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Penem prodrugs

A drug and compound technology, applied in the field of antibiotics, oral antibiotics and prodrugs, anti-infective drugs, can solve the problem of tissue carnitine loss and other issues

Inactive Publication Date: 2011-08-17
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, POM ester prodrugs are associated with tissue carnitine depletion upon hydrolysis and release of pivalate or trimethylacetate

Method used

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  • Penem prodrugs
  • Penem prodrugs
  • Penem prodrugs

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0114] Example 1: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[[(1R,3S)-tetrahydro-1-oxo-3-thienyl]sulfur] - (2-ethyl-1-oxobutoxy)methyl 4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (Compound 1).

[0115] The title compound was prepared according to the following scheme and description.

[0116]

[0117] Step 1: 2-Ethylbutanoic acid (1500 g) was added to a solution of thionyl chloride (1800 g) in dichloromethane (0.75 L) over 1 hour. The mixture was heated to reflux and monitored by GC (gas chromatography). After approximately 2 hours, the reaction mixture was concentrated by distillation at atmospheric pressure. It was then cooled to 22°C, dichloromethane (0.75 L) was added and the mixture was concentrated again at atmospheric pressure. Because the reagents used are highly corrosive, all exhaust gases are passed through a wet caustic scrubber.

[0118] Step 2: Meanwhile, a mixture of zinc chloride (18 grams) and paraformaldehyde (480 grams) was prepared. The semi-...

example 2

[0128] Example 2: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[[(1R,3S)-tetrahydro-1-oxo-3-thienyl]sulfur] -4-Thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (2-ethoxy-2-methyl-1-oxopropoxy)methyl ester ( Compound 2).

[0129] The title compound was prepared according to the following scheme and description

[0130]

[0131] In steps 1-4, 2-hydroxy-isobutyric acid is protected with benzyl bromide, alkylated with ethane iodide, deprotected and esterified to provide 2-ethoxy-isobutyric acid chloromethyl ester.

[0132] In Step 5, sodium iodide (23.9 g, 159.45 mmol, 1.6 equiv) was dissolved in acetone (96 mL) in an appropriate reaction flask. A solution of chloromethyl 2-ethoxy-isobutyrate (18 g, 99.65 mmol, 1 eq) in additional acetone (18 mL) was then added and the reaction mixture was heated to reflux for about 2 hours under nitrogen atmosphere . The reaction was monitored by GC. After complete conversion, the reaction was cooled to room temperature with stirring. ...

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Abstract

Orally bioavailable prodrugs of sulopenem, e.g., (I) and solvates and hydrates thereof, preparation thereof, formulation thereof, and use to treat and prevent infection in mammals such as humans.

Description

technical field [0001] The present invention relates to anti-infective drugs, antibiotics, oral antibiotics and prodrugs, in particular to sulopenem prodrugs, preparations and uses thereof. Background technique [0002] US Patent 5013729 describes thiopenem, a broad-spectrum antibiotic that may be named (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[ (1R,3S)-tetrahydro-1-oxo-3-thienyl]thio]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. See also J. Org. Chem., 57, 4352-61 (1992). [0003] Other penems and prodrugs are described, for example, in US Patent 4952577, US Patent 5506225, WO1992 / 003444 and WO2004 / 067532. [0004] Various preclinical and clinical studies have been performed on thiopenem and some of its prodrugs. Thiopenem itself has no significant oral bioavailability. US Patent 5013729 also discusses prodrugs of thiopenem, including the pivaloyloxymethyl prodrug of thiopenem (thiopenem POM ester). This POM ester has been shown to have oral bioavailability ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/887A61K31/431A61P31/04
Inventor 凯瑟琳·伊丽莎白·布莱格蒂安东尼·马法特戴尔·戈登·马克劳德约翰·保罗·欧'杜奈尔
Owner PFIZER PRODS ETAT DE CONNECTICUT