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.

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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

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.

https://docs.google.com/viewer?url=http%3A%2F%2Fwww.ema.europa.eu%2Fdocs%2Fen_GB%2Fdocument_library%2FSummary_of_opinion_-_Initial_authorisation%2Fhuman%2F002373%2FWC500137464.pdf

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 3^rd 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

Confirmation of Bosutinib Structure; Demonstration of Controls To Ensure Product Quality

Nonbranded/unauthorized vendors had been manufacturing/selling what they described as bosutinib, while the material supplied was actually an isomer of bosutinib. This raised concerns within the worldwide research community around the established control strategies for bosutinib. This manuscript summarizes that the appropriate testing was in place to ensure product quality, along with additional experimentation that was performed to confirm that testing (methods) can differentiate the potential isomeric compounds. Testing includes the use of IR for identity confirmation of raw materials, material characterization by NMR, single crystal X-ray to confirm structure, and evaluation of several potential isomers by HPLC, melting point, and IR, thus demonstrating the control strategy needed to ensure the product controls.

REFERENCES

1. 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.
2. 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.
3.  Derek Lowe, In The Pipeline (blog), “Bosutinib: Don’t Believe the Label!”
4. 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.
5. 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]
6. “Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia”. 05 Sep 2012.

7. 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

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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Structural and spectroscopic analysis of the kinase inhibitor …

files.figshare.com/337292/Figure_S2.doc

by NM Levinson – ‎Cited by 39 – ‎Related articles

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.

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