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US 11,565,999 B2Granted
Methods of synthesizing aztreonam derivatives
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, and methods of synthesizing aztreonam derivatives. The aztreonam derivatives can be administered orally to provide orally bioavailable aztreonam.
Claims6
A method of synthesizing an aztreonam derivative of Formula (1a):
- or a pharmaceutically acceptable salt thereof, wherein,
- R7 is selected from 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;
- and
- R8 is selected from C1-20 alkyl, C1-20 alkanecycloalkyl, C1-20 alkanearyl, C1-20 heteroalkyl, C1-20 heteroalkanecycloalkyl, C1-20 heteroalkanearyl, substituted C1-20 alkyl, substituted C1-20 alkanecycloalkyl, substituted C1-20 alkanearyl, substituted C1-20 heteroalkyl, substituted C1-20 heteroalkanecycloalkyl, and substituted C1-20 heteroalkanearyl;
- comprising (a) reacting an organyl 3-amino-2-methyl-4-oxoazetidine-1-sulfonate salt with a 2-[(2-amino-thiazol-4-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid ester in the presence of a carboxyl activating agent to provide the corresponding aztreonam sulfonyloxy organyl ester salt having the structure of Formula (1a), wherein,
- the organyl 3-amino-2-methyl-4-oxoazetidine-1-sulfonate salt has the structure of Formula (5a):
- wherein,
- R8 is selected from C1-20 alkyl, C1-20 alkanecycloalkyl, C1-20 alkanearyl, C1-20 heteroalkyl, C1-20 heteroalkanecycloalkyl, C1-20 heteroalkanearyl, substituted C1-20 alkyl, substituted C1-20 alkanecycloalkyl, substituted C1-20 alkanearyl, substituted C1-20 heteroalkyl, substituted C1-20 heteroalkanecycloalkyl, and substituted C1-20 heteroalkanearyl;
- and
- the 2-[(2-amino-thiazol-4-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid ester has the structure of Formula (7):
- wherein,
- R7 is selected from 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.
9 more elements
A method of synthesizing an aztreonam derivative of Formula (1a), comprising:
- or a pharmaceutically acceptable salt thereof, wherein,
- R8 is selected from C1-20 alkyl, C1-20 alkanecycloalkyl, C1-20 alkanearyl, C1-20 heteroalkyl, C1-20 heteroalkanecycloalkyl, C1-20 heteroalkanearyl, substituted C1-20 alkyl, substituted C1-20 alkanecycloalkyl, substituted C1-20 alkanearyl, substituted C1-20 heteroalkyl, substituted C1-20 heteroalkanecycloalkyl, and substituted C1-20 heteroalkanearyl;
- and
- (a) reacting an organyl 3-amino-2-methyl-4-oxoazetidine-1-sulfonate salt with a 2-[(2-amino-thiazol-4-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid tert-butyl ester in the presence of a carboxyl coupling agent to provide the corresponding tert-butoxy protected salt;
- and
- (b) treating the tert-butoxy protected salt with an acid to provide the corresponding aztreonam sulfonyloxy organyl ester salt, wherein,
- the organyl 3-amino-2-methyl-4-oxoazetidine-1-sulfonate salt has the structure of Formula (5a):
- wherein,
- R8 is selected from C1-20 alkyl, C1-20 alkanecycloalkyl, C1-20 alkanearyl, C1-20 heteroalkyl, C1-20 heteroalkanecycloalkyl, C1-20 heteroalkanearyl, substituted C1-20 alkyl, substituted C1-20 alkanecycloalkyl, substituted C1-20 alkanearyl, substituted C1-20 heteroalkyl, substituted C1-20 heteroalkanecycloalkyl, and substituted C1-20 heteroalkanearyl;
- and
- the 2-[(2-amino-thiazol-4-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid tert-butyl ester (7a) has the structure of Formula (7a):
8 more elements
Dependencies are inferred from the claim text.