231277-92-2 Usage
Description
Lapatinib, a new member of the 4-anilinoquinazoline class of receptor tyrosine kinase inhibitors (RTKIs), is an oral treatment for breast cancer. It has dual affinity for EGFR and HER2 tyrosine kinases and is characterized by its slow off-rate kinetics. Lapatinib is synthesized through a series of chemical reactions, including condensation, Stille coupling, and reductive amination. It is marketed under the brand name Tykerb.
Uses
Used in Oncology:
Lapatinib is used as an antineoplastic agent, specifically as a tyrosine kinase inhibitor, for the treatment of advanced or metastatic breast cancer. It is particularly effective in patients whose tumors overexpress HER2 and have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Lapatinib is used in combination with capecitabine to enhance the treatment's effectiveness.
Used in Cancer Research:
Lapatinib is also utilized in breast cancer research as an antineoplastic agent. Its dual inhibition of EGFR and HER2 tyrosine kinases makes it a valuable tool for studying the underlying mechanisms of cancer progression and the development of targeted therapies.
Used in Pharmaceutical Industry:
Lapatinib, in the form of Lapatinib Ditosylate, is a potent EGFR and ErbB2 inhibitor with IC50 values of 10.8 and 9.2 nM, respectively. Its development and synthesis contribute to the advancement of targeted cancer therapies and the pharmaceutical industry's efforts to create more effective treatments for various types of cancer.
Indications and Usage
Lapatinib is a drug targeting breast cancer developed by British GlaxoSmithKline Co.
Human ErbB receptors belong to the type I tyrosine kinase (TK) receptor family, including ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The ErbB-1 (EGFR) and ErbB-2 (HER-2) receptors are often overexpressed or otherwise altered in cancer patients. Human epidermal growth factor receptor 2 (ErbB-2, HER-2) is known to be a human oncogene closely related with breast cancer. Its high expression in breast cancer often predicts lymph node metastasis and poor tumor differentiation, with poor prognosis. HER-2 is one of the target molecules for breast cancer-specific therapy. Lapatinib can act simultaneously on both Her-1 Her-2. The biological effects of this method inhibiting the proliferation and growth of tumor cells are much larger than only acting on one target. The combination of Lapatinib with Capecitabine is used to treat patients with advanced or metastatic breast cancer with overexpression of human epidermal receptor2, already treated with anthracyclines, paclitaxel, and trastuzumab. Clinical trials have shown that Lapatinib also effectively treats HER2-type cancer patients with Herceptin resistance.
Mechanisms of Action
Lapatinib is a tyrosine kinase inhibitor which can effectively inhibit the tyrosine kinase activity of human epidermal growth factor receptors 1 and 2 (ErbB1, ErbB2). It can uniquely act in a variety of ways, ensuring that breast cancer cells cannot receive growth signals. It inhibits intracellular EGFR (ErbB-1) and HER2 (ErbB-2) ATP sites, preventing tumor cell phosphorylation and activation, blocking down-regulation signals through the homogeneity and heterogeneity of EGFR (ErbB-1) and HER2 (ErbB-1) dimerization.
Originator
GSK (US)
Clinical Use
#N/A
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: avoid with rifabutin, rifampicin and
telithromycin.
Antidepressants: avoid with St John’s wort.
Antidiabetics: avoid with repaglinide.
Antiepileptics: concentration reduced by
carbamazepine - avoid; possibly reduced
fosphenytoin and phenytoin concentration - avoid.
Antifungals: concentration increased by ketoconazole
- avoid; avoid with itraconazole, posaconazole and
voriconazole.
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis); avoid with pimozide.
Antivirals: avoid with boceprevir, ritonavir and
saquinavir.
Cytotoxics: concentration of pazopanib increased;
possible increased risk of neutropenia with docetaxel
and paclitaxel; concentration of active metabolite of
irinotecan increased, consider reducing irinotecan
dose.
Grapefruit juice: avoid concomitant us
Metabolism
Extensive hepatic metabolism, mainly by cytochrome
P450 isoenzymes CYP3A4 and CYP3A5; CYP2C19
and CYP2C8 account for some minor metabolism.
About 27% and 14% of an oral dose is recovered in the
faeces, as parent lapatinib and metabolites, respectively;
renal excretion is negligible.
References
1) Wood?et al. (2004),?A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells;? Cancer Res.,?64?6652
2) Burris?et al. (2004),?Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib;? Oncologist,?9?10
3) Chu?et al. (2005),?The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016) cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer;? Cancer Res.,?65?18
Check Digit Verification of cas no
The CAS Registry Mumber 231277-92-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,3,1,2,7 and 7 respectively; the second part has 2 digits, 9 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 231277-92:
(8*2)+(7*3)+(6*1)+(5*2)+(4*7)+(3*7)+(2*9)+(1*2)=122
122 % 10 = 2
So 231277-92-2 is a valid CAS Registry Number.
InChI:InChI=1/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)
231277-92-2Relevant articles and documents
Unexpected Single Crystal Growth Induced by a Wire and New Crystalline Structures of Lapatinib
De Araujo, Gabriel L.B.,Zeller, Matthias,Smith, Daniel,Nie, Haichen,Byrn, Stephen R.
, p. 6122 - 6130 (2016)
Single crystal growth of lapatinib free base was induced by immersion of a copper wire into a supersaturated methanolic aqueous solution yielding monoclinic anhydrous plates (space group P21/c, Form 1) and needles of a previously unknown channel hydrate (in P42212). Also, a new method has been developed herein to obtain anhydrous Form 1 via acid-base reaction of lapatinib ditosylate and sodium methoxide, avoiding the usage of an aqueous solution and hydrate formation. Anhydrous Form 2 as well as new solvates were produced via solution mediated transformation experiments, including a dichloromethane solvate with a powder X-ray diffraction pattern similar to that of anhydrous Form 2. Differential scanning calorimetry and solution equilibrium experiments helped to elucidate the interconversion pathways between Form 1, Form 2, and the solvates.
Preparation method of 6-substituted furanyl-4-substituted aminoquinazoline derivative and key intermediate thereof
-
, (2020/02/14)
The invention relates to a preparation method of a 6-substituted furanyl-4-substituted aminoquinazoline derivative and a key intermediate thereof. 2-halo-5-cyanobenzoate and 3-chloro-4-(3-fluorobenzyloxy)aniline are used as raw materials, and 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline is obtain through an amidation reaction, a formamidine salt substitution reaction and a condensation reaction; then 6-(furan-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline or 6-(5-formylfuran-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline are obtained througha Grignard reaction and an acidification reaction; and then lapatinib or selatinib are prepared through a Mannich reaction or imidization and a reductive amination reaction. The preparation method hasthe advantages that the raw materials are cheap and are easily available, selectivity of the reaction is high, purity of the product is high, and industrial production is facilitated.
A preparation method of the lapatinib
-
, (2018/03/24)
The invention discloses a lapatinib preparation method. In the synthesis method, the initial raw materials of 2-amino-5-iodobenzoic acid and a cyclization reagent are used for preparing a midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III), quinazoline sulfide (V) is generated through the midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III) under the condition of sulpho-reagent and methine halide, and a target molecule is further synthesized. Due to reaction, the lapatinib yield of a final product is increased, generation of an unstable midbody of 4-chloroquinazoline product is avoided, meanwhile, use of corrosive phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride and other chlorinating agents is avoided, and the lapatinib preparation method is suitable for industrial production.