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 , Q 3 , R 11 and R 12 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 alkyl optionally substituted with hydroxyl or amino,
Q 2 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 7 R 8 ,
Q 3 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 7 R 8 ,
each R 4 , R 5 , R 7 , R 8 and R 11 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 and R 12 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; and
each n is, independently, an integer from 0 to 4, and
wherein (i) at least one of Q 2 and Q 3 is other than hydrogen, and (ii) Q 1 is not ethyl or —C(═O)CH 3 .
2. A compound of claim 1 wherein Q 2 is other than hydrogen.
3. A compound of claim 2 wherein Q 3 is hydrogen.
4. A compound of claim 2 wherein Q 2 is optionally substituted alkyl.
5. A compound of claim 4 wherein Q 2 is substituted with hydroxyl or amino.
6. A compound of claim 1 wherein R 11 is hydrogen.
7. A compound of claim 1 wherein each R 12 is methyl.
8. 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.
9. A method of treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 1 or a composition of claim 8 .
10. A compound having the following structure (I):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Q 1 is
Q 2 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 7 R 8 ,
Q 3 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 7 R 8 ,
each R 4 , R 5 , R 7 , R 8 and R 11 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 and R 12 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; and
each n is, independently, an integer from 0 to 4, and
wherein (i) at least one of Q 2 and Q 3 is other than hydrogen, and (ii) for Q 1 , R 5 and one R 6 together with the atoms to which they are attached form a heterocyclic ring having 3 ring atoms, or R 4 and one R 6 together with the atoms to which they are attached form a carbocyclic ring having 3 ring atoms, or R 9 and one R 10 together with the atoms to which they are attached form a heterocyclic ring having 3 ring atoms.
11. A compound of claim 10 wherein Q 2 is other than hydrogen.
12. A compound of claim 11 wherein Q 3 is hydrogen.
13. A compound of claim 11 wherein Q 2 is optionally substituted alkyl.
14. A compound of claim 13 wherein Q 2 is substituted with hydroxyl or amino.
15. A compound of claim 10 wherein R 11 is hydrogen.
16. A compound of claim 10 wherein each R 12 is methyl.
17. A pharmaceutical composition comprising a compound of claim 10 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
18. A method of treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 10 or a composition of claim 17 .