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Compounds and method for the prevention and treatment of diabetic retinopathy

  • US 6,943,145 B2
  • Filed: 06/21/2002
  • Issued: 09/13/2005
  • Est. Priority Date: 09/10/1997
  • Status: Expired due to Fees
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1. A quaternary salt of the formula embedded imagewherein:

  • X−

     is the anion of a non-toxic, pharmaceutically acceptable acid;

    R1 is C1-C7 alkyl, C1-C7 haloalkyl or C7-C12 aralkyl;

    R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1-C7 alkyl, C1-C7 alkoxy, C2-C8 alkoxycarbonyl, C2-C8 alkanoyloxy, C1-C7 haloalkyl, C1-C7 alkylthio, C1-C7 alkylsulfinyl, C1-C7 alkylsulfonyl, —

    CH═

    NOR′

    ″

    wherein R′

    ″

    is hydrogen or C1-C7 alkyl, and —

    CONR′

    R″

    wherein R′ and

    R″

    , which are the same or different, are each hydrogen or C1-C7 alkyl;

    or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1-C7 alkyl, C1-C7 alkoxy, C2-C8 alkoxycarbonyl, C2-C8 alkanoyloxy, C1-C7 haloalkyl, C1-C7 alkylthio, C1-C7 alkylsulfinyl, C1-C7 alkylsulfonyl, —

    CH═

    NOR′

    ″

    wherein R′

    ″

    is hydrogen or C1-C7 alkyl, and —

    CONR′

    R″

    wherein R′ and

    R″

    , which are the same or different, are each hydrogen or C1-C7 alkyl;

    the depicted ring system is a pyridinium, quinolinium or isoquinolinium ion;

    “

    spacer”

    is an L-amino acid unit or a di- or tripeptide consisting of 2 or 3 L-amino acid units, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond;

    and “

    peptide”

    is a peptide having 2 to 20 amino acid units having growth factor inhibitory activity which is octreotide or lanreotide, wherein the N-terminal phenylalanine or napthylalanine of said peptide is bonded to the C-terminal amino acid of said spacer via a peptide bond, and wherein the C-terminal threonine of said peptide;

    (a) has a C-terminal carboxyl group —

    COOH which has been replaced with a —

    COOR4 group wherein R4 is C6-C30 polycycloalkyl-CpH2p—

    wherein p is 0, 1, 2 or 3, or C6-C30 polycycloalkenyl-CpH2p—

    wherein p is defined as above;

    (b) has a C-terminal —

    CH2OH group which has been replaced with a —

    CH2OCOR4 group wherein R4 is defined as above;

    (c) has a C-terminal —

    CONH2 group which has been replaced with a —

    CO-Gly-OR4 group wherein R4 is defined as above, said —

    CO-Gly-OR4 group regenerating the C-terminal —

    CONH2 group in vivo;

    (d) has a C-terminal —

    CONH2 group;

    or (e) has a C-terminal —

    CH2OH group;

    with the provisos that;

    (1) when the C-terminal amino acid is as defined in (a), (b) or (c) above, the side chain —

    NH2 group of lysine of the peptide is replaced with a —

    NHCOOR5 group wherein R5 is C1-C7 alkyl or benzyl; and

    (2) when the C-terminal amino acid is as defined in (d) or (e) above, then the side chain —

    NH2 group of lysine of the peptide is replaced with a —

    NHCOOR4 group wherein R4 is defined as above.

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