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 5 , R 1 , R 2 , R 3 , Z 1 and Z 2 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 hydroxyl, a protected hydroxyl, amino or a protected amino group;
Q 2 is:
Q 5 is hydroxyl, a protected hydroxyl, amino or a protected amino group;
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 and R 5 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;
each n is, independently, an integer from 0 to 4; and
each Z 1 and Z 2 is, independently, hydrogen or —OR 3 ,
wherein (i) at least one of Z 1 and Z 2 is H, (ii) at least one of R 4 and R 5 is substituted C 1 -C 6 alkyl or at least one R 6 is halogen, hydroxyl or amino, and (iii) the two adjacent —CH— groups to which Z 1 and Z 2 are attached may optionally form a double bond.
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 5 is hydroxyl.
4. A compound of claim 1 wherein Q 1 is amino.
5. A compound of claim 1 wherein Z 1 is hydroxyl and Z 2 is hydrogen.
6. A compound of claim 1 wherein Z 1 is hydrogen and Z 2 is hydroxyl.
7. A compound of claim 1 wherein Q 2 is:
wherein:
R 4 is hydrogen;
R 5 is hydrogen;
at least one R 6 is halogen; and
n is an integer from 1 to 4.
8. A compound of claim 7 wherein Q 2 is:
wherein each R 6 is halogen.
9. A compound of claim 1 wherein Q 2 is:
wherein:
R 4 is hydrogen;
R 5 is hydrogen;
at least one R 6 is hydroxyl; and
n is an integer from 1 to 4.
10. A compound of claim 9 wherein Q 2 is:
11. A compound of claim 1 having the configuration:
12. A compound of claim 1 wherein the two adjacent carbon atoms to which Z 1 and Z 2 are attached form a single bond.
13. A compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
14. 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.
15. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of claim 1 .
16. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a pharmaceutical composition of claim 14 .
17. A compound having the following structure (I):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Q 1 is hydroxyl, a protected hydroxyl, amino or a protected amino group;
Q 2 is alkyl optionally substituted with one or more halogen, hydroxyl, amino, optionally substituted cycloalkyl or optionally substituted heterocyclyl,
Q 5 is hydroxyl, a protected hydroxyl, amino or a protected amino group;
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;
each R 11 is, independently, hydrogen, halogen, amino or C 1 -C 6 alkyl;
or R 9 and one R 11 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 11 together with the atoms to which they are attached can form a carbocyclic ring having from 3 to 6 ring atoms;
each n is, independently, an integer from 0 to 4;
each p is, independently, an integer from 1 to 4; and
each Z 1 and Z 2 is, independently, hydrogen or —OR 3 ,
wherein (i) at least one of Z 1 and Z 2 is H, and (ii) the two adjacent —CH— groups to which Z 1 and Z 2 are attached may optionally form a double bond.
18. A compound of claim 17 wherein each R 1 , R 2 and R 3 are hydrogen.
19. A compound of claim 17 wherein Q 5 is hydroxyl.
20. A compound of claim 17 wherein Q 1 is amino.
21. A compound of claim 17 wherein Z 1 is hydroxyl and Z 2 is hydrogen.
22. A compound of claim 17 wherein Z 1 is hydrogen and Z 2 is hydroxyl.
23. A compound of claim 17 having the configuration:
24. A compound of claim 17 wherein the two adjacent carbon atoms to which Z 1 and Z 2 are attached form a single bond.
25. A pharmaceutical composition comprising a compound of claim 17 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
26. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of claim 17 .
27. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a pharmaceutical composition of claim 25 .
28. A compound having the following structure (INT-I):
wherein:
each R 1 is, independently, an amino protecting group;
each R 3 is, independently, a hydroxyl protecting group; and
each A is, independently, phenyl, optionally substituted with one or more halogen, hydroxyl, amino or C 1 -C 6 alkyl optionally substituted with one or more halogen, hydroxyl or amino.
29. A compound of claim 28 wherein the compound is: