IP Library › Granted Patent US 7,084,171

Granted Patent B2

US 7,084,171 · App. 10/827,602 · Granted Aug 1, 2006

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

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 7,084,171
App. No.: 10/827,602
Granted: Aug 1, 2006
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention provides a method of treating a mammal having, or at risk of, an indication associated with a TGF-beta deficiency comprising administering one or more agents that is effective to elevate the level of TGF-beta. The invention also provides novel compounds that elevate TGF-beta levels, as well as pharmaceutical compositions comprising compounds that elevate TGF-beta levels, and methods for detecting diseases associated with endothelial cell activation.

Claims (174)

1. A therapeutic method for treating a Marfan's syndrome, fibrosis, or senile dementia, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 7 is phenyl, optionally substituted by 1, 2, or 3 V; or R 7 is (C 1 –C 12 )alkyl, halo(C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkylcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 is hydrogen, nitro, halo, aryl, heteroaryl, aryl(C 1 –C 3 )alkyl, heteroaryl(C 1 –C 3 )alkyl, halo(C 1 –C 12 )alkyl, cyano(C 1 –C 12 )alkyl, (C 1 –C 4 )alkoxycarbonyl(C 1 –C 6 )alkyl, (C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkylcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V; or

R 9 and R j together are —CH 2 CH 2 —, —S—, —O—, —N(H)—, —N[(C 1 –C 6 )alkyl]—, —OCH 2 —, —OC[(C 1 –C 6 )alkyl] 2 —, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 )-4C(═O)R k , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(O)R k , -U(CH 2 ) 1-4 R k , —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 )1-3-, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R k is amino, optionally substituted with one or two (C 1 –C 6 )alkyl; or an N-heterocyclic ring optionally containing 1 or 2 additional N(R 1 ), S, or nonperoxide O, wherein RI is H (C 1 –C 6 )alkyl, phenyl, or benzyl;

R n and R o are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl; or R n and R o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof.

2. A therapeutic method for treating Parkinson's disease comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 7 is phenyl, optionally substituted by 1, 2, or 3 V; or R 7 is (C 1 –C 12 )alkyl, halo(C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkyellcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 is hydrogen, nitro, halo, aryl, heteroaryl, aryl(C 1 –C 3 )alkyl, heteroaryl(C 1 –C 3 )alkyl, halo(C 1 –C 12 )alkyl, cyano(C 1 –C 12 )alkyl, (C 1 –C 4 )alkoxycarbonyl(C 1 –C 6 )alkyl, (C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkyellcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V; or

R 9 and R j together are —CH 2 CH 2 —, —S—, —O—, —N(H)—, —N[(C 1 –C 6 )alkyl]—, —OCH 2 —, —OC[(C 1 –C 6 )alkyl] 2 —, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , —U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 ) 1-3 —, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R k is amino, optionally substituted with one or two (C 1 –C 6 )alkyl; or an N-heterocyclic ring optionally containing 1 or 2 additional N(R 1 ), S, or nonperoxide 0, wherein R 1 is H (C 1 –C 6 )alkyl, phenyl, or benzyl;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof;

provided that R 9 and R j together are not —S— when Z is C═O; R 6 is a phenyl radical substituted only at the 4-position with a group —O(—CH 2 ) 2 R k ; R k is pyrrolidino, piperidino, or hexamethyleneimino; R 7 is phenyl substituted only at the 4-position with hydroxy, (C 1 –C 2 )alkoxy, —C(═O)(C 1 –C 6 )alkyl, or benzoyl; R 8 is phenyl substituted only at the 4-position with hydroxy, (C 1 –C 2 )alkoxy, —C(═O)(C 1 –C 6 )alkyl, or benzoyl and at the 2-position with R j ; and — is a single bond.

3. A therapeutic method for treating Alzheimer's disease comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 and R j together are —CH 2 CH 2 —, —S—, —O— —N(H)—, —N[(C 1 –C 6 )alkyl]—,—OCH 2 —, —OC[(C 1 –C 6 )alkyl] 2 —, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO3H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , -U(CH 2 ) 1-4 R k , —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 ) 1-3 —, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R k is amino, optionally substituted with one or two (C 1 –C 6 )alkyl; or an N-heterocyclic ring optionally containing 1 or 2 additional N(R 1 ), S, or nonperoxide O, wherein R 1 is H (C 1 –C 6 )alkyl, phenyl, or benzyl;

R n and R p are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl; or R n and R p together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 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, nafoxidene, 4-hydroxytamoxifen, 3-hydroxytamoxifen, N-desmethyltamoxifen, cyanotamoxifen, N-desmethyltoremifene, monophenoltoremifene, or deaminotoremifene;

and provided that R 9 and R j together are not —CH 2 CH 2 —, —S—, —O— or —CH═CH— when Z is C═O; R 6 is a phenyl radical substituted only at the 4-position with a group —O(CH 2 ) 1-4 R k , R k is piperazino, heptamethyleneiminyl, imidazolinyl, pyrrolidino, piperidino, morpholinyl or hexamethyleneimino; R 7 is phenyl substituted only at the 4-position with hydroxy, halo, (C 1 –C 6 )alkoxy, or —OC(═O)(C 1 –C 6 )alkyl; R 8 is phenyl, substituted only at the 4-position with hydroxy, halo, (C 1 –C 6 )alkoxy, or —OC(═O)(C 1 –C 6 )alkyl and at the 2-position with R j ; and — is a single bond.

4. A therapeutic method for treating an autoimmune disease comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 is hydrogen, nitro, halo, aryl, heteroaryl, aryl(C 1 –C 3 )alkyl, heteroaryl(C 1 –C 3 )alkyl, halo(C 1 –C 12 )alkyl, cyano(C 1 –C 12 )alkyl, (C 1 –C 4 )alkoxycarbonyl(C 1 –C 6 )alkyl, (C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkyellcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V; or

R 9 and R j together are —CH 2 CH 2 —, —S—, —O— —N(H)—, —N[(C 1 –C 6 )alkyl]—, —OCH 2 —, —OC[(C 1 –C 6 )alkyl] 2 —, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , -U(CH 2 ) 1-4 R k , —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 ) 1-3 —, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 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;

and provided that R 9 and R j together are not —S— when Z is C═O; R 6 is a phenyl radical substituted only at the 4-position with a group —O(CH 2 ) 2 R k ; R k is pyrrolidino, piperidino, or hexamethyleneimino; R 7 is phenyl substituted only at the 4-position with hydroxy, (C 1 –C 2 )alkoxy, —C(═O)(C 1 –C 6 )alkyl, or benzoyl; R 8 is phenyl substituted only at the 4-position with hydroxy, (C 1 –C 2 )alkoxy; —C(═O)(C 1 –C 6 )alkyl, or benzoyl and at the 2-position with R; and — is a single bond.

5. The method of claim 4 wherein the autoimmune disease is lupus erythematosus.

6. The method of claim 4 wherein the autoimmune disease is rheumatoid arthritis.

7. The method of claim 4 wherein the autoimmune disease is multiple sclerosis.

8. 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:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R; and optionally substituted by 1, 2, or 3 V;

R 9 and R j together are —CH 2 CH 2 —, —S—, —O— —N(H)—, —N[(C 1 –C 6 )alkyl]—, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 1-4 C(═O)R p , -U(CH 2 ) 1-4 R k , —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 ) 1-3 —, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof;

provided the compound of formula VI is not tamexifen or raloxifene;

and provided R 9 is not halo when Z is a covalent bond; R 6 is a phenyl radical or a phenyl radical substituted only at the 4-position with a group —O(CH 2 ) 2 R k ; R 7 is a phenyl radical or a phenyl radical substituted with one halogen or (C 1 –C 6 )alkyl; and R 8 is a phenyl radical or a phenyl radical substituted only at the 4-position with a group —O(CH 2 ) 2 R k ; and — is a single bond;

and provided that R 9 is not ethyl when Z is a covalent bond; R 6 is a phenyl radical substituted only at the 4-position with a group —O(CH 2 ) 2 R k ; R k is methylamino, ethylamino, dimethylamino or diethylamino; R 7 is unsubstituted phenyl; and R 8 is 3-hydroxyphenyl; and — is a single bond.

9. 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:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 7 is phenyl, optionally substituted by 1, 2, or 3 V; or R 7 is (C 1 C 12 )alkyl, halo (C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkylcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 and R j together are —CH 2 CH 2 —, —S—, —O— —N(H)—, —N[(C 1 –C 6 )alkyl]—, —OCH 2 —, —OC[(C 1 –C 6 )alkyl] 2 —, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , -U(CH 2 ) 1-4 R k , —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 ) 1-4 —, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1 to 9 wherein Z is —(CH 2 ) 1-3 —, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, or a covalent bond.

11. The method of any one of claims 1 to 9 wherein Z is —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, or —N(R q )—.

12. The method of any one of claims 1 to 9 wherein R 6 is not phenyl or phenyl substituted by 1 or 2 V.

13. The method of any one of claims 1 to 9 wherein R 7 is not phenyl or phenyl substituted by 1 or 2 V.

14. The method of any one of claims 1 to 9 wherein R 8 is not phenyl, or phenyl substituted by 1 or 2 V.

15. A therapeutic method for treating osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 7 is phenyl, optionally substituted by 1, 2, or 3 V; or R 7 is (C 1 –C 1 12 )alkyl, halo(C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 3 –C 6 )alkylcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 and R j together are —CH 2 CH 2 —, —S—, —O—, —N(H)—, —N[(C 1 –C 6 )alkyl]—, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO(CH 2 ) 0-4 CH 3 , -U(CH 2 ) 0-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 0-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , -U(CH 2 ) 1-4 R k —, —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 ) 1-3 —, —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, —N(R q )—, or a covalent bond;

R k is amino, optionally substituted with one or two (C 1 –C 6 )alkyl; or an N-heterocyclic ring optionally containing 1 or 2 additional N(R 1 ), S, or nonperoxide O, wherein R) is H (C 1 –C 6 )alkyl, phenyl, or benzyl;

R p is H or (C 1 –C 6 )alkyl; and

R n and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof;

provided that R 9 is not methyl, ethyl, chloro, or bromo when Z is a covalent bond;

and provided that Z is not —CH 2 — when R 6 is phenyl, substituted only at the 4-position with —O(CH 2 ) 1-3 R k wherein R k is pyrrolidino, piperidino, 4-morpholino, dimethylamino, diethylamino, or hexamethyleneimino;

and provided that R 9 is not 2-chloroethyl when Z is a covalent bond;

and R 6 is phenyl, substituted only at the 4-position with —O(CH 2 ) 2 OH.

16. A therapeutic method for treating osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 and R j together are —H 2 CH 2 —, —O—, —N(H)—, —N[(C 1 –C 6 )alkyl]—, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , -U(CH 2 ) 1-4 R k , —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein u is O, N(R m ), or S;

Z is —(CH 2 ) 1-3 —, —O—, —OCH 2 , —CH 2 O—, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R n and R o are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 ) alkanoyl; or R n and R o together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof;

provided that Z is not a covalent bond when R 9 is methyl, ethyl, chloro, or bromo;

and provided that Z is not —CH 2 — when R 6 is phenyl, substituted only at the 4-position with —O(CH 2 ) 1-3 R k ; wherein R k is pyrrolidino, piperidino, 4-morpholino, dimethylamino, diethylamino, or hexamethyleneimino;

and provided that R 9 is not halo(C 1 –C 3 )alkyl when Z is a covalent bond; and R 6 is phenyl, substituted only at the 4-position with —O(CH 2 ) 2 OH.

17. A therapeutic method for treating osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 and R j together are —CH 2 CH 2 —, —O—, —N(H)—, —N[(C 1 –C 6 )alkyl]—, —OCH 2 —, —OC[(C 1 –C 6 )alkyl] 2 -, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) o-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , -U(CH 2 ) 1-4 R k —(CH 2 ) 0-4 R k or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —O—, —OCH 2 —, —CH 2 O—, —C(═O)O—, or —N(R q )—;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof.

18. A therapeutic method for treating osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:

R 6 is (C 1 –C 6 )alkyl, or aryl, optionally substituted by 1, 2, or 3 V;

R 7 is phenyl, optionally substituted by 1, 2, or 3 V; or R 7 is (C 1 –C 1 2 )alkyl, halo(C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkylcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl;

R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;

R 9 is hydrogen, nitro, halo, aryl, heteroaryl, aryl(C 1 –C 3 )alkyl, heteroaryl(C 1 –C 3 )alkyl, halo(C 1 –C 12 )alkyl, cyano (C 1 –C 12 )alkyl, (C 1 –C 4 )alkoxycarbonyl(C 1 –C 6 )alkyl, (C 1 –C 12 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkylcyclo(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkenyl, or (C 1 –C 6 )alkyl(C 3 –C 6 )cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V; or

R 9 and R j together are —CH 2 CH 2 —, —S—, —O—, —N(H)—, —N[(C 1 –C 6 )alkyl]—, —OCH 2 —, —OC[(C 1 –C 6 )alkyl] 2 —, or —CH═CH—;

— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 –C 6 )alkyl, or halo;

V is OPO 3 H 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, mercapto, (C 1 –C 4 )alkylthio, halo trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 –C 6 )alkyl, -UC(═O)(C 1 –C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , -U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , -U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , -U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , -U(CH 2 ) 1-4 R k —(CH 2 ) 0-4 R k , or -U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;

Z is —(CH 2 ) 1-3 , —O—, —OCH 2 —, —CH 2 —, —C(═O)O—, —N(R q )—, C═O, or a covalent bond;

R p is H or (C 1 –C 6 )alkyl; and

R m and R q are independently hydrogen, (C 1 –C 6 )alkyl, phenyl, benzyl, or (C 1 –C 6 )alkanoyl;

the compound is MER25;

or a pharmaceutically acceptable salt thereof;

provided R 6 is not phenyl or phenyl substituted by 1 or 2 V.

Assignments (2)

CHANGE OF NAME Recorded Aug 7, 2007

From: NEORX CORPORATION

To: PONIARD PHARMACEUTICALS, INC.

Reel/Frame 019658/0565 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 26, 2006

From: GRAINGER, DAVID J.; METCALFE, JAMES C.; KASINA, SUDHAKAR

To: NEORX CORPORATION

Reel/Frame 018454/0001 →