Antibacterial aminoglycoside analogs
View Patent ↗Compounds having antibacterial activity are disclosed. The compounds have the following structure (I) or (II): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q 1 , Q 2 , Q 3 , R 1 , R 2 , R 3 , R 11 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,
Q2 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 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 is, independently, hydrogen or methyl; and
n is an integer from 0 to 4, and
wherein (i) at least one of Q 2 and Q 3 are other than hydrogen, and (ii) if Q 1 is methyl, ethyl, i-propyl, i-butyl, —(CH 2 ) 2 OH, —CH 2 CH(OH)(CH 2 ) 2 NH 2 , —C(=O)H, —C(=O)CH(OH)CH 2 NH 2 , —C(=O)CH(OH)(CH 2 ) 2 NH 2 , —C(=O)CH(OH)(CH 2 ) 3 NH 2 , —C(=O)CH(OH)(CH 2 ) 4 NH 2 , —C(=O)N(OH)(CH 2 ) 2 NH 2 , —C(=O)CH 2 NH 2 , —C(=O)(CH 2 ) 4 NH 2 —C(=O)CH 2 NHC(CH 3 ) 3 , —C(=O)CH(CH(CH 2 ) 2 )NH 2 , —C(=O)CHNH 2 (CH 2 ) 4 NH 2 , —C(=O)(CH 2 ) 2 C(CH 3 ) 2 CH(CH 3 )OH, —C(=O)CH(OH)CH 2 NH 2 , —C(=O)OC(CH 3 ) 3 , —C(=O)(CH 2 ) 4 OH, —C(=O)CH 3 or —C(=O)NH(CH 2 ) 2 NH 2 , then Q 2 is not methyl, and (iii) if Q 1 is —C(=O)CH(OH)(CH 2 ) 2 NH 2 , then Q 3 is not —C(=O)CH(OH)(CH 2 ) 2 NH 2 .
2. A compound of claim 1 wherein Q 1 is:
wherein:
R 4 is hydrogen;
R 5 is hydrogen; and
n is an integer from 1 to 4.
3. A compound of claim 2 wherein each R 6 is hydrogen.
4. A compound of claim 3 wherein Q 1 is:
5. A compound of claim 1 wherein Q 2 is other than hydrogen.
6. A compound of claim 5 wherein Q3 is hydrogen.
7. A compound of claim 5 wherein Q 2 is optionally substituted alkyl.
8. A compound of claim 7 wherein Q 2 is substituted with hydroxyl or amino.
9. A compound of claim 1 wherein each R 1 , R 2 and R 3 is hydrogen.
10. 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.
11. A method of treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound claim 1 or a composition of claim 10 .
12. A compound having the following structure (II):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Q 1 is optionally substituted alkyl,
Q 2 is 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 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; and
each n is, independently, an integer from 0 to 4, and
wherein if Q 1 is —C(=O)CH 3 , —C(=O)CH(OH)CH 2 NH 2 , —C(=O)CH(OH)CH 2 NH 2 or —C(=O)CH(OH)(CH 2 ) 2 NH 2 , then Q 2 is not methyl, —C(=O)CH(OH)CH 2 NH 2 , —C(=O)OH(CH 3 ) 3 or
13. A compound of claim 12 wherein Q 1 is:
wherein:
R 4 is hydrogen;
R 5 is hydrogen; and
n is an integer from 1 to 4.
14. A compound of claim 13 wherein each R 6 is hydrogen.
15. A compound of claim 14 wherein Q 1 is:
16. A compound of claim 12 wherein Q 2 is optionally substituted alkyl.
17. A compound of claim 16 wherein Q 2 is substituted with hydroxyl or amino.
18. A compound of claim 12 wherein each R 1 , R 2 and R 3 is hydrogen.
19. A pharmaceutical composition comprising a compound of claim 12 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
20. 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 12 or a composition of claim 19 .