Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents
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 having the following formula VI:
or a prodrug or pharmaceutically acceptable salt thereof,
wherein:
Q1 is —NR 10 R 11 ;
Q 2 is
each Q 3 and Q 4 is —OR 7 ;
Q 5 is —OR 8 ;
each of R 1 , R 6 , R 7 and R 8 is, in each instance, H;
each R 2 and R 10 is, independently, H, C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl;
R 11 is cyano, 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, substituted C 2 -C 12 alkynyl or —(CH 2 ) n -(L 1 ) m -(CH 2 ) nn -E 1 ;
L 1 is S, O or NJ 1 ;
n is an integer from 1 to 8;
m is 0 or 1;
nn is 0 or an integer from 1 to 8;
mm is 1 or 2;
E 1 is H, hydroxyl, halogen, cyano, —NJ 1 J 2 , C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, heteroaryl, substituted heteroaryl, a heterocyclic radical, a substituted heterocyclic radical or a substituted or unsubstituted mono or poly cyclic structure that is unsaturated, partially saturated or fully saturated and optionally includes one or more heteroatoms selected from O, N and S;
each J 1 and J 2 is, independently, H, 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, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, —C(═O)—X, a heterocyclic radical or a substituted heterocyclic radical;
each X is, independently, H, C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl; and
Z 1 and Z 2 are each, independently, H or —OH.
2. A compound according to claim 1 , wherein mm is 1.
3. A compound according to claim 1 , wherein mm is 2.
4. A compound according to claim 1 , wherein each R 2 is H.
5. A compound according to claim 1 , wherein Z 1 is —OH.
6. A compound according to claim 1 , wherein R 10 is H.
7. A compound according to claim 6 , wherein R 11 is substituted C 1 -C 12 alkyl.
8. A compound according to claim 1 , wherein:
R 10 is H;
R 11 is substituted C 1 -C 12 alkyl;
each R 2 is H; and
Z 1 is —OH.
9. A compound according to claim 8 , wherein mm is 1.
10. A compound according to claim 8 , wherein mm is 2.
11. A compound according to claim 1 having the configuration:
12. A compound according to claim 11 , wherein mm is 1.
13. A compound according to claim 11 , wherein mm is 2.
14. A compound according to claim 11 , wherein each R 2 is H.
15. A compound according to claim 11 , wherein Z 1 is —OH.
16. A compound according to claim 11 , wherein R 10 is H.
17. A compound according to claim 16 , wherein R 11 is substituted C 1 -C 12 alkyl.
18. A compound according to claim 11 , wherein:
R 10 is H;
R 11 is substituted C 1 -C 12 alkyl;
each R 2 is H; and
Z 1 is —OH.
19. A compound according to claim 18 , wherein mm is 1.
20. A compound according to claim 18 , wherein mm is 2.