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Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method

  • US 5,760,246 A
  • Filed: 12/17/1996
  • Issued: 06/02/1998
  • Est. Priority Date: 12/17/1996
  • Status: Expired due to Term
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First Claim
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1. A compound which has the structure ##STR800## including pharmaceutically acceptable salts thereof, N-oxides thereof, whereinA is ##STR801## where R5 is H or lower alkyl;

  • B is a fluorenyl-type group of the structure ##STR802## R1 is heteroaryl, heteroarylamino, heteroaryloxy, heteroetrylsulfonylamino, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, the R1 group may optionally be substituted with 1, 2, 3 or 4 substituents, which can be any of the R3 or R1 groups or alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl alkylsulfonyl --PO(R13)(R14), (where R13 and R14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy);

    aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups);

    cyano, or alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may optionally be substituted with alkyl, aryl or heteroaryl), alkylsulfonylamino, arylsulfonylamino, or heteroarylsulfonylamino;

    R2 is independently any of the groups set out for R1, alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)3 Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkennyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, arylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, --PO(R13)(R14), (where R13 and R14 are independently alkyl, aryl, alkoxy. aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy. heteroarylalkoxy. cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy);

    aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups);

    cyano, H, or polyhaloalkyl, and may be optionally substituted with one to four of any of the groups defined for R3 or substituents defined for R1 ;

    L1 is a linking group containing from 1 to 10 carbons;

    in a linear chain including alkylene, alkenylene or alkynylene, which may contain, within the linking chain any of the following;

    one or two alkenes, one or two alkynes, an oxygen, an amino group, an oxo group, and may be substituted with one to five alkyl or halo groups;

    L2 may be the same or different from L1 and may independently be any of the L1 groups set out above or a single bond;

    R3, R3'"'"', R4 and R4'"'"' may be the same or different and are independently selected from H, halogen, CF3, haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cyano, Ar-, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or hetertoaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar;

    R3a and R3b are the same or different and are independently any of the R3 groups except hydroxy, nitro, amino or thio;

    ##STR803## are the same or different and independently represent a 5 or 6 membered heteroaryl ring which contains 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and

    including N-oxides;

    X is a bond, or is one of the following groups;

    ##STR804## wherein Y is O, N--R6 or S;

    n'"'"' is 0, 1 or 2;

    R6 is H, lower alkyl, aryl, --C(O)--R11 or --C(O)--O--R11 ;

    R7 and R8 are the same or different and are independently H, alkyl, aryl, halogen, --O--R12, orR7 and R8 together can be oxygen to form a ketone;

    R9, R10, R9'"'"' and R10'"'"' are the same or different and are independently H, lower alkyl, aryl or -O-R11 ;

    R9" and R10" are the same or different and are independently H, lower alkyl, aryl, halogen or --O--R11 ;

    R11 is alky or aryl;

    R12 is H, alkyl or aryl.

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