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 (1):
or a pharmaceutically acceptable salt thereof, wherein,
each R 1 is independently C 1-6 alkyl;
R 2 is a single bond;
R 3 is —C(O)—O—R 4 , wherein R 4 is selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 7-10 alkylarene, and C 5-10 heteroalkylcycloalkyl;
each of R 5 and R 6 is hydrogen; and
R 7 is 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 each R 1 is independently C 1-3 alkyl.
3. The compound of claim 1 , wherein each R 1 is methyl.
4. The compound of claim 1 , wherein R 4 is selected from C 1-6 alkyl and C 1-6 heteroalkyl.
5. The compound of claim 1 , wherein R 4 is selected from methyl, ethyl, and n-propyl.
6. The compound of claim 1 , wherein R 7 is hydrogen.
7. The compound of claim 1 , wherein R 7 is C 1-6 alkyl.
8. The compound of claim 1 , wherein R 7 is 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one, which has the structure:
9. The compound of claim 1 , wherein,
each R 1 is methyl;
R 3 is —C(O)—O—R 4 , wherein R 4 is selected from C 1-3 alkyl; and
R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
10. The compound of claim 1 , wherein the compound is 2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is methyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-methyl-1-((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl) sulfonyl)oxy)-2,2-dimethylpropanoate, or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the compound is methyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound is methyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate, or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is methyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-methyl-1-oxo-1-propoxypropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is 2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the compound is ethyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-methyl-1-((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl) sulfonyl)oxy)-2,2-dimethylpropanoate, or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is ethyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate, or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is ethyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl) sulfonyl)oxy)-2,2-dimethylpropanoate or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is ethyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-methyl-1-oxo-1-propoxypropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate, or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle.
21. The pharmaceutical composition of claim 20 , wherein the pharmaceutical composition comprises an oral dosage formulation.
22. 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.
23. The method of claim 22 , wherein administering comprises orally administering.
24. The method of claim 22 , further comprising administering a therapeutically effective amount of a β-lactamase inhibitor to the patient.
25. The method of claim 24 , wherein the β-lactamase inhibitor comprises an avibactam derivative of Formula (20), a relebactam derivative of Formula (21), a nacubactam derivative of Formula (22), a relebactam derivative of Formula (23), a nacubactam derivative of Formula (24), a pharmaceutically acceptable salt of any of the foregoing, or a combination of any of the foregoing:
wherein,
A is a single bond (—) and R 7 is hydrogen, or A is a double bond (═) and R 7 is C 1-3 alkyl;
each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;
R 3 is selected from C 1-6 alkyl, —O—C(O)—R 4 , —S—C(O)—R 4 , —NH—C(O)—R 4 , —O—C(O)—O—R 4 , —S—C(O)—O—R 4 , —NH—C(O)—O—R 4 , —C(O)—O—R 4 , —C(O)—S—R 4 , —C(O)—NH—R 4 , —O—C(O)—O—R 4 , —O—C(O)—S—R 4 , —O—C(O)—NH—R 4 , —S—S—R 4 , —S—R 4 , —NH—R 4 , —CH(—NH 2 )(—R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 5-6 aryl, substituted C 5-6 heteroaryl, and —CH═C(R 4 ) 2 , wherein,
R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 1-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and
R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; or
R 6 is selected from a moiety of Formula (10), a moiety of Formula (11), a moiety of Formula (12), and a moiety of Formula (13):
wherein,
each R 7a is independently selected from hydrogen, C 1-8 alkyl, or each R 7a and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
n is an integer from 1 to 4:
X is selected from O and NH:
R 8 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-8 to cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
R 9 is selected from hydrogen and C 1-6 alkyl;
R 10 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl; C 1-6 alkyl;
R 11 is selected from hydrogen and C 1-6 alkyl; and
R 12 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl.
26. 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 pharmaceutical composition of claim 20 .
27. The method of claim 26 , wherein administering comprises orally administering.
28. The method of claim 26 , further comprising administering a β-lactamase inhibitor to the patient.
29. The method of claim 28 , wherein the β-lactamase inhibitor comprises an avibactam derivative of Formula (20), a relebactam derivative of Formula (21), a nacubactam derivative of Formula (22), a relebactam derivative of Formula (23), a nacubactam derivative of Formula (24), a pharmaceutically acceptable salt of any of the foregoing, or a combination of any of the foregoing:
wherein,
A is a single bond (—) and R 7 is hydrogen, or A is a double bond (═) and R 7 is C 1-3 alkyl;
each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;
R 3 is selected from C 1-6 alkyl, —O—C(O)—R 4 , —S—C(O)—R 4 , —NH—C(O)—R 4 , —O—C(O)—O—R 4 , —S—C(O)—O—R 4 , —NH—C(O)—O—R 4 , —C(O)—O—R 4 , —C(O)—S—R 4 , —C(O)—NH—R 4 , —O—C(O)—O—R 4 , —O—C(O)—S—R 4 , —O—C(O)—NH—R 4 , —S—S—R 4 , —S—R 4 , —NH—R 4 , —CH(—NH 2 )(—R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 5-6 aryl, substituted C 5-6 heteroaryl, and —CH═C(R 4 ) 2 , wherein,
R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and
R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; or
R 6 is selected from a moiety of Formula (10), a moiety of Formula (11), a moiety of Formula (12), and a moiety of Formula (13):
wherein,
each R 7a is independently selected from hydrogen, C 1-8 alkyl, or each R 7a and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
n is an integer from 1 to 4:
X is selected from O and NH;
R 8 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
R 9 is selected from hydro en and C 1-6 alkyl;
R 10 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl; C 1-6 alkyl;
R 11 is selected from hydrogen and C 1 -6 alkyl; and
R 12 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl.