Durlobactam

Durlobactam

CAS 1467829-71-5

WeightAverage: 277.25
Monoisotopic: 277.03685626

Chemical FormulaC₈H₁₁N₃O₆S

FDA 5/23/2023, Xacduro, To treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex
Press Release
Drug Trials Snapshots

(2S,5R)-2-CARBAMOYL-3-METHYL-7-OXO-1,6-DIAZABICYCLO(3.2.1)OCT-3-EN-6-YL SULFATE

SULFURIC ACID, MONO((2S,5R)-2-(AMINOCARBONYL)-3-METHYL-7-OXO-1,6-DIAZABICYCLO(3.2.1)OCT-3-EN-6-YL) ESTER
ETX 2514, ETX-2514, ETX2514, WHO 10824
Durlobactam is a non-beta-lactam, beta-lactamase inhibitor used to treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.

Durlobactam is a beta-lactamase inhibitor used in combination with sulbactam to treat susceptible strains of bacteria in the genus Acinetobacter^[1] It is an analog of avibactam.

The combination therapy sulbactam/durlobactam was approved for medical use in the United States in May 2023.^[1]

PATENT

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9309245	No	2016-04-12	2033-04-02
US9623014	No	2017-04-18	2033-04-02
US9968593	No	2018-05-15	2035-11-17
US10376499	No	2019-08-13	2035-11-17

SYN

https://www.mdpi.com/1424-8247/15/3/384

Synthesis of Durlobactam

Chemically, durlobactam is [(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] hydrogen sulfate which can be prepared from the key intermediate hydroxyurea 6-hydroxy-3-methyl-7-oxo-1,6-diaza-bicyclo [3.2.1] oct-3-ene-2-carboxylic acid amide I, which is the structural isomer of III prepared to synthetize ETX-1317 [101]. Then, according to Scheme 15, compound 1 obtained in the synthesis of III (Scheme 14) was reacted with penta-1,3-diene in place of isoprene, and, by an aza-Diels−Alder reaction, compound 2 was obtained.

Scheme 15. Synthesis of durlobactam (C₈H₁₁N₃O₆S, MW = 277.36, IUPAC name, [(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] hydrogen sulphate.

Compound 2 underwent deprotection of the tert-butyl sulfinyl group to afford 3, subsequently Boc protected, to give compound 4. The saponification of the ester followed by amide coupling using ammonium acetate afforded compound 5. The reaction of alkene 5 with N-Boc-hydroxylamine in the presence of oxygen or air gave the desired compound 6 in a single step. Compound 6 was then protected with TBS group, using TBSCl to afford 7, which was Boc deprotected using zinc bromide obtaining compound 8. Cyclization of the diamine 8 with tri-phosgene provided the corresponding cyclic urea 9, which was TBS deprotected with HFPy to give the key intermediate I. This compound was then immediately sulfated with the DMF:SO₃ complex to obtain the sulfate, which was isolated as its tetrabutylammonium salt 10 by reacting with tetrabutylammonium acetate. The tetrabutylammonium salt was converted to durlobactam in the form of sodium salt by passing 10 through a column filled with Indion 225 sodium resin.

REF

https://sioc-journal.cn/Jwk_yjhx/EN/abstract/abstract350784.shtml

References

1. ^ Jump up to:^a b “FDA Approves New Treatment for Pneumonia Caused by Certain Difficult-to-Treat Bacteria”. U.S. Food and Drug Administration (Press release). 24 May 2023. Retrieved 24 May 2023.  This article incorporates text from this source, which is in the public domain.

Further reading

• Shapiro AB, Moussa SH, McLeod SM, Durand-Réville T, Miller AA (2021). “Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam”. Frontiers in Microbiology. 12: 709974. doi:10.3389/fmicb.2021.709974. PMC 8328114. PMID 34349751.
• Papp-Wallace KM, McLeod SM, Miller AA (May 2023). “Durlobactam, a Broad-Spectrum Serine β-lactamase Inhibitor, Restores Sulbactam Activity Against Acinetobacter Species”. Clinical Infectious Diseases. 76 (Supplement_2): S194 – S201. doi:10.1093/cid/ciad095. PMC 10150275. PMID 37125470.

/////////Durlobactam, Xacduro, FDA 2023, APPROVED 2023, ETX 2514, ETX-2514, ETX2514, WHO 10824