Compounds and therapies for the prevention of vascular and non-vascular pathologies
View Patent ↗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.
1. A therapeutic method for treating osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:
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 )cycloalkenyl, or (C 1 -C 6 )alkyl(C 3 -C 6 )cycloalkenyl;
R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;
R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, heteroaryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkylcyclo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkenyl, or (C 1 -C 6 )alkyl(C 3 -C 6 )cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V; or
R 9 and R j together are —CH 2 CH 2 —, —S—, —O—, —N(H)—, —N[(C 1 -C 6 )alkyl]-, or —CH═CH—;
— is a single bond or is —C(B)(D)—, wherein B and D are each independently hydrogen, (C 1 -C 6 )alkyl, or halo;
V is OPO 3 H 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, mercapto, (C 1 -C 4 )alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 -C 6 )alkyl, —UC(═O)(C 1 -C 6 )alkyl, benzyl, —OSO(CH 2 ) 0-4 CH 3 , —U(CH 2 ) 0-4 COOR p , —(CH 2 ) 0-4 COOR p , —U(CH 2 ) 0-4 OR p , —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 —, or a covalent bond;
R k is amino, optionally substituted with one or two (C 1 -C 6 )alkyl; or an N-heterocyclic ring optionally containing 1 or 2 additional N(R 1 ), S, or nonperoxide O, wherein R) is H(C 1 -C 6 )alkyl, phenyl, or benzyl;
R 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;
or a pharmaceutically acceptable salt thereof;
provided that at least one of R 6 , R 7 , R 8 , and R 9 is substituted with at least one V;
provided that at least one of R 6 and R 8 is unsubstituted;
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.
2. A therapeutic method for treating osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:
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 )cycloalkenyl, or (C 1 -C 6 )alkyl(C 3 -C 6 )cycloalkenyl;
R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;
R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, heteroaryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkylcyclo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkenyl, or (C 1 -C 6 )alkyl(C 3 -C 6 )cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V; or
R 9 and R j together are —H 2 CH 2 —, —O—, —N(H)—, —N[(C 1 -C 6 )alkyl]-, or —CH═CH—;
— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 -C 6 )alkyl, or halo;
V is OPO 3 H 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, mercapto, (C 1 -C 4 )alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 -C 6 )alkyl, —UC(═O)(C 1 -C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , —U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , —U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , —U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , —U(CH 2 ) 1-4 R k , —(CH 2 ) 0-4 R k , or —U(CH 2 ) 2-4 OC(═O) R p ; wherein U is O, N(R m ), or S;
Z is —(CH 2 ) 1-3 —, 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 )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;
or a pharmaceutically acceptable salt thereof;
provided that at least one of R 6, R 7, R 8, and R 9 are substituted with at least one V;
provided that at least one of R 6 and R 8 is unsubstituted;
provided that Z is not a covalent bond when R 9 is methyl, ethyl, chloro, or bromo;
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;
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.
3. A therapeutic method for treated osteoporosis comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula VI:
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 )cycloalkenyl, or (C 1 -C 6 )alkyl(C 3 -C 6 )cycloalkenyl;
R 8 is hydrogen or phenyl, optionally substituted at the 2-position with R j , and optionally substituted by 1, 2, or 3 V;
R 9 is hydrogen, halo, aryl, aryl(C 1 -C 3 )alkyl, heteroaryl(C 1 -C 3 )alkyl, halo(C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkylcyclo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkenyl, or (C 1 -C 6 )alkyl(C 3 -C 6 )cycloalkenyl, wherein any aryl or heteroaryl may optionally be substituted by 1, 2, or 3, V; or
R 9 and R j together are —CH 2 CH 2 —, —S—, —O—, —N(H)—, —N[(C 1 -C 6 )alkyl]-, —OCH 2 —, —OC[(C 1 -C 6 )alkyl] 2 —, or —CH═CH—;
— is a single bond or is —C(B)(D)-, wherein B and D are each independently hydrogen, (C 1 -C 6 )alkyl, or halo;
V is OPO 3 H 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, mercapto, (C 1 -C 4 )alkylthio, halo, trifluoromethyl, pentafluoroethyl, nitro, N(R n )(R o ), cyano, trifluoromethoxy, pentafluoroethoxy, benzoyl, hydroxy, —(CH 2 ) 0-4 C(═O)(C 1 -C 6 )alkyl, —UC(═O)(C 1 -C 6 )alkyl, benzyl, —OSO 2 (CH 2 ) 0-4 CH 3 , —U(CH 2 ) 1-4 COOR p , —(CH 2 ) 0-4 COOR p , —U(CH 2 ) 2-4 OR p , —(CH 2 ) 0-4 OR p , —U(CH 2 ) 1-4 C(═O)R k , —(CH 2 ) 0-4 C(═O)R k , —U(CH 2 ) 1-4 R k —(CH 2 ) 0-4 R k , or —U(CH 2 ) 2-4 OC(═O)R p ; wherein U is O, N(R m ), or S;
Z is —(CH 2 ) 1-3 , 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;
or a pharmaceutically acceptable salt thereof;
provided that at least one of R 6, R 7, R 8, and R 9 are substituted with at least one V;
provided that at least one of R 6 and R 8 is unsubstituted; and
provided R 6 is not phenyl or phenyl substituted by 1 or 2 V.
4. The method of claim 1 wherein R 6 is (C 1 -C 6 )alkyl.
5. The method of claim 1 wherein R 7 is phenyl, optionally be substituted by 1, 2, or 3 V groups.
6. The method of claim 1 wherein R 7 is phenyl, substituted by 1 V group.
7. The method of claim 6 wherein V is halo.
8. The method of claim 1 wherein R 8 is phenyl, optionally substituted by 1, 2, or 3 V groups.
9. The method of claim 1 wherein R 8 is phenyl.
10. The method of claim 1 wherein R 9 is aryl, optionally substituted by 1, 2, or 3 V groups.
11. The method of claim 1 wherein R 9 is aryl substituted by 1 V group.
12. The method of claim 11 wherein V is —U(CH 2 ) 1-4 R k , wherein U is O, and R k is an N-heterocyclic ring.
13. The method of claim 1 wherein R 6 is (C 1 -C 6 )alkyl; R 7 is phenyl substituted by 1 halo group; R 8 is phenyl; and R 9 is aryl substituted by —U(CH 2 ) 1-4 R k wherein U is O, and R k is an N-heterocyclic ring.
14. The method of claim 2 wherein R 6 is (C 1 -C 6 )alkyl.
15. The method of claim 2 wherein R 7 is phenyl, substituted by 1 V group wherein V is halo.
16. The method of claim 2 wherein R 8 is phenyl.
17. The method of claim 2 wherein R 9 is aryl substituted by 1 V group, wherein V is —U(CH 2 ) 1-4 R k , and wherein U is O, and R k is an N-heterocyclic ring.
18. The method of claim 2 wherein R 6 is (C 1 -C 6 )alkyl; R 7 is phenyl substituted by 1 halo group; R 8 is phenyl; and R 9 is aryl substituted by —U(CH 2 ) 1-4 R k wherein U is O, and R k is an N-heterocyclic ring.
19. The method of claim 4 wherein R 6 is (C 1 -C 6 )alkyl.
20. The method of claim 4 wherein R 7 is phenyl, substituted by 1 V group wherein V is halo.
21. The method of claim 4 wherein R 8 is phenyl.
22. The method of claim 4 wherein R 9 is aryl substituted by 1 V group, wherein V is —U(CH 2 ) 1-4 R k , and wherein U is O, and R k is an N-heterocyclic ring.
23. The method of claim 4 wherein R 6 is (C 1 -C 6 )alkyl; R 7 is phenyl substituted by 1 halo group; R 8 is phenyl; and R 9 is aryl substituted by —U(CH 2 ) 1-4 R k wherein U is O, and R k is an N-heterocyclic ring.