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US 2020/0339507 A1Published application
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.
Claims27
A method of synthesizing an organyl 3-amino-2-methyl-4-oxoazetidine-1-sulfonate having the structure of Formula (5):
- or a 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;
- comprising the steps of:
- (e) reacting 3-amino-2-tert-butoxycarbonylamino-butyric acid benzyl ester with an organyl sulfurochloridate having the structure of Formula (6):
- to provide the corresponding tert-butyl (2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(((3-organyloxy)sulfonyl)amino)butanoate;
- and
- (f) after removing the benzyl ester, cyclizing the resulting (1-(tert-butoxy)-3-((organyloxysulfonyl)amino)-1-oxobutan-2-yl)carbamic acid in the presence of a cyclization agent to provide the corresponding organyl 3-((tert-butoxycarbonyl)amino)-2-methyl-4-oxoazetidine-1-sulfonate having the structure of Formula (5).
4 more elements
A method of synthesizing an organyl 3-amino-2-methyl-4-oxoazetidine-1-sulfonate having the structure of Formula (5):
- or a salt thereof, wherein,
- R8 is selected from C1-20 alkyl, C1-20 alkanecycloalkyl, C1-2 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 the steps of:
- (e) reacting tert-butyl (2S,3R)-3-amino-2-(((benzyloxy)carbonyl)-amino)butanoate with an organyl sulfurochloridate of Formula (6):
- to provide the corresponding tert-butyl (2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(((3-organyloxy) sulfonyl)amino)butanoate;
- and
- (f) following removal of the benzyl ester, cyclizing the resulting 2-tert-butoxycarbonylamino-3-(2-organyloxysulfonyl-amino)-butyric acid in the presence of a cyclization agent to provide the corresponding organyl 3-((tert-butoxycarbonyl)amino)-2-methyl-4-oxoazetidine-1-sulfonate having the structure of Formula (5).
4 more elements
A method of synthesizing 2-[(2-amino-thiazol-4-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid ester, comprising the steps of:
- (a) reacting 2-[(2-amino-thiazol-4-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid tert-butyl ester and (9H-fluoren-9-yl)-methanol in the presence of a carboxyl activating agent to provide 2-[(2-amino-thiazol-4-yl)-(9H-fluoren-9-ylmethoxycarbonyl)-methyleneaminooxy]-2-methyl-propionic acid tert-butyl ester;
- (b) treating the 2-[(2-amino-thiazol-4-yl)-(9H-fluoren-9-ylmethoxycarbonyl)-methyleneaminooxy]-2-methyl-propionic acid tert-butyl ester with an acid to provide the corresponding salt;
- (c) reacting the salt with an alcohol in the presence of a carboxyl activating agent to provide the corresponding 2-[(2-amino-thiazol-4-yl)-(9H-fluoren-9-ylmethoxycarbonyl)-methyleneaminooxy]-2-methyl-propionic acid ester;
- and
- (d) removing the (9H-fluoren-9-yl)-methyl group by treating the 2-[(2-amino-thiazol-4-yl)-(9H-fluoren-9-ylmethoxycarbonyl)-methyleneaminooxy]-2-methyl-propionic acid ester with pyridine to provide the corresponding 2-[(2-amino-thiazol-4-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid ester,
- wherein 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-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.
5 more elements
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,
- R 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,
- 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;
- 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):
10 more elements
Dependencies are inferred from the claim text.