Aminoglycoside antibiotics with reduced ototoxicity

Patent metadata

Field	Value
Publication number	US-9238670-B2
Application number	US-201414212964-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

This disclosure relates generally to aminoglycoside derivatives of Formula (I) as described herein. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating bacterial infections by administering these compounds and pharmaceutical compositions to subjects in need thereof.

First claim

The invention claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein
the bond is a single bond or double bond;
each of R 11 and R 12 independently is H, C(O)R a , C(O)OR a , C(O)NHR a , C(O)NR a R b , or S(O) n R a , in which n is 1, or 2, and each of R a and R b , independently is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5 to 14-membered heteroaryl; or R a and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom; and each of R a , R b , and the 4 to 12-membered heterocycloalkyl ring formed by R a and R b , is optionally substituted;
each of R 21 , R 22 , R 23 , and R 24 , independently, is H or optionally substituted C 1 -C 6 alkyl;
each of R 31 and R 32 , independently, is H or OH;
R 41 is H or CH 2 OH; and
each of R 51 and R 52 , independently, is OH, NH 2 , unsubstituted mono-C 1 -C 6 alkylamino, or unsubstituted di-C 1 -C 6 alkylamino,
provided that at least one of R 11 and R 12 is not H; further when R 12 is C(O)R a or S(O) 2 R a , then (i) R a is not alkyl substituted with NH 2 or (ii) R a is unsubstituted alkyl or alkyl substituted with one or more -Q-T, wherein Q is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T is H, halo, cyano, —OR c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —NR d C(O)R c , —NR d C(O)OR c , —S(O) 2 R c , —S(O) 2 NR c R d , R S1 , —NHR S1 , or —N(R S1 ) 2 , in which each of R c and R d , independently is H or R S2 , each of R S1 and R S2 , independently, is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; or R c and R d , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom or 5 to 14-membered heteroaryl.

2. The compound of claim 1 , wherein R 11 is H and R 12 is not H.

3. The compound of claim 2 , wherein R 12 is C(O)R a or S(O) 2 R a .

4. The compound of claim 1 , wherein R 12 is H and R 11 is not H.

5. The compound of claim 4 , wherein R 11 is C(O)R a or S(O) 2 R a .

6. The compound of claim 1 , wherein neither of R 11 and R 12 is H.

7. The compound of claim 6 , wherein each of R 11 and R 12 independently is C(O)R a or S(O) 2 R a .

8. The compound of claim 1 , wherein each of R a and R b , independently is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5 to 14-membered heteroaryl, each optionally substituted with one or more
-Q-T, wherein Q is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T is H, halo, cyano, —OR c , —NR c R d , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —NR d C(O)R c , —NR d C(O)OR c , —S(O) 2 R c , —S(O) 2 NR c R d , or R S1 , in which each of R c and R d , independently is H or R S2 , each of R S1 and R S2 , independently, is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; or R c and R d , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom.

9. The compound of claim 8 , wherein each of R a independently is methyl or ethyl each of which is optionally substituted by one or more halo or C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 10 alkenyl, optionally substituted C 3 -C 10 alkynyl, optionally substituted C 6 -C 10 aryl, or optionally substituted 5 to 10-membered heteroaryl.

10. The compound of claim 1 , each of R 21 , R 22 , R 23 , and R 24 , independently, is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.

11. The compound of claim 10 , wherein each of R 21 , R 22 , R 23 , and R 24 , independently, is H or unsubstituted C 1 -C 6 alkyl.

12. The compound claim 1 , wherein the compound is of Formula (II) or a pharmaceutically acceptable salt thereof:

13. The compound of claim 12 , wherein the compound is of any of Formula (IIA), (IIB), or (IIC), or a pharmaceutically acceptable salt thereof:

14. A compound of Formula (III) or a pharmaceutically acceptable salt thereof:

wherein
each of R 11 and R 12 independently is H, C(O)R a , C(O)OR a , C(O)NHR a , C(O)NR a R b , or S(O) n R a , in which n is 1, or 2, and each of R a and R b , independently is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5 to 14-membered heteroaryl; or R a and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom; and each of R a , R b , and the 4 to 12-membered heterocycloalkyl ring formed by R a and R b , is optionally substituted; provided that at least one of R 11 and R 12 is not H;
R 24 is H or methyl;
R 31 and R 32 are the same and are H or OH; and
R 51 is OH, NH 2 , or NHCH 3 .

15. The compound of claim 14 , wherein the compound is of any of Formulae (IIIA)-(IIIF) or a pharmaceutically acceptable salt thereof:

16. The compound of claim 1 , wherein the compound is of Formula (IV) or a pharmaceutically acceptable salt thereof:

wherein each of R 51 and R 52 , independently, is OH or NH 2 .

17. The compound of claim 16 , wherein the compound is of any of Formulae (IVA)-(IVE) or a pharmaceutically acceptable salt thereof:

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. A method of treating a bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Leland Stanford Junior

Inventors

• Ricci Anthony J
• Greenhouse Robert J
• Cheng Alan G

Classifications

• A61P31/06

  for tuberculosis · CPC title

• A61P31/08

  for leprosy · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07H15/236 Primary

  a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin · CPC title