Antibacterial aminoglycoside analogs
View Patent ↗Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q 1 , Q 2 , R 1 , R 2 and R 3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
1. A compound having the following structure (I):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Q 1 is —NR 1 R 11 or —NR 11 R 12 ;
Q 2 is optionally substituted alkyl,
each R 1 and R 2 is, independently, hydrogen or an amino protecting group;
each R 3 is, independently, hydrogen or a hydroxyl protecting group;
each R 4 , R 5 , R 7 and R 8 is, independently, hydrogen or C 1 -C 6 alkyl optionally substituted with one or more halogen, hydroxyl or amino;
each R 6 is, independently, hydrogen, halogen, hydroxyl, amino or C 1 -C 6 alkyl;
or R 4 and R 5 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R 5 and one R 6 together with the atoms to which they are attached can form a heterocyclic ring having from 3 to 6 ring atoms, or R 4 and one R 6 together with the atoms to which they are attached can form a carbocyclic ring having from 3 to 6 ring atoms, or R 7 and R 8 together with the atom to which they are attached can form a heterocyclic ring having from 3 to 6 ring atoms;
each R 9 is, independently, hydrogen, hydroxyl, amino or C 1 -C 6 alkyl optionally substituted with one or more halogen, hydroxyl or amino;
each R 10 is, independently, hydrogen, halogen, hydroxyl, amino or C 1 -C 6 alkyl;
or R 9 and one R 10 together with the atoms to which they are attached can form a heterocyclic ring having from 3 to 6 ring atoms;
each R 11 and R 12 is, independently, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl; and
n is an integer from 0 to 4.
2. A compound of claim 1 wherein each R 1 , R 2 and R 3 are hydrogen.
3. A compound of claim 1 wherein Q 1 is —NHR 11 .
4. A compound of claim 3 wherein R 11 is substituted C 1 -C 6 alkyl.
5. A compound of claim 4 wherein R 11 is —(CH 2 ) m OH, wherein m is an integer from 1 to 6.
6. A compound of claim 5 wherein R 11 is —(CH 2 ) 3 OH or —(CH 2 ) 2 OH.
7. A compound of claim 1 wherein Q 1 is —NR 11 R 12 .
8. A compound of claim 1 wherein Q 2 is:
wherein:
R 4 is hydrogen;
R 5 is hydrogen; and
n is an integer from 1 to 4.
9. A compound of claim 8 wherein each R 6 is hydrogen.
10. A compound of claim 9 wherein Q 2 is:
11. A compound of claim 1 wherein Q 2 is:
wherein:
R 4 is hydrogen;
R 5 and one R 6 together with the atoms to which they are attached form a heterocyclic ring having from 3 to 6 ring atoms; and
n is an integer from 1 to 4.
12. A compound of claim 1 wherein Q 2 is:
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wherein:
R 4 and R 5 together with the atoms to which they are attached form a heterocyclic ring having from 4 to 6 ring atoms; and
n is an integer from 1 to 4.
13. A compound of claim 1 wherein Q 2 is:
wherein:
R 5 is hydrogen;
R 4 and one R 6 together with the atoms to which they are attached form a carbocyclic ring having from 3 to 6 ring atoms; and
n is an integer from 1 to 4.
14. A compound of claim 1 wherein Q 2 is:
wherein:
R 4 is hydrogen;
R 7 is hydrogen;
R 8 is hydrogen; and
n is an integer from 1 to 4.
15. A compound of claim 1 wherein Q 2 is:
wherein:
R 4 and one R 6 together with the atoms to which they are attached form a carbocyclic ring having from 3 to 6 ring atoms;
R 7 is hydrogen;
R 8 is hydrogen; and
n is an integer from 1 to 4.
16. A compound of claim 1 wherein Q 2 is:
wherein R 5 is hydrogen.
17. A compound of claim 1 wherein Q 2 is:
wherein:
R 7 is hydrogen; and
R 8 is hydrogen.
18. A compound of claim 1 wherein Q 2 is:
wherein R 5 is hydrogen.
19. A compound of claim 1 wherein Q 2 is:
wherein:
R 7 is hydrogen; and
R 8 is hydrogen.
20. A compound of claim 1 wherein Q 2 is:
wherein R 5 is hydrogen.
21. A compound of claim 1 wherein Q 2 is:
wherein R 9 is hydrogen.
22. A compound of claim 1 wherein Q 2 is:
wherein:
R 7 is hydrogen; and
R 8 is hydrogen.
23. A compound of claim 1 wherein Q 2 is:
wherein R 4 is hydrogen.
24. A compound of claim 1 wherein Q 2 is optionally substituted alkyl.
25. A compound of claim 1 having the configuration:
26. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
27. A method of treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of claim 1 or a pharmaceutical composition of claim 26 .