380843-75-4 Usage
Description
Bosutinib, also known as SKI-607, is a dual Src/Abl inhibitor that was approved by the US FDA in September 2012 for the treatment of relapsed or refractory chronic myeloid leukemia (CML) in patients with resistance or intolerance to prior therapy. It was initially identified as a Src inhibitor but was later found to inhibit both Bcr-Abl and Src family kinases. Bosutinib has shown efficacy in preclinical in vivo studies and has a manufacturing process for the synthesis of its monohydrate form.
Uses
Used in Oncology:
Bosutinib is used as an anticancer agent for the treatment of relapsed or refractory chronic myeloid leukemia (CML) in patients with resistance or intolerance to prior therapy. It inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines and has shown regression of CML tumors in preclinical in vivo studies.
Used in Cancer Cell Research:
Bosutinib is used as a novel Src kinase inhibitor to suppress the migration and invasion of human breast cancer cells, indicating its potential use in cancer cell research and development.
Used in Neurology:
Bosutinib is used as a peripheral vasolidator to increase cerebral blood flow, making it a potential therapeutic agent for Alzheimer's disease, cognitive impairment, and dementia.
Used in Pharmaceutical Research:
Bosutinib (SKI-606) is a novel, dual Src/Abl inhibitor with IC50 values of 1.2 nM and 1 nM, respectively, making it a valuable compound for pharmaceutical research and development.
Originator
Wyeth (United States)
Biochem/physiol Actions
Bosutinib (SKI-606) is an orally active; dual Src/Abl tyrosine kinase inhibitor with potent antiproliferative activity. It does not appear to inhibit c-Kit and PDGRF, which are thought to be the cause of numerous side effects in anticancer treatment with some other tyrosine kinase inhibitors.
Clinical Use
Protein kinase inhibitor:
Treatment of Philadelphia chromosome-positive
chronic myelogenous leukaemia resistant or
intolerant to prior therapy
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: possibly increased risk of ventricular
arrhythmias with methadone.
Anti-arrhythmics: possibly increased risk of ventricular
arrhythmias with amiodarone and disopyramide;
concentration possibly increased by dronedarone -
avoid or consider reducing dose of bosutinib.
Antibacterials: concentration possibly increased
by ciprofloxacin, clarithromycin, erythromycin and
telithromycin - avoid or consider reducing dose
of bosutinib; possibly increased risk of ventricular
arrhythmias with moxifloxacin; concentration
reduced by rifampicin and possibly rifabutin - avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone - avoid.
Antifungals: concentration increased by ketoconazole
and possibly by fluconazole, itraconazole,
posaconazole and voriconazole - avoid or consider
reducing dose of bosutinib.
Antimalarials: possibly increased risk of
ventricular arrhythmias with chloroquine and
hydroxychloroquine.
Antipsychotics: possibly increased risk of ventricular
arrhythmias with haloperidol; avoid with clozapine,
increased risk of agranulocytosis.
Antivirals: concentration possibly increased by
atazanavir, boceprevir, darunavir, fosamprenavir,
indinavir, ritonavir, saquinavir and telaprevir - avoid
or consider reducing dose of bosutinib; concentration
possibly reduced by efavirenz and etravirine - avoid.
Aprepitant: concentration possibly increased - avoid
or consider reducing dose of bosutinib.
Beta-blockers: possibly increased risk of ventricular
arrhythmias with sotalol.
Bosentan: concentration of bosutinib possibly
reduced - avoid.
Calcium channel blockers: concentration possibly
increased by diltiazem or verapamil - avoid or
consider reducing dose of bosutinib.
Cytotoxics: concentration possibly increased by
imatinib - avoid or consider reducing dose of bosutinib.
Domperidone: avoid concomitant use, risk of
ventricular arrhythmias.
Fosaprepitant: concentration possibly increased by
fosaprepitant - avoid or consider reducing dose of
bosutinib
Grapefruit juice: concentration possibly increased by
grapefruit juice - avoid or consider reducing dose of
bosutinib.
Modafinil: concentration of bosutinib possibly
reduced - avoid.
Metabolism
Mainly hepatically metabolised. The major circulating
metabolites identified in plasma are oxydechlorinated
(M2) bosutinib (19% of parent exposure) and
N-desmethylated (M5) bosutinib (25% of parent
exposure), with bosutinib N-oxide (M6) as a minor
circulating metabolite. All the metabolites are inactive.
Excretion is mainly via the faeces.
References
Golas et al. (2003), SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice; Cancer Res., 63 375
Remsing Rix et al. (2009), Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells; Leukemia, 23 477
Redaelli et al. (2009), Activity of bosutinib, Dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants; J. Clin. Oncol., 27 469
MacDonald et al. (2018), Src family kinase inhibitor bosutinib enhances retinoic acid-induced differentiation of HL-60 leukemia cells; Leuk. Lymphoma, 59 2941
Vultur et al. (2008), SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells; Mol. Cancer Ther., 7 1185
Check Digit Verification of cas no
The CAS Registry Mumber 380843-75-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 3,8,0,8,4 and 3 respectively; the second part has 2 digits, 7 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 380843-75:
(8*3)+(7*8)+(6*0)+(5*8)+(4*4)+(3*3)+(2*7)+(1*5)=164
164 % 10 = 4
So 380843-75-4 is a valid CAS Registry Number.
InChI:InChI=1/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31)
380843-75-4Relevant articles and documents
A robust, streamlined approach to bosutinib monohydrate
Withbroe, Gregory J,Seadeek, Chris,Girard, Kevin P,Guinness, Steven M,Vanderplas, Brian C,Vaidyanathan, Rajappa
, p. 500 - 504 (2013)
This article describes a systematic approach used to streamline the process for the isolation of bosutinib monohydrate, a promiscuous solvate former. A thorough understanding of the complex solid form landscape was garnered, and this knowledge was used to
Method for preparing bosutinib intermediate
-
Paragraph 0041-0078, (2020/09/20)
The invention provides a method for preparing a bosutinib intermediate. The method comprises the following steps: A, adding SM-1, 1-bromo-3-chloropropane and an acid-binding agent into a reaction solvent, controlling the temperature until the reaction is
Preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and preparation method of bosutinib
-
, (2019/10/01)
The invention provides a preparation method of a disubstituted 4-chloroquinoline-3-carbonitrile derivative and a preparation method of bosutinib. The preparation method of the disubstituted 4-chloroquinoline-3-carbonitrile derivative comprises the following steps: disubstituted o-nitrobenzoate (II) used as a raw material and acetonitrile are condensed under the action of an alkali to obtain a compound of formula III; the compound of formula III and a chloroformylating reagent undergo a chloroformylating reaction to obtain a compound of formula IV1 or formula IV2; and the compound of formula IV1 undergoes catalytic hydrogenation cyclization in the presence of a hydrogenation catalyst to prepare 7-[3-(4-methyl-1-piperazinyl)propoxy]-6-methoxy-4-chloroquinoline-3-carbonitrile (Ia), or the compound of formula IV2 is subjected to catalytic hydrogenation cyclization and anhydride amidation to prepare 6-acetamido-7-ethoxy-4-chloroquinolin-3-carbonitrile (Ib). The compound of formula Ia or Ibis used to prepare bosutinib, neratinib or pelitinib. The method of the invention has the advantages of short process flow, simplicity in operation, easiness in realization, low cost, few three wastes, high yield, high purity, and easiness in industrial production.