BOSUTINIB
Structural and spectroscopic analysis of the kinase inhibitor ...
files.figshare.com/337292/Figure_S2.doc
NMR spectroscopy on bosutinib and the bosutinib isomer. As described in the main text, the 1H NMR spectra of the compounds we purchased from LC Labs and ...
Figure S2. NMR experiments on bosutinib and
the bosutinib isomer. A) The structure of bosutinib and a putative structure
for the bosutinib isomer are shown. The blue numbers on the bosutinib structure
represent the five aromatic proton-carbon pairs. The numbers on the aniline
ring of the bosutinib isomer are 13C chemical shifts. B) NMR
spectra. In the top left panel, 1H-13C HSQC spectra of
bosutinib and the bosutinib isomer are shown. The thick black lines connect the
peaks that arise from the equivalent proton-carbon pairs in the two compounds.
The thin gray lines are intended to guide the eye to the corresponding peaks in
the 1-dimensional spectra. The peaks for the five aromatic proton-carbon pairs
in authentic bosutinib are indicated with large blue numbers. These putative
assignments are based on 13C chemical shift predictions. The bottom
panel shows the 1H NMR spectra of both compounds. The peak located
at 7.34 ppm in the bosutinib isomer sample, which integrates to 2, is indicated. The colored numbers directly next to the peaks are the
peak integrations. The panel on the upper right shows the aromatic
region of the 13C NMR spectrum of the bosutinib isomer. The peak
located at 123 ppm, which displays an integrated intensity of 2, is indicated.
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
Bosutinib Monohydrate (伯舒替尼)
(Bosulif®)
Approved sept4 2012 by FDA
PMDA SEPT26 2014
EMA MAR 27 2013
A kinase inhibitor indicated for the treatment of adult patients with Ph+ chronic myelogenous leukemia (CML).WYETH INNOVATOR
PFIZER DEVELOPER
SKI-606; SK-606
CAS No.380843-75-4 (Free form)
CAS 918639-08-4(Bosutinib Monohydrate)
Bosutinib (rINN/USAN; codenamed SKI-606, marketed under the trade name Bosulif) is atyrosine kinase inhibitor undergoing research for use in the treatment of cancer. [1] [2]Originally synthesized by Wyeth, it is being developed by Pfizer.
。
Some
commercial stocks of bosutinib (from sources other than the Pfizer
material used for clinical trials) have recently been found to have the
incorrect chemical structure, calling the biological results obtained
with them into doubt.[3]
Bosutinib received US FDA approval
on September 5, 2012 for the treatment of adult patients with chronic,
accelerated, or blast phase Philadelphia chromosome-positive (Ph+)chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.[4][5][6]
Article
Good News For Pfizer’s Orphan Drug Bosulif (Bosutinib) in Europe
January 18, 2013
The
European Medicines Agency’s (EMA) Committee for Medicinal Products for
Human Use (CHMP) on January 17, 2013, adopts a positive opinion,
recommending a conditional marketing authhorization for Pfizer’s orphan
drug Bosulif (Bosutinib) for Chronic Leukemia (CML). Bosutinib
receives orphan designation from the European Commission (EC) on August
4, 2010, for CML.
Pfizer receives FDA approval on September 4, 2012, for orphan drug Bosulif (Bosutinib) for CML. Pfizer receives on February 24, 2009, FDA Orphan Drug Designation (ODD) for Bosutinib for CML.
Per a September 2012 article in
FierceBioTech.com, a Pfizer spokesperson says that “the drug will cost
less than $8,200/month”/patient in the US. In other words, treatment
will cost approximately $98,400/patient/year. Also per FierceBiotech,“Bosulif is the 3rd new medicine from Pfizer Oncology’s pipeline to be approved by the FDA in just 13 months ….”.
ARTICLE
Pfizer’s response to compound fraud spotlights quality issues
read .........http://www.rsc.org/chemistryworld/2015/12/pfizer-bogus-bosutinib-isomer-fraud-leukaemia-drug
Synthesis
REFERENCES
- Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, Ahmed S, Redaelli S, Piazza R, Magistroni V, Andreoni F, Scapozza L, Formelli F, Gambacorti-Passerini C. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006 Dec 1;66(23):11314-22. Epub 2006 Nov 17.
- Vultur A, Buettner R, Kowolik C, et al. (May 2008). "SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells".Mol. Cancer Ther. 7 (5): 1185–94. doi:10.1158/1535-7163.MCT-08-0126.PMC 2794837. PMID 18483306.
- Derek Lowe, In The Pipeline (blog), "Bosutinib: Don't Believe the Label!"
- Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24.
- Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicus L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial. J Clin Oncol. 2012 Sep 4. [Epub ahead of print]
- "Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia". 05 Sep 2012.
- P Bowles et al, Org. Process Res. Dev., 2015, DOI: 10.1021/acs.oprd.5b00244
8 N M Levinson and S G Boxer, PLoS One, 2012, 7, e29828 (DOI: 10.1371/journal.pone.0029828)
9 N Beeharry et al, Cell Cycle, 2014, 13, 2172 (DOI: 10.4161/cc.29214)
update................
file:///C:/Users/Inspiron/Downloads/molecules-15-04261%20(1).pdf
Synthesis of Bosutinib from 3-Methoxy-4-hydroxybenzoic Acid
www.mdpi.com/1420-3049/15/6/4261/pdf
Jun 11, 2010 - Abstract: This paper reports a novel synthesis of bosutinib starting from ... C-NMR
4-(2,4-Dichloro-5-methoxyphenylamino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline- 3-carbonitrile (10). A mixture of 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-carbonitrile (9, 0.328 g, 0.7 mmol) and sodium iodide (0.11 g, 0.70 mmol) in N-methylpiperazine (4 mL) was heated at 80 ºC for 12 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography, eluting with 30% methanol in dichloromethane. The fractions containing product were collected and concentrated in vacuo. Diethyl ether was added to the residue, and the light pink solid was collected by filtration (0.28 g, 75% yield, 98.7% HPLC purity): m.p. 116–120 ºC;
1H-NMR (DMSO-d6): 1.92–1.97 (m, 2H), 2.15 (s, 3H), 2.32–2.46 (m, 10H), 3.84 (s, 3H), 3.93 (s, 3H), 4.19 (t, J = 6.3 Hz, 2H), 7.31 (br s, 2H), 7.43 (s, 1H), 7.64 (s, 1H), 8.52 (s, 1H), 9.51 (s, 1H);
13C-NMR (CDCl3): 25.96, 45.68, 52.67, 52.67, 54.24, 54.72, 54.72, 56.01, 60.71, 66.87, 89.10, 101.66, 101.66, 109.12, 113.95, 117.17, 122.99, 122.99, 128.27, 137.88, 146.15, 148.13, 148.51, 149.50, 150.43, 153.03;
MS (ES) m/z 530.2, 532.2 (M+1).
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