Bedaquiline fumarate

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P270：Bei Gebrauch nicht essen, trinken oder rauchen.

  P271：Nur im Freien oder in gut belüfteten Räumen verwenden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P301+P312：BEI VERSCHLUCKEN: Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P304+P340：BEI EINATMEN: Die Person an die frische Luft bringen und für ungehinderte Atmung sorgen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

  P330：Mund ausspülen.

  P332+P313：Bei Hautreizung: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P337+P313：Bei anhaltender Augenreizung: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P362：Kontaminierte Kleidung ausziehen und vor erneutem Tragen waschen.

  P403+P233：An einem gut belüfteten Ort aufbewahren. Behälter dicht verschlossen halten.

  P405：Unter Verschluss aufbewahren.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Bedaquiline fumarate Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Bedaquiline fumarate (BQF) is an FDA-approved antituberculosis drug that targets the enzyme ATP synthase. It is a fumarate salt prepared from equimolar amounts of bedaquiline and fumaric acid. It can be used in combination therapy for the treatment of multidrug-resistant tuberculosis in the lungs of adults (18 years of age and older). The new BQF microemulsion dosage form of BQF has improved oral bioavailability over the previous formulation, and the BQF microemulsion is cytocompatible with significantly higher cellular uptake than the control group at the highest concentration of 500 μg/ml, which could lead to further use in the effective treatment of multidrug-resistant tuberculosis^[1].

• Charakteristisch

  Bedaquiline fumarate is the first diarylquinoline analogue used in the treatment of M. tuberculosis and its main biologically active form is bedaquiline. Bedaquiline fumarate forms three degradation products associated with fumaric acid (DP1, DP2 and DP3) under photolysis conditions and the demethylation product DP4 under acidic conditions. Bedaquiline forms four degradation products associated with tertiary alcohols and tertiary amine moiety side chains (IM1, IM2, IM3, and IM4) under photolysis conditions, and DP4 under acidic conditions.Both compounds are stable under thermal, alkaline and oxidative conditions. DP1 and DP2 show that fumarates can undergo cis-trans isomerisation under light conditions. The fumarate form stabilises the side chain of bedaquiline. It is advisable to avoid contact with acids and light during storage and production^[2].

• Definition

  ChEBI: Bedaquiline fumarate is a fumarate salt prepared from equimolar amounts of bedaquiline and fumaric acid. It is used in combination therapy for the treatment of pulmonary multi-drug resistant tuberculosis by inhibition of ATP synthase, an enzyme essential for the replication of the mycobacteria. It has a role as an antitubercular agent and an ATP synthase inhibitor. It contains a bedaquiline(2+).

• Clinical Use

  Bedaquiline fumarate is a diarylquinone drug developed by Janssen Pharmaceutical which is marketed under the trade name Sirturo ®. The drug, which was approved in 2012 for the treatment of multidrug-resistant tuberculosis (MDR-TB), was developed in partnership with Johnson & Johnson and represents the first new tuberculosis therapy approved in over four decades. Bedaquiline is the first member of a new class of diarylquinone compounds whose mechanism of action inhibits Mycobaterium tuberculosis ATP synthase which deprives bacterium of energy.

• Synthese

  Of the relatively few synthetic approaches to bedaquiline (or its fumarate salt) that have been reported, the most likely process-scale route is that described by Porstmann and co-workers from Janssen Pharmaceutical, and this route is outlined in the scheme. The synthesis was initiated by first freebasing commercially available dimethylaminoketone 31 with sodium hydroxide to provide naphthylone 32 in nearly quantitative yield. Subjection of commercially available quinoline 33 to LDA removed the benzyllic proton within this system and subsequent trap with naphthylone 32 gave rise to a mixture of diastereomers whereby the major diastereomer obtained from this reaction corresponded to the bedaquiline geometry. The minor diastereomer was resolved through multiple recrystallizations and seeding techniques. This racemate of the major diastereomer subsequently underwent a chiral resolution upon treatment with BINAP derivative 34 in refluxing DMSO and then upon cooling and subjection to aqueous base in warm toluene furnished bedaquiline 35 bearing the requisite (R,S)- configuration of the two vicinal chiral centers corresponding to that of the drug. The overall yield of the conversion of 33 to enantiopure 35 was 39%. Aminoquinolinol 35 was then prepared as the corresponding fumarate salt upon treatment with fumaric acid in the presence of isopropanol, and this salt formation delivered bedaquiline fumarate (VI) in 82% yield.

  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin and erythromycin - avoid concomitant use if for more than 14 days; avoid with moxifloxacin; concentration possibly reduced by rifampicin - avoid; possibly increased risk of ventricular arrhythmias with clofazimine.
  Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid.
  Antivirals: AUC increased by ritonavir, use with caution, avoid in combination with lopinavir.

• Stoffwechsel

  Bedaquiline is metabolised mainly by the hepatic CYP3A4 isoenzyme to the N-monodesmethyl metabolite (M2), which is 4-6 times less active than the parent compound. Bedaquiline is excreted mainly in the faeces.

• Einzelnachweise

  [1] VISHWAS P PARDHI. Bedaquiline fumarate microemulsion: formulation optimization, rheological characterization and in vitro studies.[J]. Nanomedicine (London, England), 2022, 17 21: 1529-1546. DOI:10.2217/nnm-2022-0132.
  [2] KAIJING GUO; Chen M; Yanan Wang. Characterization of stress degradation products of bedaquiline fumarate and bedaquiline by LC-PDA and LC-MS[J]. Journal of pharmaceutical and biomedical analysis, 2023. DOI:10.1016/j.jpba.2023.115658.
  

Bedaquiline fumarate Upstream-Materialien And Downstream Produkte

Bedaquiline fumarate Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(177)Suppliers

845533-86-0, Bedaquiline fumarate Verwandte Suche: