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Generated: August 18, 2019

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Claims for Patent: 9,266,919

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Summary for Patent: 9,266,919
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:14/334,511
Patent Claims: 1. A method for treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound having the following structure (I): ##STR00426## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Q.sub.1 is hydrogen, ##STR00427## 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(.dbd.NH)NR.sub.4R.sub.5 , --CR.sub.10R.sub.11).sub.pR.sub.12, ##STR00428## 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(.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. The method of claim 1 wherein each R.sub.9 is methyl.

3. The method of claim 1 wherein Q.sub.1 and Q.sub.2 are other than hydrogen.

4. The method of claim 3 wherein Q.sub.3 is hydrogen.

5. The method 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. The method of claim 5 wherein Q.sub.1 is: ##STR00431##

7. The method of claim 3 wherein Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.l2.

8. The method of claim 7 wherein each R.sub.10 is hydrogen.

9. The method of claim 8 wherein each R.sub.11 is hydrogen.

10. The method 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; 6'42-Hydroxy-ethyl)-1-(3-amino-2(R)-hydroxy-propionyl)-sisomicin; 6'42-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; 6'42-Hydroxy-propanol)-1-(3-amino-2(S)-hydroxy-propionyl)-sisomicin; 6'-(Methyl-piperidin-4-yl)-1-(3-amino-2(S)-hydroxy-propionyl)-sisomicin; 6'42-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; 6'42-Hydroxy-propanol)-1-(2-amino-ethylsulfonamide)-sisomicin; 6' -(2(S)-Hydroxy-propanol)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin; 6'42-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; 6'43-Amino-propyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomicin; 6'-(Methyl-cyclopropyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomicin; 6'42-Hydroxy-3-amino-propyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomic- in; 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; 6'43-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; 6'42-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; 6'42-Hydroxy-3-amino-propyl)-1-(2-(azetidin-3-yl)-2-hydroxy-acetyl)-sisom- icin; or 6' -(Methyl-3-amino-l-hydroxy-cyclobutyl)-1-(2-(azetidin-3-yl)-2-hydroxy-ace- tyl)-sisomicin.

11. The method of claim 1 wherein each R.sub.9 is methyl.

12. The method of claim 11 wherein Q.sub.3 is hydrogen.

13. The method 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. The method of claim 13 wherein Q.sub.1 is: ##STR00433##

15. The method of claim 14 wherein Q.sub.1 is: ##STR00434##

16. The method of claim 15 wherein Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12.

17. The method of claim 16 wherein each R.sub.10 is hydrogen.

18. The method of claim 17 wherein each R.sub.11 is hydrogen.

19. The method of claim 18 wherein p is 2.

20. The method of claim 1 wherein Q.sub.1 is ##STR00435## and Q.sub.2 is --(CR.sub.10R.sub.11).sub.pR.sub.12.

21. The method of claim 20 wherein each R.sub.9 is methyl.

22. The method of claim 20 wherein Q.sub.3 is hydrogen.

23. The method of claim 20 wherein R.sub.1 is hydrogen, R.sub.2 is hydrogen and each R.sub.3 is hydrogen.

24. The method of claim 20 wherein n is 1 or 2.

25. The method of claim 23 wherein n is 1 or 2.

26. The method of claim 20 wherein each R.sub.10 is hydrogen, each R.sub.11 is hydrogen and R.sub.12 is hydroxyl.

27. The method of claim 20 wherein p is 2.

28. The method of claim 26 wherein p is 2.

29. The method 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. The method of claim 20 wherein n is 1 or 2, and p is 2.

31. The method of claim 29 wherein n is 1 or 2, and p is 2.

32. The method of claim 20 wherein Q.sub.1 is: ##STR00436##

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