AZTREONAM DERIVATIVES AND USES THEREOF
Disclosed herein are aztreonam derivatives, therapeutic methods of using the aztreonam derivatives, particularly in combination with β-lactamase inhibitors, and pharmaceutical compositions thereof. The aztreonam derivatives can be administered orally to provide orally bioavailable aztreonam.
1 . A compound of Formula (2):
or a pharmaceutically acceptable salt thereof, wherein,
each R 1 is independently selected from C 1-3 alkyl;
R 2 is selected from —C(R 8 ) 2 — and —CH 2 —C(R 8 ) 2 —, wherein each R 8 can be independently selected from C 1-3 alkyl; and
R 3 is —O—C(O)—R 4 , wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, 4(yl-methyl)-5-methyl-1,3-dioxol-2-one, and phenyl; and
R 7 can be selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
2 . The compound of claim 1 , wherein R 1 is selected from methyl and ethyl.
3 . The compound of claim 1 , wherein each R 1 is methyl.
4 . The compound of claim 1 , wherein R 2 can be —C(R 8 ) 2 —, wherein each R 8 is hydrogen.
5 . The compound of claim 1 , wherein R 2 is —CH 2 —C(R 8 ) 2 —, wherein each R 8 is hydrogen.
6 . The compound of claim 1 , wherein each R 1 is methyl and each R 8 is hydrogen.
7 . The compound of claim 1 , wherein each R 1 is methyl and each R 8 is hydrogen.
8 . The compound of claim 1 , wherein R 4 is C 1-6 alkyl.
9 . The compound of claim 1 , wherein R 4 is phenyl.
10 . The compound of claim 1 , wherein R 4 is C 1-10 heteroalkyl.
11 . The compound of claim 1 , wherein R 7 is hydrogen.
12 . The compound of claim 1 , wherein R 7 can be selected from C 1-6 alkyl and C 1-6 heteroalkyl.
13 . The compound of claim 1 , wherein the compound is selected from:
2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzoyloxy)-2,2-dimethylpropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (2);
2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-(benzoyloxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (5);
2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(propionyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (6); and
6-(4-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino) acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoic acid (8);
or a pharmaceutically acceptable salt of any of the foregoing.
14 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle.
15 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition comprises an oral formulation.
16 . A method of treating a bacterial infection in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
17 . The method of claim 16 , wherein the bacterial infection is capable of being treated by administering aztreonam to the patient.
18 . The method of claim 16 , wherein administering comprises orally administering.
19 . The method of claim 16 , further comprising orally administering a therapeutically effective amount of a β-lactamase inhibitor to the patient.
20 . The method of claim 16 , wherein administering comprises orally administering a prodrug of the β-lactamase inhibitor.