TAK 599

Description

Ceftaroline fosamil, also referred to as TAK-599, is a cephalosporin antibacterial agent that was approved in the United States in October 2010 for the IV treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Ceftaroline fosamil is the water-soluble, N-phosphono prodrug of ceftaroline (T-91825), a broad-spectrum, bactericidal agent with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) strains, multidrug resistant S. pneumonia, and common gram-negative organisms. Ceftaroline binds to PBP2a as well as other PBPs with high affinity and, as a result, retains potent activity. Ceftaroline exhibits activity against most gram-positive pathogens, including β-lactam-susceptible and -resistant S. aureus, vancomycin-resistant S. aureus, and resistant and susceptible forms of S. pneumoniae but has weak activity against Enterococcus sp. The gram-negative antibacterial activity of ceftaroline is limited mainly to respiratory pathogens such as Moraxella catarrhalis and Haemophilus influenzae.

Originator

Takeda (Japan)

Definition

ChEBI: An acetate salt obtained by reaction of ceftaroline fosamil with one equivalent of acetic acid. A prodrug for ceftaroline, used for the treatment of adults with acute bacterial skin and skin structure infections.

brand name

Teflaro

Synthesis

Reports from Takeda describe a process preparation of ceftaroline fosamil in 100 g scale which relies upon the assembly and union of fragments 112 and 114. The synthesis of fragment 112 began from commercially available benzhydryl 7b-[(phenylacetyl)amino]-3-hydroxy-3-cephem-4- carboxylate (106). The hydroxyl group within cephem 106 was reacted with methanesulfonyl chloride to produce mesylate 107 in 94% yield. The condensation of mesylate 107 with 4-(pyridin- 4-yl)thiazole-2-thiol 108 under the base condition of sodium methoxide gave compound 109 in 78% yield. Pyridinium salt 110 arose in quantitative yield upon subjection of 109 to iodomethane. Sequential deprotections of the amino group with phosphorous pentachloride and ester group with concentrated HCl afforded the dihydrochloride salt 112 in good yield.



Acyl halide fragment 114 was prepared from commercially available (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic acid (113) in 60% yield by dichlorophosphorylation of the amino group and concomitant acid chloride formation. Acid chloride 114 was then reacted with dihydrochloride salt 112 in the presence of sodium acetate to give N-phosphono cephem 115 in 77% yield. The crystallization of 115 in an aqueous acetic acid solution gave rise to the stable acetic acid solvate ceftaroline fosamil acetate (IX).

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: effects of coumarins may be enhanced.

Metabolism

Ceftaroline fosamil (prodrug) is converted into the active ceftaroline in plasma by phosphatase enzymes. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite, ceftaroline M-1.
Ceftaroline is mainly eliminated by the kidneys. Renal clearance is approximately equal, or slightly lower than the glomerular filtration rate in the kidney, and in vitro transporter studies indicate that active secretion does not contribute to the renal elimination of ceftaroline.