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US 2019/0100516 A1Published application
Aztreonam derivatives and uses thereof
AssigneeArixa Pharmaceuticals, Inc.
InventorsERIC M. GORDON, MATTHEW A.J. DUNCTON, JOHN FREUND
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Abstract
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.
Claims31
A compound of Formula (1):
- wherein,
- each R1 is independently selected from C1-6 alkyl, or each R1 and the geminal carbon atom to which each R1 is bonded forms a C3-6 cycloalkyl ring, a C3-6 heterocycloalkyl ring, a substituted C3-6 cycloalkyl ring, or a substituted C3-6 heterocycloalkyl ring;
- R2 is selected from a single bond, C1-6 alkanediyl, C1-6 heteroalkanediyl, C5-6 cycloalkanediyl, C5-6 heterocycloalkanediyl, C6 arenediyl, C5-6 heteroarenediyl, substituted C1-6 alkanediyl, substituted C1-6 heteroalkanediyl, substituted C5-6 cycloalkanediyl, substituted C5-6 heterocycloalkanediyl, substituted C6 arenediyl, and substituted C5-6 heteroarenediyl;
- R3 is selected from C1-6 alkyl, —O—C(O)—R4, —S—C(O)—R4, —NH—C(O)—R4, —O—C(O)—O—R4, —S—C(O)—O—R4, —NH—C(O)—O—R4, —C(O)—O—R4, —C(O)—S—R4, —C(O)—NH—R4, —O—(O)—O—R4, —O—C(O)—S—R4, —O—C(O)—NH—R4, —S—S—R4, —S—R4, —NH—R4, —CH(—NH2)(—R4), C5-6 heterocycloalkyl, C5-6 heteroaryl, substituted C5-6 cycloalkyl, substituted C5-6 heterocycloalkyl, substituted C5-6 aryl, and substituted C5-6 heteroaryl, wherein,
- R4 is selected from hydrogen, C1-8 alkyl, C1-8 heteroalkyl, C5-8 cycloalkyl, C5-8 heterocycloalkyl, C5-10 cycloalkylalkyl, C5-10 heterocycloalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C1-8 alkyl, substituted C1-8 heteroalkyl, substituted C5-8 cycloalkyl, substituted C5-8 heterocycloalkyl, substituted C5-10 cycloalkylalkyl, substituted C5-10 heterocycloalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, and substituted C5-10 heteroarylalkyl;
- R5 is selected from hydrogen, C1-6 alkyl, C5-8 cycloalkyl, C6-12 cycloalkylalkyl, C2-6 heteroalkyl, C5-8 heterocycloalkyl, C6-12 heterocycloalkylalkyl, substituted C1-6 alkyl, substituted C5-8 cycloalkyl, substituted C6-12 cycloalkylalkyl, substituted C2-6 heteroalkyl, substituted C5-8 heterocycloalkyl, and substituted C6-12 heterocycloalkylalkyl;
- R6 is selected from hydrogen, C1-6 alkyl, C5-8 cycloalkyl, C6-12 cycloalkylalkyl, C2-6 heteroalkyl, C5-8 heterocycloalkyl, C6-12 heterocycloalkylalkyl, substituted C1-6 alkyl, substituted C5-8 cycloalkyl, substituted C6-12 cycloalkylalkyl, substituted C2-6 heteroalkyl, substituted C5-8 heterocycloalkyl, and substituted C6-12 heterocycloalkylalkyl;
- and
- R7 is selected from hydrogen, C1-6 alkyl, C5-8 cycloalkyl, C6-12 cycloalkylalkyl, C2-6 heteroalkyl, C5-8 heterocycloalkyl, C6-12 heterocycloalkylalkyl, substituted C1-6 alkyl, substituted C5-8 cycloalkyl, substituted C6-12 cycloalkylalkyl, substituted C2-6 heteroalkyl, substituted C5-8 heterocycloalkyl, and substituted C6-12 heterocycloalkylalkyl.
6 more elements
A method of synthesizing a derivative of aztreonam comprising:
- reacting 3-amino-2-tert-butoxycarbonylamino-butyric acid benzyl ester and a chlorosulfonyloxy ester in the presence of a base to provide the corresponding ((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxy ester;
- hydrogenating the ((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxy ester to provide the corresponding (2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoic acid ester;
- and
- cyclizing the (2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoic acid ester in the presence of a cyclization agent to provide the corresponding β-lactam.
1 more element
A method of synthesizing a derivative of aztreonam comprising:
- reacting tert-butyl (2S,3R)-3-amino-2-(((benzyloxy)carbonyl)-amino)butanoate and a chlorosulfonyloxy ester in the presence of a base to provide the corresponding tert-butyl (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoate ester;
- and
- following removal of the tert-butyl ester, cyclizing the (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoate ester in the presence of a cyclization agent to provide the corresponding β-lactam.
Dependencies are inferred from the claim text.