Dasatinib

Bezeichnung:Dasatinib

CAS-Nr302962-49-8

Englisch Name:Dasatinib

CBNumberCB4506696

SummenformelC22H26ClN7O2S

Molgewicht488.01

MOL-Datei302962-49-8.mol

Dasatinib physikalisch-chemischer Eigenschaften

Schmelzpunkt	275-286°C
Dichte	1.408±0.06 g/cm3(Predicted)
storage temp.	Sealed in dry,Store in freezer, under -20°C
Löslichkeit	Soluble in DMSO (up to 200 mg/ml).
pka	10.94±0.70(Predicted)
Aggregatzustand	White powder.
Farbe	White or off-white
Stabilität	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 2 months.
InChIKey	ZBNZXTGUTAYRHI-UHFFFAOYSA-N
SMILES	S1C(C(NC2=C(C)C=CC=C2Cl)=O)=CN=C1NC1C=C(N2CCN(CCO)CC2)N=C(C)N=1
CAS Datenbank	302962-49-8(CAS DataBase Reference)

Sicherheit

HS Code

29341000

Gefahreninformationscode (GHS)

Dasatinib Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Dasatinib, developed and marketed by Bristol Myers, is the first approved oral tyrosine kinase inhibitor which binds to multiple conformations of ABL kinase for the treatment of two leukemia indications: chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Dasatinib is a highly potent, ATPcompetitive ATPcompetitive kinase inhibitor which, at nanomolar concentrations, inhibits BCR-ABL, SRC family, c-KIT, EPHA2 and PDGFR-B.
Chemische Eigenschaften
Pale-Yellow Solid
Class: non-receptor tyrosine kinase
Treatment: CML, ALL
Oral bioavailability = 14–34%
Elimination half-life = 3–5 h
Protein binding = 96%
Originator
Bristol–Myers Squibb (US)
Definition
ChEBI: Dasatinib (anhydrous) is an aminopyrimidine that is 2-methylpyrimidine which is substituted at position 4 by the primary amino group of 2-amino-1,3-thiazole-5-carboxylic acid and at position 6 by a 4-(2-hydroxyethyl)piperazin-1-yl group, and in which the carboxylic acid group has been formally condensed with 2-chloro-6-methylaniline to afford the corresponding amide. A multi-targeted kinase inhibitor, it is used, particularly as the monohydrate, for the treatment of chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia. Note that the name 'dasatinib' is used to refer to the monohydrate (USAN) as well as to anhydrous dasatinib (INN). It has a role as a tyrosine kinase inhibitor, an anticoronaviral agent and an antineoplastic agent. It is a secondary amino compound, a tertiary amino compound, an organochlorine compound, an aminopyrimidine, a member of 1,3-thiazoles, a monocarboxylic acid amide, a N-arylpiperazine and a N-(2-hydroxyethyl)piperazine. It is a conjugate base of a dasatinib(1+).
Trademarks
Sprycel (Bristol-Myers Squibb).
Allgemeine Beschreibung
Dasatinib is available in 20-, 50-, and 70-mg tablets fororal administration in the treatment of CML and ALL thatare Ph1 positive. Although dasatinib is more potent thanimatinib, bioavailability is much lower with values rangingbetween 14% to 34%. The agent is extensively metabolizedwith as many as 29 metabolites seen as result of oxidationby primarily CYP3A4 and phase II conjugation.The agent may act as an inhibitor of CYP3A4 andCYP2C8. Metabolism does give an active metabolite, but this accounts for only 5% of the total and is not believed tobe important for the overall activity of the agent. Dasatinibis 95% protein bound with a terminal half-life of 3 to5 hours. The majority of the drug and metabolites are eliminatedin the feces. The most common side effects are skinrash, nausea, diarrhea, and fatigue. Serious side effects includemyelosuppression appearing as neutropenia andthrombocytopenia, bleeding of the brain and GI tract, andfluid retention.
Synthese
A concise and efficient route was developed for the synthesis of dasatinib. Reaction of 2-chlorothioa-zole (18) with n-butyllithium at low temperature followed by addition of 2-chloro-6-methylphenyl isocyanate (19) gave anilide 20 in 86% yield. The amide 20 was protected as corresponding 4-methoxy benzyl (PMB) anilide 22 in 95% yield which was subsequently reacted with 4- amino-6-chloro-2-methylpyrimidine (23) in the presence of sodium hydride in hot THF to give compound 24 in 83% yield. The PMB protecting group was then removed with triflic acid to give compound 25 in 99% yield. Compound 25 was reacted with 1-(2-hydroxyethyl)piperazine (26) in refluxing dioxane to give dasatinib (III) in 91% yield.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antacids: absorption possibly reduced by antacids, give at least 2 hours apart.
Antibacterials: metabolism accelerated by rifampicin - avoid.
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Antivirals: avoid with boceprevir.
Ulcer healing drugs: avoid with histamine H2 antagonists; concentration reduced by proton pump inhibitors.
Stoffwechsel
Dasatinib is extensively metabolised, mainly via the cytochrome P450 isoenzyme CYP3A4, forming an active metabolite.
Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of [14C]-labelled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinib accounted for 0.1% and 19% of the dose in urine and faeces, respectively, with the remainder of the dose as metabolites.
Lager
Store at -20°C
Einzelnachweise
1) Lombardo et al. (2004), Discovery of N-2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a duel Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays; J. Med. Chem., 47 6658 2) Nam et al. (2005), Action of the Src family kinase inhibitor dasatinib (BMS-354825), on human prostate cancer cells; Cancer Res., 65 9185 3) Johnson et al. (2005), Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells; Clin. Cancer Res., 11 6924

Dasatinib Upstream-Materialien And Downstream Produkte

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