Claims for Patent: 8,383,596

Summary for Patent: 8,383,596

Title:	Antibacterial aminoglycoside analogs
Abstract:	Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): ##STR00001## including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q.sub.1, Q.sub.2, Q.sub.3, R.sub.8 and R.sub.9 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
Inventor(s):	Aggen; James Bradley (Burlingame, CA), Goldblum; Adam Aaron (Berkeley, CA), Linsell; Martin Sheringham (San Mateo, CA), Dozzo; Paola (San Francisco, CA), Moser; Heinz Ernst (San Mateo, CA), Hildebrandt; Darin James (Mountain View, CA), Gliedt; Micah James (Sunnyvale, CA)
Assignee:	Achaogen, Inc. (South San Francisco, CA)
Application Number:	12/487,427
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,383,596
Patent Claims:	1. A compound having the following structure (I): ##STR00426## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Q.sub.1 is hydrogen, ##STR00427## Q.sub.2 is hydrogen, 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(.dbd.NH)NR.sub.4R.sub.5, --(CR.sub.10R.sub.11).sub.pR.sub.12, ##STR00428## Q.sub.3 is hydrogen, 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(.dbd.NH)NR.sub.4R.sub.5, --(CR.sub.10R.sub.11).sub.pR.sub.12, ##STR00429## each R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.8 and R.sub.10 is, independently, hydrogen or C.sub.1-C.sub.6 alkyl, or R.sub.1 and R.sub.2 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R.sub.2 and R.sub.3 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R.sub.1 and R.sub.3 together with the atoms to which they are attached can form a carbocyclic ring having from 4 to 6 ring atoms, or R.sub.4 and R.sub.5 together with the atom to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms; each R.sub.6 and R.sub.7 is, independently, hydrogen, hydroxyl, amino or C.sub.1-C.sub.6 alkyl, or R.sub.6 and R.sub.7 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms; each R.sub.9 is, independently, hydrogen or methyl; each R.sub.11 is, independently, hydrogen, hydroxyl, amino or C.sub.1-C.sub.6 alkyl; each R.sub.12 is, independently, hydroxyl or amino; each n is, independently, an integer from 0 to 4; each m is, independently, an integer from 0 to 4; and each p is, independently, an integer from 1 to 5, and wherein (i) at least two of Q.sub.1, Q.sub.2 and Q.sub.3 are other than hydrogen, and (ii) if Q.sub.1 is hydrogen, then at least one of Q.sub.2 and Q.sub.3 is --C(.dbd.NH)NR.sub.4R.sub.5. 2. A compound of claim 1 wherein R.sub.8 is hydrogen. 3. A compound of claim 1 wherein each R.sub.9 is methyl. 4. A compound of claim 1 wherein Q.sub.1 and Q.sub.2 are other than hydrogen. 5. A compound of claim 4 wherein Q.sub.3 is hydrogen. 6. A compound of claim 4 wherein Q.sub.1 is: ##STR00430## wherein: R.sub.1 is hydrogen; R.sub.2 is hydrogen; and each R.sub.3 is hydrogen. 7. A compound of claim 6 wherein Q.sub.1 is: ##STR00431## 8. A compound claim 4 wherein Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12. 9. A compound of claim 8 wherein each R.sub.10 is hydrogen. 10. A compound of claim 9 wherein each R.sub.11 is hydrogen. 11. A compound of claim 4 wherein the compound is: 6'-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin; 6'-(2-Hydroxy-ethyl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin; 6'-(2-Hydroxy-propanol)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin; 6'-(Methyl-piperidin-4-yl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin; 6'-(Methyl-cyclopropyl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin; 6'-(3-Amino-propyl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin; 6'-Methyl-cyclopropyl-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin; 6'-Methyl-piperidinyl-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin; 6'-(2-Hydroxy-ethyl)-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin; 6'-(2-Hydroxy-propanol)-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin; 6'-(3-Amino-propyl)-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin; 6'-(Methyl-piperidin-4-yl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin; 6'-(Methyl-cyclopropyl)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin; 6'-(2-Hydroxy-propanol)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin; 6'-(Methyl-piperidin-4-yl)-1-(3-amino-2(S)-hydroxy -propionyl)-sisomicin; 6'-(2-Hydroxy-ethyl)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin; 6'-(3-Amino-propyl)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin; 6'-(Methyl-cyclopropyl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin; 6'-(2-Hydroxy-propanol)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin; 6'-(3-Amino-2-hydroxy-propyl)-1-(3-amino-2(S)-hydroxy -propionyl)-sisomicin; 6'-(2-Hydroxy-ethyl)-1-(2-hydroxy-acetyl)-sisomicin; 6'-(3-Amino-propyl)-1-(2-amino-ethylsulfonamide)-sisomicin; 6'-(2-Hydroxy-propanol)-1-(2-amino-ethylsulfonamide)-sisomicin; 6'-(2(S)-Hydroxy-propanol)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin; 6'-(2-Hydroxy-ethyl)-1-(2-amino-ethylsulfonamide)-sisomicin; 6'-(Methyl-trans-3-amino-cyclobutyl)-1-(4-amino-2(S) -hydroxy-butyryl)-sisomicin; 6'-(2-Hydroxy-ethyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl) -sisomicin; 6'-(2-Hydroxy-4-amino-butyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomic- in; 6'-(Methyl-cyclopropyl)-1-(3-hydroxy-azetidin-3-yl-acetyl) -sisomicin; 6'-(2-Hydroxy-ethyl)-1-(3-hydroxy-azetidin-3-yl-acetyl) -sisomicin; 6'-(Methyl-(1-hydroxy-3-methylamino-cyclobutyl)-1-(4-amino -2(S)-hydroxy-butyryl) -sisomicin; 6'-(3-Amino-propyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl) -sisomicin; 6'-(Methyl-cyclopropyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl) -sisomicin; 6'-(2-Hydroxy-3-amino-propyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomi- cin; 6'-(3-Amino-propyl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin; 6'-(Methyl-pyrrolidin-2-yl)-1-(4-amino-2(S)-hydroxy -butyryl)-sisomicin; 6'-(3-Amino-propyl)-1-(3-hydroxy-azetidin-3-yl-acetyl) -sisomicin; 6'-(3-Amino-propyl)-1-(1-hydroxy-3-amino-cyclobutyl-acetyl) -sisomicin; 6'-(Methyl-trans-3-amino-cyclobutyl)-1-(3-amino-2(S) -hydroxy-propionyl)-sisomicin; 6'-(Methyl-trans-3-amino-cyclobutyl)-1-(1-hydroxy-3-amino -cyclobutyl-acetyl)-sisomicin; 6'-(2-Hydroxy-ethyl)-1-(1-hydroxy-3-amino -cyclobutyl -acetyl)-sisomicin; 6'-Methylcyclopropyl-1-(2-(azetidin-3-yl)-2-hydroxy-acetyl) -sisomicin; 6'-(Methyl-trans-3-amino-cyclobutyl)-1-(2-(azetidin-3-yl)-2-hydroxy-acety- l)-sisomicin; 6'-(2-Hydroxy-ethyl)-1-(2-(azetidin-3-yl)-2-hydroxy -acetyl)-sisomicin; 6'-(3-Amino-propyl)-1-(2-(azetidin-3-yl)-2-hydroxy -acetyl)-sisomicin; 6'-(Methyl-trans-3-amino-cyclobutyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)- -sisomicin; 6'-(2-Hydroxy-3-amino-propyl)-1-(2-(azetidin-3-yl)-2-hydroxy-acetyl)-siso- micin; or 6'-(Methyl-3-amino-1-hydroxy-cyclobutyl)-1-(2-(azetidin-3-yl)-2-- hydroxy-acetyl)-sisomicin. 12. 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. 13. 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 12. 14. A compound of claim 4 wherein the compound is 6'-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin. 15. A compound of claim 2, wherein each R.sub.9 is methyl. 16. A compound of claim 15, wherein Q.sub.3 is hydrogen. 17. A compound of claim 16, wherein Q.sub.1 is: ##STR00432## wherein: R.sub.1 is hydrogen; R.sub.2 is hydrogen; and each R.sub.3 is hydrogen. 18. A compound of claim 17, wherein Q.sub.1 is: ##STR00433## 19. A compound of claim 18, wherein Q.sub.1 is: ##STR00434## 20. A compound of claim 19, wherein Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12. 21. A compound of claim 20, wherein each R.sub.10 is hydrogen. 22. A compound of claim 21, wherein each R.sub.11 is hydrogen. 23. A compound of claim 22, wherein p is 2. 24. A compound of claim 23, wherein R.sub.12 is hydroxyl. 25. A pharmaceutical composition comprising a compound of claim 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 26. A method for treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 24 or a composition of claim 25. 27. A pharmaceutical composition comprising 6'-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 28. A method for treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a composition of claim 27. 29. A compound of claim 1, wherein Q.sub.1 is ##STR00435## and Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12. 30. A compound of claim 29 wherein R.sub.8 is hydrogen. 31. A compound of claim 29 wherein each R.sub.9 is methyl. 32. A compound of claim 29 wherein Q.sub.3 is hydrogen. 33. A compound of claim 29 wherein R.sub.1 is hydrogen, R.sub.2 is hydrogen and each R.sub.3 is hydrogen. 34. A compound of claim 29, wherein n is 1 or 2. 35. A compound of claim 33, wherein n is 1 or 2. 36. A compound of claim 29, wherein each R.sub.10 is hydrogen, each R.sub.11 is hydrogen and R.sub.12 is hydroxyl. 37. A compound of claim 29, wherein p is 2. 38. A compound of claim 36, wherein p is 2. 39. A compound of claim 29, wherein R.sub.1 is hydrogen, R.sub.2 is hydrogen, each R.sub.3 is hydrogen, each R.sub.10 is hydrogen, each R.sub.11 is hydrogen and R.sub.12 is hydroxyl. 40. A compound of claim 29, wherein n is 1 or 2, and p is 2. 41. A compound of claim 39, wherein n is 1 or 2, and p is 2. 42. A compound of claim 29, wherein Q.sub.1 is: ##STR00436## 43. A pharmaceutical composition comprising a compound of claim 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 44. A method for treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 29 or a composition of claim 43.