Cabazitaxel

Bezeichnung:Cabazitaxel

CAS-Nr183133-96-2

Englisch Name:Cabazitaxel

CBNumberCB42517227

SummenformelC45H57NO14

Molgewicht835.93

MOL-Datei183133-96-2.mol

Cabazitaxel physikalisch-chemischer Eigenschaften

Schmelzpunkt	180 °C
Siedepunkt	870.7±65.0 °C(Predicted)
Dichte	1.31
storage temp.	Inert atmosphere,Store in freezer, under -20°C
Löslichkeit	Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
Aggregatzustand	White solid.
pka	11.20±0.46(Predicted)
Farbe	White to Off-White
InChIKey	BMQGVNUXMIRLCK-JACFBOAKNA-N

Sicherheit

S-Sätze:	24/25
HS Code	29329990

Gefahreninformationscode (GHS)

Cabazitaxel Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
In June 2010, the U.S. FDA approved cabazitaxel (also referred to as XRP6258 and RPR 116258A) in combination with the steroid prednisone for the treatment of metastatic Castration-Resistant Prostate Cancer (mCRPC) for patients who were previously treated with a docetaxelcontaining regimen for late-stage disease.
Cabazitaxel is a semisynthetic analog of the natural product taxol, which is isolated from the bark of the yew tree. Cabazitaxel is a microtubule inhibitor that binds to the taxol-binding site of tubulin. Similar to other tubulin inhibitors of the taxol class, cabazitaxel inhibits microtubule disassembly resulting in mitotic blockade and cell death. Docetaxel, also a semisynthetic taxol analog, was approved by the FDA for the treatment of mCRPC in 2004. However, docetaxel is a substrate for P-gp, which is thought to contribute to the constitutive and acquired resistance of cancer cells to taxanes. Cabazitaxel has poor affinity for P-gp and showed antitumor activity in preclinical in vitro studies and in vivo tumor models that overexpress this protein. Cabazitaxel is synthesized on a commercial scale from 10-deacetylbaccatin .
Chemische Eigenschaften
White solid
Originator
Sanofi-Aventis (France)
Verwenden
A novel semi-synthetic taxane with antitumor activity used for the treatment of castration-resistant prostate cancer. A microtubule inhibitor.
Verwenden
Cabazitaxel (Jevtana, XRP6258) is a semi-synthetic derivative of a natural taxoid.
Definition
ChEBI: A tetracyclic diterpenoid that is 10-deacetylbaccatin III having O-methyl groups attached at positions 7 and 10 as well as an O-(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hy roxy-3-phenylpropanoyl group attached at position 13. Acts as a microtubule inhibitor, binds tubulin and promotes microtubule assembly and simultaneously inhibits disassembly.
Trademarks
Jevtana
Clinical Use
Cabazitaxel was developed by Sanofi-Aventis as an intravenous injectable drug for the treatment of hormone-refractory metastatic prostate cancer. As a microtubule inhibitor, cabazitaxel differs from docetaxel because it exhibits a much weaker affinity for P-glycoprotein (P-gp), an adenosine triphosphate (ATP)-dependent drug efflux pump. Cancer cells that express P-gp become resistant to taxanes, and the effectiveness of docetaxel can be limited by its high substrate affinity for P-gp. Clinical studies confirmed that cabazitaxel retains activity in docetaxel-resistant tumors. Common adverse events with cabazitaxel include diarrhea and neutropenia. Cabazitaxel in combination with prednisone is an important new treatment option for men with docetaxel-refractory metastatic CRPC (castration-resistant prostate cancer).
Synthese
The semi-synthesis of cabazitaxel started from 10- deacetylbaccatin III (15) which can be prepared from 7-xylosyl-10-deacetylbaccatin natural product mixture according to a literature process procedure (the Scheme). 10-Deacetylbaccatin III was protected with triethylsilyl chloride (TESCl) in pyridine to afford the corresponding 7,13-bis-silyl ether in 51% yield, which was methylated with MeI and NaH in DMF to give 10-methoxy-7,13-bis silyl ether 16 in 76% yield. After de-silylation of 16 with triethylamine trihydrofluoride complex at room temperature, triol 17 was obtained in 77% yield. Selective methylation of 17 with MeI and NaH in DMF at 0 oC provided 7,10-dimethyl ether 18 in 74% yield. Compound 18 was condensed with commercially available oxazolidinecarboxylic acid 19 in the presence of dicyclohexylcarbodiimide/dimethylaminopyridine (DCC/DMAP) in ethyl acetate at room temperature to generate ester 20 in 76% yield. The oxazolidine moiety of compound 20 was selectively hydrolyzed under mild acidic conditions to yield the hydroxy Boc-amino ester derivative cabazitaxel (III) in 32% yield.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antibacterials: Avoid with clarithromycin, rifabutin, rifampicin and telithromycin.
Antidepressants: Avoid with St John's wort.
Antiepileptics: Avoid with carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone.
Antifungals: Avoid with itraconazole, ketoconazole and voriconazole.
Antipsychotics: Avoid with clozapine (increased risk of agranulocytosis).
Antivirals: Avoid with atazanavir, indinavir, ritonavir and saquinavir.
Stoffwechsel
Extensively metabolised in the liver (>95%), mainly by the CYP3A4 isoenzyme (80-90%). Cabazitaxel is the main circulating compound in human plasma. Seven metabolites were detected in plasma (including 3 active metabolites issued form O-demethylations), with the main one accounting for 5% of parent exposure. Excreted as metabolites into the urine (4%) and faeces (76%).

Cabazitaxel Upstream-Materialien And Downstream Produkte

Cabazitaxel Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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