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): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R8 and R9 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):	James Bradley Aggen, Adam Aaron Goldblum, Martin Sheringham linsell, Paola Dozzo, Heinz Ernst Moser, Darin James Hildebrandt, Micah James Gliedt
Assignee:	Cipla USA Inc
Application Number:	US12/487,427
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): or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Q1 is hydrogen, Q2 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(═NH)NR4R5, —(CR10R11)pR12, Q3 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(═NH)NR4R5, —(CR10R11)pR12, each R1, R2, R3, R4, R5, R8 and R10 is, independently, hydrogen or C1-C6 alkyl, or R1 and R2 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R2 and R3 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R1 and R3 together with the atoms to which they are attached can form a carbocyclic ring having from 4 to 6 ring atoms, or R4 and R5 together with the atom to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms; each R6 and R7 is, independently, hydrogen, hydroxyl, amino or C1-C6 alkyl, or R6 and R7 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms; each R9 is, independently, hydrogen or methyl; each R11 is, independently, hydrogen, hydroxyl, amino or C1-C6 alkyl; each R12 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 Q1, Q2 and Q3 are other than hydrogen, and (ii) if Q1 is hydrogen, then at least one of Q2 and Q3 is —C(═NH)NR4R5. 2. A compound of claim 1 wherein R8 is hydrogen. 3. A compound of claim 1 wherein each R9 is methyl. 4. A compound of claim 1 wherein Q1 and Q2 are other than hydrogen. 5. A compound of claim 4 wherein Q3 is hydrogen. 6. A compound of claim 4 wherein Q1 is: wherein: R1 is hydrogen; R2 is hydrogen; and each R3 is hydrogen. 7. A compound of claim 6 wherein Q1 is: 8. A compound claim 4 wherein Q2 is —(CR10R11)pR12. 9. A compound of claim 8 wherein each R10 is hydrogen. 10. A compound of claim 9 wherein each R11 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)-sisomicin; 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)-sisomicin; 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-acetyl)-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)-sisomicin; 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 R9 is methyl. 16. A compound of claim 15, wherein Q3 is hydrogen. 17. A compound of claim 16, wherein Q1 is: wherein: R1 is hydrogen; R2 is hydrogen; and each R3 is hydrogen. 18. A compound of claim 17, wherein Q1 is: 19. A compound of claim 18, wherein Q1 is: 20. A compound of claim 19, wherein Q2 is —(CR10R11)pR12. 21. A compound of claim 20, wherein each R10 is hydrogen. 22. A compound of claim 21, wherein each R11 is hydrogen. 23. A compound of claim 22, wherein p is 2. 24. A compound of claim 23, wherein R12 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 Q1 is and Q2 is —(CR10R11)pR12. 30. A compound of claim 29 wherein R8 is hydrogen. 31. A compound of claim 29 wherein each R9 is methyl. 32. A compound of claim 29 wherein Q3 is hydrogen. 33. A compound of claim 29 wherein R1 is hydrogen, R2 is hydrogen and each R3 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 R10 is hydrogen, each R11 is hydrogen and R12 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 R1 is hydrogen, R2 is hydrogen, each R3 is hydrogen, each R10 is hydrogen, each R11 is hydrogen and R12 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 Q1 is: 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.