Compounds and therapies for the prevention of vascular and non-vascular pathologies
First Claim
Patent Images
1. 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:
-
whereinR6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo, (C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp,—
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof.
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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.
182 Citations
35 Claims
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1. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl, optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo, (C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp,—
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof. - View Dependent Claims (10, 11, 12, 13, 14)
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2. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof.
-
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3. 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:
-
wherein R6 is (C1-C6)alkyl or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl,(C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof.
-
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4. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2 or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof. - View Dependent Claims (5, 6, 7)
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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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V, R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C4)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof.
-
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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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(C2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof.
-
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15. A therapeutic method for preventing or treating a condition or symptom associated with osteoporosis comprising administer to a mammal in need of such therapy, an effective amount of a compound of formula VI:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl option substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoroethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro to together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof;
and provided that Z is not —
CH2—
when R6 is phenyl, substituted only at the 4-position with —
O(CH2)1-3Rk;
wherein Rk is pyrrolidino, piperidino, 4-morpholino, dimethylamino, diethylamino, or hexamethyleneimino.
-
-
16. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C314 C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C6)alkylthio, halo, trifluoromethyl, pentafluoroethyl nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof;
and provided that Z is not —
CH2—
when R6 is phenyl, substituted only at the 4-position with —
O(CH2)1-3 Rk;
wherein Rk is pyrrolidino, piperidino, morpholino, dimethylamino, diethylamino, or hexamethyleneimino.
-
-
17. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C6)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C1-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1, 2, or 3 V;
R9 is heteroaryl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl(C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm) or S;
Z is —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, or —
N(Rq)—
;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof.
-
-
18. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkoxy,(C1-C6)alkylcyclo(C1 -C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is hydrogen or phenyl optionally substituted by 1, 2, or 3 V;
R9 is heteroalkyl, heteroaryl(C1-C3)alkyl, (C1-C4)alkoxycarbonyl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Rn), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
the compound is MER25;
or a pharmaceutically acceptable salt thereof;
provided R6 is not phenyl or phenyl substituted by 1 or 2 V.
-
-
19. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
, —
N(H)—
, —
N{(C1-C6)alkyl}—
, —
OCH2—
, —
OC{(C1-C6)alkyl}2—
, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, (CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(C2)1-3—
, —
O—
, OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein Rl is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which the are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof. - View Dependent Claims (28, 29, 30, 31)
-
-
20. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
, —
N(H)—
, —
N{(C1-C6)alkyl}—
, —
OCH2—
, —
OC{(C1-C6)alkyl}2—
, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V iS OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof;
provided that R9 and Rj together are not —
S—
when Z is C═
O;
R6 is a phenyl radical substituted only at the 4-position with a group O(CH2)2Rk;
Rk is pyrrolidino, piperidino, or hexamethyleneimino;
R7 is phenyl substituted only at the 4-position with hydroxy, (C1-C2)alkoxy, —
C(═
O)(C1-C6)alkyl, or benzoyl;
R8 is phenyl substituted only at the 4-position with hydroxy, (C1-C2)alkoxy, —
C(═
O)(C1-C6)alkyl, or benzoyl and at the 2-position with Rj; and
—
—
—
—
—
is a single bond.
-
-
21. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
—
N(H)—
, —
N{(C1-C6)alkyl}—
, —
OCH2—
, —
OC{(C1-C6)alkyl}2—
, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro) cyano, trifluoroethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof;
and provided that R9 and Rj together are not —
CH2CH2—
, —
S—
, —
O—
or —
CH═
CH—
when Z is C═
O;
R6 is a phenyl radical substituted only at the 4-position with a group —
O(CH2)1-4Rk, Rk is piperazino, heptamethyleneiminyl, imidazolinyl, pyrrolidino, piperidino, morpholinyl or hexamethyleneimino;
R7 is phenyl substituted only at the 4-position with hydroxy, halo, (C1-C6)alkoxy, or —
OC(═
O)(C1-C6)alkyl;
R8 is phenyl, substituted only at the 4-position with hydroxy, halo, (C1-C6)alkoxy, or —
OC(═
O)(C1-C6)alkyl and at the 2-position with Rj; and
—
—
—
—
—
is a single bond.
-
-
22. 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:
-
wherein R6 is (C1-C6)alkyl or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
—
N(H)—
, —
N{(C1-C6)alkyl}—
, —
OCH2—
, —
OC{(C1-C6)alkyl}2—
, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein R1 is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5 or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof;
and provided that R9 and Rj together are not —
S—
when Z is C═
O;
R6 is a phenyl radical substituted only at the 4-position with a group —
O(CH2)2Rk;
Rk is pyrrolidino, piperidino, or hexamethyleneimino;
R7 is phenyl substituted only at the 4-position with hydroxy, (C1-C2)alkoxy, —
C(═
O)(C1-C6)alkyl, or benzoyl;
R8 is phenyl substituted only at the 4-position with hydroxy, (C1-C2)alkoxy, —
C(═
O)(C1-C6)alkyl, or benzoyl and at the 2-position with Rj; and
—
—
—
—
—
is a single bond.- View Dependent Claims (23, 24, 25)
-
-
26. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
—
N(H)—
, —
N{(C1-C6)alkyl}—
, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein Rl is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof;
provided the compound of formula VI is not raloxifene.
-
-
27. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
—
N(H)—
, —
N{(C1-C6)alkyl}—
, —
OCH2—
, —
OC{(C1-C6)alkyl}2—
, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein Rl is H(C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof.
-
-
32. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
, —
N(H)—
, —
N{(C1-C6)alkyl}-, or —
CH═
C—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C6)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(R1), S, or nonperoxide O, wherein Rl is H (C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof;
and provided that Z is not —
CH2—
when R6 is phenyl, substituted only at the 4-position with —
O(CH2)1-3Rk;
wherein Rk is pyrrolidino, piperidino, 4-morpholino, dimethylamino, diethylamino, or hexamethyleneimino.
-
-
33. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are R9 and Rj together are —
CH2CH2—
, —
O—
, —
N(H)—
, —
N{(C1-C6)alkyl}-, or —
CH═
CH—
,—
—
—
—
13 is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORl, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein Rl is H(C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof;
and provided that Z is not —
CH2—
when R6 is phenyl, substituted only at the 4-position with —
O(CH2)1-3Rk;
wherein Rk is pyrrolidino, piperidino, 4-morpholino, dimethylamino, diethylamino, or hexamethyleneimino.
-
-
34. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl, or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
O—
, —
N(H)—
, —
N{(C1-C6)alkyl}-, —
OCH2—
, —
OC{(C1-C6)alkyl}2—
, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl, or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH2)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, or —
N(Rq)—
;
Rk is amino optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein Rl is H(C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rq are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof.
-
-
35. 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:
-
wherein R6 is (C1-C6)alkyl, or aryl, optionally substituted by 1, 2, or 3 V;
R7 is phenyl, optionally substituted by 1, 2, or 3 V;
or R7 is (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkylcyclo(C1-C6)alkyl, (C3-C6)cycloalkenyl or (C1-C6)alkyl(C3-C6)cycloalkenyl;
R8 is phenyl substituted at the 2-position with Rj, and optionally substituted by 1, 2, or 3 V;
R9 and Rj together are —
CH2CH2—
, —
S—
, —
O—
, —
N(H)—
, —
N{(C1-C6)alkyl}-, —
OCH2—
, —
OC{(C1-C6)alkyl}2-, or —
CH═
CH—
;
—
—
—
—
—
is a single bond or is —
C(B)(D)—
, wherein B and D are each independently hydrogen, (C1-C6)alkyl or halo;
V is OPO3H2, (C1-C6)alkyl, (C1-C6)alkoxy, mercapto, (C1-C4)alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(Rn)(Ro), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —
(CH2)0-4C(═
O)(C1-C6)alkyl, —
UC(═
O)(C1-C6)alkyl, benzyl, —
OSO2(CH2)0-4CH3, —
U(CH2)1-4COORp, —
(CH2)0-4COORp, —
U(CH2)2-4ORp, —
(CH2)0-4ORp, —
U(CH2)1-4C(═
O)Rk, —
(CH2)0-4C(═
O)Rk, —
U(CH2)1-4Rk, —
(CH)0-4Rk, or —
U(CH2)2-4OC(═
O)Rp;
wherein U is O, N(Rm), or S;
Z is —
(CH2)1-3—
, —
O—
, —
OCH2—
, —
CH2O—
, —
C(═
O)O—
, —
N(Rq)—
, C═
O, or a covalent bond;
Rk is amino, optionally substituted with one or two (C1-C6)alkyl;
or an N-heterocyclic ring optionally containing 1 or 2 additional N(Rl), S, or nonperoxide O, wherein Rl is H(C1-C6)alkyl, phenyl, or benzyl;
Rn and Ro are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or Rn and Ro together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring;
Rp is H or (C1-C6)alkyl; and
Rm and Rl are independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or (C1-C6)alkanoyl;
or a pharmaceutically acceptable salt thereof;
provided R6 is not phenyl or phenyl substituted by 1 or 2 V.
-
Specification
-
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Litigation Campaign Assessment
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Current AssigneeBoston Scientific Scimed (Boston Scientific Corporation), UAB Research Foundation (University of Alabama System)
-
Original AssigneeNeoRx Corporation
-
InventorsGrainger, David J., Kasina, Sudhakar, Metcalfe, James C.
-
Primary Examiner(s)Lambkin, Deborah C.
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Application NumberUS09/567,558Time in Patent Office781 DaysField of Search514/445, 514/651, 514/685US Class Current514/445CPC Class CodesA61K 31/275 Nitriles; IsonitrilesA61K 31/381 having five-membered ringsC07D 333/38 Carbon atoms having three b...G01N 2333/495 Transforming growth factor ...G01N 2333/71 for growth factors; for gro...G01N 2800/108 OsteoporosisG01N 2800/323 Arteriosclerosis, StenosisG01N 33/74 involving hormones or other...
