Thio-substituted, Nitrogen-containing, heterocyclic phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism

Abstract

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: ##STR1## (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 NR.sub.1 ; (c) R is COOH, SO.sub.3 H, PO.sub.3 H.sub.2, or P(O)(OH)R.sup.4, wherein R.sup.4 is substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; (d) each R1 is independently selected from --SR.sup.6 ; --R.sup.8 SR.sup.6 ; nil; hydrogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; unsubstituted or substituted aryl; hydroxy; --CO.sub.2 R.sup.3 ; --O.sub.2 CR.sup.3 ; --NR.sup.3.sub.2 ; --OR.sup.3 ; --C(O)N(R.sup.3).sub.2 ; --N(R.sup.3)C(O)R.sup.3 ; substituted or unsubstituted benzyl; nitro; or combinations thereof; (e) R.sup.2 is one or more substituents on atoms in the Z moiety and is independently selected from --SR.sup.6 and --R.sup.8 SR.sup.6 ; where R.sup.6 is H; --CO.sub.2 R.sup.3 ; --O.sub.2 CR.sup.3 ; --NR.sup.3.sub.2 ; --N(R).sup.3 C(O)R.sup.3 ; and nil; hydrogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; unsubstituted or substituted aryl; hydroxy; substituted or unsubstituted benzyl; nitro; or combinations thereof; (f) each R.sup.3 is independently selected from hydrogen; substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; or R.sup.8 SR.sup.6 ; (g) R.sup.5 is selected from --SR.sup.6 ; R.sup.8 SR.sup.6, hydrogen; hydroxy; amino; halogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; and (h) R.sup.6 is independently selected from H; --C(O)R.sup.7 ; C(S)R.sup.7 ; C(O)NR.sup.7.sub.2 ; C(S)NR.sup.7.sub.2 ; .sup.C(O)(OR7); and C(S)(OR.sup.7); wherein R.sup.7 is hydrogen; or unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; (i) R.sup.8 is a substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; and at least one of R.sup.1, R.sup.2, R.sup.3 or R.sup.5 must be SR.sup.6 or R.sup.8 SR.sup.6.

Dependencies are inferred from the claim text.