Heterocycle-substituted diphosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism

A heterocycle-substituted diphosphonic acid, or a pharmaceutically-acceptable phosphonic acid salt thereof, having the general structure:

• ##STR14## wherein:
• (a) Z is a saturated six membered heterocycle, wherein said heterocycle has two ring nitrogen atoms;
• (b) Q is a covalent bond or a moiety selected from the group consisting of oxygen, sulfur, or --NR.sup.2 --;
• (c) m and n are integers from 0 to 10, and m+n is from 0 to 10;
• (d) R.sup.1 is selected from the group consisting of hydrogen;
• halogen;
• alkyl having from 1 to 6 carbon atoms;
• phenyl;
• benzyl;
• hydroxy, and the C.sub.1 -C.sub.6 esters thereof, unsubstituted amino, and C.sub.1 -C.sub.6 acylamino;
• amino and C.sub.1 -C.sub.6 acylamino substituted with one alkyl group having from 1 to 6 carbon atoms;
• amino substituted independently with two alkyl groups having from 1 to 6 carbon atoms;
• ammonium substituted independently with three alkyl groups having from 1 to 6 carbon atoms, having a pharmaceutically-acceptable counter-ion;
• and --CO.sub.2 H, the pharmaceutically-acceptable salts thereof, the C.sub.1 -C.sub.6 esters thereof, the unsubstituted amide thereof, and the amide thereof substituted with one or two alkyl groups having from 1 to 6 carbon atoms;
• except that when n=0 and Q is oxygen, sulfur or nitrogen, then R.sup.1 is selected from the group consisting of hydrogen;
• alkyl having from 1 to 6 carbon atoms;
• phenyl;
• benzyl;
• and -- CO.sub.2 H, the pharmaceutically-acceptable salts thereof, the C.sub.1 -C.sub.6 esters thereof, the unsubstituted amide thereof, and the amide thereof substituted with one or two alkyl groups having from 1 to 6 carbon atoms;
• (e) R.sup.2 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
• (f) R.sup.3 and R.sup.4 are substituents on one or more carbon atoms of said heterocycle, independently selected from the group consisting of hydrogen;
• halogen;
• alkyl having from 1 to 3 carbon atoms;
• unsubstituted amino and C.sub.1 -C.sub.3 acylamino;
• amino and C.sub.1 -C.sub.6 acylamino substituted with one alkyl group having from 1 to 3 carbon atoms;
• amino substituted independently with two alkyl groups having from 1 to 3 carbon atoms;
• ammonium substituted independently with three alkyl groups having from 1 to 3 carbon atoms, having a pharmaceutically-acceptable counter-ion;
• hydroxy, or the C.sub.1 -C.sub.6 esters thereof, ether having from 1 to 3 carbon atoms;
• --CO.sub.2 H, the pharmaceutically-acceptable salts thereof, the C.sub.1 -C.sub.3 esters thereof, the unsubstituted amide thereof, and the amide thereof substituted with one or two alkyl groups having from 1 to 3 carbon atoms;
• and nitro;
• and wherein the Q-containing chain is not attached to the heterocyclic ring at a nitrogen atom of the heterocyclic ring;
• and wherein further when m=0 and Q is oxygen, nitrogen or sulfur, then Q is bonded to the heterocyclic ring at a carbon atom not bonded directly to a nitrogen atom in the heterocyclic ring except that when Q is nitrogen then Q may also be bonded to the heterocyclic ring by a diazinilidene or ylidene structure.