Compounds and therapies for the prevention of vascular and non-vascular pathologies

A therapeutic method for preventing or treating a condition or symptom associated with Parkinson's disease comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR21## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2).sub.0-4 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, C.dbd.O, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R.sub.1), S, or nonperoxide O, wherein R.sub.1 is H (C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof.

A therapeutic method for preventing or treating a condition or symptom associated with Alzheimer's disease comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR22## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.21)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.13 --C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 --C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2).sub.0-4 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, C.dbd.O, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R.sub.1), S, or nonperoxide O, wherein R.sub.1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o, together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof;
• provided the compound of formula VI is not toremifene, tamoxifen, monophenoltamoxifen, 4-hydroxytoremifene, clomifene, 4-hydroxytamoxifen, 3-hydroxytamoxifen, N-desmethyltamoxifen, cyanotamoxifen, N-desmethyltoremifene, monophenoltoremifene, or deaminotoremifene.

A therapeutic method for preventing or treating a condition or symptom associated with an autoimmune disease comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR23## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.1 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2).sub.04 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, C.dbd.O, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R,), S, or nonperoxide O, wherein R.sub.1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof;
• provided that the compound is not toremifene, tamoxifen, 4-hydroxytamoxifen, 3-hydroxytamoxifen, 4-hydroxytoremifene or N-desmethyltoremifene.

A therapeutic method for lowering serum cholesterol comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR24## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2).sub.0-4 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, C.dbd.O, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R,), S, or nonperoxide O, wherein R.sub.1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof;
• provided the compound of formula VI is not tamoxifen;
• and provided R.sup.9 is not halo when Z is a covalent bond;
• R.sup.6 is a phenyl radical or a phenyl radical substituted only at the 4-position with a group --O(CH.sub.2).sub.2 R.sub.k ;
• R.sup.7 is a phenyl radical or a phenyl radical substituted with one halogen or (C.sub.1 -C.sub.6)alkyl;
• and R.sup.8 is a phenyl radical or a phenyl radical substituted only at the 4-position with a group --O(CH.sub.2).sub.2 R.sub.k ;
• and -- is a single bond;
• and provided that R.sup.9 is not ethyl when Z is a covalent bond;
• R.sup.6 is a phenyl radical substituted only at the 4-position with a group --O(CH.sub.2).sub.2 R.sub.k ;
• R.sub.k is methylamino, ethylamino, dimethylamino or diethylamino;
• R.sup.7 is unsubstituted phenyl;
• and R.sup.8 is 3-hydroxyphenyl;
• and -- is a single bond.

A therapeutic method for enhancing or promoting wound healing, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR25## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2).sub.0-4 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is 0, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, C.dbd.O, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R,), S, or nonperoxide O, wherein R.sub.1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;,
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof.

A therapeutic method for preventing or treating a condition or symptom associated with osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR26## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2).sub.0-4 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R,), S, or nonperoxide O, wherein R1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof;
• provided that R.sup.9 is not methyl, ethyl, chloro, or bromo when Z is a covalent bond;
• and provided that Z is not --CH.sub.2 -- when R.sup.6 is phenyl, substituted only at the 4-position with --O(CH.sub.2).sub.1-3 R.sub.k ;
• wherein R.sub.k is pyrrolidino, piperidino, 4-morpholino, dimethylamino, diethylamino, or hexamethyleneimino;
• and provided that R.sup.9 is not 2-chloroethyl when Z is a covalent bond;
• and R.sup.6 is phenyl, substituted only at the 4-position with --O(CH.sub.2).sub.2 OH.

A therapeutic method for preventing or treating a condition or symptom associated with osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR27## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2)O.sub.4 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, C.dbd.O, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R.sub.1), S, or nonperoxide O, wherein R.sub.1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof;
• provided that Z is not a covalent bond when R.sup.9 is methyl, ethyl, chloro, or bromo;
• and provided that Z is not --CH.sub.2 -- when R.sup.6 is phenyl, substituted only at the 4-position with --O(CH.sub.2).sub.1-3 R.sub.k ;
• wherein R.sub.k is pyrrolidino, piperidino, 4-morpholino, dimethylamino, diethylamino, or hexamethyleneimino;
• and provided that R.sup.9 is not halo(C.sub.1 -C.sub.3)alkyl when Z is a covalent bond;
• and R.sup.6 is phenyl, substituted only at the 4-position with --O(CH.sub.2).sub.2 OH.

A therapeutic method for preventing or treating a condition or symptom associated with osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR28## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2).sub.0-4 R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, or --N(R.sub.q)--;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R.sub.1), S, or nonperoxide O, wherein R.sub.1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof.

A therapeutic method for preventing or treating a condition or symptom associated with osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

• ##STR29## wherein R.sup.6 is (C.sub.1 -C.sub.6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
• R.sup.7 is phenyl, optionally substituted by 1, 2, or 3 V;
• or R.sup.7 is (C.sub.1 -C.sub.12)alkyl, halo(C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkylcyclo(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkenyl, or (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.6)cycloalkenyl;
• R.sup.8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
• R.sup.9 is hydrogen, halo, aryl, aryl(C.sub.1 -C.sub.3)alkyl, halo(C.sub.1 -C.sub.12)alkyl, cyano(C.sub.1 -C.sub.12)alkyl, or (C.sub.1 -C.sub.12)alkyl, wherein any aryl may optionally be substituted by 1, 2, or 3, V;
• or
• -- is a single bond or is --C(B)(D)--, wherein B and D are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, or halo;
• V is OPO.sub.3 H.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mercapto, (C.sub.1 -C.sub.4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R.sub.n)(R.sub.o), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, --(CH.sub.2).sub.0-4 C(.dbd.O)(C.sub.1 -C.sub.6)alkyl, --UC(.dbd.O)(C.sub.1 -C.sub.6)alkyl, benzyl, --OSO.sub.2 (CH.sub.2).sub.0-4 CH.sub.3, --U(CH.sub.2).sub.1-4 COOR.sub.p, --(CH.sub.2).sub.0-4 COOR.sub.p, --U(CH.sub.2).sub.2-4 OR.sub.p, --(CH.sub.2).sub.0-4 OR.sub.p, --U(CH.sub.2).sub.1-4 C(.dbd.O)R.sub.k, --(CH.sub.2).sub.0-4 C(.dbd.O)R.sub.k, --U(CH.sub.2).sub.1-4 R.sub.k, --(CH.sub.2)R.sub.k, or --U(CH.sub.2).sub.2-4 OC(.dbd.O)R.sub.p ;
• wherein U is O, N(R.sub.m), or S;
• Z is --(CH.sub.2).sub.1-3 --, --O--, --OCH.sub.2 --, --CH.sub.2 O--, --C(.dbd.O)O--, --N(R.sub.q)--, C.dbd.O, or a covalent bond;
• R.sub.k is amino, optionally substituted with one or two (C.sub.1 -C.sub.6)alkyl;
• or an N-heterocyclic ring optionally containing 1 or 2 additional N(R.sub.1), S, or nonperoxide O, wherein R.sub.1 is H(C.sub.1 -C.sub.6)alkyl, phenyl, or benzyl;
• R.sub.n and R.sub.o are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• or R.sub.n and R.sub.o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
• R.sub.p is H or (C.sub.1 -C.sub.6)alkyl;
• and
• R.sub.m and R.sub.q are independently hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, benzyl, or (C.sub.1 -C.sub.6)alkanoyl;
• the compound is MER25;
• or a pharmaceutically acceptable salt thereof;
• provided R.sup.6 is not phenyl or phenyl substituted by 1 or 2 V.