Antibacterial 4,6-substituted 6′, 6″ and 1 modified aminoglycoside analogs
The present invention is directed to analogs of aminoglycoside compounds as well as their preparation and use as prophylactic or therapeutics against microbial infection.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 and R 2 is, independently, H or an amino protecting group;
each R 3 is, independently, H or a hydroxyl protecting group;
R 4 and R 5 are each, independently, H, amino protecting group, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or substituted C 2 -C 12 alkynyl;
Q 1 is cyano, azido, or NR 8 R 9 ;
Q 2 is NH 2 or N(CH 2 R 6 )R 7 ;
R 6 and R 7 are each, independently, H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical, substituted C 7 -C 9 alicyclic radical, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or substituted C 2 -C 12 alkynyl; and
R 8 and R 9 are each, independently, H, CN, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical, substituted C 7 -C 9 alicyclic radical, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or substituted C 2 -C 12 alkynyl;
wherein said substituents are each, independently, NJ 1 J 2 or C 5 -C 20 aryl; and
wherein each J 1 and J 2 is, independently, H, C 1 -C 12 alkyl or C 5 -C 20 aryl.
2. The compound of claim 1 wherein each R 1 and R 2 is H.
3. The compound of claim 1 wherein each R 3 is H.
4. The compound of claim 1 wherein Q 1 is NR 8 R 9 .
5. The compound of claim 4 wherein one of said R 8 and R 9 is H and the other of said R 8 and R 9 is C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical or substituted C 7 -C 9 alicyclic radical.
6. The compound of claim 1 wherein Q 1 is NH 2 .
7. The compound of claim 6 wherein R 7 is H or C 1 -C 12 alkyl.
8. The compound of claim 6 wherein R 6 is C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical or substituted C 7 -C 9 alicyclic radical.
9. The compound of claim 8 wherein R 6 is substituted C 1 -C 12 alkyl.
10. The compound of claim 1 wherein one of R 4 and R 5 is H and the other of R 4 and R 5 is C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl.
11. The compound of claim 1 wherein each of R 1 , R 4 and R 5 are H.
12. The compound of claim 1 wherein Q 1 is azido or cyano.
13. The compound of claim 1 having the configuration:
14. A method of treating a bacterial infection in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of claim 1 .