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US6117911A Expired / Lapsed US ⏱️ 0.0 years remaining

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

Assignee: Poniard Pharmaceuticals Inc
•
Filing: 1998-04-09
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Granted: 2000-09-12
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Expires: 2018-04-09
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Abstract

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.

Inventors

  • 👤 David J. Grainger
  • 👤 James C. Metcalfe
  • 👤 Sudhakar Kasina

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-10-23 11:44
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/275; A61K31/33; A61K31/38; A61K31/381; C; C07; C07D; C07D333/00; C07D333/02; C07D333/04; C07D333/26; C07D333/38; G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/74; G01N2333/00; G01N2333/435; G01N2333/475; G01N2333/495; G01N2333/705; G01N2333/71; G01N2800/00; G01N2800/10; G01N2800/108; G01N2800/32; G01N2800/323

Claims Analysis

Total Claims: 28
Claim 1
Independent Claim 481 words
A therapeutic method for preventing or treating a condition or symptom associated with 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: ##STR20## wherein 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 ) 04 CH 3 , --U(CH 2 ) 1-4 COOR p , --(CH 2 ) 04 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 0, 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 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.
Claim 2
Dependent Claim 481 words
A therapeutic method for preventing or treating a condition or symptom associated with 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: ##STR20## wherein 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 ) 04 CH 3 , --U(CH 2 ) 1-4 COOR p , --(CH 2 ) 04 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 0, 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 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.
Claim 3
Dependent Claim 477 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 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 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.
Claim 4
Dependent Claim 477 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 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 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.
Claim 5
Dependent Claim 498 words
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 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 21 )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 13 --C 6 )cycloalkenyl; R 8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 --C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 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 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; 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.
Claim 6
Dependent Claim 498 words
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 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 21 )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 13 --C 6 )cycloalkenyl; R 8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 --C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 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 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; 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.
Claim 7
Dependent Claim 488 words
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 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 1 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 ) 04 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,), S, or nonperoxide O, wherein R 1 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; provided that the compound is not toremifene, tamoxifen, 4-hydroxytamoxifen, 3-hydroxytamoxifen, 4-hydroxytoremifene or N-desmethyltoremifene.
Claim 8
Dependent Claim 488 words
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 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 1 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 ) 04 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,), S, or nonperoxide O, wherein R 1 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; provided that the compound is not toremifene, tamoxifen, 4-hydroxytamoxifen, 3-hydroxytamoxifen, 4-hydroxytoremifene or N-desmethyltoremifene.
Claim 9
Dependent Claim 12 words
The method of claim 4 wherein the autoimmune disease is lupus erythematosus.
Claim 10
Dependent Claim 12 words
The method of claim 4 wherein the autoimmune disease is rheumatoid arthritis.
Claim 11
Dependent Claim 12 words
The method of claim 4 wherein the autoimmune disease is multiple sclerosis.
Claim 12
Dependent Claim 624 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 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,), S, or nonperoxide O, wherein R 1 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; provided the compound of formula VI is not tamoxifen; 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.
Claim 13
Dependent Claim 624 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 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,), S, or nonperoxide O, wherein R 1 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; provided the compound of formula VI is not tamoxifen; 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.
Claim 14
Dependent Claim 468 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 0, 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,), S, or nonperoxide O, wherein R 1 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.
Claim 15
Dependent Claim 468 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 0, 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,), S, or nonperoxide O, wherein R 1 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.
Claim 16
Independent Claim 37 words
The method of any one of claims 1, 2, 3, 4, 8, and 9 wherein Z is --(CH 2 ) 1-3 --, --O--, --OCH 2 --, --CH 2 O--, --C(═O)O--, --N(R q )--, or a covalent bond.
Claim 17
Independent Claim 29 words
The method of any one of claims 1, 2, 3, 4, 8, and 9 wherein Z is --O--, --OCH 2 --, --CH 2 O--, --C(═O)O--, or --N(R q )--.
Claim 18
Independent Claim 28 words
The method of any one of claims 1, 2, 3, 4, 8, and 9 wherein R 6 is not phenyl or phenyl substituted by 1 or 2 V.
Claim 19
Independent Claim 28 words
The method of any one of claims 1, 2, 3, 4, 8, and 9 wherein R 7 is not phenyl or phenyl substituted by 1 or 2 V.
Claim 20
Independent Claim 28 words
The method of any one of claims 1, 2, 3, 4, 8, and 9 wherein R 8 is not phenyl, or phenyl substituted by 1 or 2 V.
Claim 21
Dependent Claim 556 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 )--, 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,), S, or nonperoxide O, wherein R1 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; 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.
Claim 22
Dependent Claim 556 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 )--, 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,), S, or nonperoxide O, wherein R1 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; 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.
Claim 23
Dependent Claim 564 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 )O 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 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; 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.
Claim 24
Dependent Claim 564 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 )O 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 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; 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.
Claim 25
Dependent Claim 466 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 --O--, --OCH 2 --, --CH 2 O--, --C(═O)O--, or --N(R q )--; 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 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.
Claim 26
Dependent Claim 466 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 --O--, --OCH 2 --, --CH 2 O--, --C(═O)O--, or --N(R q )--; 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 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.
Claim 27
Dependent Claim 487 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 )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 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; provided R 6 is not phenyl or phenyl substituted by 1 or 2 V.
Claim 28
Dependent Claim 487 words
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 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 by 1, 2, or 3 V; R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, cyano(C 1 -C 12 )alkyl, or (C 1 -C 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 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 )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 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; provided R 6 is not phenyl or phenyl substituted by 1 or 2 V.

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