Tedizolid Phosphate

Bezeichnung:Tedizolid Phosphate

CAS-Nr856867-55-5

Englisch Name:Tedizolid Phosphate

CBNumberCB72676152

SummenformelC17H16FN6O6P

Molgewicht450.32

MOL-Datei856867-55-5.mol

Tedizolid Phosphate physikalisch-chemischer Eigenschaften

Schmelzpunkt	>235°C (dec.)
Siedepunkt	725.6±70.0 °C(Predicted)
Dichte	1.75±0.1 g/cm3(Predicted)
storage temp.	under inert gas (nitrogen or Argon) at 2-8°C
Löslichkeit	DMSO (Slightly, Sonicated)
Aggregatzustand	Solid
pka	1.81±0.10(Predicted)
Farbe	White to Off-White
Stabilität	Hygroscopic
InChIKey	QCGUSIANLFXSGE-GFCCVEGCSA-N
SMILES	O1[C@@H](COP(O)(O)=O)CN(C2=CC=C(C3=CC=C(C4=NN(C)N=N4)N=C3)C(F)=C2)C1=O

Gefahreninformationscode (GHS)

Tedizolid Phosphate Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Tedizolid phosphate was approved by the US FDA in June 2014 for treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive pathogens, including MRSA. Tedizolid phosphate was discovered by Dong-A Pharmaceuticals in South Korea and developed in the USA by Cubist Pharmaceuticals (acquired from Trius Therapeutics in 2013, became a wholly owned subsidiary of Merck in 2015). The worldwide commercialization rights for tedizolid phosphate are divided between Cubist in the USA, Canada, and EU, and Bayer in Asia–Pacific, Latin America, and Africa. This second-generation oxazolidinone prodrug is rapidly converted to the active form tedizolid in the presence of endogenous phosphatases. It inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit of the ribosome, preventing formation of the 70S ribosomal initiation complex, and is 4-fold to 16-fold more potent against staphylococci and enterococci compared to linezolid. 251 With high oral bioavailability (approximately 90%) and long half-life (approximately 12 hours), tedizolid phosphate is the first oxazolidinone antibiotic which can be dosed once daily either orally or intravenously.
Verwenden
Tedizolid, known as TR-700, is an oral and i.v administered intracellular antibacterial drug.
Definition
ChEBI: A phosphate monoester resulting from the formal condensation of equimolar amounts of phosphoric acid with the hydroxy group of tedizolid . It is a prodrug of tedizolid, used for the treatment of acute bacterial skin infections caused by certain susceptibl bacteria, including Staphylococcus aureus (including methicillin-resistant strains (MRSA) and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis.
Clinical Use
Reversible non-selective MAO inhibitor:
Antibacterial agent
Nebenwirkungen
Tedizolid phosphate was well tolerated following the oral administration of a once-daily 200-mg dose for three days. No serious adverse events (AEs) were reported; the most commonly reported AEs were mild bradycardia (n = 2), headache (n = 1), and nausea (n = 1)[1].
Synthese
Commercial 5-bromo-2-cyanopyridine (260) was treated with sodium azide and ammonium chloride in DMF to produce tetrazole 261, which was isolated by precipitation of the tetrazole ammonium salt. Subsequent methylation with methyl iodide in THF/DMF (3:1) afforded a 3.85:1 mixture of 262 and the corresponding N1-regioisomer. Acidification with 6 M HCl followed by treatment with 50% aqueous NaOH (to pH 10.6) enabled isolation of 262 in 96% isomeric purity; crude 262 was further purified by recrystallization from isopropyl acetate and obtained in 33% yield from 261. A Suzuki reaction of 262 with boronic acid 263 (which was prepared from commercial 4-bromo-3-fluoroaniline (267) as described in Scheme, via carboxybenzyl (Cbz) protection and lithiation/borylation) followed by recrystallization from ethyl acetate produced triaryl system 264. Deprotonation of the carbamate within 264 using lithium hexamethyldisilazide (LiHMDS) followed by reaction with R-(-)-glycidyl butyrate (265) in the presence of 1,3-dimethyl tetrahydropyrimidin-2 (1H)-one (DMPU) generated tedizolide 266 in 85% yield. Reaction with POCl3 in THF at 1¨C2 ?? followed by subjection to sodium hydroxide and subsequent acidification furnished tedizolid phosphate (XXXIII) in 76% yield across the three steps.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Alcohol: some alcoholic and de-alcoholised drinks contain tyramine which can cause hypertensive crisis.
Alpha-blockers: avoid concomitant use with indoramin; enhanced hypotensive effect.
Analgesics: CNS excitation or depression with pethidine, other opioids and nefopam - avoid; increased risk of serotonergic effects and convulsions with tramadol - avoid.
Antidepressants: enhancement of CNS effects and toxicity; avoid MAOIs, SSRIs and vortioxetine for 2 weeks after use; care with all antidepressants.
Antiepileptics: antagonism of anticonvulsant effect; avoid carbamazepine with or within 2 weeks of MAOIs.
Antimalarials: avoid concomitant use with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: effects enhanced by clozapine.
Atomoxetine: possible increased risk of convulsions - avoid concomitant use and for 2 weeks after use.
Bupropion: avoid with or for 2 weeks after MAOIs.
Dapoxetine: increased risk of serotonergic effects, avoid with or for 2 weeks after MAOIs.
Dexamfetamine and lisdexamfetamine: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs.
Dopaminergics: avoid concomitant use with entacapone and tolcapone; hypertensive crisis with levodopa and rasagiline - avoid for at least 2 weeks after stopping MAOI; hypotension with selegiline.
5HT1 agonist: risk of CNS toxicity with sumatriptan, rizatriptan and zolmitriptan - avoid sumatriptan and rizatriptan for 2 weeks after MAOI.
Metaraminol: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs.
Methyldopa: avoid concomitant use.
Opicapone: avoid concomitant use.
Sympathomimetics: hypertensive crisis with sympathomimetics - avoid.
Tetrabenazine: risk of CNS excitation and hypertension - avoid.
Stoffwechsel
Tedizolid phosphate is converted by endogenous plasma and tissue phosphatases to the microbiologically active moiety, tedizolid.
Tedizolid is eliminated in excreta, primarily as a noncirculating sulfate conjugate. Following single oral administration of [14C]-labelled tedizolid under fasted conditions, the majority of elimination occurred via the liver with 81.5% of the radioactive dose recovered in faeces and 18% in urine.
Einzelnachweise
[1] Wong, Elaine, and Saba Rab. “Tedizolid phosphate (sivextro): a second-generation oxazolidinone to treat acute bacterial skin and skin structure infections.”P & T : a peer-reviewed journal for formulary management vol. 39,8 (2014): 555-79.

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