Doripenem hydrate

Description

Doripenem hydrate is a carbapenem derivative antibacterial agent that is more stable to renal dehydropeptidase I than IMIPENEM, but does not need to be given with an enzyme inhibitor such as CILASTATIN. It is used in the treatment of infections such as HOSPITAL-ACQUIRED PNEUMONIA, and complicated intra-abdominal or urinary-tract infections, including PYELONEPHRITIS.
Doripenem hydrate was first approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on July 25, 2005, then approved by the U.S. Food and Drug Administration (FDA) on Oct 12, 2007, and approved by European Medicines Agency (EMA) on July 25, 2008. It was developed by Shionogi and Janssen, then marketed as Finibax® in Japan and as Doribax® in the US by Shionogi and as Doribax® by Janssen in BE.

Chemical Properties

Doripenem Hydrate occurs as a white to pale yellow-brown-white crystalline powder. It is sparingly soluble in water, slightly soluble in methanol, and practically insoluble in ethanol (99.5). It is gradually colored to pale yellow-brown-white by light.

Uses

Doripenem (doripenem monohydrate) is an ultra-broad spectrum injectable antibiotic. It is a beta-lactam and belongs to the subgroup of carbapenems. It is particularly active against Pseudomonas aeruginosa

Uses

Doripenem monohydrate is a broad spectrum antibiotic belonging to the class of antibiotics called carbapenems.

Application

Doripenem monohydrate can be used as the precursor for the preparation of doripenem which may be used as an analytical reference standard for the determination of doripenem in:
Bovine muscle by liquid chromatography combined with tandem mass spectrometry (LC-MS/MS).
Bulk drug and formulations by high performance thin layer chromatography (HPTLC).
Medicinal products by capillary electrophoresis coupled to ultraviolet (UV) detector as well as micellar electrokinetic chromatography (MEKC) with UV detection.

Definition

ChEBI: Doripenem hydrate is a member of carbapenems.

Biochem/physiol Actions

Doripenem is an ultra-broad spectrum carbopenem antibiotic. Doripenem is active against both gram-positive and gram-negative bacteria.

Synthesis

The general procedure for the synthesis of (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(aminosulfonylamino)-methyl]-3-pyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid hydrate from the condensation of doripenem is as follows: 20 g of doripenem -PNB was dissolved in 100 mL of tetrahydrofuran. To the solution was added 200mL of an aqueous solution containing potassium monophosphate (KH2PO4) at 30°C, followed by 160g of zinc powder. The reaction mixture was stirred at 30-35°C for 2 hours. Upon completion of the reaction, the zinc powder was removed by filtration. The filtrate was washed three times with dichloromethane to remove tetrahydrofuran and impurities present in the water. Then, adsorbent resin SP-207 was added to adsorb doripenem. The reaction mixture was filtered and the resin was washed with 1 L of water to remove the potassium phosphate salt and impurities. 200 mL of ethyl acetate and water were added to the reactor and the mixed solution was heated to 100 °C with stirring, followed by filtration and elution of doripenem. The aqueous layer was separated and the leached solution containing the target product was precipitated by dropwise addition of crystals and stirred at 0-5 °C for 1 hour. It was filtered at room temperature and dried under reduced pressure to give 10.26 g of doripenem monohydrate (90% yield).

Mode of action

Doripenem hydrate is a β-lactam antibiotic of the carbapenem class. It is effective against extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, a microbe resistant to many first line beta-lactam antibiotics and certain cephalosporins. Doripenem hydrate is sparingly soluble in aqueous solution.
β-lactams interfere with PBP (penicillin binding protein) activity involved in the final phase of peptidoglycan synthesis. PBP's are enzymes which catalyze a pentaglycine crosslink between alanine and lysine residues providing additional strength to the cell wall. Without a pentaglycine crosslink, the integrity of the cell wall is severely compromised and ultimately leads to cell lysis and death. Resistance to β-lactams is commonly due to cells containing plasmid encoded β-lactamases; however, carbapenems, including doripenem, are highly resistant to β-lactamases.

References

[1]. yutaka nishino, makoto kobayashi, taneyoshi shinno, et al. practical large-scale synthesis of doripenem: a novel 1a-methylcarbapenem antibiotic. organic process research & development, 2003, 7:846-850.
[2]. masakatsu tsuji, yoshikazu ishii, akira ohno, et al. in vitro and in vivo antibacterial activities of s-4661, a new carbapenem. antimicrobial agents and chemotherapy, 1998, 42(1): 94-99.
[3]. yunhua chen, elizabeth garber, qiuqu zhao, et al. in vitro activity of doripenem (s-4661) against multidrug-resistant gram-negative bacilli isolated from patients with cystic fibrosis. antimicrobial agents and chemotherapy, 2005, 49(6):2510-2511.