2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide

Bezeichnung:2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide

CAS-Nr879085-55-9

Englisch Name:2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide

CBNumberCB52500590

SummenformelC19H14Cl2N2O3S

Molgewicht421.3

MOL-Datei879085-55-9.mol

2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide physikalisch-chemischer Eigenschaften

Schmelzpunkt	179-181°C
Siedepunkt	561.6±50.0 °C(Predicted)
Dichte	1.440
storage temp.	-20°
Löslichkeit	Soluble in DMSO (up to 200 mg/ml) or in Ethanol (up to 10 mg/ml with warming)
Aggregatzustand	White solid.
pka	10.72±0.70(Predicted)
Farbe	Off-white or beige
Stabilität	Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 3 months.
InChI	InChI=1S/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)
InChIKey	BPQMGSKTAYIVFO-UHFFFAOYSA-N
SMILES	C(NC1=CC=C(Cl)C(C2=NC=CC=C2)=C1)(=O)C1=CC=C(S(C)(=O)=O)C=C1Cl

Sicherheit

HS Code	29333990
Giftige Stoffe Daten	879085-55-9(Hazardous Substances Data)

Gefahreninformationscode (GHS)

2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
In January 2012, the US FDA approved vismodegib (also referred to as GDC-0449) for the treatment of adults with metastatic basal cell carcinoma (BCC), with locally advanced BCC that has recurred following surgery or who are not candidates for surgery or radiation. Vismodegib inhibits the Hh sig?naling pathway by functioning as an antagonist of SMO thereby inhibiting the activation of Hedgehog target genes, resulting in decreased downstream pro?duction of proliferation factors. The IC₅₀ of vismodegib in a Hedgehog?responsive cell line derived from human embryonic palatal mesenchyme cells was 2.8 nM. In preclinical in vivostudies, vismodegib at 12.5 mg/kg (bid) caused complete regression of tumors in a Hh pathway dependent medulloblas?tomaallograft model generated from Ptch+/-mice. A synthesis of vismodegib starting from 2-chloro-5-nitro aniline and employing a Negishi coupling with 2-pyridyl zinc iodide as a key step has been reported.
Chemische Eigenschaften
White Solid
Originator
Curis/Genentech (United States)
Verwenden
Vismodegib targets the Hedgehog (Hh) pathway. Inhibition of the Hh signaling may be effective in the treatment and prevention of many types of human cancers. Potent Hedgehog inhibitor.
Verwenden
Vismodegib (GDC-0449) is a potent, novel and specific hedgehog inhibitor with IC50 of 3 nM and also inhibits P-gp with IC50 of 3.0 μM.
Definition
ChEBI: A benzamide obtained by formal condensation between the carboxy group of 2-chloro-4-(methylsulfonyl)benzoic acid and the anilino group of 4-chloro-3-(pyridin-2-yl)aniline. Used for the treatment metastatic basal cell carcinoma.
Trademarks
Erivedge
Clinical Use
Antineoplastic agent:
Treatment of basal cell carcinoma which is inappropriate for surgery or radiotherapy
Synthese
The synthesis began with selective iodination of commercial carboxylic acid 179, affording trisubstituted arene 180 in 73% yield. A Curtius reaction then converted 180 to carbamate 181 in 84% 52 yield, and this was followed by a palladium(0)-catalyzed borylation of 181 which furnished Suzuki coupling partner 182 in 91% yield. Pinacol borane 182 was exposed to commercial 2-bromopyridine under conventional cross-coupling conditions to furnish biaryl 183, which underwent Boc-deprotection in quantitative conversion to generate 184. Amide bond formation with acid chloride 185 (readily available from the corresponding commercial acid) produced vismodegib (XXVIII) in 99% yield.
target
Hedgehog
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly reduced by rifampicin - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid.
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Stoffwechsel
Vismodegib is hepatically metabolised by CYP2C9 and CYP3A4, however more than 98
% of total systemic vismodegib is not metabolised. Metabolic pathways of vismodegib include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in faeces are produced in vitro by recombinant CYP2C9 and CYP3A4/5.
Vismodegib is slowly eliminated by a combination of metabolism and excretion of parent drug, the majority is recovered in the faeces (82
%). Vismodegib and its metabolites are eliminated mainly by the hepatic route.
Lager
Store at -20°C
Einzelnachweise
1) Rominger et al. (2009), Evidence for allosteric interactions of antagonist binding to the smoothened receptor; J. Pharmacol. Exp. Therap., 329 995 2) Tian et al. (2012), The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells; Anticancer Res., 32 89 3) Zhang et al. (2009), Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp; Neoplasia, 11 96 4) Cirrone and Harris (2012), Vismodegib anf the hedgehog pathway: a new treatment for basal cell carcinoma; Clin. Ther., 34 2039 5) Wu et al. (2017), Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines; Exp. Ther. Med., 13 2529 6)Singh et al. (2011) Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms; PLoS One 6?e27306 7) Rudin et al. (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449; N. Engl. J. Med., 361?1173 8) Von Hoff et al. (2009) Inhibition of the hedgehog pathway in advanced basal-cell carcinoma; N. Engl. J. Med., 361?1164

2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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