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.

Bedaquiline fumarate Upstream-Materialien And Downstream Produkte

Upstream-Materialien

Downstream Produkte

Bedaquiline fumarate Anbieter Lieferant Produzent Hersteller Vertrieb H?ndler.

Firmenname	Telefon	E-Mail	Land	Produktkatalog	Edge Rate
Chengdu Aupone Pharmaceutical Co.Ltd.	+86-28-+86-28-87843998-6060-6060 +8618631098571	lijiaqi@aupone.com	China	55	58
Shanghai Famo Biotech Co Ltd	+86-36680037 +86-18550473860	mayan@famobiotech.com;sales@famobiotech.com	China	528	58
Henan Fengda Chemical Co., Ltd	+86-371-86557731 +86-13613820652	info@fdachem.com	China	20258	58
BEIJING SJAR TECHNOLOGY DEVELOPMENT CO., LTD.	+86-18600796368 +86-18600796368	sales@sjar-tech.com	China	484	58
Capot Chemical Co.,Ltd.	+86-（0）57185586718 +86-13336195806	sales@capot.com	China	29685	60
Henan Tianfu Chemical Co.,Ltd.	+86-0371-55170693 +86-19937530512	info@tianfuchem.com	China	21632	55
Hangzhou FandaChem Co.,Ltd.	008657128800458; +8615858145714	FandaChem@Gmail.com	China	7352	55
ATK CHEMICAL COMPANY LIMITED	+undefined-21-51877795	ivan@atkchemical.com	China	32965	60
Lianyungang happen teng technology co., LTD	15950718863	wang666xt@163.com	CHINA	295	58
career henan chemical co	+86-0371-86658258 +8613203830695	sales@coreychem.com	China	29869	58

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