Inhibitors of advanced glycation end products
The present invention provides compounds of the formula, wherein A, B, G, R 2 , R 6 , and X are defined herein, pharmaceutical compositions of the same, and methods for treating or inhibiting development of AGE- and/or ALE-associated complications in subjects in need thereof.
1. A compound of the formula,
or a pharmaceutically acceptable salt thereof, wherein
X is N or N—O;
G is —H;
A is of the formula,
wherein
Y is N or N-oxide; and
ring C is:
(i) monocyclic;
(ii) saturated; and
(iii) contains 1 or 2 total heteroatoms, and 5 or 6 total atoms, wherein
the remaining heteroatom moiety is O, S, or NR N1 , and the carbon atoms are each optionally substituted with one or two R C wherein
R N1 is —H, -oxide, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 1 -C 6 )alkynyl, —(C 1 -C 6 )haloalkyl, or —(C 1 -C 6 )alkanoyl;
each R C is independently —Z 1 -M-Z 2 —R Z , wherein
Z 1 , M and Z 2 are absent, and
R Z is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 1 -C 6 )alkynyl, or —(C 1 -C 6 )haloalkyl, —(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )alkylaryl, -heterocycle, -aryl, or -heteroaryl;
B is imidazolyl wherein each carbon atom is substituted by R 3 , wherein
each R 3 is independently R Z3 , wherein
R Z3 is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )alkylaryl, -heterocycle, -aryl, or -heteroaryl; and
R 2 , and R 6 are independently —H, -halogen, —NO 2 , —CN, or R Z6 wherein R Z6 is —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
2. The compound according to claim 1 , wherein
ring C contains 2 heteroatoms, and 5 total atoms, wherein
the remaining heteroatom moiety is O, S, or NR N1 , and the carbon atoms are each optionally substituted with one or two R C .
3. The compound according to claim 1 , wherein
ring C contains 2 heteroatoms, and 6 total atoms, wherein
the remaining heteroatom moiety is O, S, or NR N1 , and the carbon atoms are each optionally substituted with one or two R C .
4. The compound according to claim 1 , wherein
R Z3 is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
5. The compound according to claim 1 , wherein
R 2 and R 6 are each independently —H, -halogen, —NO 2 , —CN, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
6. The compound according to claim 1 , wherein
R N′ is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
7. The compound according to claim 1 , wherein
ring C contains 2 heteroatoms, and 5 total atoms, wherein
the remaining heteroatom moiety is O or NR N1 , and the carbon atoms are each optionally substituted with one or two R C .
8. The compound according to claim 1 , wherein
ring C contains 2 heteroatoms, and 6 total atoms, wherein
the remaining heteroatom moiety is O or NR N1 , and the carbon atoms are each optionally substituted with one or two R C .
9. The compound according to claim 8 , wherein
R Z3 is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
10. The compound according to claim 8 , wherein
R 2 and R 6 are each independently —H, -halogen, —NO 2 , —CN, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
11. The compound according to claim 8 , wherein
R N′ is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
12. The compound according to claim 8 , wherein
ring C contains 2 heteroatoms, and 5 total atoms, wherein
the remaining heteroatom moiety is NR N1 , and the carbon atoms are each optionally substituted with one or two R C .
13. The compound according to claim 8 , wherein
ring C contains 2 heteroatoms, and 6 total atoms, wherein
the remaining heteroatom moiety is NR N1 , and the carbon atoms are each optionally substituted with one or two R C .
14. The compound according to claim 13 , wherein
R Z3 is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
15. The compound according to claim 13 , wherein
R 2 and R 6 are each independently —H, -halogen, —NO 2 , —CN, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
16. The compound according to claim 13 , wherein
R N′ is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
17. The compound according to claim 1 , wherein
ring C contains 2 heteroatoms, and 5 total atoms, wherein
the remaining heteroatom moiety is NR N1 , and the carbon atoms are unsubstituted;
R Z3 is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl;
R 2 and R 6 are each independently —H, -halogen, —NO 2 , —CN, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl; and
R N′ is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
18. The compound according to claim 1 , wherein
ring C contains 2 heteroatoms, and 6 total atoms, wherein
the remaining heteroatom moiety is O, S, or NR N1 , and the carbon atoms are unsubstituted;
R Z3 is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl;
R 2 and R 6 are each independently —H, -halogen, —NO 2 , —CN, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl; and
R N′ is —H, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )haloalkyl.
19. The compound according to claim 1 that is:
4-(1H-imidazol-2-yl)-2-methyl-5-((4-methylpiperazin-1-yl)methyl)pyridin-3-ol
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.