 )-alkyl or Y-phenyl, where phenyl may be substituted one to three times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyloxy, hydroxy, amino, (C 1 -C 6 )-alkyloxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl;   Y is —CH 2 —;   R2 is hydrogen or (C 5 -C 10 )-alkyl; or   R1 and R2 together with the nitrogen atom carrying them may form a monocyclic, saturated 5- to 6-membered ring system or a bicyclic saturated or partly unsaturated 9- to 10-membered ring system whose individual members of the ring systems may be replaced by one to three atoms or atomic groups from the series —CHR4-, —CR4R5-, ═(C—R4)-, —NR5-, —C(═O)—, —O— or —S—, with the proviso that two units from the series —O— or —S— may not be adjacent;   R3, R3a are identically or differently hydrogen or (C 1 -C 6 )-alkyl; and   R4, R5 are identically or differently (C 1 -C 10 -alkyl, (C 1 -C 6 )-alkyloxy, halogen, trifluoromethyl, trifluoromethoxy, COOR3, cyano, aryl, cyclopropyl or (C 1 -C 3 )-alkylene-phenyl, where aryl may be substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyloxy, O—(C 1 -C 3 )-alkylene-phenyl, trifluoromethyl, trifluoromethoxy, hydroxy, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, CO—(C 1 -C 6 )-alkyl or CO—O—(C 1 -C 6 )-alkyl, amino; or   a tautomer thereof or a physiologically tolerated salt thereof.   
   
   
       6 . The compound of the formula I as claimed in  claim 1 , wherein:
 NR1R2 is a monocyclic saturated 5- to 6-membered ring system which comprises in position 4 an atom or atomic member from the series —CHR4-, —CR4R5-, —NR5-, —(C═O) or is a bicyclic saturated or partly unsaturated 9- to 10-membered ring system whose individual members of the ring system may be replaced by one or two atomic groups from the series —CHR4-, —(C=R4)-, ═(C—R4)-, —NR5- or —(C═O)—.   
   
   
       7 . The compound of the formula I as claimed in  claim 1 , wherein:
 R1 and R2 together with the nitrogen atom carrying them form a monocyclic, saturated 5- to 6-membered ring system or a bicyclic saturated or partly unsaturated 9- to 10-membered ring system, whose individual members of the ring systems may be replaced by an atomic group from the series —CHR4- or —NR5.   
   
   
       8 . The compound of the formula I as claimed in  claim 1 , wherein:
 X is identically or differently ═C(—R)— or ═N—, where one X is ═N—;   R is identically or differently hydrogen or Cl;   NR1 R2 is piperidine which comprises in position 4 the atomic member —CHR4-; or is piperazine which comprises in position 4 the atomic member —NR5; and   R4, R5 are (C 1 -C 8 )-alkyl, phenyl, —(C 1 -C 2 )-alkylene-phenyl, naphthyl, pyrrolidin-2-one or benzofuranyl, where phenyl may be substituted once, twice or three times by methyl, ethyl, t-butyl, methoxy, ethoxy, F, Cl, Br, OH, CF 3 , NH 2 , CO—OCH 3 , CO—CH 3 , phenyl or —O-benzyl.   
   
   
       9 . The compound of the formula I as claimed in  claim 1 , wherein:
 NR1 R2 is piperidine which comprises in position 4 the atomic member —CHR4-, or is piperazine which comprises in position 4 the atomic member —NR5; and   R4, R5 are methyl or phenyl which may be substituted once or twice by methyl, methoxy, ethoxy, F, Cl, Br, OH, CF 3 , NH 2 , CO—OCH 3 , CO—CH 3 , phenyl or —O-benzyl.   
   
   
       10 . The compound of the formula I as claimed in  claim 1 , wherein:
 X is identically or differently ═C(—R—)— or ═N—, where one X is ═N—;   R is identically or differently hydrogen or Cl;   NR1R2 is tetrahydroquinoline or tetrahydroisoquinoline which may be substituted once or twice by methoxy.   
   
   
       11 . The compound of the formula I as claimed in  claim 1 , wherein:
 R2 is hydrogen.   
   
   
       12 . The compound of the formula I as claimed in  claim 1 , wherein:
 R1 is (C 6 -C 12 )-alkyl or Y-phenyl, where phenyl may be substituted one to three times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyloxy, hydroxy, amino, (C 1 -C 6 )-alkyloxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;   Y is —CH 2 —; and   R2 is hydrogen.   
   
   
       13 . The compound of the formula I as claimed in  claim 1 , wherein:
 X is identically or differently ═C(—R)— or ═N—, where one X is ═N—;   R is identically or differently hydrogen or Cl;   R1 is hexyl or Y-phenyl, where phenyl is optionally substituted by methyl;   Y is —CH 2 —; and   R2 is hydrogen.   
   
   
       14 . The compound of the formula I as claimed in  claim 1 , wherein:
 X in position 4, 5 and 6 is identically or differently ═C(—R)—, and in position 7 is ═N—.   
   
   
       15 . The compound of the formula I, as claimed in  claim 1 , wherein:
 X optionally in position 4 or 7 is ═C(—R)— with R=hydrogen or ═N—, and in position 5 or 6 is ═C(—R)— wherein R is not hydrogen.   
   
   
       16 . A pharmaceutical composition comprising one or more compounds of the formula I as claimed in  claim 1  or a tautomer thereof or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient. 
   
   
       17 . A method for the treatment of disorders of fatty acid metabolism and glucose utilization disorders comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       18 . A method for the treatment of disorders in which insulin resistance is involved comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       19 . A method for the treatment of diabetes mellitus and the sequelae associated therewith comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       20 . A method for the treatment of dyslipidemia and its sequelae comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       21 . A method for the treatment of conditions associated with the metabolic syndrome comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       22 . A method for the treatment of conditions associated with a reduced HDL level comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       23 . A method for the treatment of atherosclerotic disorders comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       24 . A method for the treatment of disorders in which insulin resistance is involved comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of the formula I as claimed in  claim 1  or a pharmaceutically acceptable salt thereof in combination with at least one other active ingredient. 
   
   
       25 . A process for producing a medicament comprising one or more of the compounds of the formula I as claimed in  claim 1 , which comprises mixing said compounds with a pharmaceutically suitable carrier to form a mixture and converting said mixture into a form suitable for administration. 
   
   
       26 . A process for preparing compounds of the formula I as claimed in  claim 1 , which comprises:
 a) acylating triazolopyridine derivative of the formula II with a carbamoyl chloride of the formula III; or   b) reacting in two stages firstly with phosgene or its equivalents chosen from trichloromethyl chlorocarbonate, ditrichloromethyl carbonate or 4-nitrophenyl chloroformate and in a second step with amines of the formula IV;   
     
       
         
         
             
             
         
       
       wherein X, R1 and R2 are as defined in  claim 1 ; and, where appropriate, separating the regioisomers. 
     
   
   
       27 . A process for preparing compounds of the formula I, wherein R2 is hydrogen as claimed in  claim 1 , which comprises:
 reacting triazolopyridine derivatives of the formula II with isocyanates of the formula V: O═C═N—R1, and, where appropriate, separating the regioisomers; and   
     
       
         
         
             
             
         
       
       wherein X and R1 are as defined in  claim 1 .