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 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
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 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 (i) at least one of Q 2 and Q 3 are other than hydrogen, and (ii) if Q 1 is —C(═O)CH(OH)CH 2 NH 2 , —C(═O)CH(OH)(CH 2 ) 2 NH 2 , or —C(═O)CH(OH)(CH 2 ) 3 NH 2 , then Q 2 is not methyl or —C(═O)OC(CH 3 ) 3 , and (iii) if Q 1 is —C(═O)CH(OH)CH 2 NH 2 or —C(═O)CH(OH)(CH 2 ) 2 NH 2 , then Q 3 is not —C(═O)OC(CH 3 ) 3 , —C(═O)OCH 2 Ph, —C(═O)CH(OH)CH 2 NH 2 or —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 Q 3 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 of 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
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 (i) if Q 1 is —C(═O)CHOH(CH 2 ) 2 NHR 5 , then Q 2 is not optionally substituted alkyl, and (ii) if Q 1 is —C(═O)CH(OH)(CH 2 ) 2 NHC(═NH)NH 2 , —C(═O)CH(CH 3 )CH 2 NH 2 , —CH 2 CH(OH)(CH 2 ) 2 NH 2 , —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 , or —C(═O)CHF(CH 2 ) 2 NH 2 , then Q 2 is not methyl, ethyl, —CH(═NH), —C(CH 3 )(═NH), —C(═NH)NH 2 , —C(═O)CH 3 , —C(═O)(CH 2 ) 2 CO 2 H, —C(═O)CH(OH)(CH 2 ) 2 NH 2 ,
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 .