Claims for Patent: 8,822,424

Summary for Patent: 8,822,424

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 (Cupertino, CA), Gliedt; Micah James (Sunnyvale, CA)
Assignee:	Achaogen, Inc. (South San Francisco, CA)
Application Number:	13/734,729
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,822,424
Patent Claims:	1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and 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, 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.8 is hydrogen; 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 pharmaceutical composition of claim 1 wherein each R.sub.9 is methyl. 3. A pharmaceutical composition of claim 1 wherein Q.sub.1 and Q.sub.2 are other than hydrogen. 4. A pharmaceutical composition of claim 3 wherein Q.sub.3 is hydrogen. 5. A pharmaceutical composition of claim 3 wherein Q.sub.1 is: ##STR00430## wherein: R.sub.1 is hydrogen; R.sub.2 is hydrogen; and each R.sub.3 is hydrogen. 6. A pharmaceutical composition of claim 5 wherein Q.sub.1 is: ##STR00431## 7. A pharmaceutical composition of claim 6 wherein Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12. 8. A pharmaceutical composition of claim 7 wherein each R.sub.10 is hydrogen. 9. A pharmaceutical composition of claim 8 wherein each R.sub.11 is hydrogen. 10. A pharmaceutical composition of claim 3 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)-sisomici- n; 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)-sis- omicin; 6'-(2-Hydroxy-ethyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomici- n; 6'-(2-Hydroxy-4-amino-butyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisom- icin; 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-b- utyryl)-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)-s- isomicin; 6'-(Methyl-trans-3-amino-cyclobutyl)-1-(1-hydroxy-3-amino-cyclob- utyl-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)-sisom- icin; or 6'-(Methyl-3-amino-1-hydroxy-cyclobutyl)-1-(2-(azetidin-3-yl)-2-h- ydroxy-acetyl)-sisomicin. 11. A pharmaceutical composition of claim 1 wherein each R.sub.9 is methyl. 12. A pharmaceutical composition of claim 11 wherein Q.sub.3 is hydrogen. 13. A pharmaceutical composition of claim 12 wherein Q.sub.1 is: ##STR00432## wherein: R.sub.1 is hydrogen; R.sub.2 is hydrogen; and each R.sub.3 is hydrogen. 14. A pharmaceutical composition of claim 13 wherein Q.sub.1 is: ##STR00433## 15. A pharmaceutical composition of claim 14 wherein Q.sub.1 is: ##STR00434## 16. A pharmaceutical composition of claim 15 wherein Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12. 17. A pharmaceutical composition of claim 16 wherein each R.sub.10 is hydrogen. 18. A pharmaceutical composition of claim 17 wherein each R.sub.11 is hydrogen. 19. A pharmaceutical composition of claim 18 wherein p is 2. 20. A pharmaceutical composition of claim 1 wherein Q.sub.1 is ##STR00435## and Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12. 21. A pharmaceutical composition of claim 20 wherein each R.sub.9 is methyl. 22. A pharmaceutical composition of claim 20 wherein Q.sub.3 is hydrogen. 23. A pharmaceutical composition of claim 20 wherein R.sub.1 is hydrogen, R.sub.2 is hydrogen and each R.sub.3 is hydrogen. 24. A pharmaceutical composition of claim 20 wherein n is 1 or 2. 25. A pharmaceutical composition of claim 23 wherein n is 1 or 2. 26. A pharmaceutical composition of claim 20 wherein each R.sub.10 is hydrogen, each R.sub.11 is hydrogen and R.sub.12 is hydroxyl. 27. A pharmaceutical composition of claim 20 wherein p is 2. 28. A pharmaceutical composition of claim 26 wherein p is 2. 29. A pharmaceutical composition of claim 20 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. 30. A pharmaceutical composition of claim 20 wherein n is 1 or 2, and p is 2. 31. A pharmaceutical composition of claim 29 wherein n is 1 or 2, and p is 2. 32. A pharmaceutical composition of claim 20 wherein Q.sub.1 is: ##STR00436##