417716-92-8

Basic information

• Product Name: Lenvatinib
• Synonyms: 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide;E7080;E7080 (Lenvatinib);Lenvatinib (E7080);ER-203492-00;1-(4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenyl)-3-cyclopropylurea;4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide XEN445;E70801-(4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenyl)-3-cyclopropylurea
• CAS NO: 417716-92-8
• Molecular Formula: C₂₁H₁₉ClN₄O₄
• Molecular Weight: 426.85
• EINECS: 1592732-453-0
• Product Categories: FGF receptor antagonist;Inhibitors
• Mol File: 417716-92-8.mol

Chemical Properties

• Boiling Point: 627.242 °C at 760 mmHg
• Flash Point: 333.144 °C
• Appearance: /
• Density: 1.46
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.697
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (up to 20 mg/ml)
• PKA: 13.09±0.70(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: Lenvatinib(CAS DataBase Reference)
• NIST Chemistry Reference: Lenvatinib(417716-92-8)
• EPA Substance Registry System: Lenvatinib(417716-92-8)

Safety Data

• Hazardous Substances Data: 417716-92-8(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Lenvatinib is used as an anti-cancer agent for the treatment of differentiated thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. It works by inhibiting multiple receptor tyrosine kinases, such as VEGFR2 and VEGFR3, which play a crucial role in tumor angiogenesis, growth, and progression. Lenvatinib has demonstrated efficacy in reducing tumor growth and inducing tumor regression in preclinical models, such as the H146 small cell lung cancer mouse xenograft model.
Used in Drug Development:
Lenvatinib is used as a multi-kinase inhibitor in the development of novel drug formulations for the treatment of various types of thyroid cancer that do not respond to radioiodine. Its mesylate salt form is utilized in these formulations to enhance the drug's therapeutic potential and improve patient outcomes.

Thyroid cancer drugs

Lenvatinib is a thyroid cancer drug developed by Eisai Corporation of Japan (Code: E7080), belonging to the inhibitor of oral multi-receptor tyrosine kinase (RTK) and can inhibit the kinase activity of the vascular endothelial growth factor (VEGF) Receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib can also inhibit the involvement of other RTKs in pathological angiogenesis, tumor growth, and cancer progression except for their normal cellular functions including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor (PDGFR [alpha]), KIT, and RET. [Indications]: Lenvatinib is suitable for the treatment of patients of thyroid cancer of local recurrence or metastasis type, progressivity type and radioactive iodine-refractory differentiated type. On February 13, 2015, the US FDA approved anticancer drug Lenvatinib for the treatment of thyroid cancer. Lenvatinib is a multi-target enzyme inhibitor, being capable of inhibiting the VEGFR2 and VEGFR3 (vascular endothelial growth factor receptor). The trade name of Lenvatinib is Lenvima. On May 20, 2015, the European Medicines Agency (EMA) approved Lenvatinib for the treatment of invasive, locally advanced or metastatic differentiated (papillary, follicular, Hurthle type) thyroid cancer (DTC). In the trial, the median survival time for patients of radioactive iodine-refractory DTC treated with Lenvatinib was 18 months while the value for patients who take placebo is only 3 months. In Europe, Lenvatinib will compete with Bayer's kinase inhibitor sorafenib (trade name: Nexavar), which had been respectively approved by EMA and the US Food and Drug Administration for the treatment of radioactive iodine refractory DTC in 2014 and 2013, respectively. At the time, Sorafenib had been reported to be the first targeted therapeutics to be marketed for the past 40 years in the treatment of refractory DTCs. The marketing applications of Lenvatinib in Switzerland, South Korea, Canada, Singapore, Russia, Australia and Brazil are also under review. Information regarding the pharmacological effects, clinical evaluation, and indication of the thyroid cancer drug Lenvatinib were compiled and edited by Tongtong from lookchem (2015-09-22).

Biological activity

Lenvatinib (E7080) is a multi-target inhibitor with the most potent effect on VEGFR2 (KDR)/VEGFR3 (Flt-4) with an IC50 of 4 nM/5.2 and weaker effect on VEGFR1/Flt-1. The selectivity of targeting on VEGFR 2/ 3 is about 10 times as high as that of targeting on FGFR1 and PDGFRα/β. Phase 3.

In vitro study

E7080 can effectively inhibit the angiogenesis, also significantly inhibit the VEGF/KDR and SCF/KIT signaling pathway. Based on the in vitro receptor tyrosine and serine/threonine kinase assays, the IC50 of E7080 in inhibiting Flt-1, KDR, and Flt-4 were 22, 4.0 and 5.2 nM, respectively. In addition to these kinases, E7080 can also inhibit FGFR1 and PDGFR tyrosine kinases, acting on FGFR1, PDGFRα and PDGFRβ with IC50 values of 46, 51 and 100 nM, respectively. When E7080 acted respectively on HUVECs stimulated by VEGF and VEGF-C, respectively, and effectively inhibit VEGFR2 and VEGFR3 phosphorylation with IC50 of 0.83 nM and 0.36 nM, respectively. Recent studies have shown that treatment with 1 μM and 10 μM and E7080, through inhibiting the FGFR and PDGFR signaling pathway, can significantly inhibit cell migration and invasion.

In vivo studies

Orally administration of E7080 at a dose of 30 mg/kg and 100 mg/kg for the treatment of H146 xenograft tumor model can inhibit the tumor growth in a dose-dependent manner. At 100 mg/kg, it can result in tumor regression. Moreover, treatment with a dose of 100 mg/kg of E7080, compared with the VEGF antibody and Imatinib treatment, can reduce the microvascular density more.

Feature

E7080 is an orally active multi-target kinase inhibitor.

References

1) Matsui et al. (2008), E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition; Int. J. Cancer, 122 664 2) Matsui et al. (2008), Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R)2 and VEGF-R3 kinase; Clin. Cancer Res., 14 5459 3) Glen et al. (2011), E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion; BMC Cancer, 11 309 4) Yamamoto et al. (2014), Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage; Vasc. Cell, 6 18

InChI:InChI=1/C21H19ClN4O4/c1-29-19-10-17-13(9-14(19)20(23)27)18(6-7-24-17)30-12-4-5-16(15(22)8-12)26-21(28)25-11-2-3-11/h4-11H,2-3H2,1H3,(H2,23,27)(H2,25,26,28)

Upstream product

• 417721-36-9 4‐chloro‐7‐methoxyquinoline‐6‐carboxamide 
• 796848-79-8 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl urea 
• 417722-95-3 {4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]-2-chlorophenyl}amino-carboxylic acid phenyl ester 
• 765-30-0 Cyclopropylamine 
• 17609-80-2 4-amino-3-chlorophenol 
• 52671-64-4 4-Amino-3-chlorophenol hydrochloride 
• 417722-93-1 4?(4?amino?3?chlorophenoxy)?7?methoxyquinoline?6?carboxamide 
• 1885-14-9 phenyl chloroformate 
• 530-62-1 1,1'-carbonyldiimidazole 
• 201811-58-7 (2-chloro-4-hydroxy-phenyl)carbamic acid tert-butyl ester 
• 1033090-34-4 N-cyclopropyl-1H-imidazole-1-carboxamide 
• 417724-81-3 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide 
• 4747-72-2 isocyanatocyclopropane 
• 491-11-2 3-chloro-4-nitrophenol 

Downstream Products

• 857890-35-8 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide p-toluenesulfonate 
• 857890-39-2 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide methanesulfonate 
• 857890-47-2 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate 
• 857890-31-4 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide hydrochloride 
• 857890-33-6 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide hydrobromide 
• 857890-37-0 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide sulfate 
• 417722-93-1 4?(4?amino?3?chlorophenoxy)?7?methoxyquinoline?6?carboxamide 

Relevant articles and documents

Novel method for the synthesis of lenvatinib using 4-nitrophenyl cyclopropylcarbamate and their pharmaceutical salts

4-Nitrophenyl cyclopropylcarbamate was deployed as a novel synthon for the synthesis of anticancer drug lenvatinib. 4-Nitrophenyl cyclopropylcarbamate was prepared by the reaction of 4-nitrophenyl chloroformate and cyclopropyl amine in acetonitrile at room temperature. Furthermore, lenvatinib was synthesized by reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide with 4-nitrophenyl cyclopropylcarbamate in good yields. Apart from the synthesis of lenvatinib, citrate, phosphate, malate and oxalate salts of?lenvatinib were also reported in good yields.

Synthesis method of lenvatinib

The invention relates to a systhesis method of lenvatinib. The method comprises the following steps: by taking 2-chloro-4-methyl hydroxybenzoate and 4-chloro-7-methoxyquinoline-6-amide as starting raw materials, carrying out substitution reaction to obtain 4-[3-chloro-4-methoxycarbonyl phenoxy]-7-methoxy-6-quinolinecarboxamide, carrying out an alkaline hydrolysis reaction to obtain 4-(3-chloro-4-carboxyphenoxy)-7-methoxy-6-quinolinecarboxamide, carrying out a Curtius rearrangement reaction on the 4-(3-chloro-4-carboxyphenoxy)-7-methoxy-6-quinolinecarboxamide and diphenyl azide phosphate (DPPA), and carrying out a reaction on the obtained product and cyclopropylamine to obtain lenvatinib through a one-pot method. The invention provides a novel method for synthesizing lenvatinib. The method has the advantages of simple reaction steps, simple and easily available raw materials, simple operation and low production cost.

Preparation method of lenvatinib and preparation method of lenvatinib intermediate

The invention discloses a preparation method of lenvatinib and a preparation method of a lenvatinib intermediate. The preparation method of an amide compound as shown in a formula II comprises the following step: in a solvent, carrying out amidation react

Synthetic method of anti-cancer drug lenvatinib

The invention provides a synthetic method of an anti-cancer drug lenvatinib. The synthetic method comprises the following steps of synthesis of a compound 2, synthesis of a compound 4, synthesis of acompound 5, synthesis of a compound 6, synthesis of a compound 7, synthesis of a compound 8, synthesis of a compound 9, synthesis of a compound 10, synthesis of a compound 11 and synthesis of a compound 12. Synthesis of a compound 2 is as follows: sequentially adding raw materials of Meldrum's acid (40g, 277.8 mmol) and trimethyl orthoformate (147g, 1.387 mol) into a 500ml of three-neck flask, slowly performing heating to 90 DEG C for reaction under a stirring condition, slowly performing cooling to room temperature under a solution stirring condition after the reaction is finished, performingfiltering after crystallization, recrystallizing a product by using petroleum ether/ethyl acetate according to a ratio of 5: 1, and performing drying to obtain a faint yellow product 2; by improvingthe synthesis method of the anti-cancer drug lenvatinib, the synthesis method has the advantages of reasonable design, simple operation flow, easily available raw materials, stable yield and easinessin industrial production, so that the problems and defects of the synthesis method are effectively solved and overcome.

Preparation method of lenvatinib

The invention discloses a preparation method of lenvatinib, which comprises the following steps: by using 4-nitro-2-chlorobenzonitrile as an initial raw material, introducing nitro into molecules forelectron withdrawing, thereby greatly lowering the elect

Preparation method of high-purity lenvatinib

The invention relates to a preparation method of lenvatinib, which comprises the following steps: by using 3-chloro-4-nitrophenol and 7-methoxy-4-chloro-quinoline-6-formamide as raw materials, generating 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-formamide, and carrying out catalytic hydrogenation reaction to generate 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-formamide; and then carrying out a reaction with N-cyclopropyl-1H-imidazole-1-formamide in an organic weak base environment, so as to generate the final product lenvatinib. The method has the advantages of short route, recyclable solvent, environmental protection, simple steps, mild conditions, high total yield of the route, high purity of the obtained product, and easy industrialization.

Preparation method of lenvatinib intermediate

The invention discloses a preparation method of a lenvatinib intermediate. The preparation method comprises the following steps: carrying out a nucleophilic substitution reaction among a compound shown as a formula I, a compound shown as a formula II and

Synthesis method of lenvatinib and new intermediate

The invention discloses a synthesis method of lenvatinib and a new intermediate. The method comprises the following steps: step 1, taking 4-amino-3-chlorophenol hydrochloride and 4-chloro-7-methoxy-6-amido quinoline as initial raw materials, and carrying

Preparation method of high-purity lenvatinib mesylate crystal form C

The invention belongs to the technical field of pharmaceutical chemicals and especially relates to a preparation method of a lenvatinib mesylate crystal form C. According to the method, the conditions of high temperature, acid serving as a solvent and the

PROCESS FOR THE PREPARATION OF LENVATINIB

The present invention relates to a process for the preparation of Lenvatinib of formula (I) from 4-amino-3-chloro-phenol and 4-chloro-7-methoxyquinoline-6-carboxamide.