Inhibitors of microsomal triglyceride transfer protein and method
First Claim
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1. A compound which has the structure ##STR296## where Q is ##STR297## R1 is a fluorenyl-type group of the structure ##STR298## R1 is an indenyl-type group of the structure ##STR299## Z1 and Z2 are the same or different and are independently a bond, O, S, ##STR300## with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond;
- R11 is alkylene, alkenylene or alkynylene of up to 10 carbon atoms;
arylene or mixed arylene-alkylene;
R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl, with the provisos that(1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is ##STR301## or a bond and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl;
Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 2 to 5 carbon atoms;
R13, R14, R15, and R16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;
R15a and R16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
R6 is hydrogen or C1 -C4 alkyl or C1 -C4 alkenyl;
all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 set out above;
##STR302## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members;
oran N-oxide ##STR303## thereof;
a stereoisomer thereof;
or a pharmaceutically acceptable salt thereof.
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Abstract
Compounds are provided which inhibit microsomal triglyceride transfer protein and thus are useful for lowering serum lipids and treating atherosclerosis and related diseases. The compounds have the structure ##STR1## wherein R1 to R6, Q, and X are as defined herein.
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Citations
15 Claims
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1. A compound which has the structure ##STR296## where Q is ##STR297## R1 is a fluorenyl-type group of the structure ##STR298## R1 is an indenyl-type group of the structure ##STR299## Z1 and Z2 are the same or different and are independently a bond, O, S, ##STR300## with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond;
- R11 is alkylene, alkenylene or alkynylene of up to 10 carbon atoms;
arylene or mixed arylene-alkylene;
R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl, with the provisos that(1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is ##STR301## or a bond and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl; Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 2 to 5 carbon atoms;
R13, R14, R15, and R16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;R15a and R16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl; R6 is hydrogen or C1 -C4 alkyl or C1 -C4 alkenyl;
all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 set out above;
##STR302## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members;
oran N-oxide ##STR303## thereof;
a stereoisomer thereof;
or a pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
- R11 is alkylene, alkenylene or alkynylene of up to 10 carbon atoms;
Specification