THIO-SUBSTITUTED NITROGEN-CONTAINING HETEROCYCLIC PHOSPHONATE COMPOUNDS FOR TREATING ABNORMAL CALCIUM AND PHOSPHATE METABOLISM

摘要

The present invention relates to thio-substituted, nitrogen-containing heterocyclic phosphonate compounds, including bisphosphonates, phosphonoalkylphosphinates, phosphonocarboxylates, and phosphonosulfonates, and the pharmaceutically-acceptable salts and esters thereof useful for the treatment and prevention of osteoporosis and arthritis. These compounds have the general structure: IMAGE (a) Z is a monocyclic or polycyclic heterocyclic ring moiety containing one or more heteroatoms selected from O, S, or N, at least one of which is N; (b) Q is covalent bond; O, S, N, or NR1; (c) R is COOH, SO3H, PO3H2, or P(O)(OH)R4, wherein R4 is substituted or unsubstituted C1-C8 alkyl; (d) each R1 is independently selected from -SR6; -R8SR6; nil; hydrogen; unsubstituted or substituted C1-C8 alkyl; unsubstituted or substituted aryl; hydroxy; -CO2R3; -O2CR3; -NR32; -OR3; -C(O)N(R3)2; -N(R3)C(O)R3; substituted or unsubstituted benzyl; nitro; or combinations thereof; (e) R2 is one or more substituents on atoms in the Z moiety and is independently selected from -SR6 and -R8SR6; where R6 is H; -CO2R3; -O2CR3; -NR32; -N(R)3C(O)R3; and nil; hydrogen; unsubstituted or substituted C1-C8 alkyl; unsubstituted or substituted aryl; hydroxy; substituted or unsubstituted benzyl; nitro; or combinations thereof; (f) each R3 is independently selected from hydrogen; substituted or unsubstituted C1-C8 alkyl; or R8SR6; (g) R5 is selected from -SR6; R8SR6, hydrogen; hydroxy; amino; halogen; unsubstituted or substituted C1-C8 alkyl; and (h) R6 is independently selected from H; -C(O)R7; C(S)R7; C(O)NR72; C(S)NR72; C(O)(OR7); and C(S)(OR7); wherein R7 is hydrogen; or unsubstituted or substituted C1-C8 alkyl; (i) R8 is a substituted or unsubstituted C1-C8 alkyl; and at least one of R1, R2, R3 or R5 must be SR6 or R8SR6.